DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's list of claims filed on 10-29-2025 have been received and entered. Claims 5-7, 11-14, 16-19, 21-25, 29, 32-35, 40-41, 43-56, 58-91, 93-97, 99 have been canceled. Claims 1-4, 8-10, 15, 20, 26-28, 30-31, 36-39, 42, 57, 92, 98, 100 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-4, 8-10, 15, 20, 26-28, 30-31, 36-39, 42, 57, 92, 100) in the reply filed on 10-29-2025 is acknowledged.
Claim 98 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10-29-2025.
Claims 1-4, 8-10, 15, 20, 26-28, 30-31, 36-39, 42, 57, 92, 100 and species gastrointestinal tissue, xenograft, primary cells, APC, gastrointestinal tract, epithelial cells having a polarity, lamina propria and lamina muscularis are under consideration.
Priority
This application is US application filed on 05/06/2022 that claims priority from US provisional application no 63/184,967 filed on 05/06/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12-20-2022 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claims 1, 20 and 42 are objected to because of the following informalities: In the instant case,
Claim 1, last line – the phrase “one or more biological functions of normal or diseased cells or tissue” is grammatically confusing because it’s not necessarily clear that the words “normal” and “diseased” are intended to modify each of the words “cells” and “tissue”. It would be remedial to amend claim 1 to read “…wherein the population of cells or tissue provides one or more biological functions of normal cells or tissue, diseased cells or tissue, or one or more markers of said biological functions”.
Claim 20 employ the acronyms for “APC” and “SMAD4”. Each of these terms should be identified by its full name, followed by its acronyms in parenthesis at its recitation in the text of the claims.
In claim 42, the number “-42” should read “42”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 8-10, 15, 20, 26-28, 30-31, 36-39, 42, 57, 92 and 100 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
The base claims 1, 3, 57, recite “An ex vivo tissue composition ”, and base claim 100 recites “A system … comprises ….. a tissue explant”. Here, because the cell population is a composition of matter, the claim is to at least one statutory category of invention (Step 1: YES).
Step 2(A), Prong 1: Does the claim recite an abstract idea, law of nature or natural phenomenon?
Under the broadest reasonable interpretation, the terms of the claim are presumed to have their plain meaning consistent with the specification as it would be interpreted by one of ordinary skill in the art. See MPEP 2111. Base claim 1 recites an ex vivo tissue composition comprising (i) a tissue explant from a mammalian source tissue in planar contact with a substrate; and (ii) a population of cells or tissue within the tissue explant, wherein the population of cells or tissue provides one or more biological functions of normal or diseased cells or tissue, or one or more markers of said biological functions. Base claim 3 recites an ex vivo tissue composition comprising (i) a tissue explant in planar contact with a substrate thereby providing a luminal and a basolateral surface, wherein the tissue explant comprises epithelium from a mammalian gastrointestinal tract comprising an architecture, wherein said tissue explant comprises said architecture; and (ii) a population of cells or tissue within the tissue explant. Base claim 57 recites an ex vivo tissue composition comprising: (i) a tissue explant in planar contact with a substrate thereby providing a luminal and a basolateral surface, wherein the tissue explant comprises intestinal epithelium from a source tissue, wherein said source tissue comprises intestinal epithelium from a large mammalian gastrointestinal tract, wherein said source tissue comprises an architecture comprising epithelial cells having a polarity, wherein the tissue explant comprises said architecture; and (ii) a tumorigenic intestinal organoid within the tissue explant. . Base claim 100 recites a system for use in a high-throughput colorectal cancer cytotoxicity screening assay, wherein the system comprises: (i) a substrate comprising a plurality of microwells; (ii) a tissue explant from a source tissue comprising epithelium from a large mammalian gastrointestinal tract, wherein the gastrointestinal tract epithelium comprises epithelial cells having a polarity in the tissue explant; and (iii) a tumorigenic colon organoid injected within the tissue explant; thereby allowing measurement of cytotoxicity toward the tumorigenic organoid through the tissue explant.
