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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/14/2026 has been entered. Applicant's amendment and response filed on 04/14/2026 has been received and entered into the case.
Amendments
In the reply filed on 04/14/2026, Applicant has amended claims 1 and 23.
Claim Status
Claims 1, 3-5, 8-12 and 15-23 are pending.
Claims 15-19 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. The election was made without traverse in the reply filed on 05/31/2023.
Claims 1, 3-5, 8-12 and 20-23 are considered on the merits.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 22 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Specifically, claim 22 draws to the culture medium comprises EREG at a concentration between 0.1 ng/mL and 5 ng/mL, which does NOT narrow the scope of claim 1 since amended claim 1 now recites the same limitation. Essentially, due to applicant’s own claim language, the EREG concentration embodiment of claim 22 is axiomatically included in the scope of claim 1.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
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, 8-12 and 20-23 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Specifically, instant claims encompass a genus of method of culturing a genus of intestinal cells (including any type of cells isolated from intestine) or tissue, comprising culturing in culture medium comprising a genus of agent for activating Wnt signaling at any concentration, NRG1 at any concentration, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for any duration to result in the formation of intestinal organoids expressing OLFM4 and LGR5, while the specification only discloses a method of culturing freshly isolated fetal duodenum epithelium (see specification, p. 14, last para) or intestinal stem cells (e.g., derived from pluripotent stem cells, see specification, p. 1 “Field of the invention”, also see p. 3, para 1) comprising culturing the cells or tissue in culture medium comprising WNT3A/RSPO3 for activating Wnt signaling, NRG1 at 100 ng/mL, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for about 11 days to result in the formation of intestinal organoids expressing OLFM4 and LGR5 (see e.g., specification, p. 24, Example 6 for culturing with NRG1 and p. 27 and Fig 11 for culturing with EREG).
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
SCOPE OF THE INVENTION
Independent claim 1 encompasses a genus of method of culturing a genus of intestinal cells (including any type of cells isolated from intestine, such as smooth muscle cells or vascular endothelial cells) or tissue, comprising culturing the cells or tissue in culture medium comprising a genus of agent for activating Wnt signaling (including ligands, small molecules, direct or indirect activators, direct or indirect inhibitors of repressors, in the form of proteins, chemicals or nucleic acids) at any concentration, NRG1 at any concentration, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for any duration to result in the formation of intestinal organoids expressing OLFM4 and LGR5. However, the specification only discloses a single species of method of culturing freshly isolated fetal duodenum epithelium (see specification, p. 14, Example 1, last para) or intestinal stem cells (e.g., derived from pluripotent stem cells, see specification, p. 1 “Field of the invention”, also see p. 3, para 1, but there is no working example) comprising culturing the cells or tissue in culture medium comprising WNT3A/RSPO3 for activating Wnt signaling, NRG1 at 100 ng/mL, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for about 11 days to result in the formation of intestinal organoids expressing OLFM4 and LGR5 (see e.g., specification, p. 24, Example 6 for culturing with NRG1 and p. 27 and Fig 11 for culturing with EREG).
Dependent claims 3-5, 8-12 and 20-23 encompass the intestinal organoids, the cells being stem cells, the tissue being human fetal intestinal tissue, the culturing being in a 3D scaffold, the medium further comprising R-spondin and Noggin, the agent for activating Wnt signaling being Wnt3A. However, the specification only discloses a combination of the limitations as discussed above.
ACTUAL REDUCTION TO PRACTICE
Accordingly, Applicant did not demonstrate a reduction to practice of a genus of method of culturing a genus of intestinal cells or tissue in an EGF-free culture medium comprising a genus of agent for activating Wnt signaling at any concentration, NRG1 at any concentration, and EREG at a concentration of 0.1 – 5 ng/mL, for any duration to result in the formation of intestinal organoids, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of method.
DISCLOSURE OF STRUCTURE
The Applicant claims a genus of method of culturing a genus of intestinal cells or tissue in an EGF-free culture medium comprising a genus of agent for activating Wnt signaling at any concentration, NRG1 at any concentration, and EREG at a concentration of 0.1 – 5 ng/mL, for any duration to result in the formation of intestinal organoids, but has provided no other starting cells or tissue other than the specific freshly isolated fetal duodenum epithelium or intestinal stem cells that are cultured in a medium comprising a specific Wnt activator WNT3A and/or RSPO3, with NRG1 at a specific concentration of 100 ng/mL and EREG at the claimed concentration, for about 11 days to form intestinal organoids. Certainly, a skilled artisan could culture other type of cells isolated from intestine, such as smooth muscle cells or endothelial cells, in a medium comprising other Wnt signaling activators and NRG1 at other concentrations for any duration. However, the prior art is silent on the culturing would result in formation of intestinal organoids. Furthermore, neither the specification nor the art indicates a relationship between the structure of the claimed genus of starting cells, media compositions, concentrations or durations, and the outcome of intestinal organoids.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned above, a skilled artisan could culture other type of cells isolated from intestine in a medium having other compositions, concentrations or durations. However, the prior art is silent on the culturing would predictably result in the formation of intestinal organoids.
