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 .
Priority
This application was filed Sept. 30, 2020, and is a 371 application of PCT/US2019/026654 filed on April 9, 2019, which claims benefit to a provisional application 62/655,1155 filed on April 9, 2018, is acknowledged.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/26/2026 has been entered.
Status of the Claims
In the response filed Feb. 26, 2026, Applicants have added new claim 34 and have canceled claims 4, 6-7, 13-20, 23-24, and 26-27.
Currently, claims 1-3, 5, 8-12, 21-22, 25, and 28-34 are under examination.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement (see Specification “McConnel et al., Cell Rep. 17:2173-2182, 2016, e.g. page 8), 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Notably, the disclosure statement filed 11/30/2023 and 9/30/2020 lists Search Reports. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Rejections - 35 USC § 103
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 1-3, 5, 8-12, 21-22, 25, and 28-34 are rejected under 35 U.S.C. 103 as being unpatentable over in view Lars Norman Sachs and Jarno Drost (WO2016/083613A2, 2016; hereinafter as “Sachs”; prior art of record) in view of Lu et al., (US20130071927 A1, 2013, previously cited 01/08/2024), Clevers et al., (WO 2012/168930 A2, 2012; cited IDS 9/30/2020, prior art of record), McConnell, et al. (Cell reports 17.9: 2173-2182, 2016; prior art of record), Xu, Xia, et al. (Biotechnology progress 26.3: 781-788, 2010, hereinafter as “Xu”), Hegab, et al. (Stem cell research 15.1: 109-121, 2015; prior art of record), Guo, Zhiru, Kyle Draheim, and Stephen Lyle (Journal of Visualized Experiments: JoVE 49: 2561, 2011, hereinafter as “Guo”).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the final Official action mailed on Oct. 22, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claims 1-3, 5, 8, 12, 21-22, 25, and 28-34, Sachs discloses a method of culturing adult stem cells (i.e. epithelial stem cells) to increase efficiency of obtaining organoids (see e.g. page 1, 24, 31, 35, 43, and 49, fig. 18, 25-26), comprising: providing a quantity of adult stem cells (see e.g. abstract and claim 1), culturing the quantity of adult stem cells in the culture media for at least 8 days (see e.g. page 5, 58, 68, 109 and 112, fig. 15). Further, Sachs discloses the culture media having the presence of at least a Rho-associated kinase (ROCK) inhibitor (i.e. Y27632 or HA1077)(see e.g. page 29, 32,39, 50, and 117, claim 13 and 27), SMAD inhibitor (i.e. TGFβ inhibitor, SB-431542)(see e.g. Table 1, page 27, claim 12, 15 and 27), a p53 stabilizing agent (see e.g. page 36, 65, 73), and culturing the quantity of adult stem cells in the media (see e.g. page 58, 112, fig. 14-15). Further, Sachs discloses expanding (i.e. subculturing) (see e.g. 55-58, 66-67, and 69-70) the quantity of adult stem cells having to increase efficiency of obtaining organoids (see e.g. 55-58, 66-67, and 69-70).
Sachs does not explicitly state wherein culturing the adult stem cells with a ROCK inhibitor for at least 8 days, and a p53 inhibitor that is pifithrin-α, and an increase colony forming efficiency and increase organoid size as compared to culturing in the presence of a ROCK inhibitor alone.
Although Sachs discloses wherein the ROCK inhibitor (i.e. Y27632 or HA1077) is added to the culture medium for at least 7 days (see e.g. page 46) and discloses culturing adult epithelial stem cells for 3 days to 10 weeks (see e.g. page 58).
However, the prior art of Lu discloses that colonies in the presence of ROCK inhibitor continued to grow in size and density over 8-10 days (see e.g. Example 4-6, fig. 6).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie obvious for a person of ordinary skill in the art to have modified the method of culturing adult stem cells, as taught by Sachs, and incorporate at least eight days of culturing in the presence of a ROCK inhibitor, as taught by Lu, with a reasonable expectation of success because one of ordinary skill in the art would have known that the colonies in the presence of ROCK inhibitor continue to grow in size and density over 8-10 days (as taught by Lu)(see e.g. Example 4-6, fig. 6). Further, a person of ordinary skill in the art would have considered optimizing the culturing time with the ROCK inhibitors because Sachs discloses culturing with a ROCK inhibitor after seeding (see e.g. page 46) and Lu discloses at least eight days (see e.g. fig. 6), which a person of ordinary skill in the art would have done through routine optimization, which renders the claimed time period prima facie obvious.
As stated supra, Sachs does not explicitly state wherein the p53 stabilizing agent is the p53 inhibitor pifithrin-α.