In the instant case, markedly difference from product of nature analysis is as described below:
Regarding the claimed tissue/ tissue explant in base claims 1, 3, 57, 100 the specification of claimed invention teaches that “the disclosure provides an ex vivo tissue composition comprising an isolated tissue explant from a source tissue and a population of cells or tissue providing one or more biological functions of normal or diseased cells or tissue, or one or more markers of said biological functions, within said tissue explant. Tissue explants described herein maintain features of in vivo tissue from which they are derived.” (Page 10, 2nd para.); “the tissue explant described herein comprises a fully intact extracellular matrix.” (Page 25, 3rd para.); and include natural layers and cell types: “the tissue explant comprises one or more of intestinal enterocytes, tight junctions, mucin secreting goblet cells, intestinal stem cells, intestinal endocrine cells, microfold cells, mucosubstances, intact crypts, or neural cells.” (Page 3, 6th para.). The specification of claimed invention also teaches “Mice and Swine small intestine tissue harvest” (Page 75 last para), and “Intestinal organoid isolation and culture” (Page 76, 1st para). Additionally, the specification of the claimed invention teaches that “As used herein, "substrate" refers to a surface or layer that underlies something, for example, a cell, cell culture, cell culture material, etc., or on which processes occur. In some embodiments, a substrate is a surface or material on which an organism lives, grows, and/or optionally obtains nourishment.” (Page 75, 4th para.) and “The cell culture surface/substrate can be made of any material suitable for culturing mammalian cells” (Page 49, 4th para.). The specification of claimed invention also does not define and provide any guidance for what to be encompassed for the term “microwells” that would exclude product of nature. Thus, the claims encompass cells/tissue composition that is not markedly different from product of nature composition.
Further, base claim 3 additionally recites “a tissue explant in planar contact with a substrate thereby providing a luminal and a basolateral surface”. Base claim 57 additionally recites “epithelial cells having a polarity”. Base claim 100 additionally recites “wherein the gastrointestinal tract epithelium comprises epithelial cells having a polarity in the tissue explant”. In the instant case, the specification of claimed invention teaches that “ ‘planar contact’ refers to the placement of the tissue explant on a substrate, such that the tissue explant interacts with a two-dimensional surface of the substrate. Planar contact can be determined by methods known to those of skill in the art” (Page 73, 4th para.); “the tissue explant described herein is in a planar position, thereby providing a luminal surface and a basolateral surface” (Page 25, 4th para.); and “As used herein, "a basolateral surface" refers to the orientation of the tissue explant when contacted with a substrate, such that the tissue explant comprises apical/luminal-basolateral polarity. In some embodiments, the basolateral surface is opposite of the apical surface, i.e., the luminal surface” (Page 68, 2nd para). Thus, placing a tissue explant in planar contact with a substrate would have orientation with apical/luminal-basolateral polarity, and the tissue explant are not modified/engineered to be markedly different characteristics from a “product of nature”.
Base claim 57 additionally recites “a tumorigenic intestinal organoid within the tissue explant”. Base claim 100 additionally recites “a tumorigenic colon organoid injected within the tissue explant”. In the instant case, the specification of claimed invention teaches that “the tumorigenic intestinal organoid is derived from cancerous intestinal tissue” (Page 5, 2nd para.). Thus, isolated tumorigenic intestinal organoid from cancerous intestinal tissue is not functionally and structurally different from naturally occurring tumorigenic intestinal tissue. Also, there is no limitations to specify the claimed a tumorigenic colon organoid injected within a tissue to be different from naturally occurring tumor within a naturally occurring tissue such as in the metastasis phenomenon. It is well known in the art that cancer cells can travel throughout the body in a process called metastasis. These cells break away from a primary tumor and use the blood or lymphatic system as a pathway to spread to distant organs and tissues, where they can form new, secondary tumors.
