CTNF 18/432,439 CTNF 89236 DETAILED ACTION This action is in reply to papers filed 2/8/2024. Claims 1-2, 4, 6-14 are pending and examined herein . Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Examiner’s Note All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240218334A1, Published 7/4/2024. Claim Rejections - 35 USC § 112 07-30-02 AIA 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. 07-34-01 Claims 1, 2 and 13 are 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. 07-34-05 AIA Claim 1 recites the limitation " the differentiated mammalian epithelial cells " in line 9 . There is insufficient antecedent basis for this limitation in the claim. The metes and bounds of claim 2 are unclear. Claim 2 is drawn to, inter alia, “…wherein the monolayer is generated by a method further comprising: culturing the primary cells under conditions sufficient to allow proliferation of the cells and formation of organoids; seeding the cells...” However, it is wholly unclear where this step belongs in independent claim 1. This is because every step in the method of generating the monolayer in claim 1 does not require an organoid. For example, the steps are drawn towards obtaining a primary stem cells, maintaining the stem cells to form a monolayer and then contacting the cells of the monolayer with DAPT and RANKL. Where are the organoids of claim 2 found in the steps of claim 1? Claim 13 recites, inter alia, “…and the cell”. There is a lack of clarity with this recitation as independent claim 1 recites many ‘cells’. Therefore, it is unclear which ‘the cell’ claim 13 refers to. Clarification is requested. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. Prior Art Rejection 1 07-21-aia AIA Claim (s) 1-10 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Albritton et al. (PgPub US20180002672A1, Published 1/4/2018, Ref 8 in IDS filed 3/21/2024), Rouch et al . (PLoS One. 2016 Jan 28;11(1):e0148216., Ref 44 in IDS filed 3/21/2024), Jung et al . (FASEB J. 2018 Jan;32(1):111-122., Ref 24 in IDS filed 3/21/2024), Pletscher-Frankild et al. (Methods. 2015 Mar;74:83-9., Ref 40 in IDS filed 3/21/2024), Fasciano et al. (J Vis Exp. 2019 Jul 26;(149):10.3791/59894., Ref 19 in IDS filed 3/21/2024), Ortega et al. (PgPub 20170191030A1, Published 7/6/2017) and Li et al. (Human Molecular Genetics, Volume 13, Issue 16, 15 August 2004, Pages 1715–1725., Ref 26 in IDS filed 3/21/2024) .. Albritton is drawn to methods of generating gastrointestinal (organoid) epithelial tissue constructs (Title; Pg. 10, para. 121). Regarding claim 1 ,in-part, Albritton et al. teach a method of making an ex vivo model system, comprising: culturing a monolayer of differentiated human (Pg. 3, para. 39) epithelial cells, wherein the monolayer comprises enterocytes with microvilli (Pg. 10, para. 125) and mucus-producing goblet cells (Pg. 10, para. 123-124 ), having an apical surface (Pg. 10, para. 126) and a basolateral surface. A basolateral surface comprises a basal surface, which is taught by Albritton (Pg. 9, para. 115). Albritton teaches the epithelial cells are derived from primary stem cells obtained from the small intestine of a mammalian subject with an inflammatory gut condition (as further in claim 1 ) (Pg. 3, para. 39; Pg. 6, para. 89) and comprises intestinal crypt cells (as in claim 4 ) (Pg. 7, para. 96). Albritton notes that the ability to create these tissues from healthy and diseased sources and from cells of differing genetic backgrounds will be important for screening drugs, study of disease mechanisms, and study of basic biology. Further, Albritton teaches that addition of various other cell types (e.g. other cells found co-existing with the particular epithelial tissue in vivo) co-cultured on or within the biomimetic scaffold will be valuable for understanding cell-cell interactions and the effect of drugs and metabolites on the tissue (Pg. 5, para. 62). However, Albritton fails to teach the other cells are Microfold (M) cells (as further in claim 1). Before the effective filing date of the claimed invention, Rouch et al. teach the single layer of epithelial cells that lines the entire intestinal tract is the primary physical barrier separating the intestinal lumen and its content from the intestinal lamina propria and the body’s interior. Rouch teaches various mechanisms have been proposed to explain enteral uptake of viruses and microbes, including disruptions of the epithelial barrier, transcytosis across enterocytes, infection of juxtaposed dendritic cells and/or lymphocytes, and through microfold (M) cells located within the follicle-associated epithelium (FAE) that overlies Peyer’s patches, or are scattered along the villus-independent of Peyer’s patches. Rouch adds that these cells represent a major site for the sampling of gut luminal antigens, and are important for enteral uptake of various commensal