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 .
Election/Restrictions
Applicant’s election without traverse of Sox2 as the single specific transcription factor DNA-binding domain, and the combination of KRAB, DNMT3A, and DNMT3L as the single specific combination of epigenetic effector domains in the reply filed on 06/22/2026 is acknowledged.
Claims 1-13, and 15-21 are pending and under examination.
The search in examination of the transcription factor DNA binding and the epigenetic effector domain was extended to the PAX3 DNA binding domain and the Engrailed repressor, respectively.
Priority
Receipt is acknowledged of certified copies of papers, for EPO 21157246.6 of filling date 02/15/2021, required by 37 CFR 1.55.
Drawings
The drawings are objected to because 37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."" In the current case, the view numbers for Figures 1-16 are preceded by the word "Figure" instead of the abbreviation "FIG.".
37 CFR 1.84(p)(1) states “Reference characters (numerals are preferred), sheet numbers, and view numbers must be plain and legible, and must not be used in association with brackets or inverted commas, or enclosed within outlines, e.g., encircled. They must be oriented in the same direction as the view so as to avoid having to rotate the sheet.” In addition, 37 CFR 1.84(i) states “All views on the same sheet should stand in the same direction and, if possible, stand so that they can be read with the sheet held in an upright position. If views wider than the width of the sheet are necessary for the clearest illustration of the invention, the sheet may be turned on its side so that the top of the sheet, with the appropriate top margin to be used as the heading space, is on the right-hand side.” In the current case, the orientation of the figure label (e.g., “Figure 2”) is inconsistent with the orientation of the figure panels and their reference letters. When the sheet is rotated to the right for viewing, the graphs, figures, and reference letters (e.g., “a”, “b”, and “c”) are reading left-to-right, but the “Figure 2” label is not. This issue is found in FIG. 2, 5, 6, 7, 8, 9, 10C, 12, 13, 15, and 16. For instance, FIG. 11 is acceptable.
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 disclosure is objected to because of the following informalities: The Brief Description of the Drawings recite colors: "red arrows" and "white arrows (pg. 10, lines 21-22), "red arrows" (pg. 87, line 8). It would be remedial to amend the specification to describe figures without recitation of color. Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink (pg. 103, lines16-18, lines 21-27; pg. 104, lines 4-9, line 15; pg. 106, line 29) and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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 Objections
Claims 4 and 5 are objected to because of the following informalities: multiple acronyms are recited but not defined in claims, e.g., KRAB, DNMT3A, DNMT3L. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-13, and 15-21 are 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.
Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim 1 recites “wherein the transcription factor is…” in line 3. There is insufficient antecedent basis for this limitation in the claim. It is noted the first recitation of transcription factor (TF) is in the same claim as “transcription factor DNA-binding domain”, lines 1-2. It is unclear whether the ESF requires (i) an oncogenic or cancer-associated TF and (ii) DNA-binding domain from any TF. It is unclear whether the ESF requires to have a DNA-binding domain from an oncogenic or cancer-associated TF.
Claim 1 recites “an oncogenic transcription factor” in line 3. The specification states this term “refers to a transcription factor that may transform a healthy cell into a cancer cell, for example through causation of inappropriate gene expression patterns, which can for example promote tumor initiation and progression” (pg. 22, lines 15-18). It is unclear what degree or type of gene expression change is sufficient to constitute “an inappropriate gene expression pattern” or when such changes are sufficient to determine that transcription factor may transform a healthy cell into a cancer cell. Accordingly, the metes and bounds of the claim cannot be ascertained with reasonable certainty.
Claim 1 recites “a cancer-associated transcription factor” in lines 3-4. The specification states this term “refers to a transcription factor that may induce tumorigenic properties but cannot transform a healthy cell into cancer cell” (pg. 22, lines 20-22). The specification does not provide a clear definition for one ordinary skill in the art to determine whether a transcription factor fall within the scope of the claim. It is unclear what degree or type of “tumorigenic properties” is sufficient to satisfy this definition, or how one ordinary skill in the art would objectively determine whether a transcription factor is capable of inducing such properties while being incapable of transforming a healthy cell into a cancer cell. Accordingly, the metes and bounds of the claim cannot be ascertained with reasonable certainty.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6 and 10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 6 is drawn to a polynucleotide comprising a nucleic acid sequence encoding the ESF of claim 1. However, claim 6 fails to include all of the limitations of claim 1 from which it depends, including the requirement for transcription factor DNA-binding domain and epigenetic effector domain which are proteins, as opposed to only a nucleic acid sequence encoding for them.
Claim 10 is drawn to a cell comprising the ESF of claim 8. The ESF is a protein but claim 8 is drawn to a vector. Thus, claim 10 fails to include all of the limitations of claim 8 from which it depends, including the requirement for the vector of claim 8.
