DETAILED ACTION
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 Response to Election/Restriction Filed, Amendment, and Arguments/Remarks, filed 04 May 2026, have been entered. Claims 1-2, 15-16, 20-21, 41-42, 44-45, 57-59, 62-64, 66-68, and 70-71 were previously pending in the application. Applicant canceled claims 15, 41, 57-58, 62-64, 66-68, and 70-71 and added new claims 77-87. Claims 1-2, 16, 20-21, 42, 44-45, 59, and 77-87 are currently pending. Claims 1, 20, and 44 are independent claims. Applicant’s election with traverse of the invention of Group I, drawn to a method of obtaining an intestinal organoid-derived monolayer, is acknowledged.
Applicant argues that the elected invention of Group I features steps for forming a monolayer derived from organ-specific organoids, and those steps are also featured in the claims encompassed in Group II and Group V; therefore, claims could be examined together without imposing a serious search burden.
However, this is not agreed.
Applicant’s traversal argues that there would not be a serious search burden on Examiner if the restriction is not required. However, this is not found persuasive. Applicant alleges that there would be no burden on the examiner in examining all of the species at once, relying on M.P.E.P. §802.02. Chapter 800, however, is limited to a discussion of the subject of restriction and double patenting under Title 35 of the United States Code and Title 37 of the Code of Federal Regulations as it relates to national applications filed under 35 U.S.C. 111(a). The discussion of unity of invention under the Patent Cooperation Treaty Articles and Rules as it is applied as an International Searching Authority, International Preliminary Examining Authority, and in applications entering the National Stage under 35 U.S.C. 371 as a Designated or Elected Office in the U.S. Patent and Trademark Office is covered in M.P.E.P. §1850 and is dictated by PCT Rules 13.1 and 13.2. See M.P.E.P. §801. Burden is not a consideration in a finding of lack of inventive unity; rather, according to M.P.E.P. §1850, the only consideration is whether the inventions share a special technical feature. Therefore, the requirement is still deemed proper and is therefore made FINAL.
Claims 20-21, 42, 44-45, 59, and 85-87 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-2, 16, and 77-84 are currently pending in the application and under examination to which the following grounds of rejection are applicable. An action on the merits follows.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2022/069354, filed 11 July 2022, which claims priority to GB2109913.0, filed 09 July 2021. Filing of a certified copy of the GB2109913.0, filed 09 July 2021, is acknowledged.
Thus, the earliest possible priority for the instant application is 09 July 2021.
Information Disclosure Statement
The information disclosure statements filed 22 December 2023 and 04 June 2024 have been considered by the Examiner.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for Figures 3-12, 16-21, 23-24, and 26 that appear on several sheets are followed by "(continued)" instead of a capital letter such as FIG. 1A, FIG. 1B, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term “Notch1 Pathway Reporter Kit” in [pg 27 ln 24], “Advanced Dulbecco's Modified Eagle Medium with Ham's Nutrient Mixture F-12” in [pg 77 ln 2-3], “CellTiter-Glo 3D” in [pg 87 ln 13], “DMEM” in [pg 93 ln 9], “Advanced DMEM/F12” in [pg 93 ln 13, 16, pg 94 ln 8], “GlutaMax” in [pg 93 ln 14, pg 94 ln 9, pg 98 ln 2, 4, 24], “Matrigel” in [pg 93 ln 23, 30, 32, pg 94 ln 4, 5, pg 98 ln 10, 12, 17, 20], “Transwells” or “transwell” in [pg 93 ln 26, 32, pg 94 ln 4, 5, pg 98 ln 11, 14, 17, 20], “Primocin” in [pg 94 ln 11, pg 98 ln 7], “ADMEM/F12” in [pg 98 ln 4, 24], which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that the specification has not been inspected sufficiently to identify all instances of trade names and/or marks used in commerce. It is Applicant’s responsibility to ensure complete compliance.
The disclosure is further objected to because of the following informalities: the Brief Description of the Drawings does not include a description of each panel. Specifically, the descriptions of Figure 6 does not include individual descriptions of panels A-H. See MPEP 608.01(f), which states, “When there are drawings, there shall be a brief description of the several views of the drawings and the detailed description of the invention shall refer to the different views by specifying the numbers of the figures, and to the different parts by use of reference letters or numerals”. Further, MPEP 608.01(f) instructs Examiners such that “If the drawings show Figures 1A, 1B, and 1C and the brief description of the refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1B, and 1C.” Appropriate correction is required.
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.
Claim(s) 1-2, 16, and 77-84 are rejected under 35 U.S.C. 103 as being unpatentable over Hosic et al. [2019, Cellular and Molecular Bioengineering, 13(5), 487-505, IDS, cited in a prior action]; in view of Basak et al. [2017, Cell Stem Cell, 20(2), 177-190, IDS] and Nickerson et al. [2021, Microbiology Spectrum, 9(1), e00003-21, 1-40, published online 09 June 2021].