The breadth of the claims encompasses a genus of method of culturing a genus of intestinal cells or tissue in an EGF-free culture medium comprising a genus of agent for activating Wnt signaling at any concentration, NRG1 at any concentration, and EREG at a concentration of 0.1 – 5 ng/mL, for any duration to result in the formation of intestinal organoids, yet the present specification provides no guidance nor description what starting cells/tissue. what agent for activating Wnt signaling, what concentrations or what durations, other than the specific tissue/cells, the specific agent for activating Wnt signaling, the specific concentration of NRG1 and the specific culture durations, to form intestinal organoids. Therefore, the skilled artisan would not know what rational approach to take to use the claimed genus of method, with any predictable outcome on the formation of intestinal organoids. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of method.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of using the claimed invention is not well established. Although the method of culturing intestinal cells was known in the state of the art, one of skill in the art would neither expect nor predict the appropriate outcome of formation of intestinal organoids produced according to the claimed genus of method.
In fact, instant specification discloses that the method of culturing intestinal cells to form intestinal organoids is highly unpredictable. Specifically, Applicant discloses that in established enteroid cultures, robust re-establishment of enteroids was observed after 10 days in the standard EGF condition. In contrast, almost no enteroid recovery was observed in the control and in the NRG1-only supplemented cultures (Example 5, p. 23, last para), while in freshly isolated intestinal crypts culture, all groups (control, EGF, NRG1 and EGF plus NRG1) re-established enteroids and there was no difference in enteroid forming efficiency between the EGF and NRG1 groups (see Example 6, p. 24). Thus, the instant specification discloses that even culturing similar intestinal cells (i.e., dissociated from established enteroids vs. freshly isolated intestinal crypts) in a similar culture condition (the same NRG1 supplemented at the same concentration and the same culture duration), the outcome of obtaining intestinal organoids is vastly different (no enteroid formed in NRG1 group in the former vs. “all groups re-established enteroids” in the latter) (see Example 5, p. 23, last para for no enteroid formed in NRG1 group and see Example 6, p. 24 for enteroid re-established/formed). Accordingly, the instant specification evidences that the claimed method of culturing intestinal cells/tissue to form intestinal organoids was not well established.
Applicant has claimed a genus of method for culturing a genus of intestinal cells or tissue to form intestinal organoids, yet the present specification has not disclosed such methods other than culturing a specific type of intestinal cell/tissue in a medium comprising a specific agent for activating Wnt signaling and NRG1 at a specific concentration for a specific duration to form intestinal organoids, has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of method. Furthermore, the state of the art indicated that using the claimed genus of method of culturing the claimed genus of intestinal cells/tissue in the claimed genus of condition to form intestinal organoids is not well established and would require undue experimentation, and one of skill in the art would neither expect nor predict the claimed outcome of the formation of intestinal organoids produced according to the claimed genus of method.
CONCLUSION
The Examiner concludes that there is insufficient written description of the instantly claimed genus of method of culturing the claimed genus of intestinal cells/tissue in the claimed genus of condition to form intestinal organoids. Specifically, Applicant has only provided one single species of method of culturing a specific type of intestinal cell/tissue in a medium comprising a specific agent for activating Wnt signaling and NRG1 at a specific concentration for a specific duration to form intestinal organoids, thus does not provide sufficient number of species to represent the entire scope of the claimed extremely broad genus of method. Therefore, the Examiner concludes that there is insufficient written description to show that Applicant was in possession of the claimed genus of method of culturing a genus of intestinal cells or tissue in an EGF-free culture medium comprising a genus of agent for activating Wnt signaling at any concentration, NRG1 at any concentration, and EREG at a concentration of 0.1 – 5 ng/mL, for any duration to result in the formation of intestinal organoids.