microorganisms, and viral and bacterial pathogens (Pg. 2/16, para. 1). Towards this end, Rouch cultured and differentiated human intestinal crypts containing Lgr5+ intestinal stem cells (ISCs) into an epithelial layer with functional M cells (as further in claim 1 ) with characteristic morphological and functional properties. Rouch notes that their study was the first to demonstrate that M cells can be induced to form from primary human intestinal epithelium, and that S. Typhimurium preferentially infect these cells in an in vitro setting. Rouch et al. adds that they anticipate that this model can be used to generate large numbers of M cells for further functional studies of these key cells of intestinal immune induction and their impact on controlling enteric pathogens and the intestinal microbiome (Abstract-‘Conclusion’) . However, neither Albritton nor Rouch teach the cells of the monolayer express one or more exogenous biosensors responsive to an inflammation-related signal comprising at least one promoter that binds to the inflammation-related signal and drives expression of a detectable output protein upon binding of the inflammation-related signal to the promoter (as further in claim 1) and wherein said biosensor is responsive to IL-8 (as in claim 14). Before the effective filing date of the claimed invention, Jung et al. teach human intestinal organoids (hIOs) derived from human pluripotent stem cells (hPSCs) have immense potential as a source of intestines. Therefore, Jung notes that an efficient system is needed for visualizing the stage of intestinal differentiation. Jung teaches gene expression data from the Human Protein Atlas revealed that the transcription factor KLF5 was found in particularly high levels in the digestive organs, whereas the intestine-specific transcription factor ISX was exclusively expressed in the intestinal tract. With this information, Jung and colleagues sought to determine whether expression of KLF5 and ISX increased during directed differentiation of hPSCs into intestinal tissue in vitro (Abstract; Pg. 113, Col. 2, para. 4). Specifically, Jung generated genetically engineered hiPSC lines that allow for the identification and tracking of differentiating intestinal cells. This approach is based on the use of intestine lineage-specific promoters of KLF and ISX to direct the expression of a reporter gene and selection marker. Jung used monomeric Cherry (mCherry) and enhanced green fluorescent protein (eGFP) as intestinal biosensors (i.e. KLF5 mCherry or ISX eGFP ) (as further in claim 1 and as in claim 9 ) (Abstract; Pg. 113, Col. 2, para. 4) to investigate the in vitro differentiation potentiality to improve the hIO differentiation protocols for hiPSC-derived hIOs. Jung also performed in vivo transplantation experiments to monitor hIOs in 3D structures in real time. Jung adds that the results from this study can provide an efficient and selective fluorescent reporter system for the derivation of intestine lineage cells from hiPSCs and offer an approach for studying the clinical application of cell-based transplantation therapy to ensure the success of cell delivery by visualizing engrafted hIOs (Pg. 118, paragraph bridging Col. 1. and Col. 2; Pg. 120, paragraph bridging Col. 1 and Col. 2). And although Jung teaches an intestinal biosensor cell line via the stable transfection of hiPSCs with either the KLF5 mCherry or ISX eGFP promoter reporter, Jung fails to teach the biosensor is an inflammation related gene (as further in claim 1), such as IL8 (as in claim 14). Before the effective filing date of the claimed invention, Pletscher-Frankid taught linking human genes to the diseases in which they are involved lies at the very heart of molecular medicine. Such links can be made through a variety of different types of studies, including classical pedigree-based genetics studies of Mendelian and complex diseases, genome-wide association studies (GWAS), somatic mutation frequencies, transcriptomics and proteomics studies, and detailed molecular biology studies of individual proteins. Because the relevant data come from so many types of experiments performed by researchers working in different disciplines, such as geneticists and molecular biologists, all the relevant data are not collected in a single place, making it difficult to get a comprehensive overview of which genes are involved in which diseases. However, due to the vast amount of research being performed on the topic, much has been written in the biomedical literature about the associations between genes and diseases. Extracting disease–gene associations from text is thus an obvious use case for text mining (Pg. 83, paragraph bridging Col. 1 and Col. 2) . Towards this end, Pletscher-Frankid developed a dictionary-based named entity recognition (NER) tool for Disease Ontology concepts and combined