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.
Claim Status
Claims 1-2, 5-8, 10-12, 14-18, 21-22, and 26 were previously pending in the instant application.
Claims 8, 18, 21, and 26 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Claims 18, 21, and 26 are drawn to a nonelected invention while claim 8 is drawn to a nonelected species because TS2/16 is a mouse monoclonal antibody and is not a humanized antibody.
Receipt is acknowledged of the Amendments to the claims filed on 16 June, 2025. Claims 18, 21, 22, and 26 are cancelled. Claims 1, 2, 6, 7, 10-12, and 16 are amended. Claims 27-33 are newly added.
Therefore, claims 1-2, 5-7, 10-12, 14-17, and 27-33 are pending and under examination as elected in the instant action.
Information Disclosure Statement
The information disclosure statement filed 16 June, 2025 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
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.
Withdrawn Rejections/Objections in view of Applicant’s Amendments/Argments
Drawings
The objection to the drawings is withdrawn in view of Applicant’s submission of replacement sheets. The replacement sheets correctly present axis labels for all previously objected to drawings.
Claim Objections
The objection to claim 10 is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claim 10 to recite “a 10%, 20%, or a 50%”.
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 6 recites the term “optionally”. Claim 6 is interpreted as not requiring any limitations occurring after recitation of the term “optionally”.
Claim Rejections - 35 USC § 112
The rejection of claims 1-2, 5-7, 10-12, 14-17, and 22 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 is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claim 1 to remove the previously rejected indefinite language and cancelled claim 22.
Claim Rejections - 35 USC § 101
The rejection of claim 22 under 35 U.S.C. 101 because the claim does not fall within at least one of the four categories of patent eligible subject matter is withdrawn in view of Applicant’s amendments to the claims. Applicant has cancelled claim 22.
Maintained Rejections in Response to Applicant’s Amendments/Arguments
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5-7, 10-12, and 14-17 remain rejected and new claims 27-33 are 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 to address claim limitations introduced in new claims 27-33 and has been withdrawn with regard to claim 22 because claim 22 has been cancelled by Applicant.
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). The method of Sato is feeder cell-free as in instant claim 29 (Sato, page 46, lines 4-29). Sato also discloses that the method comprises culturing the cells in contact with an ECM as in instant claim 11 (Sato, page 46, lines 4-29). Sato also teaches that the ECM is comprised of collagen, fibronectin, and laminin (Sato, page 6, lines 3-6). Sato also teaches that synthetic hydrogel can be used instead of ECM (Sato, page 5, lines 7-30) and that the synthetic hydrogel comprises collagen and laminin (Sato, page 6, lines 23-27). Sato also discloses that the matrix is 3 dimensional as in instant claim 14 (Sato, page 16, lines 2-3). Sato also teaches that the presence of an ECM allows 3-dimmensional organoids to be cultured and that those organoids could not be cultured in the absence of an ECM (Sato, page 6, lines 17-21). 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). Sato also teaches that the medium comprises a BMP inhibitor, a mitogenic growth factor, and a Wnt agonist as in instant claims 17 and 32 (Sato, Abstract).
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. Further, while Sato teaches that the cells can be grown on a synthetic matrix, this stops short of an explicit disclosure of the active step of contacting the cells with a synthetic matrix as in instant claims 12 and 15 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 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). 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 where the interaction with ECM proteins is a critical component of the method.
It is noted that the instant specification contains no specific definition of “exogenous extracellular matrix” and describes commercially available extracellular matrices as exogenous extracellular matrices while distinguishing synthetic matrices like hydrogels (Instant specification, pages 16-17, lines 24-36 and 1-2 respectively). Therefore, the claim term “exogenous extracellular matrix” is interpreted consistent with its broadest reasonable interpretation in light of the specification as excluding synthetic matrices and a prior art teaching of a synthetic matrix would meet the limitation in claim 15 requiring no contact with “an exogenous extracellular matrix” as interpreted.
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 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.
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 claims 1-2, 5-7, 11, 14, 16-17, and 27-33 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 and the teaching of Sato that contacting the colonic stem cells with ECM was critical for producing the organoids. Further, it would have been prima facie obvious to have used a synthetic hydrogel matrix as taught by Broguiere in the method of producing organoids from colonic stem cells of Sato, Chi-Rosso, and Arroyo to arrive at the invention claimed in instant claims 12, 15, and 28 with a reasonable expectation of success because they would have been motivated to do so to save money, research novel protein interactions, and to develop more therapeutically relevant organoids.
Regarding the intended result limitations recited in amended claims 1, and 10, and newly added claim 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 newly added claims 30, and 33, Broguiere teaches that the method comprises seeding a cell suspension of epithelial cells into a hydrogel (Broguiere, page 2, fourth full paragraph). Thus, Broguiere teaches that the cells are in a suspended state.
Regarding newly added claim 27, Chi-Rosso and Arroyo teach TS2/16, and the instant specification evidences this antibody’s binding of the β1 subunit of integrin (instant specification, Table 1).
Therefore, claims 1-2, 5-7, 10-12, and 14-17 remain rejected and new claims 27-33 are newly rejected for being obvious over Sato in view of Chi-Rosso, Arroyo, and Bruguiere.