(Scope of Enablement)
Claims 1, 3-5, 8-12 and 20-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of culturing freshly isolated fetal duodenum epithelium tissue or intestinal stem cells comprising culturing the cells or tissue in a culture medium comprising WNT3A/RSPO3 for activating Wnt signaling, NRG1 at 100 ng/mL, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for about 11 days to result in the formation of intestinal organoids expressing OLFM4 and LGR5 (see e.g., specification, p. 14, last para for intestinal tissue, p. 1 “Field of the invention” and p. 3, para 1 for intestinal stem cells, see p. 24, Example 6 for culturing with NRG1 and p. 27 and Fig 11 for culturing with EREG), does not reasonably provide enablement for a genus of method of culturing a genus of intestinal cells (including any type of cells isolated from intestine) or tissue, comprising culturing the cells or tissue in a culture medium comprising a genus of agent for activating Wnt signaling at any concentration, NRG1 at any concentration, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for any duration to result in the formation of intestinal organoids expressing OLFM4 and LGR5. 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 factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of method of culturing a genus of intestinal cells (including any type of cells isolated from intestine, such as smooth muscle cells or vascular endothelial cells) or tissue, comprising culturing the cells or tissue in culture medium comprising a genus of agent for activating Wnt signaling (including ligands, small molecules, direct or indirect activators, direct or indirect inhibitors of repressors, in the form of proteins, chemicals or nucleic acids) at any concentration, NRG1 at any concentration, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for any duration to result in the formation of intestinal organoids expressing OLFM4 and LGR5. However, the specification only discloses a single species of method of culturing freshly isolated fetal duodenum epithelium (see specification, p. 14, Example 1, last para) or intestinal stem cells (e.g., derived from pluripotent stem cells, see specification, p. 1 “Field of the invention”, also see p. 3, para 1, but there is no working example) comprising culturing the cells or tissue in culture medium comprising WNT3A/RSPO3 for activating Wnt signaling, NRG1 at 100 ng/mL, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for about 11 days to result in the formation of intestinal organoids expressing OLFM4 and LGR5 (see e.g., specification, p. 24, Example 6 for culturing with NRG1 and p. 27 and Fig 11 for culturing with EREG). Thus, the specification fails to describe the genus of methods.
ACTUAL REDUCTION TO PRACTICE
Accordingly, Applicant did not demonstrate a reduction to practice of a genus of method of culturing a genus of intestinal cells/tissue under a genus of condition to form intestinal organoids. Since the specification only discloses and provides guidance for a single species of method of culturing a specific type of intestinal cell/tissue in a medium comprising a specific agent for activating Wnt signaling and NRG1 at a specific concentration for a specific duration to form intestinal organoids, the absence of working examples necessitates further experimentation. Therefore, the specification does not provide sufficient guidance on how to use the claimed genus of methods.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The state of the art teaches that a method of culturing intestinal cells/tissue to form intestinal organoids is not a highly successful technique or has highly variable results.
In fact, instant specification discloses that the method of culturing intestinal cells to form intestinal organoids is highly unpredictable. Specifically, Applicant discloses that in established enteroid cultures, robust re-establishment of enteroids was observed after 10 days in the standard EGF condition. In contrast, almost no enteroid recovery was observed in the control and in the NRG1-only supplemented cultures (Example 5, p. 23, last para), while in freshly isolated intestinal crypts culture, all groups (control, EGF, NRG1 and EGF plus NRG1) re-established enteroids and there was no difference in enteroid forming efficiency between the EGF and NRG1 groups (see Example 6, p. 24). Thus, the instant specification discloses that even culturing similar intestinal cells (i.e., dissociated from established enteroids vs. freshly isolated intestinal crypts) in a similar culture condition (the same NRG1 supplemented at the same concentration and the same culture duration), the outcome of obtaining intestinal organoids is vastly different (no enteroid formed in NRG1 group vs. “all groups re-established enteroids”) (see Example 5, p. 23, last para for no enteroid formed in NRG1 group of established enteroids and see Example 6, p. 24 for enteroid re-established/formed from freshly isolated intestinal crypts). Accordingly, the instant specification evidences that the claimed method of culturing intestinal cells/tissue to form intestinal organoids was not well established.
Since the state of the art did not provide guidance for culturing the claimed genus of intestinal cells/tissue under the claimed genus of condition to form intestinal organoids encompassed by instant invention, it is incumbent upon the instant specification to do so. The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; … in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that the method of culturing a genus of intestinal cells/tissue under the claimed genus of condition to form intestinal organoids is prone to influence by multiple factors, and is highly unpredictable, and the specification does not provide ample guidance, one would be burdened with undue experimentation to use the claimed invention to form intestinal organoids by culturing the claimed genus of intestinal cells/tissue under the claimed genus of condition.
In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to use the invention beyond the scope of a method of culturing freshly isolated fetal duodenum epithelium tissue or intestinal stem cells comprising culturing the cells or tissue in a culture medium comprising WNT3A/RSPO3 for activating Wnt signaling, NRG1 at 100 ng/mL, and EREG at a concentration of 0.1 – 5 ng/mL, but not comprising EGF, for about 11 days to result in the formation of intestinal organoids expressing OLFM4 and LGR5.
Examiner’s comment
Based on the limited genus of method of culturing intestinal cells/tissue disclosed by Applicant’s specification to have the claimed outcome of formation of intestinal organoids, the prior art of Jarde et al., have been applied to make obvious this limited genus of method of culturing intestinal cells/tissue.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1, 3-5, 8-12 and 20-23 set forth in the prior Office action mailed on 01/14/2026 is withdrawn in light of Applicant’s amendment to claim 1 to recite new limitation “wherein the culture medium comprises EREG at a concentration between 0.1 ng/mL and 5 ng/mL”.
