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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 23 March 2026 has been entered.
Claims 1-2, 5-8, 10-12, 14-17, and 27-33 were previously pending in the instant application.
Claims 8 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Receipt is acknowledged of the Amendments to the claims filed on 23 March 2026. Claims 1, 6, 15, and 31 are amended. Claim 27 is canceled. Claim 34 is newly added.
Therefore, claims 1-2, 5-7, 10-12, 14-17, and 28-34 are pending and under examination as elected in the instant action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02 September 2025, and 18 February 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2020/063855, filed 18 May, 2020, which claims priority to a Kingdom of Great Britain and Norther Ireland Application No. GB1906978.0, filed 17 May, 2019. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copies of papers required by 37 CFR 1.55 have been filed in this application on 15 November, 2021.
The earliest possible priority for the instant application is 17 May, 2019.
Claim Interpretation
The elected species of “colorectal stem cell” and “TS2/16” are being applied to all claims under examination. For example, claim 1 is being interpreted consistent with the elected species as being directed to “A method for culturing colorectal stem cells or an organoid comprising colorectal stem cells, wherein the method comprises culturing said colorectal stem cells in a culture medium suitable for colorectal stem cells, wherein the culture method further comprises contacting the colorectal stem cell or organoid comprising colorectal stem cells with TS2/16, and wherein an organoid is obtained or the method results in the growth of the organoid.”
Claim Objections
Claim 1 is objected to because of the following informalities: “or” appears to have been inadvertently crossed out in line six of the claim resulting in incorrect grammar in the claim. Appropriate correction is required.
Claim 5 is objected to because it recites an improper Markush group. The claim should be amended to recite “the integrin agonist is selected from the group consisting of” . Appropriate correction is required.
Claims 17 and 32 are objected to because of the following informalities: “BMP” appears to be boldened in each claim. It should not be emboldened to improve consistency in the claims. Appropriate correction is required.
Claim 34 is objected to because of the following informalities: the list is missing either “and” or “or” to separate the listed antibodies. Appropriate correction is required.
Maintained Rejections in Response to Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 103
Claims 1-2, 5-7, 10-12, 14, 16-17, and 28-30 remain rejected and claim 34 is newly rejected under 35 U.S.C. 103 as being unpatentable over WO2010090513 A2 (published: 12 August, 2010) (hereinafter “Sato”) (Submitted by applicant on the IDS filed: 05 July, 2022) in view of Chi-Rosso, Gloria, et al. Journal of Biological Chemistry 272.50 (1997): 31447-31452. (hereinafter “Chi-Rosso”), Arroyo, Alicia G., et al. The Journal of cell biology 117.3 (1992): 659-670. (hereinafter “Arroyo”) and Broguiere, Nicolas, et al. "Growth of epithelial organoids in a defined hydrogel." Advanced Materials 30.43 (2018): 1801621. (hereinafter “Broguiere”). This rejection has been modified as necessitated by Applicant’s amendments to the claims and has been partially withdrawn with respect to claims 15, and 31-33.
Applicant has amended claims 15 and 31 to explicitly exclude contact with any extracellular matrix components. Since the prior art of record discusses TS2/16 in the context of ECM adhesion, claims 15 and 31-33 are no longer obvious over the prior art of record.
Sato discloses a medium suitable for culturing colonic epithelial stem cells and a method for culturing colonic epithelial stem cells in contact with an extracellular matrix (ECM) and the suitable medium (Sato, page 1, lines 4-8; page 2, lines 7-24). Sato also discloses that the method results in the growth of organoids (Sato, page 3, lines 1-10).
Sato does not disclose or teach the step of contacting the colonic stem cells with TS2/16 as in instant claims 1-2, 5-7, 10-12, 14-17, and 27-33 as elected.