Response to Arguments
Applicant argues (1) that there is no culturing of cells with integrin agonists in Chi-Rosso or any teaching or suggestion that integrin agonists such as TS2/16 should be included in cell media for culturing purposes, (2) that there would be no reasonable expectation of success from combining the teachings of Chi-Rosso and Sato, (3) that Arroyo does not teach cell culture, and (4) that Chi-Rosso and Arroyo represent “basic research” which would not be obviously applied directly to complex organoid culture. These arguments have been fully considered but are not found persuasive for the following reasons.
(1) Applicant states: “Applicant respectfully asserts that the Examiner has misinterpreted Chi-Rosso and that Chi- Rosso does not teach "the addition of TS2/16 to epithelial cell cultures increases their adherence to ECM proteins" as is asserted by the Examiner on page 9 of the Office Action. Chi-Rosso focuses on elucidating the mechanisms underlying cell adhesion, more specifically the role of FNIII repeats in mediating adhesion. The study employs cell adhesion assays (assays that quantitate the adhesion of cells to an immobilized substrate) to demonstrate basic cell adhesion interactions. There is no culturing of cells with integrin agonists in Chi-Rosso, or any teaching suggesting that integrin agonists such as TS2/16 should be included in cell media for culturing purposes.” (Remarks, page 9).
In response, Applicant is reminded 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 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 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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Thus, Applicant’s argument that Chi-Rosso does not teach TS2/16 added to epithelial cell cultures is not found to be persuasive. Perhaps, Applicant is resting this argument on a narrow interpretation of the word “culture” and somehow excluding the conditions of Chi-Rosso from this definition. Were this to be the case, it is noted that no definition of the word “culture” appears in the instant specification and the broadest reasonable interpretation of this term encompasses a cell in a medium and the adhesion assays of Chi-Rosso comprise a cell (293 cell) in a medium (Hepes supplemented with salts and glucose) (Chi-Rosso, page 31447, “Cell Adhesion Assays” heading).
(2) Applicant states: “Basic research, like the study in Chi-Rosso, explores mechanisms in a controlled environment without addressing the complexities of practical applications such as cell culture systems or organoid culture systems. These findings do not directly inform practical applications in organoid culture, which involves a complex interplay of cellular and extracellular factors. In fact, Chi-Rosso states that "PMA and antibody TS2/16 are clearly not physiological activators of β1 integrins." Chi-Rosso appears to suggest that the results of the study do not necessarily reflect real physiological condition. This underscores the non-obviousness of the claims, since one of ordinary skill in the art would not reasonably expect that the results of the study would be useful for a complex, physiologically relevant environment such as organoid culture.” (remarks, pages 9-10).
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). 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 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 obtaining these properties with the use of TS2/16 in the culturing of organoids composed of cells which depend on integrin signaling. Further, with regard to Applicant’s assertion that Chi-Rosso appears to suggest that the results of the study do not necessarily reflect real physiological condition which underscores non-obviousness of the instant invention, it is noted that Chi-Rosso makes this statement in the first paragraph of the discussion and such a statement appears to be conceding that PMA and TS2/16 aren’t literally physiological activators because they are in-fact not physiologically present whereas MN2+ is physiologically present, and does not, as Applicant suggests, appear to suggest “that the results of the study do not necessarily reflect real physiological condition”. Thus, this argument is not found persuasive.
(3) Applicant states: “Arroyo features cell adhesion assays and does not relate to cell culture.” (Remarks, page 10).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Sato teaches the culture of epithelial cells to produce organoids and Chi-Rosso and Arroyo 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). Thus, this argument is not found persuasive.
(4) Applicant states: “Merely knowing that anti-β1 antibodies enhance binding of U-937 cells to fibronectin in a cell adhesion assay does not equate to a teaching or suggestion to use an integrin agonist to enhance complex culturing of three-dimensional organoids.” (Remarks, page 10), and “there is a distinct difference between basic research and the complexity of organoid culture, which makes it non-obvious to apply findings from basic research studied in very controlled environments directly to complex organoid culture. Therefore, one of ordinary skill in the art would not have been motivated to use an integrin agonist in the method of Sato based on the teachings of Chi-Rosso and Arroyo.” (Remarks, page 10).
This argument appears to operate on the bare assertion that any information gained from assays that can be described as “basic” by Applicant cannot be used to inform methods which Applicant would describe as “complex”. Applicant has provided no evidence to support the classifications of “basic” and “complex” nor why such a distinction in science would preclude the applicability of “basic” findings to “complex” methods. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). Further, this argument runs wholly contrary to the iterative nature of scientific endeavors. Complex methods are necessarily informed by basic research because, were this not to be the case, scientific advancement would be necessarily hindered. As evidence of this, see the background information sections of each of the cited references. These sections cite more “basic” or rudimentary research which has informed the experimental design of each reference (designs which, from the perspective of the cited “basic” research, would be seen as “complex”). Even the instant inventors cite 28 different (more “basic”) references for having informed their scientific process (Instant specification, “REFERENCES”). Thus, this argument is not found to be persuasive.
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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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