However, the prior art of Clevers discloses an adult stem cell culture medium with the p53 inhibitor pifithrin-α for expansion and differentiation in order to obtain epithelial stem cell organoids (see e.g. par. 4)(see e.g. page 7, Fig. 13). Additionally, the prior art of Lu discloses that is was known in the prior art to culture adult stem cells with a p53 inhibitor such as pifithrin-α (see e.g. abstract, para. 45-47, claim 6, table 2), because p53 inhibitors are cell protectants that increase viability of single cells after passaging (see e.g. para. 37).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie obvious for a person of ordinary skill in the art to have modified the method of culturing adult stem cells, as taught by Sachs, and incorporate the p53 inhibitor pifithrin-α, as taught by Clevers and Lu, with a reasonable expectation of success because one of ordinary skill in the art would want to increase viability of adult stem cells after passaging (as taught by Lu)(see e.g. para. 37) and increase the amount and size of the organoids after passaging (as taught by Lu and Clevers)(see e.g. para. 37 and table 2, respectively).
As stated supra, although the prior art of Sachs, Clevers, and Lu, do not explicitly disclose an increase colony forming efficiency and increase organoid size as compared to culturing in the presence of a ROCK inhibitor alone.
However, the prior art of McConnell teaches that p53 regulates size (see e.g. fig. S2, pg.2188), proliferation, and differentiation of airway epithelial progenitors (i.e. organoids) (see e.g. abstract, fig. 1).
Regarding claim 1, 9-11, and 34, McConnell discloses increase colony forming efficiency of progenitors (i.e. organoids) (see e.g. abstract, page 2173-2175, 2187-2188, and 2194, fig. 1-2 and fig.S2), and that the number of cells per patch was significantly increased (i.e. proliferation), with p53-deficient cells generating patches twice as large as that in control (see e.g. Figure S2C). Further, the prior art of Xu discloses that when culturing stem cells with the combination of a Rho-associated kinase (ROCK) inhibitor and a p53 inhibitor can enhance the cell survival rate and colony formation, and reduce DNA-induced apoptosis, especially when compared to culturing in the presences of a ROCK inhibitor alone (see e.g. abstract, page 783, 786-786, fig. 2-6). Additionally, the prior art of Hegab discloses that even though ROCK inhibitors increase colony forming efficiency of lung epithelial stem cell organoids, the ROCK inhibitor (ROCK-I) treatment alone has the least impact on increasing the colony number and size (see e.g. page 118).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie obvious for a person of ordinary skill in the art to have modified the method of culturing adult stem cells, as taught by Sachs, and incorporate a p53 inhibitor of PTA-α and a ROCK inhibitor, as taught by McConnell, Xu, and Hegab, with a reasonable expectation of success because a person of ordinary skill in the art would have wanted to increase colony forming efficiency and increase organoid size in order to obtain maximum amount of organoids (as taught by McConnell)(see e.g. abstract, fig. 1-2, and fi.S2), especially when compared to culturing in the presences of a ROCK inhibitor alone (as taught by Xu, see e.g. abstract, page 783, 786-786, fig. 2-6; and Hegab see e.g. page 118, fig. 5).
Regarding claims 28, 30, and 32, as states supra, Sachs discloses wherein the adult stem cells are from a lung (see e.g. page 2, 43-47, 55, 62-65, 69, 76-78, and claims 24, 31-32, Example 5).
Regarding claims 29, 31, and 33, as states supra, Sachs discloses wherein the adult stem cells from the lung are from lung epithelial cells (see e.g. page 2, 43-47, 55, 62-65, 69, 76-78, and claims 24, 31-32, Example 5).
Regarding claim 34, as states supra, Sachs discloses a method of culturing adult stem cells (i.e. epithelial stem cells) to increase efficiency of obtaining organoids (see e.g. page 1, 24, 31, 35, 43, and 49, fig. 18, 25-26). Further, Sachs discloses pre-culturing the quantity of adult stem cells on a pre-warned 24-well suspension culture plate for gelation (see e.g. page 109, Example 1). Sachs discloses a preferred extracellular matrix (ECM) for use in a method of the invention comprises at least two distinct glycoproteins, such as two different types of collagen (see e.g. page 53). Further, Sachs discloses wherein culturing adults stem cells is in contact with an ECM that comprises collagen for at least 4 passages (see e.g. pages 52-53).
Sachs does not explicitly disclose pre-culturing for about 24 hours.
However, the prior art of Guo discloses that before culturing the adult stem cells may be seeded on a plate for about one day (i.e. about 24 hours) before culturing (see e.g. page 1, section 2).
Further, it is noted that the MPEP § 2144.05 (II) states, “Generally, differences in time, concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In the instant case, neither the specification nor Applicant have provided evidence that the claimed time range of about 24 hours of pre-culturing is critical, thus the teaching of about one day, as taught by Guo, renders the claimed time of pre-culturing as obvious.