Chi-Rosso teaches that the TS2/16 antibody binds to integrin receptors to change their conformation to an active state (Chi-Rosso, page 31447, second full paragraph), that many ECM proteins are composed, in part, of fibronectin type III repeats (FNIII) including fibronectin, tenascin, and collagens (Chi-Rosso, page 31447, second full paragraph), and that the addition of TS2/16 to epithelial cell cultures increases their adherence to ECM proteins at least in part due to their RGD-containing FNIII repeats and the epithelial cells’ activated integrin receptors (Chi-Rosso, page 31447, third full paragraph; page 31449, sixth full paragraph; FIG. 2). Arroyo teaches that TS2/16 increases cell adhesion to ECM proteins like collagen, laminin, and fibronectin (Arroyo, Abstract). Broguiere teaches the growth of epithelial organoids from intestinal stem cells on synthetic hydrogels comprised of soft fibrin matrices supplemented with RGD peptide and laminin (Broguiere, Abstract; Figure. 4). Broguiere specifically teaches that integrin binding to RGD domains is one of the key requirements for organoid growth (Broguiere, page 2, last partial paragraph, page 3, first partial paragraph). Thus, a person having ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to add TS2/16 to epithelial cell cultures to increase cell adhesion to ECM because the teachings of Chi-Rosso and Arroyo suggest to a person having ordinary skill in the art to do so and Broguiere teaches that binding of the cells to ECM through RGD-integrin interactions is a key requirement for organoid growth.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have added TS2/16 as taught by Chi-Rosso and Arroyo to the method of culturing colonic stem cells of Sato to increase cell adhesion to the ECM and arrive at the invention claimed in instant claim 1 as elected with a reasonable expectation of success and they would have been motivated to do so by the teachings of Chi-Rosso and Arroyo which suggest to add TS2/16 to epithelial cell cultures where the interaction with ECM is a critical component of the method, the teaching of Sato that contacting the colonic stem cells with ECM was critical for producing the organoids, and the teaching of Broguiere that binding of epithelial cells to ECM through RGD-integrin interactions is a key requirement for organoid growth.
Regarding claim 2, TS2/16 is an antibody which interacts with the β subunit of integrin (See Arroyo, Abstract).
Regarding claims 5-7, TS2/16 is an anti-integrin antibody (See Arroyo, Abstract).
Regarding the intended result limitations recited in amended claims 1, 10, and 31, the patentability of a method claim is determined by the active steps required by the claim not by the results obtainable by the method. Further, a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005) (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). Because the combined teachings of Sato, Chi-Rosso, Arroyo, and Broguiere render obvious the active steps required by the pending claims, they also render obvious the recited intended results.
Regarding claim 11, Sato discloses that the method comprises culturing the cells in contact with an ECM (Sato, page 46, lines 4-29).
Regarding claim 12, while Sato teaches that the cells can be grown on a synthetic matrix (Sato, page 5, lines 7-30), this stops short of an explicit disclosure of the active step of contacting the cells with a synthetic matrix as in instant claim 12 as elected.
Broguiere teaches the growth of epithelial organoids from intestinal stem cells on synthetic hydrogels comprised of soft fibrin matrices comprised of RGD-domain containing proteins and laminin (which itself comprises RGD-domains) (Broguiere, Abstract; Figure. 4). Broguiere teaches that their synthetic hydrogels are advantageous because they allow for novel investigative techniques which anchor proteins of interest to the fibrin scaffolds, they are more cost effective, and they allow for potential clinical applications of organoids by relying on one undefined factor (laminin) (Broguiere, page 8, first full paragraph). Thus, a person having ordinary skill in the art would have been motivated to use the synthetic hydrogel of Broguiere to culture epithelial stem cells for organoid production to save money, research novel protein interactions, and to develop more therapeutically relevant organoids.
Regarding claim 14, Sato discloses that the matrix is 3 dimensional (Sato, page 16, lines 2-3).
Regarding claim 16, it is noted that the instant specification contains no specific definition of “colorectal”. Therefore, “colorectal” is given its broadest reasonable interpretation to encompass colonic cells. Thus, the disclosure of colonic stem cells by Sato meets the limitations of instant claim 16 (Sato, page 46, lines 4-29).
Regarding claim 17, Sato teaches that the medium comprises a BMP inhibitor, a mitogenic growth factor, and a Wnt agonist (Sato, Abstract).
Regarding claim 28, Broguiere teaches that the method comprises seeding a cell suspension of epithelial cells into a hydrogel (Broguiere, page 2, fourth full paragraph; Figure 1).
Regarding claim 29, the method of Sato is feeder cell-free (Sato, page 46, lines 4-29).
Regarding claim 30, Broguiere teaches culturing cells in a suspended state in a hydrogel (Broguiere, page 2, fourth full paragraph; Figure 1).
Regarding claim 34, Arroyo and Chi-Rosso teach TS2/16.
Therefore, claims 1-2, 5-7, 10-12, 14, 16-17, and 28-30 remain rejected and claim 34 is newly for being obvious over Sato in view of Chi-Rosso, Arroyo, and Bruguiere.