Regarding claim 1, Hosic teaches a method of obtaining an intestinal organoid-derived monolayer comprising: i. dissociating one or more intestinal organoids into a suspension of single cells and small organoid fragments [pg 489 col 2 ¶ 2, Figure 1]; seeding a Transwell® semi-permeable membrane with the suspension [pg 489 col 2 ¶ 2, Figure 1]; culturing the semi-permeable membrane with said suspension in the presence of an expansion medium until a monolayer is formed [pg 489 col 2 ¶ 2, Figure 1]; and culturing the monolayer in the presence of a differentiation medium [pg 489 col 2 ¶ 2, Figure 1].
Hosic does not teach wherein the differentiation medium comprises a Notch inhibitor, an EGFR pathway inhibitor, and a Wnt agonist.
However, Basak teaches a differentiation media for enabling differentiation of hormone-producing enteroendocrine cells from intestinal organoids [title]. Basak teaches that culturing intestinal organoids in an expansion media comprising EGF, the Wnt agonist R-spondin1, and Noggin [pg e2 ¶ 3], followed by culturing in a differentiation medium further comprising the EGFR inhibitor Gefitinib, the EGFR and ErbB-2 inhibitor Afatinib, the MEK inhibitor PD0325901, or the ERK inhibitor SCH772984, wherein EGF is withdrawn from the media, and wherein the differentiation media additionally comprises the Notch inhibitor DAPT [pg e2 ¶ 5, pg e3 ¶ 1]. Therefore, Basak teaches a differentiation media which comprises a Notch inhibitor (i.e., DAPT), an EGFR pathway inhibitor (i.e., Gefitinib, Afatinib, PD0352904, of SCH772984), and a Wnt agonist (i.e., R-spondin1).
Additionally, Basak teaches that they inhibited Wnt signaling using two independent methods: (1) withdrawal of R-spondin1 from the culture medium and (2) IWP2 treatment which inhibits Wnt3 secretion by Paneth cells, wherein R-spondin1 withdrawal caused rapid loss of Lgr5GFPDTR expression, but IWP2 treatment (iWnt) posed a slower Wnt inhibition that depended on dilution of ligands through proliferation, thereby gradually downregulating Lgr5GFPDTR expression while stem cells differentiated into KI67+ Lgr5- cells while still maintaining Lgr5GFPDTR+ KI67+ cells [pg 178 col 1 ¶ 3, Figure S1A]. Therefore, given the teachings of Basal that the combination of Wnt inhibitor and R-spondin1 in the differentiation media posed a slower Wnt inhibition that allowed maintaining Lgr5GFPDTR+ KI67+ proliferating intestinal stem cells, the ordinarily skilled artisan at the time of filing would have been motivated to maintain a Wnt agonist, such as Rspondin1, in the differentiation media in combination with a Wnt secretion inhibitor to maintain a fraction of Lgr5GFPDTR+ KI67+ cells within the cell population.
Basak further teaches that combined inhibition of Wnt secretion, Notch, and MAPK pathways efficiently generates a diversity of enteroendocrine cell (EEC) hormone-expression subtypes in vitro, which uncouples Wnt-dependent stem cell maintenance from EGF-dependent proliferation and provides an approach for the study of the elusive EECs in a defined environment [abstract]. Basak also teaches that the combined inhibition of WNT/Notch/EGFR pathways resulted in a massive increase in EECs while inhibiting Paneth cell differentiation and combined inhibition of WNT/NOTCH/MEK increased CHGA+ (a marker for enteroendocrine cells) EEC numbers [pg 183 col 2 ¶ 2, Figure 5]. Therefore, the ordinarily skilled artisan at the time of filing the instant application would have been motivated to differentiate expanded intestinal organoid-derived cells in vitro by culturing them in a differentiation medium comprising a Notch inhibitor and an EGFR pathway inhibitor, along with the Wnt agonist and Wnt secretion inhibitor, to promote differentiation of hormone-secreting enteroendocrine cells.
Regarding claim 2, Hosic teaches wherein transepithelial electrical resistance (TEER) measurements across intestinal cell monolayers indicates barrier integrity [pg 492 col 2 ¶ 2].
However, Hosic does not teach wherein in step (iii), the monolayer is cultured in the presence of the expansion medium until the monolayer reaches a TEER value of about 100 Ω-cm2.
Nickerson teaches a method of obtaining an intestinal organoid-derived monolayer comprising dissociating one or more intestinal organoids into a suspension of single cells, seeding a semi-permeable membrane with the suspension, culturing the semi-permeable membrane with the suspension in the presence of an expansion medium until a monolayer is formed, and culturing the monolayer in the presence of a differentiation medium comprising a Notch inhibitor and a Wnt agonist [Supplemental Methods pg 4-6, 14]. Nickerson additionally teaches that after 7 to 10 days in expansion culture, TEER values should stabilize and reach a value in the appropriate range for the specific intestinal segment derived organoids, wherein human induced pluripotent stem cell-derived enterocyte-like cells (hiPS-ELC) exhibit TEER on a Transwell® support of 100 Ω-cm2 and human intestinal epithelial cells (hIECS) from the small intestine exhibit TEER on Transwell® support of 98.9 Ω-cm2 [Supplementary Methods page 6, Table 1]. Therefore, given the protocol teachings of Nickerson to monitor TEER of the monolayer and to culture the monolayer until the TEER values stabilize prior to differentiation, the ordinarily skilled artisan at the time of filing the instant application would have been motivated to culture the monolayer in expansion media until the TEER values stabilize, such as culturing until it reaches a value of about 100 Ω-cm2 for hiPS-ELC or hIECS.