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie obvious for a person of ordinary skill in the art to have modified the method of culturing cells, as taught by Sachs, and incorporate pre-culturing the quantity of adult stem cells on collagen plates for about 24 hours, as taught by Guo, with a reasonable expectation of success because one of ordinary skill in the art would know that coated collagen plates enhance long-term survival of stem cells and allow for the culturing of three-dimensional tissue organoids (as taught by Sachs)(see e.g. page 53).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that Sachs and Clevers do not teach the use of a p53 inhibitor, specifically pifithrin-α (Remarks, page 5-6).
Applicant’s arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
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, as stated supra, Sachs does teach the use of a p53 stabilizing agents (see e.g. page 36, 65, 73), and is not cited for teaching the p53 inhibitor pifithrin-α. Additionally, it is noted that Applicant acknowledges that Sach teaches the use of p53 stabilizing agents (remarks, page 6). In the instant case, the prior art of Clevers and the prior art of prior art of Lu discloses that is was known in the prior art to culture adult stem cells with a p53 inhibitor such as pifithrin-α (see e.g. page 7 and claim 6, respectively). As discussed above, prior to the effective filing date of the instant claimed invention, it would have been prima facie obvious for a person of ordinary skill in the art to have modified the method of culturing adult stem cells, as taught by Sachs, and incorporate the p53 inhibitor pifithrin-α, as taught by Clevers and Lu, with a reasonable expectation of success because one of ordinary skill in the art would want to increase viability of adult stem cells (as taught by Lu)(see e.g. para. 37) in order to obtain the optimal amount of epithelial stem cell organoids after passaging (as taught by Lu and Clevers)(see e.g. para. 37 and table 2, respectively). Furthermore, it would have been obvious to one of ordinary skill in the art to substitute the p53 inhibitor pifithrin-α, as taught by Clevers and Lu, for the p53 stabilizing agent, as taught by Sachs, with a reasonable expectation of success because the prior art of Sachs, Clevers, and Lu all disclose methods for culturing adult stem cells.
Applicant argues that Sachs in combination with Clevers would not result in a reasonable expectation of success because Clevers shows zero effects for pifithrin-α (Remarks, page 5-6). Applicant asserts that Clevers teaches away from using pifithrin-α because it had no effects towards optimizing their human intestinal organoid cultures (Remarks, page 6).
Applicant’s arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). In the instant case, it is noted that Clevers cites pifithrin-α as a list of reagents that were used for optimization of human intestinal organoid cultures and recites that no activity was observed (see page 119, Table 2, Example 1). However, Clevers does not teach away, because the activity scale was based on plating efficiency compared with the control after 4 days of culture (see page 120). Further, the prior art of Lu is also now cited for teaching the p53 inhibitor pifithrin-α and discloses that although “small colonies became clearly visible 4 days after passage, but they expanded considerably in size by day 7” (see e.g. Examples 4-6, fig. 6). Therefore, prior to the effective filing date of the instant claimed invention, it would have been prima facie obvious for a person of ordinary skill in the art to have modified the method of culturing adult stem cells, as taught by Sachs, and incorporate the p53 inhibitor pifithrin-α, as taught by Clevers and Lu, with a reasonable expectation of success because one of ordinary skill in the art would want to increase the optimal amount and size of organoids after passaging (as taught by Lu and Clevers)(see e.g. para. 37 and table 2, respectively).
Applicant argues that Clevers list pifithrin-α in a long list of inhibitors and was tested for intestinal organoid cultures and not adult stem cells (Remarks, page 6).
Applicant’s arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the references individually (i.e. Clevers), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, as stated supra, Sachs and Clevers both disclose methods for culturing epithelial stem cells which read on the adult stem cells as claimed. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, the claim recites “increasing organoid size” (see e.g. claim 1 lines 7-8) and does not specify the type of organoid. Further, Clevers discloses that the adult “stem cell culture medium improved culture plating efficiency by at least 50% and more than 100% (see table 2)”(see e.g. page 86-87). Therefore, it is unclear why applicant argues that Clevers tests for intestinal organoid cultures and not adult stem cells. As discussed above, Clevers discloses an adult stem cell culture medium with the p53 inhibitor pifithrin-α for expansion and differentiation in order to obtain epithelial stem cell organoids (see e.g. par. 4)(see e.g. page 7, Fig. 13).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Ikeyama et al., (US2018/0066231A1, published March 8, 2018); Somaiah, Chinnapaka, et al. (PloS one 10.12: e0145068, published 2015).
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JOSEPHINE GONZALES, PhD
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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