Response to Arguments
Applicant argues (1) neither Chi-Rosso nor Arroyo provides any guidance as to how or why introducing a factor that promotes binding of cells to ECM would be better for culturing epithelial stem cells to form organoids, (2) that there would be no reasonable expectation of success from the teachings of Broguiere, and (3) that there would be no reasonable expectation of success from the teachings Arroyo. These arguments have been fully considered but are not found persuasive for the following reasons.
(1) Applicant states: “Neither Chi-Rosso nor Arryo provides any guidance as to how or why introducing a factor that promotes binding of cells to ECM would be better for culturing epithelial stem cells to form organoids. Absent a teaching or suggestion in the cited references that organoid formation and growth would be improved if binding of cells to ECM was increased, one of ordinary skill in the art could not glean from the cited references that there must be a benefit instead of a detriment to organoid formation and growth if cell adhesion to the ECM is promoted, and thus one of ordinary skill in the art would not be motivated to add TS2/16 to an already functional culture method according to Sato.” (Remarks, page 10).
In response, it is noted that Chi-Rosso teaches that the TS2/16 antibody binds to integrin receptors to change their conformation to an active state (Chi-Rosso, page 31447, second full paragraph), that many ECM proteins are composed, in part, of RGD-containing fibronectin type III repeats (FNIII) including fibronectin, tenascin, and collagens (Chi-Rosso, page 31447, second full paragraph), and that the addition of TS2/16 to epithelial cell cultures increases their adherence to ECM proteins at least in part due to their RGD-containing FNIII repeats and the epithelial cells’ activated integrin receptors (Chi-Rosso, page 31447, third full paragraph; page 31449, sixth full paragraph; FIG. 2). In particular, see FIG. 2 of Chi-Rosso, where the TS2/16 antibody was added to a culture of 293 cells.
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In addition, the rejection has been modified to include relevant teachings from Broguiere to address Applicant’s concern that “Absent a teaching or suggestion in the cited references that organoid formation and growth would be improved if binding of cells to ECM was increased, one of ordinary skill in the art could not glean from the cited references that there must be a benefit instead of a detriment to organoid formation and growth if cell adhesion to the ECM is promoted.” Specifically, Broguiere teaches that integrin binding to RGD domains is one of the key requirements for organoid growth (Broguiere, page 2, last partial paragraph, page 3, first partial paragraph). Accordingly, it is the Office’s position that the prior art of record does teach that organoid formation and growth are improved if binding to ECM is increased because binding to ECM is one of the key requirements for organoid growth. Indeed even Applicants acknowledge that “the presence of extracellular matrix in a culture medium is a known requirement for efficient epithelial stem cell growth” (Specification, [0361]). Accordingly, this argument has been fully considered but has not been found persuasive.
(2) Applicant states: “Broguiere increased the interaction between organoids and ECM by "doubling or tripling the RGD densities" yet found that there was no effect on organoid colony formation, "suggesting that the natural RGD concentration on fibrin is sufficient for optimally promoting organoid growth." (pg. 3 of 12, left column) Therefore, one of ordinary skill in the art could not have predicted with a reasonable expectation of success that increasing interaction between organoids and ECM using an integrin agonist would have a positive effect on organoid formation and growth.” (remarks, page 10).
In response, it is noted that obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Here, the rejection is based upon a combination of Sato, Chi-Rosso, Arroyo, and Broguiere. Along with the cited language by Applicant, Broguiere also teaches “We found that upon addition of soluble RGD organoid formation was inhibited, suggesting that RGD domains on the matrix are necessary for organoid growth,” and that Matrigel provides a relatively low concentration of laminin which might be too low to provide a biological effect (Broguiere, page 3, first partial paragraph). This was likely the reason for the supplementation of the hydrogel of Broguiere with laminin (which itself contains RGD domains). Chi-Rosso teaches that the addition of TS2/16 to epithelial cell cultures increases their adherence to ECM proteins at least in part due to their RGD-containing FNIII repeats and the epithelial cells’ activated integrin receptors (Chi-Rosso, page 31447, third full paragraph; page 31449, sixth full paragraph; FIG. 2) and Arroyo teaches that TS2/16 increases cell adhesion to ECM proteins like collagen, laminin, and fibronectin (Arroyo, Abstract). A person having ordinary skill in the art would have had a reasonable expectation of increasing cell adhesion with the use of TS2/16 in the culturing of organoids composed of cells which depend on integrin signaling insofar as Chi-Rosso and Arroyo teach this property and they would have reasonably expected increased cell adhesion (binding) to ECM to improve the production of organoids insofar as Broguiere teaches this dynamic. Accordingly, this argument has been fully considered but has not been found persuasive.
