DETAILED ACTION
Claims 1-20 are currently pending.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-17, in the reply filed on 6/2/2026 is acknowledged.
Claims 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/2/2026.
Priority
This application claims benefit as a CON of PCT/US22/034148 (filed 6/20/2022) which claims benefit from provisional U.S. Application No. 63/212, 210 (filed 6/18/2021).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/28/2024 and 4/18/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings submitted on 12/15/2023 and 3/25/2024 are objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)). The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). 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. View numbers must be preceded by the abbreviation “FIG.” Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation “FIG.” must not appear.
Additionally, it is noted that the sequencing and karyotype information at FIG. 5B is illegible and the text of Figures 13C, 29J and 30C is out of focus/illegible.
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.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (Figure 5B) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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 1-17 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 claim(s) contains 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. Claim 1 recites the following:
An in vitro method for inducing differentiation of stem cells, comprising activation of wingless (Wnt) signaling, activation of fibroblast growth factor (FGF) signaling, and sacral neural crest patterning in the stem cells to obtain a population of differentiated cells expressing at least one marker indicating a sacral neural crest lineage; or comprising contacting the stem cells with at least one activator of Wnt signaling, at least one activator of FGF signaling, and at least one molecule that induces sacral neural crest patterning.
Dependent claims 2-17 either depend directly from claim 1, or incorporate the method of claim 1.
Claim 1 encompasses inducing differentiation of stem cells to obtain a population of differentiated cells expressing at least one marker indicating a sacral neural crest lineage comprising contacting the stem cells with any amount of said one activator of Wnt signaling (e.g., 0.00001 µM or 100 M) and for any time period (e.g., 5 minutes).
Likewise, claim 1 encompasses contacting the stem cells with any amount of said activator of FGF signaling and any amount of said one molecule that induces sacral neural crest patterning, and for any time period.
Upon review of the specification, the specification shows that Applicants have not provided sufficient description of the invention as currently claimed.
In the instant case the only references in the specification to obtaining a population of differentiated cells expressing at least one marker indicating a sacral neural crest lineage are directed to employing specific culturing steps that require defined time periods and defined amounts of the recited activator of Wnt signaling, activator of FGF and at least one molecule that induces sacral neural crest patterning (FIG. 1; Specification (published as US 2024/0279601) at paragraphs [0136]-[0137], [0140]0[0141], [0144], [0147], [0156]-[0157], [0165]-[0166], [0170], [0173]-[0174], [0317]-[0318] and [0321] –[0333]). For example, the specification at Exemplary Method A [0173] recites the following method for inducing in vitro differentiation of stem cells into cells expressing at least one marker indicating a sacral neural crest lineage:
“…contacting the stem cells with at least one inhibitor of SMAD signaling (e.g., SB431542, e.g., at a concentration of about 10 PM) for about 15 days (e.g., 16 days or 17 days, e.g., from day 4 through day 20), at least one BMP (e.g., BMP4, e.g., at a concentration of about 1 ng/ml) for about 20 days (e.g., 20 days or 21 days, e.g., from day 0 to day 20), at least one activator of Wnt signaling (e.g., CHIR99021) for about 20 days (e.g., 20 days or 21 days, e.g., from day 0 to day 20) (wherein the concentration of the at least one activator of Wnt signaling contacted with the cells is about 3 μM for about 3 days (e.g., 3 days, or 4 days, e.g., from day 0 to day 3), and the concentration of at least one activator of Wnt signaling is about 1.5 μM for about 15 days (e.g., 16 days or 17 days, e.g., from day 4 to day 20)), at least one activator of FGF signaling (e.g., FGF2, e.g., at a concentration of about 100 ng/ml) for about 3 days (e.g., 3 days, or 4 days, e.g., from day 0 to day 3), and at least one molecule that induces sacral neural crest patterning (e.g., GDF11, e.g., at a concentration of about 50 ng/ml) for about 3 days (e.g., 3 days or 4 days, e.g., from day 0 to day 3)).”
The specification at [0137] sets forth the concentration range of the Wnt activator. The specification at [0141] sets forth the concentration range of the FGF activator. The specification at [0147] sets forth the concentration range of the molecule that induces sacral neural crest patterning.