The dependent claims are analyzed for the claimed tissue being markedly different from product of nature as described below. These dependent claims do not distinguish the claimed tissue being markedly different from product of nature for at least some of the embodiments encompassed by the claims:
Claim 2 specifies “the source tissue is selected from gastrointestinal tissue, liver tissue, heart tissue, skin tissue, pancreas tissue, and kidney tissue”. Claim 4 specifies the population of cells or tissue is a xenograft, an allograft, an autograft, a biopsy from a subject, and/or derived from a primary tissue. Claim 8 specifies the subject is a human. Claim 9 specifies the population of cells or tissue is an organoid. Claim 10 specifies the organoid comprises cells of an immortalized cell line, primary cells, stem cells, cells from a normal tissue or cells from a diseased tissue. Claim 15 specifies diseased tissue is a cancerous tissue or a tissue comprising a population of cells comprising at least one genetic mutation. Claim 20 specifies the genetic mutation is in at least one of the APC, p53, or SMAD4 genes. Claim 26 specifies the organoids form tumors after placement within the tissue explant. However, there is no limitations to specify the claimed tumor within a tissue to be different from naturally occurring tumor within a naturally occurring tissue such as in the metastasis phenomenon. It is well known in the art that cancer cells can travel throughout the body in a process called metastasis. These cells break away from a primary tumor and use the blood or lymphatic system as a pathway to spread to distant organs and tissues, where they can form new, secondary tumors. Claim 28 specifies the population of cells or tissue is derived from tissue of the gastrointestinal tract, liver, pancreas, kidney, spleen, lung, skin or heart. Claim 30 specifies the architecture comprises epithelial cells having a polarity, small intestine epithelium, circular muscular layer, mucosa layer, submucosa layer, and/or intestinal villi. Claim 31 specifies the tissue explant comprises a fully intact extracellular matrix, wherein the fully intact extracellular matrix comprises lamina propria, lamina muscularis, or lamina propria and lamina muscularis. Claim 36 specifies the tissue explant comprises an intestinal mucosal layer and a submucosal layer. Claim 37 specifies the population of cells or tissue is between the mucosa layer and the submucosa layer. Finally, claim 42 recites the population of cells or tissue is injected into the tissue explant; however, there is no limitation in the claim to specify injecting/transplanting cells or tissue for coculturing would result in markedly different from naturally occurring metastasis phenomenon. It is well known in the art that cancer cells can travel throughout the body in a process called metastasis. These cells break away from a primary tumor and use the blood or lymphatic system as a pathway to spread to distant organs and tissues, where they can form new, secondary tumors.
Thus, the claims encompass cells and tissues that are not markedly different from naturally occurring cells and tissues. There is no modification or engineered construct is present in the claims to markedly distinguish the claimed tissue from naturally occurring tissue. Because there is no difference between the claimed cell population and naturally occurring tissue for at least some of the embodiments encompassed by the claims, the claimed cells do not have markedly different characteristics, and thus are a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014). (Step 2A, Prong I: YES).
Step 2(A), Prong 2: Do the claims recite additional elements that integrate the judicial exception into a practical application?
In view of foregoing analysis, it is apparent that the claims recite judicial exceptions that are product of nature. While the claims would still be patent-eligible if "the claims as a whole integrate the recited judicial exceptions (product of nature) into a practical application of the exception". However, the instant claims 1, 3, 57 do not integrate the judicial exceptions into a practical application of the recited judicial exceptions. Additionally, claim 100 recites “allowing measurement of cytotoxicity toward the tumorigenic organoid”; however, measurement of cytotoxicity toward the tumorigenic organoid can be performed in in vivo tissue: the specification of the claimed invention teaches that “… the tissue explant described herein maintains the in vivo architecture of the gastrointestinal tract (e.g., small intestine) from which it was derived. In addition, the tissue composition comprises the components necessary for measuring cytotoxicity of therapeutic compounds….” (Page 52, 3rd para.). Thus, the measurement of cytotoxicity can be performed in vivo context.
In summary, there are no additional elements recited in the claims, considered individually or in combination, that integrate the judicial exception of product of nature into a practical application of the judicial exception and the claims are therefore considered to be directed to the judicial exceptions recited in claims 1 (Step 2A, Prong II: NO).
Step 2(B): Does the claim recite additional elements that amount to significantly more than the judicial exception?
The elements recited in the claims, other than the naturally occurring cells are discussed below:
The base claims 1, 3, 57 recite “a substrate”; the base claim 100 recites “a substrate comprising a plurality of microwells”; claim 27 recites the substrate comprises a plurality of microwells, and wherein the population of cells or tissue is placed within the tissue explant in a location that corresponds to a microwell; claim 92 specifies the substrate comprises a first plate comprising the plurality of microwells and a second plate, wherein the tissue explant is between the first and second plates. However, placing cell or tissues on or inside a substrate such as a plurality of microwells for cell culturing/improving cell survival is well-understood, routine, conventional activity in the field.