(3) Applicant states: “Arroyo shows that "a dramatic change in U-937 cellular morphology was observed after anti-31 TS2/16 mAb treatment" which caused U-937 cells, "which are normally round," to "extend many long thin protrusions known as microspikes or filopodia." (pg. 665, left column) In contrast, as described in paragraph [0217] of the instant specification, organoid culture and formation features both a combination maintaining an expanding population of epithelial stem cells and the presence of differentiated cell types that are characteristic of the epithelial tissue of origin. "The epithelial organoids also have a distinctive structure that arises rapidly as the cells expand, differentiate and self-organise in vitro." Based on Arroyo, one of ordinary skill in the art could not have predicted with a reasonable expectation of success that TS2/16, which causes cells that are normally round to morph into cells with long thin protrusions, would have a positive effect on organoid growth and formation.” (Remarks, pages 10-11).
In response, it is noted that obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Here, the rejection is based upon a combination of Sato, Chi-Rosso, Arroyo, and Broguiere. Sato teaches the culture of epithelial cells to produce organoids and Chi-Rosso, Arroyo, and Broguiere provide teachings for TS2/16 and the motivation to add TS2/16 to epithelial cell cultures to increase cell adhesion to ECM proteins like collagen, laminin, and fibronectin (Arroyo, Abstract) (Chi-Rosso, page 31447, third full paragraph; page 31449, sixth full paragraph; FIG. 2) (Broguiere, page 3, first partial paragraph). Applicant asserts that the morphology change noted in Arroyo prevents a finding that a person having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art of record. It is unclear how one arrives at this conclusion as nothing in Arroyo would lead a person having ordinary skill in the art not to reasonably expect that the addition of TS2/16 to epithelial cells in culture would increase cell adhesion. Indeed it isn’t just Arroyo but also Chi-Rosso that teaches this effect for TS2/16. Chi-Rosso teaches that the addition of TS2/16 to epithelial cell cultures increases their adherence to ECM proteins at least in part due to their RGD-containing FNIII repeats and the epithelial cells’ activated integrin receptors (Chi-Rosso, page 31447, third full paragraph; page 31449, sixth full paragraph; FIG. 2). It is noted that Applicant’s argument here appears to require the prediction of a positive effect from the addition of TS2/16 but that is not the standard being applied. The standard is whether a person having ordinary skill in the art would have reasonably expected to obtain similar properties upon combining the references. It is the Office’s position that such a person would have had this expectation and that it would have been reasonable considering the prior art of record. Accordingly, this argument has been fully considered but has not been found persuasive.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15, and 31-33 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 claims contain 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 15 and 31 broadly read on a method for producing an organoid from epithelial stem cells or for culturing an organoid comprising epithelial stem cells comprising culturing “in a culture medium suitable for epithelial stem cells supplemented with an integrin agonist for a length of time sufficient for formation of an organoid from said epithelial stem cell or growth of the organoid comprising epithelial stem cells” and in the absence of any extracellular matrix (ECM) components. These claims broadly encompass a vast genus of methods in which the culture medium can comprise anything but ECM components and any possible integrin agonist yet which produce the recited functional property of being capable of inducing the formation of an organoid or capable of growing an organoid comprising any type of epithelial stem cell. Dependent claims 32-33 limit the scope slightly by requiring a Wnt agonist, a BMP inhibitor, a mitogenic growth factor, and/or a TGF-β inhibitor in the medium and by requiring suspension culture respectively. However, the scope of these claims continue to read on any amount of these additives along with any other potential additives so long as there is no ECM and any integrin agonist. Consequently, claims 15, and 31-33 encompass a vast genus of methods in which any integrin agonist may be used alongside essentially any other additives except for ECM and which result in either the formation of or the growth of organoids from any type of epithelial stem cell.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). Further, A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See MPEP 2163(II)(A)(3)(a)(ii).