New 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, 11-12 and 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over Jarde et al (Cell Stem Cell. October 1, 2020; 27: 646–662. Prior art of record) in view of Sato et al., (Scientific Reports. May 22, 2020; 10:8308, p. 1-15. Prior art of record) and RnD Systems (Information sheet of Recombinant Human Epiregulin. Published on 2/6/2018. Downloaded from https://www.rndsystems.com/products/recombinant-human-epiregulin-protein_1195-ep, downloaded on 1/5/2026. P. 1. Prior art of record).
With respect to claim 1, Jarde teaches a method of culturing single intestinal epithelial cells or intestinal crypts (see e.g., p. e4, “Single cell organoid culture” and “Organoid culture” sections), thus teaches the preamble a method of culturing intestinal cells or tissue.
Jarde teaches the single intestinal epithelial cells are isolated by FACS and cultured in vitro in a culture medium comprising R-spondin 1, CHIR, WNT-3a (i.e., agents for activating Wnt signaling), and neuregulin 1 (NRG1, an EGF family ligand) (see e.g., p. e4, “Single cell organoid culture” section).
Jarde teaches “NRG1 treatment dramatically increased (by 50%) the ability of Lgr5-GFPhigh, Lgr5-GFPmed, and Lgr5-GFPlow cells to form organoids compared to EGF (Figure 6H)” (p. 657, left col, line 2), and organoids treated with NRG1 exhibit a dramatic increase in complexity with multiple buds, which are similar to in vivo crypt domains (Figures 7D and 7E) (p. 657, left col, last para), thus teaches the culturing results in the formation of intestinal organoids.
Jarde teaches NRG1 treatment promotes stem cell proliferation evidenced by expression of the stem cell markers Lgr5 and Olfm4 being upregulated in NRG1-treated tissues (Figure 7F) (p. 657, left col, last para), thus teaches the intestinal organoids express OLFM4 and LGR5.
However, Jarde does not teach the culture medium comprises Epiregulin.
Nevertheless, Jarde acknowledges they “did not evaluate the function of other members of the EGF family of ligands. It is possible that these ligands, in conjunction with NRG1, contribute to supporting intestinal tissue regeneration following injury” (p. 659, right col, “Limitations of Study” section, line 3). Regarding EGF family of ligands, Jarde teaches in “Introduction” that the ligands include EGF, epiregulin, and neuregulin (NRG) 1-4 (p. 647, left col, para 2). It is noted that Jarde has evaluated the function of EGF in conjunction with NRG1 in supporting intestinal tissue regeneration (see e.g., Fig 1F, Fig 6H and Fig 7D-7E, “EGF+NRG1” group). Thus, Jarde clearly contemplates evaluating other EGF family ligands, including epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury.
Regarding epiregulin supporting intestinal tissue regeneration following injury, Sato teaches “Immediately after irradiation exposure, the production of EGF family proteins is markedly upregulated in the intestinal epithelial cells and surrounding stromal cells to promote epithelial regeneration. To mimic the in vivo situation, we added epiregulin to the organoid culture of irradiated crypt epithelial cells” (p. 3, last 4 lines, also see p. 13, “Organoid culture” and Fig 5D-5E), thus suggests epiregulin is upregulated in vivo following injury to promote intestinal tissue regeneration. Sato teaches the culture medium for intestinal organoid assay comprises RspoI (i.e., R-spondin 1) and CHIR-99021 (the same agents used by Jarde for activating Wnt signaling), EGF and Epiregulin (p. 13, “Organoid culture”).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of culturing intestinal cells or tissue in vitro in culture medium comprising an agent for activating Wnt signaling and NRG1 for intestinal organoids formation disclosed by Jarde, by combining an additional EGF family ligand Epiregulin in the culture medium as suggested by Jarde and taught by Sato with a reasonable expectation of success. Since Jarde suggests to evaluate other EGF family ligands, including Epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury (Jarde, p. 659, right col, “Limitations of Study” section, and “Introduction”, p. 647, left col, para 2), and since Sato suggests Epiregulin is upregulated in vivo following injury to promote intestinal tissue regeneration and reduces to practice culturing intestinal cells in vitro in culture medium comprising Epiregulin in an intestinal organoid assay (p. 3, last 4 lines, also see p. 13, “Organoid culture” and Fig 5D-5E), one of ordinary skill in the art would have had a reason to combine Epiregulin in the culture medium of Jarde in order to evaluate the function of Epiregulin in conjunction with NRG1 in supporting intestinal tissue regeneration following injury (Jarde, p. 659, right col, “Limitations of Study” section, line 3). Furthermore, since both media of Jarde and Sato comprise the same agents for activating Wnt signaling (R-spondin 1 and CHIR, see Jarde, p. e4, “Single cell organoid culture” section and Sato, p. 13, “Organoid culture”), and both Jarde and Sato teach the presence of active Wnt signaling is required for intestinal tissue regeneration (e.g., Jarde, p. 654, right col, end of para 1; Sato, end of p. 3-p. 4 and Fig 5D-5E, it is noted that Sca1-negative cells have higher regeneration efficiency and higher Wnt signaling since YAP target genes (such as Sca1) are inversely correlated with Wnt target genes, see Sato abstract and p. 2, end of last full para), one of ordinary skill in the art would have had a reasonable expectation of success in combining Epiregulin in conjunction with NRG1, in the medium comprising an agent for activating Wnt signaling, to support regeneration of intestinal tissue following injury.