it with a co-occurrence scoring scheme to efficiently and accurately extract disease–gene associations from Medline (Pg. 88, Col. 1 ‘Conclusions’). In the ‘Supplementary Table S3’, Pletscher-Frankid identifies ‘ISX’ (Pg. 48) and ‘IL-8’ (Pg. 45) (as further in claim 1 and as in claim 14 ) as genes involved in gastrointestinal system disease. However, none of Albritton et al., Rouch et al., Jung et al. and Pletscher-Frankild et al. teach a method generating the monolayer as set forth in claim 1. Before the effective filing date of the claimed invention, Fasciano et al. teach a method for the differentiation of M cells in a transwell epithelial polarized monolayer system of the intestine using human ileal enteroids. Specifically, and with respect to claim 1 ,in-part, Fasciano teaches obtaining primary stem cells from a mammalian subject (Pg. 2, Protocol ’Note’); culturing the primary cells under conditions sufficient to allow proliferation of the cells and formation of organoids (enteroids) (Pg. 2, Protocol ‘Step 1’); seeding the cells into a culture plate comprising a permeable support device (Pg. 2, Protocol ‘Step 2-3’); maintaining the cells under conditions to allow for sufficient proliferation to form a monolayer having an apical and basolateral surface (Pg. 2, ‘Note’; Pg. 7, para. 3). Fasciano teaches that once monolayers are ~80% confluent, usually between days 1-3 post-seeding, replacing basolateral media with M cell media comprising RANKL (Pg. 2-3 ‘Replacing Medium’) for M cell induction wells and replace the media in upper chamber (i.e. apical) with differentiation media. Fasciano teaches the differentiation media comprises, inter alia, A-8301. Fasciano notes that the monolayer comprises enterocytes, goblet cells and M cells (paragraph bridging Pg. 3 and Pg. 4). However, Fasciano et al. fails to teach contacting the apical surface with DAPT (as recited in claim 1). Before the effective filing date of the claimed invention, Ortega et al. taught improved culture methods and culture media for expanding epithelial stem cells and obtaining organoids (Abstract), wherein such epithelial stem cells include intestinal epithelial stem cells (Pg. 15, para. 213). In one embodiment, Ortega teaches the differentiation medium comprises the TGF-beta inhibitor A-8301 and the Notch inhibitor, DAPT (as recited in claim 1 ) (Pg. 2, para. 26-34). Ortega teaches the organoids are obtained from diseases cells, such as cells from the inflammatory bowel disease Crohn’s disease (as in claim 6 and claim 7 ) (Pg. 24, para. 341; Pg. 25, para. 43). Ortega notes that an advantage of the culturing of epithelial cells in this media is that this results in the organoids and/or cell populations being formed in which the number of chromosomes remains stable when the cells or organoids are cultured long-term (Pg. 17, para. 234). And although Jung et al. teach an intestinal biosensor cell line via the stable transfection of intestinal cells with ISX eGFP promoter reporter and KLF5 mCherry promoter reporter (Abstract; Pg. 113, Col. 2, para. 4) and Pletscher-Frankid provided motivation to substitute the ISX biosensor for the inflammation related gene IL8, none of these references- or any of the previously cited references- teach the cells of the monolayer express a plurality of biosensors (as further in claim 8). Before the effective filing date of the claimed invention, Li et al. taught Crohn's disease (CD) is a chronic, relapsing inflammation affecting the gastrointestinal tract, most commonly the terminal ileum. It is characterized by chronic, intermittent inflammation of the intestines resulting in abdominal pain, diarrhea and, in children, growth retardation. Continuing, Li teaches comprehensive studies in primary mononuclear cells in CD patients comparing the functional effects of the individual disease-associated mutations, as well as comparing functional consequences in heterozygous carriers of established risk alleles have not been reported. Cytokines involved in the immediate innate immune responses include interleukin-8 (IL-8) and interleukin-1β (IL-1β) (as further in claim 8 ) (Pg. 1715, Col. 1, para. 1; Pg. 1716, Col. 1, para 1). When taken with the teachings of Albritton et al., Rouch et al., Jung et al. and Pletscher-Frankild et al., wherein the combination teaches an ex vivo intestinal organoid comprising a monolayer of enterocytes with microvilli, mucus-producing goblet cells and functional M cells, wherein said intestinal cells are derived from the gut of a subject having an inflammatory disease and wherein the cells are transfected with an IL-8 eGFP biosensor for the purposes of monitoring the in vivo environment into which the intestinal cells are transplanted thereto, one of ordinary skill in the art would have found it prima facie obvious to transfect a first population of intestinal cells with an