The working examples provided by Applicant teach the culture of human epithelial colon stem cells in a suspended 3D state in a hydrogel to enable 3D spheroid formation in a medium comprising DMEM/F12 medium supplemented with B27 supplement, nicotinamide, N-acetylcysteine, noggin, R-spondin 1, EGF, a Wnt surrogate A83-01, and a P38 inhibitor (SB202190) in the absence of ECM (Specification, [0361]-[0363]). To this culture, TS2/16-conditioned medium was added to induce growth of the cells (Specification, [0364]-[0365]). To the extent the working examples teach other integrin agonists, they teach only 12G10 and HUTS-4 as two antibodies that can induce nearly identical high affinities for cyclic RGD peptide and which were added under identical culture conditions as the TS2/16 to produce the same result (Specification, [0373]-[0375]). The working examples also teach the culture of pancreatic epithelial stem cell organoid fragments in a different medium with no ECM and with TS2/16 (Specification, [0390]-[0393]). The working examples teach no other integrin agonists other than TS2/16, 12G10 and HUTS-4 antibodies (12G10 and HUTS-4 being two antibodies that can induce nearly identical high affinities for cyclic RGD peptide as TS2/16). The working examples teach no culture conditions which produce an organoid in the absence of ECM from epithelial stem cells other than human colon epithelial stem cells cultured in a 3D hydrogel. While the working examples exemplify pancreatic epithelial stem cells cultured without ECM, these are only shown in fragmented organoids and only with TS2/16 antibody.
Thus, insofar as there is support in the specification for claims to a method of generating an organoid or for culturing an organoid comprising epithelial stem cells in the absence of ECM components, it is only with respect to TS2/16, 12G10 and HUTS-4 antibodies and such a method still requires suspension of the cells in a 3D hydrogel. Further, the specification displays the generation of organoids from epithelial stem cells cultured in the absence of ECM and in the presence of TS2/16, 12G10 or HUTS-4 only where the medium comprises nicotinamide, N-acetylcysteine, noggin, R-spondin 1, EGF, a Wnt surrogate A83-01, and a P38 inhibitor (SB202190).
The art at the time of filing generally teaches that ECM is required for organoid generation from epithelial stem cells (See 35 U.S.C. 103 rejection above). Specifically, Broguiere teaches the supplementation of synthetic hydrogels with laminin (an ECM component) to provide RGD domains which Broguiere teaches are necessary for organoid growth (Broguiere, page 3, first partial paragraph). Sato teaches a medium suitable for culturing colonic epithelial stem cells and a method for culturing colonic epithelial stem cells in contact with an extracellular matrix (ECM) and the suitable medium (Sato, page 1, lines 4-8; page 2, lines 7-24). Sato also discloses that the method results in the growth of organoids (Sato, page 3, lines 1-10). Where the art at the time of filing teaches TS2/16 antibodies, the research focuses on epithelial cell adhesion to ECM proteins like collagen, laminin, and fibronectin being increased by TS2/16 (Arroyo, Abstract) and suggests that the addition of TS2/16 to epithelial cell cultures increases their adherence to ECM proteins at least in part due to their RGD-containing FNIII repeats and the epithelial cells’ activated integrin receptors (Chi-Rosso, page 31447, third full paragraph; page 31449, sixth full paragraph; FIG. 2). Thus, the art at the time of filing evidences unpredictability with regard to producing organoids from epithelial stem cells in the absence of ECM insofar as the art generally teaches that ECM is required and is one of the core facilitators of TS2/16 antibody’s affects on cell adhesion and organoid growth.
Therefore, in view of the vast genus claimed, the limitation of a taught corresponding structure for performing the claimed functions to epithelial stem cells cultured in a 3D hydrogel in the presence of TS2/16, 12G10 or HUTS-4 and in a medium comprising nicotinamide, N-acetylcysteine, noggin, R-spondin 1, EGF, a Wnt surrogate A83-01, and a P38 inhibitor (SB202190), and the unpredictability evidenced by the art at the time of filing for producing organoids from epithelial stem cells without any ECM components, the specification would not represent to the skilled artisan that the inventors had possession of a representative number of species for the genus claimed.
Citation of other relevant art
Short, Sarah P., Patricia W. Costacurta, and Christopher S. Williams. "Using 3D organoid cultures to model intestinal physiology and colorectal cancer." Current colorectal cancer reports 13 (2017): 183-191. Relevant to the instant application because it surveys the state of the art for colonic stem cell produced organoids and highlights importance of 3D structure within culture for production of organoids.
Conclusion
No claim is allowed.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
