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 .
Response to Amendment
The amendment filed 7/14/2026, amending claim(s) 1 is acknowledged.
Applicant’s amendments to the claims have overcome the 112(a) Written Description rejection previously set forth in the Final Office Action mailed 04/07/2026.
Claims 1, 3, 4, 6-8, 11-16, and 18 are pending.
Claims 11-13 are still withdrawn.
Claims 1, 3, 4, 6-8, 14-16, and 18 are pending and currently under examination.
Priority
Claim 1 has been amended to recite “at least 7 days”. As such, Applicant's claim for the benefit of a prior-filed provisional application 62/856,481 filed on 06/03/2019 and PCT/US2020/03564 filed 06/03/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Rejections - 35 USC § 103 – Maintained
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.
Claim(s) 1, 3, 4, 6-8, 14-16, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li (Li, Xingnan, Akifumi Ootani, and Calvin Kuo. "An air–liquid interface culture system for 3D organoid culture of diverse primary gastrointestinal tissues." Gastrointestinal Physiology and Diseases: Methods and Protocols. New York, NY: Springer New York, 2016. 33-40.) and further in view of Lania (Lania, Giuliana, et al. "Constitutive alterations in vesicular trafficking increase the sensitivity of cells from celiac disease patients to gliadin." Communications biology 2.1 (2019): 190.).
Regarding claims 1 and 15, Li teaches a method for producing an air-liquid interface culture system for a 3D organoid culture of gastrointestinal tissues (+ in vitro organoid culture derived by method – claim 15). Specifically, Li teaches culturing mammalian (e.g., murine) small intestine tissue biopsy sample (pg. 38, Note 4) in a gel with an air-liquid interface (pg. 36, “3.3 Assembly of ALI 3D Primary Culture System”). Although Li is silent on the biopsy small comprising native intestinal immune cells, Li teaches using wild-type small intestine tissue (and the entire piece of tissue, including the epithelial layer, lamina propria, and muscles (pg. 39, Note 6)), and does not teach processing the tissue to remove specific cell types. Thus, absent evidence to the contrary, one of ordinary skill in the art would conclude the small intestine biopsy small taught by Li comprises intestinal epithelium and native intestinal immune cells. Additionally, Li teaches culturing the biopsy sample in a culture medium that supports maintenance and activity of both epithelial and immune cells for a period of at least 7 days (pg. 36, “3.3 Assembly of ALI 3D Primary Culture System”; Fig. 3).
Li does not teach the produced organoid culture model being an organoid culture model for celiac disease, and
after culturing the small intestine tissue for a period of at least 7 days, adding to the mammalian organoid culture model gluten-derived peptides in a dose effective to activate the native intestinal immune cells;
and measuring at least one hallmark of celiac disease in said mammalian organoid culture model, wherein the hallmark of celiac disease is one or more of gliadin-presentation to T cells, T cell expansion, T cell activation, epithelial-cell death, and increased epithelial cell proliferation. Li also does not teach a method for screening a candidate agent for an effect on a mammalian tissue, or for determining the presence of active celiac disease or a predisposition to celiac disease in an individual (claims 16, 18).
Li does teach that the ALI method allows robust culture from genetically engineered mice and in vitro Cre- dependent oncogene activation, tumor suppressor inactivation, or viral transduction, and that this 3D ALI organoid system has tremendous potential for bridging the gap between 2D cell line-based research and animal model-based in vivo studies in gastrointestinal biology.
Lania teaches collecting biopsy samples from the duodenum (i.e., small intestine) of celiac disease (CD) (claims 6 and 7) and control patients (i.e., compared to a control – claims 14 and 18). Biopsy fragments were then cultivated, followed by being cultured with 100 microgram/ml (i.e., 0.5 microM to 100 microM, an effective dose according to [0037 of the specification]) P31-43 (i.e., gluten-derived peptides of wheat gliadin from 8 to 35 amino acids in length- claim 3; deamidated gliadin peptides- claim 4) and EGF (claim 8) (pg. 9-10, “Organ culture studies”) (i.e., screening a candidate agent (e.g., gliadin peptide) for an effect on a mammalian tissue – claim 16).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method taught by Li with the method steps of obtaining, culturing, then exposing duodenum biopsy samples from CD patients to deamidated gliadin peptides 8 to 35 amino acids in length as taught by Lania. One would have a reasonable expectation for success because the method of Li teaches cultivating and exposing an organoid model to various antibodies (pg. 37, “3.5 Embedding of Primary Organoids for Histological Analysis”, Step 4) and conditions such as viral vectors (pg. 39, Note 8), and it is routine in the art to test (i.e., expose) organoid models to varying agents (e.g., gluten-derived peptides) to evaluate their effect on biological processes. There is nothing of the methods of Li nor Lania to suggest that an artisan would be unable to expose the organoid cultured via the method of Li with the gliadin taught by Lania. An artisan would be motivated to combine the methods because as taught by Lania, the reasons why P31-43 is dangerous to the CD small intestinal mucosa are unknown, and using cellular models such as organoids may help artisans understand the role of gluten-derived peptides in celiac disease (Abstract; pg. 2, col 2, para 2-pg. 3, col 1, paras 1-2).
Response to Arguments
Applicant's arguments filed 07/14/2026 have been fully considered but they are not persuasive.
In response to applicant's argument that:
“Lania does not teach or suggest measuring gliadin presentation to T cells, T cell expansion, and T cell activation. Lania also does not teach or suggest that such features of celiac disease would be reproducible in their model.”
This argument is not persuasive because the claims recite “measuring [determining the effect of the agent] at least one hallmark of celiac disease in said mammalian organoid culture model, wherein the hallmark of celiac disease is one or more of gliadin-presentation to T cells, T cell expansion, T cell activation, epithelial-cell death, and increased epithelial cell proliferation.” Lania measures the effect of gliadin peptide exposure on enterocytes (a type of epithelial cell). For example, Lania found that in the presence of P31-43 CD enterocytes presented a persistent
reduced ability to dispose of the EGF load in the early endocytic vesicles (e.g., pg. 6, col 1) (e.g., measuring epithelial cell proliferation, as reduced degradation of EGFR increases enterocyte proliferation, e.g., pg. 2, col 1, and 2)). Therefore, the teachings of Lania fulfill the limitations of the claimed method(s). The Applicant fails to distinctly point out how the teachings of Lanai is silent with respect to measuring epithelial cell death or proliferation (e.g., why would the results of Lanai, such as reduced decay of EGFR, not read on measuring epithelial cell proliferation, in view of the known relation between EGFR and epithelial cell proliferation?).
Additionally, it is unclear how Lania does not suggest that such features of celiac disease would be reproducible in their model because the model taught by Lania investigates the effects of gliadin peptides in biopsies from celiac patients. The Applicant fails to distinctly point out how the teachings of Lania are not applicable to studying celiac disease.
Conclusion
No claims are allowed.
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 ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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