Claim 38 recites the composition is maintained in culture for 24 hours, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more, and claim 39 specifies the composition does not require an exogenous growth factor to be maintained in culture. However, culturing time and optimization of culture medium’s compositions are also well-understood, routine, conventional activity in the field.
These additional claim elements do not add an inventive concept beyond routine, conventional, or well-understood activities. Thus, the claims recite a naturally occurring tissues that do not differ markedly, if at all, from naturally occurring cell tissue. Therefore, the answer to step 2B of the 101 Subject Matter Eligibility Test is ''No" (Step 2B: NO).
Conclusion: Given the analysis above, it is reasonable to conclude that claims 1-4, 8-10, 15, 20, 26-28, 30-31, 36-39, 42, 57, 92 and 100 encompass embodiments that are not directed to patent-eligible subject matter.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 8 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 8 is directed to the subject is a human. Claim 8 is depending from claim 4 which recites “the population of cells or tissue is …. a biopsy from a subject”. Since the subject can be human, the scope of the claim 8 encompass human organism.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 27-28, 30-31, 36-39, 92 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Traverso et al (Pub. No.: US 2019/0064153 Al, Pub. Date: Feb. 28, 2019) (Applicants’ own work).
Regarding to claims 1 and 3, Traverso et al teach “ an in vitro cellular composition comprising: (i) a substrate comprising a plurality of microwells; and (ii) a tissue explant comprising intestinal epithelium from a large, non-human, mammalian gastrointestinal tract, wherein the intestinal epithelium comprises epithelial cells having a polarity in the tissue explant, wherein the tissue explant is in planar contact with the substrate, thereby providing a luminal surface and a basolateral surface of the in vitro cellular composition, and wherein the polarity of the epithelial cells is maintained in the in vitro cellular composition.” (see claim 1, page 41); “wherein the tissue explant comprises small intestine epithelium, circular muscular layer and intestinal villi” (see claim 2, page 41). Traverso et al teach “wherein the tissue explant mimics in vivo architecture of the gastrointestinal tract from which it was derived” (claim 35, page 41).
Traverso et al teach biological markers : “Mucin 2 (Muc 2) as well as Caudal type homeobox 2 (CDX2) are both markers for the mucin secreting goblet cells within the intestinal epithelium. In some embodiments, goblet cells are identified by the presence of Mucin 2 (Muc 2) and/or Caudal type homeobox 2 (CDX2).” ([0390], page 18).
Regarding to claim 2, Traverso et al teach “the present disclosure is based, in part, on the discovery that tissue explants derived from the gastrointestinal tract can be utilized in high-throughput screening assays for at least drug absorption, drug dissolution, drug induced gastrointestinal toxicity, and endocrine system modulation” ([0004], page 1).
Regarding to claim 4, Traverso et al teach a biopsy/ primary tissue from a subject: “small intestinal tissue was isolated from freshly procured intact gastrointestinal tract from pigs” ([0528], page 34),
Regarding to claims 27-28, 30, Traverso et al teach “ an in vitro cellular composition comprising: (i) a substrate comprising a plurality of microwells; and (ii) a tissue explant comprising intestinal epithelium from a large, non-human, mammalian gastrointestinal tract, wherein the intestinal epithelium comprises epithelial cells having a polarity in the tissue explant, wherein the tissue explant is in planar contact with the substrate, thereby providing a luminal surface and a basolateral surface of the in vitro cellular composition, and wherein the polarity of the epithelial cells is maintained in the in vitro cellular composition.” (see claim 1, page 41).
Regarding to claim 31, Traverso et al teach “the fully intact extracellular matrix comprises lamina propria, lamina muscularis, or lamina propria and lamina muscularis” (claim 7, page 41).
Regarding to claims 36-37, Traverso et al teach “In some embodiments, the tissue explant is derived from stomach, or gastric, tissue. The stomach is a muscular, hollow, dilated part of the alimentary canal. It comprises a mucosal layer comprising mucosal epithelium and lamina propria; which is surrounded by a submucosal layer comprising loose connective tissue” ([0404], page 20).
Regarding to claim 38, Traverso et al teach “the in vitro cellular composition is maintained for 24 hours, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks or more” ([0459], page 26).
Regarding to claim 39, Traverso et al teach “the tissue explant described herein does not require an exogenous growth factor to be maintained in culture” ([0016], page 1).
