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 .
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.
Withdrawn Rejections
The 103 rejections and the non-statutory double patenting rejections are withdrawn in response to the amendments.
Priority
This application, Serial No. 17/266,029 was filed on 02/04/2021, and is a 35 U.S.C. 371 national stage entry of PCT Application No. PCT/JP2019/031328 filed on 08/08/2019. Acknowledgement is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) based on an application filed in Japan on 08/08/2018. Acknowledgement is also made of the English translation filed 09/03/2024 of the application filed in Japan on 08/08/2018.
Status of the Claims
Claims 1, 3-5, and 7-20 are pending; claims 1, 3-5 and 7-8 are amended; claims 2 and 6 are cancelled; claims 9-20 are withdrawn. Claims 1, 3-5 and 7-8 are examined below.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-5 and 7-8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an enablement rejection.
The claims recite “organoids consisting of cancer stem cells”.
However, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification does not reasonably provide enablement for a step of three-dimensionally culturing organoids consisting of cancer stem cells, let alone recovering the organoids consisting of cancer stem cells from the three-dimensional culture.
Furthermore, the specification does not provide sufficient evidence that the claimed method of three-dimensionally culturing the organoids consisting of cancer stem cells is effective. The only evidence provided of organoids consisting of cancer stem cells is Figure 1, showing a cartoon diagram of PLR123 single cells clustering in Matrigel. However, organoids are not the same as cell clusters. Although the specification paragraph 63 discloses that “a "cell cluster" includes organoids formed by three-dimensionally culturing a tissue after treatment with an anticancer agent”, there is no disclosure regarding that organoids can also be considered cell clusters. The specification further admits that the step of three-dimensionally culturing organoids consisting of cancer cells wherein the cancer stem cells were first treated with at least one anticancer agent produces an organoid that contains differentiated cells (“For example, when an organoid cultured from the stem cell line PLR123 derived from colon cancer is treated with an anticancer agent and further three-dimensionally cultured by a culture method of the present disclosure, a treatment-resistant cell cluster having the characteristics of an anticancer agent-resistant colon cancer tissue and containing differentiated cells is formed” para. 37, “Analysis showed that the expression of the stem cell markers LGR5, CD44, and PROMl was decreased, and the expression of differentiation markers KRT20, VILl, FABPl, CAI, CDXI, CDX2, CDHl 7, and GPA33 was increased in the 3D-cultured organoids (day 10), inferring that the cells had differentiated (n = 3, Fig. 3)” para. 90, “From the above, it was shown that PLR123 organoids reproduce traits peculiar to differentiated colorectal cancer” para. 91, “While almost no LGR5 expression was observed in the organoids immediately after SN-38 treatment, it was confirmed that a part of the cells in the regrowing organoids became LGR5-positive, supporting the results of the pathological analysis (Fig. 8)” para. 95). Therefore, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied.
In re Wands, 858F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation.
In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The nature of the invention is a biological/chemical case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the claimed method(s), with a reasonable expectation of success, because it would not have been predictable from the disclosure that the claimed culturing step and recovering step would function as claimed with respect to organoids consisting of cancer stem cells (see MPEP § 2164.03).
In regard to Wands factors (C), (D) and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a).
Accordingly, Taniguchi (US 2017/0285002 A1, cited on the IDS dated 08/12/2021) suggests that organoids require multiple types of cells in order for the organoid structure to form (“Rich stroma (αSMA-positive cells) as well as a duct-like structure (constituted by EpCAM-positive cells) is observed in the pancreatic cancer organoid transplantation group. On the other hand, a pancreatic duct structure is not confirmed in a group transplanted with an aggregate prepared from established pancreatic cancer cells only (photographs of the middle column), and this group manifests structurally poor tissue” para. 22).
Furthermore, Fujii et al. J Toxicol Pathol 2018; 31: 81–85-Cite No. NPL3 of IDS 4/19/2024 (“Fujii”) teaches that the “[d]efining characteristics of an organoid are as follows: 1) they consist of multiple organ-specific cell types, 2) they show some organ-specific functionality, and 3) they are grouped together and have a spatial structure that is similar to an organ” (page 81 col. 1 para. 2).