Regarding the culture medium not comprising EGF, as a first matter, Jarde teaches the small intestine organoids “treated with NRG1 and without EGF were much larger” and “EGF was no longer required, demonstrating that NRG1 can substitute for EGF” (p. 649, left col, para 1, lines 4 & 8, see Fig 1E-1G for NRG1 only), and “similar phenotypes were observed when single cells were supplemented with NRG1 in the absence of EGF (Figure S7E)” (p. 657, left col, para 1, line 7). Thus, Jarde explicitly teaches NRG1 can substitute for EGF and teaches a culture medium supplemented with NRG1 in the absence of EGF. Accordingly, one of ordinary skill in the art would have chosen the culture medium comprising NRG1 and Epiregulin, in the absence of EGF, as suggested by Jarde in view of Sato with a reasonable expectation of success.
Furthermore, as stated supra, Jarde reduces to practice evaluating a combination of EGF and NRG1 in supporting intestinal tissue regeneration (see e.g., Fig 1F, Fig 6H and Fig 7D-7E, “EGF+NRG1” group) and clearly contemplates evaluating other EGF family ligands, including epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury (p. 659, right col, “Limitations of Study” section, line 3). Sato teaches the culture medium for intestinal organoid culture comprises a combination of EGF and Epiregulin (p. 13, “Organoid culture”). Accordingly, one of ordinary skill in the art would have substituted with a third possible combination of NRG1 and Epiregulin, in the absence of EGF, as suggested by Jarde and Sato in order to evaluate other EGF family ligands, including epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury.
However, Sato uses epiregulin at a concentration of 500 ng/mL (p. 13, para “Organoid culture”), but Jarde and Sato are silent on using EREG at the claimed concentration in claims 1 and 22-23.
RnD Systems teaches the ED50 of recombinant human epiregulin (EREG) is 0.125 - 0.75 ng/mL, measured in a cell proliferation assay (see p. 1, section “Specifications”, row “Activity”, and section “DATA”, left panel “Bioactivity”), thus teaches EREG is used for supporting cell proliferation at a concentration between 0.1 ng/mL and 5 ng/mL in claims 1 and 22, and the concentration being about 1 ng/mL in claim 23.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of culturing intestinal cells/tissue in a culture medium comprising EREG as suggested by Jarde in view of Sato, by substituting the concentration of EREG with a concentration between 0.1 ng/mL and 5 ng/mL, about 1 ng/mL, as suggested by RnD Systems with a reasonable expectation of success. Since RnD Systems teaches the ED50 of recombinant human EREG is 0.125 - 0.75 ng/mL measured in a cell proliferation assay (see p. 1, section “Specifications”, row “Activity”, and section “DATA”, left panel “Bioactivity”) thus suggests EREG at a concentration in this range is capable of supporting cell proliferation, one of ordinary skill in the art would have had a reason to substitute with the claimed lower concentration as suggested by RnD Systems in order to support intestinal cell proliferation with a lower amount of agents.
Furthermore, regarding the differences in concentration of EREG from Sato, MPEP states “generally, differences in 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” and “where 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”. See MPEP 2144.05(II)(A). In the instant case, Sato uses epiregulin at a concentration of 500 ng/mL to support intestinal organoid growth (p. 13, para “Organoid culture”), and RnD Systems reduces to practice EREG at 0.125 - 0.75 ng/mL being capable of supporting cell proliferation (see p. 1, section “Specifications”, row “Activity”, and section “DATA”, left panel “Bioactivity”). Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have applied the claimed EREG concentrations because they are the result of “routine optimization”.
With respect to claim 3, directed to the intestinal organoids being intestinal enteroids, enteroids are known to be organoids derived from the small intestine and the specification recites “intestinal epithelial organoids, which are commonly referred to as enteroids” (p. 3, line 4). As discussed supra, Jarde teaches culturing with NRG1 promotes single cells to form intestinal organoid and these single cells are epithelial cells isolated from small intestinal tube (p. e4, “Single cell organoid culture” section), and Sato teaches culturing intestinal crypt epithelial cells in organoid culture (p. 13, “Organoid culture”), thus teaches the intestinal organoids are small intestinal epithelial organoids (i.e., enteroids).