Regarding to claim 92, Traverso et al teach “the tissue explant described herein is placed on an interface apparatus comprising a standard plate, a thin middle plate, and an upper load plate (see FIGS. 2A and 2M for exemplary setups). The tissue explant is placed over the through holes of the middle plate and the upper load plate is then placed onto the tissue explant to compress it onto the middle plate and around the through holes, while mounted on the standard plate. In some embodiments, each plate comprises 6, 12, 24, 48, 96, 384 or 1536 microwells” ([0436], page 24).
Thus, claims 1-4, 27-28, 30-31, 36-39, 92 are anticipated by Traverso et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 8-10, 15, 20, 26, 42, 57, 100 are rejected under 35 U.S.C. 103 as being unpatentable over Traverso et al (Pub. No.: US 2019/0064153 Al, Pub. Date: Feb. 28, 2019) (Applicant own work) in view of Nadauld et al (Pub. No.: US 2014/0302491 A1, Pub. Date: Oct. 9, 2014).
The teachings of Traverso et al above are incorporated herein in their entirety.
Traverso et al do not teach the population of cells or tissue is injected into the tissue explant and organoids with mutation form tumors after placement within the tissue explant. Nadauld et al cure the deficiency.
Regarding claims 8, 9, 10, Nadauld et al teach “FIG. 16. Primary adult human colon organoid air liquid interface culture” ([0025], page 3); “The phrase “mammalian cells” means cells originating from mammalian tissue. …… “Mammalian used herein includes human, equine, bovine, porcine, canine, feline, rodent, e.g. mice, rats, hamster, primate, etc. “Mammalian tissue cells” and “primary cells have been used interchangeably”.”
Regarding claims 15 and 20, Nadauld et al teach “introducing cancer drivers (e.g. expressible coding sequences, anti-sense and RNAi agents, etc.) that provide for transformation of the explant cells into carcinomas, e.g. APC; Kras; p53: SMAD4; etc.” ([0108], page 11) and “Primary organoids with oncogene manipulation (c.f. KRas, p53, APC) allow both positive selection and expansion of starting material which can be replated from single cell Suspensions to generate secondary organoids in multi-well format” ([0159], page 15).
Regarding claims 26 and 42, Nadauld et al teach “The term “contacting refers to the placing of candidate cells or candidate agents into the explant culture as described herein. Contacting also encompasses co-culture of candidate cells with tissue explants for at least 1 hour, or more than 2 hrs. or more than 4 hrs. in culture medium prior to placing the tissue explants in a semi-permeable substrate. Alternatively, contacting refers to injection of candidate cells into the explant, e.g. into the lumen of an explant.” ([0048], page 4),“The term “candidate cells' refers to any type of cell that can be placed in co-culture with the tissue explants” ([0046], page 4), and “The explant cells may be modified such that they are transformed into proto-oncogenic or oncogenic cells, e.g. by providing cancer drivers—oncogenic factors or inhibitors of tumor suppressor genes, e.g. nucleic acids for the overexpression of KrasG12D; nucleic acids that suppress expression of APC, p53, or Smad4, etc.—for example, to assess the effects of therapeutic agents on tumors.” ([0006], page 1); “AKPS organoids serially expanded in ALI can be transplanted subcutaneously into immunodeficient NSG mice (the APC flox/flox; villin-CreER mice are mixed background) (FIG.5G, H); with robust tumor take with AKPS (8/8 mice) but not APC-null cells (0/8), indicating full oncogenic transformation.” ([0144], page 14).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Traverso et al by placing or injecting of candidate cells, which have been transformed into proto-oncogenic or oncogenic cells, into the explant culture for screening for agents to prevent or treat disease as taught by Nadauld et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Nadauld et al teach “These organoid models of diverse cancer are a significant advance over conventional transformed cell lines as they are (a) primary tissue, (b) have not been repetitively passaged, (c) are grown in a more physiologic 3D environment, (d) accurately recapitulate multilineage differentiation and cellular ultrastructure of the cognate normal organs, and (e) allow multiple concomitant oncogene manipulation. Our ability to engineer complex combinatorial driver modules within physiologic 3D primary organoid culture, via (1) Cre-mediated activation of floxed alleles and/or (2) robust retroviral co-infection, is a major innovation that strongly addresses the need to model the concerted action of oncogenic loci in TCGA data sets, whose massive complexity is compounded by combinatorial driver action.” ([0129], page 13) and “the adaptation of these oncogene-engineered primary 3D organoids across diverse tissues in a multi-well format allowing viral transduction, compound Screening and measurement of proliferation. These innovations greatly facilitate high-through put approaches to combinatorial gene validation and to drug screening/responses including chemotherapy and targeted biologics.” ([0129], page 13). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Nadauld et al were successful in culturing intestinal organoids, and introduction of transforming events into organoids (example 2, page 14), with working example and data.