IL-8 eGFP biosensor and a second population of intestinal cells with an IL-1β mCherry biosensor (as in claim 10 ). The skilled artisan would have been motivated to make such a modification in order to accurately account for the in vivo environment of a subject with Chron’s disease as Li notes that these two interleukins are involved in the immediate innate immune response in CD patients. Moreover, one of ordinary skill in the art would have found it prima facie obvious to generate the monolayer in the manner described in Fasciano et al. in view of Ortega et al. That is, the skilled artisan would have generated the monolayer of differentiated epithelial cells comprising enterocytes with microvilli, mucus-producing goblet cells and M cells by seeding primary epithelial stem cells from a subject on a Transwell permeable support, maintaining the cells under conditions to allow for proliferation to form a monolayer having an apical and basolateral surface, and contacting the basolateral surface to form M cells, as taught in Fasciano because Fasciano teaches the use of transwells provide a two-chamber system that allows for the creation of defined apical and basolateral surfaces such that the 4-5 different types of epithelial intestinal cells can polarize to express surface markers on each side relative to that found in the intestine ( see Fasciano at Pg. 7, para. 3). The skilled artisan would have also contacted the apical surface of the monolayer with a differentiation medium comprising DAPT as taught in Ortega because Ortega achieved success in expanding epithelial intestinal cells when these cells were cultured in a medium comprising, inter alia, DAPT. Thus, the modifications would have been prima facie obvious. Prior Art Rejection 2 07-21-aia AIA Claim (s) 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Albritton et al. (PgPub US20180002672A1, Published 1/4/2018, Ref 7 in IDS filed 3/21/2024), Rouch et al . (PLoS One. 2016 Jan 28;11(1):e0148216., Ref 44 in IDS filed 3/21/2024), Jung et al . (FASEB J. 2018 Jan;32(1):111-122., Ref 24 in IDS filed 3/21/2024), Pletscher-Frankild et al. (Methods. 2015 Mar;74:83-9., Ref 40 in IDS filed 3/21/2024), Fasciano et al. (J Vis Exp. 2019 Jul 26;(149):10.3791/59894., Ref 19 in IDS filed 3/21/2024), Ortega et al. (PgPub 20170191030A1, Published 7/6/2017) and Li et al. (Human Molecular Genetics, Volume 13, Issue 16, 15 August 2004, Pages 1715–1725., Ref 26 in IDS filed 3/21/2024) as applied to claims 1-10 and 14 and further in view of Lu et al . (PgPub US20170360850A1, Published 12/21/2017, Ref 7 in IDS filed 3/21/2024) . The teachings of Albritton et al., Rouch et al., Jung et al., Pletscher-Frankild et al., Fasciano et al., Ortega et al. and Li et al. are relied upon as detailed above. However, none of the aforementioned references teach the biosensor is responsive to nitric oxide and the promoter comprises NorR (as in claim 12) or that the biosensor is responsive to inflammation-H2O2 and the promoter is OxySp (as in claim 11 or claim 13). Before the effective filing date of the claimed invention, Lu et al. teach genetically engineered organisms useful for the diagnosis and treatment of inflammatory bowel disease (Abstract; Pg. 3,para. 29). Specifically, Lu teaches a recombinant probiotic cell comprising: a sensor circuit, comprising: (a) a first promoter operably linked to a nucleic acid encoding a regulatory protein responsive to an input signal; and (b) a second promoter responsive to the regulatory protein and operably linked to a nucleic acid encoding a first output protein, wherein activity of the second promoter is altered when bound by the regulatory protein (Pg. 2, para. 20). Lu teaches the the promoter of (a) is a constitutively-active promoter. Lu teaches the regulatory protein is selected from the group consisting of oxyR, NorR(as in claim 12 , in-part), and NsrR. Lu teaches the input signal is hydrogen peroxide (H2O2) (as in claim 11 , in-part and as in claim 13, in-part) or nitric oxide (NO) (as further in claim 12 ) (Pg. 2, para. 21). Lu adds that the promoter of (b) is oxySp (as in further in claim 11 and claim 13) (Pg. 2, para. 25). When taken with the teachings of Albritton et al., Rouch et al., Jung et al., Pletscher-Frankild et al., Fasciano et al., Ortega et al., and Li et al., wherein the combination teaches an ex vivo intestinal organoid comprising a monolayer of enterocytes with microvilli, mucus-producing goblet cells and functional M cells derived from a subject having inflammatory bowel disease, wherein the intestinal cells express at least one biosensor responsive to an inflammation related signal, one of ordinary skill in the art would have found it prima facie obvious to the transfect the intestinal cells with a biosensor responsive to H2O2 or nitric oxide because Lu teaches them to inflammation related signals (see Lu at para. 44). Thus, the modification would have been prima facie obvious . Double Patenting 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. 