A review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of inducing differentiation of stem cells to obtain a population of differentiated cells expressing at least one marker indicating a sacral neural crest lineage comprising by contacting the stem cells with any amount activator of Wnt signaling, any amount of FGF signaling and any amount of molecule that induces sacral neural crest patterning, and for any time period.
Further regarding claim 16, it is noted claim 16 is directed to the conditions for maturing the sacral neural crest lineage cells to cells that express at least one enteric neuron marker or at least one enteric glia cell marker, and claim 16 encompasses contacting the differentiated cells with any amount of said growth factor and any amount of said Wnt activator. However, a review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of maturing the sacral neural crest lineage cells to cells that express at least one enteric neuron marker or at least one enteric glia cell marker by contacting the differentiated cells with any amount of said growth factor and any amount of said Wnt activator.
In the instant case the only references in the specification to obtaining cells that express at least one enteric neuron marker or at least one enteric glia cell marker are directed to employing specific culturing steps that require defined time periods and defined reagents (FIG. 17A, [0330]).
Accordingly, the claims as currently drafted are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 14 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 14 recites the phrases “primordial germ cell-like pluripotent stem cells” and “enhanced pluripotent stem cells”. It is noted the terms “cell-like” and “enhanced” in claim 14 are relative terms which render the claim indefinite. The terms “cell-like” and “enhanced” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear as to what Applicant is intending to cover by the recitation of “primordial germ cell-like pluripotent stem cells”. In what manner do the pluripotent stem cells have to be like or similar to a primordial germ cell. Do the pluripotent stem cells have to be obtained from eggs or sperm, or obtained before reaching the gonads, or do the stem cells have to express gamete cell markers.
Likewise, it is unclear as to what Applicant is intending to cover by the recitation “enhanced pluripotent stem cells”. In what manner are the pluripotent stem cells “enhanced”? Are the stem cells enhanced in the manner of migratory property or doubling time property, as compared to a more differentiated lineage? Are the stem cells enhanced in the manner of requiring a specific phenotype, as compared to a more differentiated lineage? See MPEP 2173.05(b)(III).
Appropriate clarification is appreciated.
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.
Claim(s) 1-14 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Ashton et al., (US 2016/0068806; IDS 4/18/2025) (“Ashton”), as evidenced by Ge et al., (Molecular and Cellular Biology, July 2005, Vol 25, No. 14, p. 5846-5858; see PTO-892) (“Ge”) and Madhu et al., (Stem Cells International, Vol 2016, Article ID 1035374, 13 pages; see PTO-892) (“Madhu”).
Ashton is directed to in vitro methods of directed differentiation for precise patterning of posterior neuroectoderm from human pluripotent stem cells (hPSCs), wherein the hPSCs are differentiated into caudal lateral epiblasts, posterior neuroectoderm or posterior neuroepithelium, or motor neurons having specified HOX gene expression pattern mirroring a desired position along the rostral-caudal axis during hindbrain and spinal cord development (Abstract).
Regarding claims 1, 6 and 14, Ashton at paragraphs [0116]-[0118] teaches the specific steps of the directed differentiation method that results in a population of differentiated cells expressing Hoxd10 after the third culture period. Specifically, as follows:
Culturing hPSCs during a first culture period of about one to two days with a neural differentiation base medium (E6) to obtain a first cell population;
culturing the first cell population for a second culture period of about one day to about four days in neural differentiation base medium supplemented with an FGF to obtain a second cell population that is Sox2+, Otx2+, Brachyury−, and Pax6−; and
culturing the second cell population for a third culture period of about one day to about seven days in neural differentiation base medium comprising an FGF (e.g., FGF2, FGF8a, FGF8b, FGF8f, FGF17, or FGF18) and an activator of β-catenin pathway signaling (e.g., CHIR) to obtain caudal lateral epiblasts that are Sox2+/Brachyury−/Pax6−/Otx2−.
Fig. 7A specifically illustrates the in vitro method for inducing differentiation of stem cells to a population of differentiated cells expressing HoxD10 and HoxA11 (Fig. 7B, lumbar/sacral gene expression at day 12), i.e., at least one marker indicating a sacral neural crest lineage.
Fig. 8C further illustrates HoxD10 expression profiles generated after RA (retinoic acid) treatment in relation to the time of culturing in the presence of CHIR99021 (“CHIR”).