With respect to claim 4, directed to culturing resulting in stem cell maintenance, and claim 5, directed to the cells being stem cells, as discussed supra, Jarde teaches culturing intestinal stem cells (Lgr5-GFPhigh) with NRG1 results in more organoids and increased overall cell numbers (Fig 6H, and Fig S7E in page 40) and “these results clearly demonstrate that NRG1 promotes a proliferative signature in stem and progenitor cells and induces these cells to express higher levels of stem cell markers” (p. 657, left col, para 2, line 1), and Sato teaches the culturing Sca1--negative Lgr5-derivatives (i.e., intestinal stem cells) with Epiregulin results in regeneration of Lgr5hi intestinal stem cells (see p. 4 and Fig 5F and legend), thus teaches culturing intestinal stem cells with NRG1 and Epiregulin results in stem cell maintenance.
With respect to claim 11 directed to culture medium further comprising an R-spondin and Noggin, and claim 12 limiting the R-spondin being R-spondin 1, Jarde teaches a single cell organoid culture medium further comprises “100 ng/mL Noggin and 1 ug/mL R-spondin 1” (p. e4, “Single cell organoid culture” section, line 6), and Sato teaches the organoid assay medium comprises RspoI (i.e., R-spondin 1) and Noggin (p. 13, “Organoid culture”).
With respect to claim 20 directed to the agent capable of activating Wnt signaling being Wnt3A, as stated supra, Jarde teaches the medium for culturing intestinal cells comprises Wnt3A that is capable of activating Wnt signaling (p. e4, “Single cell organoid culture” section, line 8).
With respect to claim 21 directed to the intestinal organoids having a budded morphology with putative crypt-like domains budding off of a central lumen, Jarde teaches the “organoids treated with NRG1 and without EGF were much larger, with buds composed of numerous rapidly proliferating cells” (p. 649, 1st para) and “organoids treated with NRG1 exhibit a dramatic increase in complexity with multiple buds, which are similar to in vivo crypt domains” (p. 657, left col, last para, see Fig 1F, Fig 4H and Fig 7D for examples of organoids having a budded morphology with putative crypt-like domains budding off of a central lumen).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 04/14/2026 are acknowledged.
Applicant first argues that Jarde states that other EGF family ligands were not evaluated and that such ligands may contribute to tissue regeneration in conjunction with NRG1. This statement does not disclose any specific combination of NRG1 with epiregulin in organoid culture and does not provide any teaching that such a combination would function in an EGF free system (Remarks, p. 6, para 2). Sato does not disclose or suggest removing EGF when epiregulin is used, and does not describe an epiregulin containing medium that lacks EGF (Remarks, p. 6, para 3). The cited art does not disclose a culture medium that includes both NRG1 and epiregulin in the absence of EGF as required by the claims (Remarks, p. 6, para 4).
Applicant’s arguments have been fully considered but they are not persuasive.
In regard to the specific combination of NRG1 with epiregulin, as stated supra, Jarde acknowledges they “did not evaluate the function of other members of the EGF family of ligands. It is possible that these ligands, in conjunction with NRG1, contribute to supporting intestinal tissue regeneration following injury” (p. 659, right col, “Limitations of Study” section, line 3). Regarding EGF family of ligands, Jarde teaches in “Introduction” that the ligands include EGF, epiregulin, and neuregulin (NRG) 1-4 (p. 647, left col, para 2). Thus, Jarde clearly suggests evaluating other EGF family ligands, including epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury. Since Jarde only discloses 5 ligands besides NRG1 (EGF, epiregulin, and NRG 2-4), one of ordinary skill in the art would have immediately envisaged the taught option of epiregulin in conjunction with NRG1 among the limited genus of options as suggested by Jarde alone. See MPEP 2131.02 (III).
In regard to the context of an EGF free system, as a first matter, Jarde explicitly teaches NRG1 can substitute for EGF and teaches a culture medium supplemented with NRG1 in the absence of EGF (p. 649, left col, para 1, lines 4 & 8, see Fig 1E-1G for NRG1 only). Accordingly, one of ordinary skill in the art would have chosen the culture medium comprising NRG1 and Epiregulin, in the absence of EGF, as suggested by Jarde in view of Sato with a reasonable expectation of success.
Furthermore, Jarde reduces to practice evaluating a combination of EGF and NRG1 in supporting intestinal tissue regeneration (see e.g., Fig 1F, Fig 6H and Fig 7D-7E, “EGF+NRG1” group) and clearly contemplates evaluating other EGF family ligands, including epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury (p. 659, right col, “Limitations of Study” section, line 3). Sato teaches the culture medium for intestinal organoid culture comprises a combination of EGF and Epiregulin (p. 13, “Organoid culture”). Accordingly, one of ordinary skill in the art would have substituted with a third possible combination of NRG1 and Epiregulin, in the absence of EGF, as suggested by Jarde and Sato in order to evaluate other EGF family ligands, including epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury.