Also, Buzzelli et al. Stem Cell Research Volume 27, March 2018, Pages 109-120-Cite No. NPL1 of IDS 4/19/2024 (“Buzzelli”) teaches that organoids further contain progenitor cells (“To validate that organoids contained progenitor cells and represent human disease, we assessed the expression of EpCAM and MUC2 in human pathological specimens and organoids by immunofluorescence (Fig. 2A–D). The proliferation mark, Ki-67 was also used. EpCAM is an antigen expressed by progenitor cells in multiple carcinomas (Baeuerle and Gires, 2007; Ricci-Vitiani et al., 2007; Yamashita et al., 2009), while MUC2 is a mucin expressed by normal colon epithelia, but differentially expressed in adenocarcinomas (Ajioka et al., 1996; Bu et al., 2010). All human pathological specimens and organoid cultures showed global expression of EpCAM and positive Ki-67 staining (Fig. 2A & B)” page 112 col. 1 para. 2).
Jiang et al. Front. Bioeng. Biotechnol., 21 July 2025 Sec. Organoids and Organ-On-A-Chip Volume 13 - 2025 | https://doi.org/10.3389/fbioe.2025.1607488 (“Jiang”) teaches that “[a]n organoid is a combination of organ-specific cell types developed from stem cells or organ progenitor cells and organized in an organ-specific manner that emulates the process of in vivo cell sorting and spatial lineage qualification (Lancaster and Knoblich, 2014). This process exhibits three characteristics: (i) Specificity: The presence of specific cell types from different organs; (ii) Functionality: The ability to perform the functions of organs, including contraction, secretion, filtration, and so on; and (iii) Spatiality: Immortalized cancer cell lines, while widely accessible, undergo genetic drift during long-term culture, losing the heterogeneity and microenvironmental context of original tumors” (page 1 para. 2).
Given the cited teachings of the prior art that organoids require a heterogenous population of cells, the cited references demonstrate that the use of organoids consisting of cancer stem cells is unpredictable.
While the level of skill in the art is high, the amount of guidance provided regarding how to culture and recover the claimed organoids consisting of cancer stem cells is scant. Accordingly, the amount of experimentation required to determine how to culture and recover the recited organoids consisting of cancer stem cells is quite extensive.
Due to the large quantity of experimentation necessary to determine how to culture and recover the recited organoids consisting of cancer stem cells, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the limited state of the prior art, the unpredictability of the effects of complex biological molecules on diseased physiological systems, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. §112 first paragraph.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 5 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claim recites “wherein the cancer stem cells are colorectal cancer cells”.
However, it is not clear how the cancer stem cells are colorectal cancer cells because these are two different kinds of cells. The specification suggests that specific culture conditions are required for a cancer stem cell to differentiate into a colorectal cancer cell (“A cancer stem cell-derived tissue is multicellular cell cluster formed as proliferation and differentiation of cancer stem cells proceed. By adjusting the culture conditions, usually, cancer stem cell-derived tissues having common histochemical characteristics are formed from the same cancer stem cells, or cancer stem cell-derived tissues containing cells that differentiated and have different characteristics are formed from the same cancer stem cells” para. 39). Note, though, that by inducing differentiation of the cancer stem cells into colorectal cancer cells, the cancer stem cell ceases to be. Therefore, a person having ordinary skill in the art would not be able to recognize what exactly is being claimed by “wherein the cancer stem cells are colorectal cancer cells”. For these reasons the claim is indefinite.
Response to Arguments
Applicant’s arguments, see pages 6-9, filed 11/5/2025, with respect to the rejection(s) of claim(s) 1, under 103 and nonstatutory double patenting have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made under 112a lack of enablement.
Applicant remarks that “Taniguchi actually teaches away from the presently claimed invention because Taniguchi teaches that it is necessary to co-culture cancer cells with human umbilical vein endothelial cells (HUVECs) and human mesenchymal stem cells (hMSCs) in order to reconstitute cancer organoids… Taniguchi also teaches that when cancer cells were cultured without HUVECs and hMSCs the cancer cells formed cell "aggregates" rather than organoids” (page 7 paras. 4-5). The Examiner finds this argument persuasive. Taniguchi is used in this Office Action as it provides evidence that the claims are not enabled. See the lack of enablement rejection set forth above. Applicant further remarks that “The OA' s additionally cited references do not cure these deficits of Taniguchi with respect to the rejection under 35 USC § 103” (page 8 para. 2). Indeed, there is no reference found that teaches “organoids consisting of cancer stem cells” given that this teaching seems to not be enabled.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FERNANDO IVICH whose telephone number is (703)756-5386. The examiner can normally be reached M-F 9:30-6:00 (E.T.).
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677