08-34 AIA Claim s 1-2, 4 and 6-14 rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-7 of U.S. Patent No. US11926849 . Although the claims at issue are not identical, they are not patentably distinct from each other because of the following: Instant claims are drawn to an ex vivo model system, comprising: enterocytes with microvilli, mucus-producing goblet cells, and Microfold (M) cells, having an apical surface and a basolateral surface wherein the enterocytes with microvilli, mucus-producing goblet cells, and Microfold (M) cells express one or more exogenous biosensors responsive to an inflammation-related signal comprising at least one promoter that binds to the inflammation related signal and drives expression of a detectable output protein upon binding of the inflammation-related signal to the promoter wherein the differentiated mammalian epithelial cells are generated by a method comprising: obtaining primary stem cells from the intestine of a mammalian subject with an inflammatory gut condition; maintaining the cells under conditions to allow for sufficient proliferation to form a monolayer having an apical and basolateral surface and consisting of differentiated cells; contacting the apical surface of the monolayer with DAPT and the basolateral surface of the monolayer with RANKL, in amounts sufficient to form enterocytes with microvilli, mucus-producing goblet cells, and M cells. The claims of the ‘849 patent are drawn to an ex vivo model system, comprising: a monolayer consisting of differentiated mammalian epithelial cells, wherein the monolayer consists of enterocytes with microvilli, mucus-producing goblet cells, and Microfold (M) cells, having an apical surface and a basolateral surface, and wherein cells of the monolayer express one or more exogenous biosensors responsive to an inflammation-related signal comprising at least one promoter that binds to the inflammation-related signal and drives expression of a detectable output protein upon binding of the inflammation-related signal to the promoter wherein the differentiated mammalian epithelial cells are generated by a method comprising: obtaining primary stem cells from a mammalian subject; culturing the primary cells under conditions sufficient to allow proliferation of the cells and formation of organoids; seeding the cells of the organoid into a culture plate comprising a permeable support device; maintaining the cells under conditions to allow for sufficient proliferation to form a monolayer having an apical and basolateral surface; contacting the apical surface with DAPT and the basolateral surface with RANKL, in amounts sufficient to induce differentiation of the cells to form enterocytes with microvilli, mucus-producing goblet cells, and M cells. It is clear that all the elements of the application claims are to be found in patent claims (as the application claims fully encompasses patent claims). The difference between the application claims and the patent claims lies in the fact that the patent claim includes many more elements and is thus much more specific. For example, patent claims require the monolayer to only consist of enterocytes with microvilli, mucus-producing goblet cells, and Microfold (M) cells. Thus the invention of claims of the patent is in effect a “species” of the “generic” invention of the application claims. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman , 29 USPQ2d 2010 (Fed. Cir. 1993). Since application claims is anticipated by claims of the patent, it is not patentably distinct from claims of the patent. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632 Application/Control Number: 18/432,439 Page 2 Art Unit: 1632 Application/Control Number: 18/432,439 Page 3 Art Unit: 1632 Application/Control Number: 18/432,439 Page 4 Art Unit: 1632 Application/Control Number: 18/432,439 Page 5 Art Unit: 1632 Application/Control Number: 18/432,439 Page 6 Art Unit: 1632 Application/Control Number: 18/432,439 Page 7 Art Unit: 1632 Application/Control Number: 18/432,439 Page 8 Art Unit: 1632 Application/Control Number: 18/432,439 Page 9 Art Unit: 1632 Application/Control Number: 18/432,439 Page 10 Art Unit: 1632 Application/Control Number: 18/432,439 Page 11 Art Unit: 1632 Application/Control Number: 18/432,439 Page 12 Art Unit: 1632 Application/Control Number: 18/432,439 Page 13 Art Unit: 1632 Application/Control Number: 18/432,439 Page 14 Art Unit: 1632 Application/Control Number: 18/432,439 Page 15 Art Unit: 1632 Application/Control Number: 18/432,439 Page 16 Art Unit: 1632 Application/Control Number: 18/432,439 Page 17 Art Unit: 1632 Application/Control Number: 18/432,439 Page 18 Art Unit: 1632
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