Regarding to claim 57, Traverso et al teach “ an in vitro cellular composition comprising: (i) a substrate comprising a plurality of microwells; and (ii) a tissue explant comprising intestinal epithelium from a large, non-human, mammalian gastrointestinal tract, wherein the intestinal epithelium comprises epithelial cells having a polarity in the tissue explant, wherein the tissue explant is in planar contact with the substrate, thereby providing a luminal surface and a basolateral surface of the in vitro cellular composition, and wherein the polarity of the epithelial cells is maintained in the in vitro cellular composition.” (see claim 1, page 41); “wherein the tissue explant comprises small intestine epithelium, circular muscular layer and intestinal villi” (see claim 2, page 41). Traverso et al teach “wherein the tissue explant mimics in vivo architecture of the gastrointestinal tract from which it was derived” (claim 35, page 41).
Although Traverso et al teach the tissue explant is modified to generate a pathological condition such as colon cancer, Traverso et al do not teach a tumorigenic intestinal organoid within the tissue explant.
Nadauld et al teach generation of a tumorigenic intestinal organoid by engineering a 4-geneAPC/KRas/p53/Smada (AKPS) module by infecting APC-null colon organoids with 3 ecotropic retroviruses ([0143],page 14), and AKPS organoids serially expanded in air-liquid interface (ALI) can be transplanted subcutaneously into immunodeficient NSG mice ([0144], page 14). Further, Nadauld et al teach placing of candidate cells into the explant culture or injection of candidate cells into the explant, e.g. into the lumen of an explant ([0048], page 4), “The term “candidate cells” refers to any type of cell that can be placed in co-culture with the tissue explants” ([0046], page 4), and “Organoids of interest include those comprising unmodified cells, and those comprising experimentally modified cells as described herein, including cancer cells, infected cells, cells treated with potentially cytotoxic agents and the like. Also included are stem cells, cancer stem cells, progenitor cells or differentiated or oncogenically transformed progeny thereof.” ([0083], page 8).
Regarding to claim 100, Traverso et al teach “a cell culture system for use in a high-throughput drug absorption screening assay, wherein the cell culture system comprises: (i) a substrate comprising a plurality of microwells; and (ii) a tissue explant comprising intestinal epithelium from a large, non-human, mammalian gastrointestinal tract, wherein the intestinal epithelium comprises epithelial cells having a polarity in the tissue explant, wherein the tissue explant is in planar contact with the substrate, thereby providing a luminal surface and a basolateral surface, and wherein the polarity of the epithelial cells is maintained in the cell culture system, thereby allowing measurement of absorption of a drug through the tissue explant.” (see claim 54, page 41).
Although Traverso et al teach the tissue explant is modified to generate a pathological condition such as colon cancer, Traverso et al do not teach a tumorigenic colon organoid injected within the tissue explant.
Nadauld et al teach generation of a tumorigenic intestinal organoid by engineering a 4-geneAPC/KRas/p53/Smada (AKPS) module by infecting APC-null colon organoids with 3 ecotropic retroviruses ([0143],page 14), and AKPS organoids serially expanded in air-liquid interface (ALI) can be transplanted subcutaneously into immunodeficient NSG mice ([0144], page 14). Further, Nadauld et al teach placing of candidate cells into the explant culture or injection of candidate cells into the explant, e.g. into the lumen of an explant ([0048], page 4), “The term “candidate cells” refers to any type of cell that can be placed in co-culture with the tissue explants” ([0046], page 4), and “Organoids of interest include those comprising unmodified cells, and those comprising experimentally modified cells as described herein, including cancer cells, infected cells, cells treated with potentially cytotoxic agents and the like. Also included are stem cells, cancer stem cells, progenitor cells or differentiated or oncogenically transformed progeny thereof.” ([0083], page 8).
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632