Applicant further argues that the cited art does not show that epiregulin concentration is a parameter that has been recognized to affect organoid formation or maintenance in an EGF free intestinal organoid system. The claimed range of 0.1 ng/mL to 5 ng/mL is far removed from that disclosure and is not taught or suggested by the cited references (Remarks, p. 6-7).
Applicant’s arguments have been fully considered but they are not persuasive.
As stated supra, RnD Systems teaches the ED50 of recombinant human epiregulin (EREG) is 0.125 - 0.75 ng/mL, measured in a cell proliferation assay (see p. 1, section “Specifications”, row “Activity”, and section “DATA”, left panel “Bioactivity”), thus one of ordinary skill in the art would have immediately recognized that epiregulin concentration is a parameter to affect cell proliferation, and would be a parameter to affect intestinal cell proliferation in the context of culturing intestinal cells/tissue as suggested by Jarde in view of Sato and RnD Systems.
In regard to the claimed range of 0.1 ng/mL to 5 ng/mL being far removed from that disclosure and is not taught or suggested by the cited references, the concentration range of ED50 of EREG for supporting cell proliferation taught by RnD Systems, 0.125 - 0.75 ng/mL, is encompassed within the claimed range of 0.1 ng/mL to 5 ng/mL in claims 1 and 22, and overlaps with the claimed range of about 1 ng/mL in claim 23. Thus, one of ordinary skill in the art would have had a reason to substitute with the claimed lower concentration as suggested by RnD Systems in order to support intestinal cell proliferation with a lower amount of agent.
Furthermore, regarding the differences in concentration of EREG from Sato, MPEP states “generally, differences in 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” and “where 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”. See MPEP 2144.05(II)(A). In the instant case, Sato uses epiregulin at a concentration of 500 ng/mL to support intestinal organoid growth (p. 13, para “Organoid culture”), and RnD Systems reduces to practice EREG at 0.125 - 0.75 ng/mL being capable of supporting cell proliferation (see p. 1, section “Specifications”, row “Activity”, and section “DATA”, left panel “Bioactivity”). Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have applied the claimed EREG concentrations because they are the result of “routine optimization”.
Applicant finally argues that the claimed method produces results that would not have been expected from the cited art. The application provides specific experimental data demonstrating that the use of low concentrations of epiregulin in an EGF free medium containing a Wnt activator and NRG1 produces a distinct organoid phenotype, including that enteroids grown with epiregulin display a budding morphology and the lowest concentration of epiregulin tested, about 1 ng/mL, produced the most differentiated cell types and spatial organization within these enteroids forming crypt like domains (Remarks, p. 7).
Applicant’s arguments have been fully considered but they are not persuasive.
In regard to the enteroids displaying a budding morphology and having spatial organization forming crypt like domains when grown in low concentrations of epiregulin in an EGF free medium, as stated supra, Jarde teaches the “organoids treated with NRG1 and without EGF were much larger, with buds composed of numerous rapidly proliferating cells” (p. 649, 1st para) and “organoids treated with NRG1 exhibit a dramatic increase in complexity with multiple buds, which are similar to in vivo crypt domains” (p. 657, left col, last para, see Fig 1F, Fig 4H and Fig 7D for examples of organoids having a budded morphology with putative crypt-like domains budding off of a central lumen, and see Fig7E for more than 50% organoids having more than 7 buds per organoid).
In regard to more differentiated cell types when grown in low concentrations of epiregulin in an EGF free medium, Jarde teaches “increased capacity of NRG1-treated progenitor cells to initiate organoid cultures and support subsequent growth” and “treatment with NRG1 enhanced intestinal tissue regeneration by increasing crypt density, cell proliferation, and the efficient reappearance of the stem cell pool” (p. 657, left col, para 2 and right col, 1st full para.). Thus, one of ordinary skill in the art would have immediately expected that enhanced intestinal tissue regeneration by NRG1 treatment would be resulted from multilineage differentiation, i.e., more differentiated cell types, from the increased intestinal stem cells.
Therefore, the purported unexpected result of distinct organoid phenotype when grown in low concentrations of epiregulin in an EGF free medium containing a Wnt activator and NRG1, would not have been different from that of intestinal organoids cultured with NRG1 in an EGF free medium as taught by Jarde.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Jarde et al (Cell Stem Cell. 2020; 27: 646–662, published on October 1, 2020. Prior art of record) in view of Sato et al., (Scientific Reports. May 22, 2020; 10:8308, p. 1-15. Prior art of record) and RnD Systems (Information sheet of Recombinant Human Epiregulin. Published on 2/6/2018. downloaded on 1/5/2026, Downloaded from https://www.rndsystems.com/products/recombinant-human-epiregulin-protein_1195-ep. P. 1. Prior art of record), as applied to claim 1 above, and further in view of Fordham et al (Cell Stem Cell. 2013; 13: 734-744. Prior art of record).