Regarding claims 16, Hosic teaches wherein the monolayer comprises Lgr5+ stem cells, goblet cells, and enterocytes [pg 492 col 2 ¶ 1, Figure 2].
Basak teaches that following culturing in the differentiation media, the organoid comprises at least Lgr5+ stem cells, Praneth cells, and enteroendocrine cells [pg 183 col 2 ¶ 2, Figure 5].
Regarding claims 77-79, as discussed above, Hosic teaches wherein transepithelial electrical resistance (TEER) measurements across intestinal cell monolayers indicates barrier integrity [pg 492 col 2 ¶ 2], and that primary intestinal monolayers exhibited TEER values (818, 1008, 974, and 1097 Ω-cm2) equal to or greater than TEER as compared to Caco-2 monolayers (604 Ω-cm2) [pg 493 col1 ¶ 1, Figure 3]. Therefore, Hosic teaches generation of intestinal monolayers with TEER values greater than 500 and greater than 1000 Ω-cm2.
However, Hosic does not teach generation of intestinal monolayers having TEER values greater than 1500 Ω-cm2.
Nickerson teaches TEER values for vary for specific intestinal segment derived organoids/ organoid-derived monolayers, wherein the TEER values range from about 100 Ω-cm2 for hiPS-ELC or hIECS on the low end up to 1,500 Ω-cm2 for human primary intestinal epithelial cells (hinEpCs)-derived small intestine and 1,500 or 1,000-5,000 Ω-cm2 for intestinal porcine enterocyte cell (IPEC)-J2-cell line-derived porcine jejunum [Supplementary Methods page 6, Table 1]. Therefore, given the teachings of Nickerson that TEER values vary with the specific intestinal segment from which the organoid-derived monolayer is formed, and the teachings of Nickerson of TEER values reported in the literature for intestinal monolayers which exceed 1,500 Ω-cm2, an ordinarily skilled artisan at the time of filing the instant application would expect to achieve TEER values in the monolayer more than 1500 Ω-cm2, such as for IPEC-J2-derived porcine jejunum monolayers.
Regarding claims 80-82, Hosic teaches wherein the expansion medium, called WENR medium, comprises the receptor tyrosine kinase ligand EGF, the BMP inhibitor noggin, the Wnt agonists Wnt-3A and R-spondin3, nicotinamide, and the p38 MAPK inhibitor SB202190 [pg 489 col 1 ¶ 1, col 2 ¶ 2].
Regarding claim 83, Basak teaches wherein the NOTCH inhibitor in the differentiation medium is the gamma secretase inhibitor DAPT; the EGFR pathway inhibitor is any of EGFR inhibitor Gefitinib, the EGFR and ErbB-2 inhibitor Afatinib, the MEK (i.e., RAS-RAF-MAPK pathway) inhibitor PD0325901, or the ERK (i.e., RAS-RAF-MAPK pathway) inhibitor SCH772984; and the Wnt agonist is Rspondin3 and Wnt conditioned medium [pg e2 ¶ 3, 5, pg e3 ¶ 1].
Regarding claim 84, Hosic teaches wherein the intestinal organoid comprises Lgr5+ stem cells [pg 488 col 2 ¶ 1, pg 492 col 2 ¶ 1, pg 499 col 2 ¶ 2, pg 500 col 1 ¶ 2].
Basak teaches that following culturing in the differentiation media, the organoid comprises at Lgr5+ stem cells [pg 183 col 2 ¶ 2, Figure 5].
Given the motivation taught by Basak to maintain a Wnt agonist, such as Rspondin1, in the differentiation media in combination with a Wnt secretion inhibitor to maintain a fraction of Lgr5GFPDTR+ KI67+ cells within the cell population; the further motivation taught by Basak to differentiate expanded intestinal organoid-derived cells in vitro by culturing them in a differentiation medium comprising a Notch inhibitor and an EGFR pathway inhibitor, along with the Wnt agonist and Wnt secretion inhibitor, to promote differentiation of hormone-secreting enteroendocrine cells; the motivation taught by Nickerson to culture the monolayer in expansion media until the TEER values stabilize, such as culturing until it reaches a value of about 100 Ω-cm2 for hiPS-ELC or hIECS; and the expectation taught by Nickerson to achieve TEER values in the differentiated monolayer of more than 1500 Ω-cm2, such as for IPEC-J2-derived porcine jejunum monolayers reported to have TEER values of 1500 or 1000-5000 Ω-cm2; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the method of Hosic to utilize the differentiation medium of Basak to enrich the differentiated intestinal monolayer cells with hormone-producing EECs while maintaining a population of Lgr5+ stem cells with a reasonable expectation of success.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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