Thus, Ashton exemplifies an in vitro method for inducing differentiation of human pluripotent stem cells comprising culturing the stem cells in E6 medium that is supplemented with FGF8b at days 1-9 (i.e., activator of FGF signaling), supplemented with CHIR at days 2-9 (i.e., activator of Wnt signaling), supplemented with GDF11 (i.e., a molecule that induces sacral neural crest patterning), and at any time after 2 days of culture, supplement RA for 4 days (fig. 7A-B; Fig 8B-C). Thus, Ashton anticipates claims 1, 6 and 14.
Regarding claims 2 and 5, Ashton exemplifies contacting the cells with GDF11 for 3 days (days 6-8) (Fig. 7A), thus anticipating claims 2 and 5.
Regarding claim 3, Ashton exemplifies contacting the cells with FGF for 8 days (days 1-8) (Fig. 7A), thus anticipating claim 3.
Regarding claims 4 and 7, Ashton exemplifies contacting the cells with CHIR99021 for 7 days (days 2-8) (Fig. 7A; [0130]; [0165]), thus anticipating claims 4 and 7.
Regarding claims 8-9, Ashton teaches contacting the cells with dorsomorphin at days 6-12 to assess preventing dorsal patterning without affecting caudal(sacral) patterning, as illustrated by HoxD10 expression in Fig. 7E ([0165]; Fig. 7A and 7E).
Madhu evidences that dorsomorphin inhibits activin/nodal/TGF-b and BMP pathways (Introduction, page 2, left col, fourth para, last sentence).
Thus, Ashton anticipates claims 8-9.
Regarding claims 10 and 11, Ashton exemplifies contacting the cells with GDF11 and Ge evidences that GDF11 is synonymous with BMP11 (Abstract), thus Ashton anticipates claims 10 and 11.
Regarding claim 12, Ashton’s Fig. 7E illustrates that at least 89% of the cells (i.e., at least 70%) express HoxD10 by day 12 of initiating induction (i.e., at least about 20 days), thus anticipating claim 12.
Regarding claim 13, Fig. 7A of Ashton specifically illustrates the in vitro method for inducing differentiation of stem cells to a population of differentiated cells expressing HoxD10 and HoxA11 (Fig. 7B, lumbar/sacral gene expression at day 12), thus anticipating claim 13.
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) 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Ashton, as evidenced by Ge and Madhu, as applied to claims 1-14 above, and further in view of Studer et al., (US 2018/0291339; IDS 10/29/2024) (“Studer”).
The teaching of Ashton, as evidenced by Ge and Madhu is set forth above.
Regarding claim 15-17, it is noted that Ashton does not further teach subjecting the differentiated sacral neural crest cells to further maturation wherein the cells express at least one enteric neuron marker or at least one enteric glia cell marker. However, Studer is directed to in vitro methods of inducing differentiation of stem cells to enteric neural crest lineage since said cells are useful for treating enteric nervous system disorders, e.g. Hirschsprung’s disease, and the cells are useful for screening compounds suitable for treating enteric nervous system disorders (Abstract).
Studer, at paragraphs [0026]-[0035], teaches inducing vagal neural crest patterning and further differentiation to enteric neural crest cells expressing enteric markers including Tuj1, EDNRB, PHOX2A, PHOX2B, HAND2 and ASCL1 (enteric neuron markers), and SOX10 (enteric glia cell marker) (claim 17), and the one or more molecule that enhances maturation of enteric nervous system precursors into enteric neurons are selected from the group consisting of growth factors and Wnt activators (claim 16).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further subject the sacral neural crest cells to further maturation to enteric neural crest lineage, expressing enteric neuron markers.
The person of ordinary skill in the art would have been motivated to modify the method of Ashton to include subjecting the differentiated sacral neural crest cells to conditions favoring maturation to enteric neural crest lineage expressing enteric neuron markers, as taught by Studer, for the predictable result of successfully producing enteric neural cells since said cell population is useful for treating enteric nervous system disorders, e.g. Hirschsprung’s disease, and the cells are useful for screening compounds suitable for treating enteric nervous system disorders, thus meeting the limitation of claims 15-17.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Ashton and Studer because each of these teachings are directed at methods of producing cell populations useful in regenerative medicine from human pluripotent stem cells.
Conclusion
No claim is allowed. No claim is free of prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
Prosecution Insights