Claim 8 is directed to the intestinal tissue or cells being human intestinal tissue or cells. Claim 9 further limits the human intestinal tissue being fetal intestinal tissue.
As discussed supra, Jarde in view of Sato teach a method of culturing intestinal cells to form intestinal organoids. Jarde and Sato teach the cells are isolated from mice (Jarde, p. e4, “Organoid culture” and “Single cell organoid culture” sections, and Sato, p. 12, last two sections). Jarde teaches human small intestinal tissues from adult patients are collected following surgery (p. e4, “Human small intestinal tissue” section) and are used for immunofluorescent analysis for NRG1 expression (see supplemental Fig S3B).
However, Jarde, Sato and RnD Systems do not teach the tissue or cells used in culturing is human fetal intestinal tissue in claims 8-9.
Fordham teaches a method for culturing human fetal intestinal tissue in vitro to make fetal enterospheres (title, abstract), thus teaches claims 8-9. Fordham teaches “fetal human intestinal tissue at around gestational week 10 was dissected and dissociated” to be cultured into formation of “human Fetal Enterospheres (hFEnS). hFEnS are highly proliferative and can be passaged repeatedly by mechanical dissociation for over 2 months” (p. 735, right col, para 2). Fordham does a transplantation study and finds the FEnS can differentiate into intestinal tissues in an injury model, and teaches hFEnS comprise a population of expandable fetal enteric progenitors from human that can be used as a transplantable source and have the potential to be used in regenerative medicine (p. 742, right col, para 2, lines 1&7).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of culturing mouse intestinal tissue/cells to form intestinal organoids suggested by Jarde in view of Sato and RnD Systems, by substituting the mouse intestinal tissue/cells with human fetal intestinal tissue as taught by Fordham with a reasonable expectation of success. Since Fordham teaches human fetal enterospheres are highly proliferative that serve as a transplantable source and can be used in regenerative medicine (see Fordham p. 742, right col, para 2, lines 1&7), one of ordinary skill in the art would have had a reason to substitute the mouse tissue with human fetal intestinal tissue in order to obtain expandable, transplantable human Fetal Enterospheres for use in regenerative medicine. Furthermore, as stated supra, since Jarde teaches that both human and mouse small intestine express NRG1, there would have been a reasonable expectation of success in substituting mouse with human cells in the method of Jarde.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 04/14/2026 are acknowledged and have been discussed above.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Jarde et al (Cell Stem Cell. 2020; 27: 646–662, published on October 1, 2020. Prior art of record) in view of Sato et al., (Scientific Reports. May 22, 2020; 10:8308, p. 1-15. Prior art of record) and RnD Systems (Information sheet of Recombinant Human Epiregulin. Published on 2/6/2018. downloaded on 1/5/2026, Downloaded from https://www.rndsystems.com/products/recombinant-human-epiregulin-protein_1195-ep. P. 1. Prior art of record), as applied to claim 1 above, and further evidenced by Matrigel-Wikipedia (Wikipedia. December 9, 2019, downloaded from https://en.wikipedia.org/w/index.php?title=Matrigel&oldid=930001942, downloaded on 7/25/23. Prior art of record).
Claim 10 is directed to the culturing being in a 3D scaffold comprising laminin, nidogen, collagen, hepatic sulfate proteoglycans, and TGF-β.
As discussed supra, Jarde in view of Sato teach a method of culturing intestinal cells to form intestinal organoids. Both Jarde and Sato teach the culturing is in Matrigel that solidifies during culturing at 37°C (Jarde, p. e4, “Organoid culture” and “Single cell organoid culture”, and Sato, p. 13, “Organoid culture”), thus teach culturing intestinal cells/tissue in Matrigel, which solidifies to form a 3D scaffold.
However, Jarde and Sato do not specifically teach the scaffold comprising laminin, nidogen, collagen, hepatic sulfate proteoglycans and TGF-β in claim 10.
Matrigel-Wikipedia discloses that Matrigel is a basement membrane matrix that is commercially available and can be used as a 3D scaffold for cell culture (p. 1, para 1 and para “metastasis model”). Matrigel-Wikipedia evidences Matrigel comprises “laminin, nidogen, collagen, hepatic sulfate proteoglycans and growth factors like TGF-β” (p. 2, para “constituents”), related to claim 10.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have expected that the method of culturing intestinal cells/tissue in a 3D scaffold Matrigel as suggested by Jarde in view of Sato and RnD Systems would have been in a 3D scaffold comprising laminin, nidogen, collagen, hepatic sulfate proteoglycans and TGF-β as evidenced by Matrigel-Wikipedia.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 04/14/2026 are acknowledged and have been discussed above.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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