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 1-13, and 15-21 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”. MPEP § 2163 further states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species.
Claim 1 is drawn to an epigenetic silencer factor comprising a genus of transcription factors (TFs) that is an oncogenic TF or a cancer-associated TF. The specification discloses the oncogenic TF “may transform a healthy cell into a cancer cell” (pg. 22, lines 15-18), and the cancer-associated TF “may induce tumorigenic properties but cannot transform a healthy cell into a cancer cell” (pg. 22, lines 20-22). Accordingly, the claimed genus is not defined by structure. It is defined primarily by the functional or biological properties of the TF rather than structural characteristics sufficient to identify the members of the genus, or a known correlation between structure and function.
The specification identifies approximately 38 TFs that fall within the claimed genus (pg. 22, lines 24-27). The specification further provides examples of ESFs comprising Sox2, TEAD1, and c-MYC (pg. 83, lines 26-29; pg. 87, line 22). However, the specification fails to identify common structural characteristics that would allow one skilled in the art to recognize members of the genus. The specification also fails to disclose a recognized correlation between structure and function to demonstrate possession of the entire genus. MPEP 2163 explains that "[f]or inventions in an unpredictable art, an adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus", and "when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus". Therefore, these examples are not representative of the full scope of the claimed genus because they constitute a small subset of the potentially vast number of TFs having substantially different DNA binding domains, cofactors, and biological and pathological properties encompassed by the breadth of the claim.
Regarding the state of the art, Lambert (Cell, 2018, 172: 650-665) teaches TFs represent ~8% of all human genes and are associated with a wide array of diseases and phenotypes (pg. 661, col. 1, para. 1). Lambert further teaches TFs are categorized in numerous TF families having distinct DNA binding domains and regulatory functions (pg. 652-655). Particularly, only a handful of well-characterized mammalian TFs contain a known DNA binding domain, for instance, the CERS/Lass-type Homeodomains are not likely to be DNA binding proteins at all (pg. 652, col. 2, para. 1 and 2). Further, TFs are structurally and evolutionarily distinct, for example C2H2-zinc fingers generally bind double-stranded DNA while CCC-zinc fingers typically bind single-stranded RNA (pg. 652, col. 2, para. 2).
The prior art also demonstrates that a TF is oncogenic or cancer-associated is not a property that can be determined predictably. Vishnoi (Cancers, 2020, 12(2296):1-32) teaches diverse classes of oncogenic TFs, each comprising numerous TFs, that participate in cancer through different mechanisms including tumor growth, metastasis, chemoresistance, epithelial-mesenchymal transition, metabolism, and cancer stem cells maintenance (caption Fig. 1). Vishnoi further teaches TFs can be both oncogenic and tumor-suppressive in different cancers (pg. 2, para. 1), TF expression is cell-specific and cancer-specific in pathological conditions as TF profiles change with the landscape of the cancer, given that many cancers present themselves with specific deregulations that characterize the hallmarks for specific subtypes of cancer (pg. 18, para. 3). In addition, β-catenin is categorized as an oncogenic TF, but it does not contain a DNA binding domain, as evidenced by Rahmani (The Journal of Biological Chemistry, 2005, 280(13):13019-13028) (abstract).
The breadth of the claims encompasses TFs from numerous structurally and functionally distinct families, and the property of “oncogenic” or “cancer-associated” is cell- and cancer-specific. However, the prior art teaches that merely knowing that a protein is a TF or that it participates in cancer does not establish that the TF will function as an “oncogenic” or “cancer-associated” TF as claimed. Further, the prior art teaches that even if a TF is oncogenic or cancer-associated, it may not contain a DNA-binding domain.
Further, dependent claims 2-13, and 15-21 are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein. Dependent claims recite a Markush group of TFs but these TFs are not a representative number of species to reflect the variation within the genus, given the unpredictability of identifying other members within the genus based on teachings of prior art.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of TFs that are oncogenic or cancer-associated, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of TFs, wherein the TF is oncogenic or cancer-associated.
Claims 12-13 and 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of reducing tumor growth in glioblastoma multiforme models comprising administering the ESF of claim 1 or a vector encoding therefor, does not reasonably provide enablement for a method of any treatment or treating any cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of the Claims
Claims 12 and 19 are directed to a method of any type of treatment comprising administering an epigenetic silencer factor (ESF) comprising (i) an oncogenic or cancer-associated transcription factor (TF) DNA binding domain and (ii) an epigenetic effector domain. Claims 13 and 20 are directed to a method of treating any type of cancer comprising administering the same ESF. The claims are not limited to a particular TF, epigenetic effector domain, target gene or genomic locus, disease or specific type of cancer, or therapeutic mechanism. Accordingly, the claims encompass administering any ESF for treating any disease or condition, or any cancer.
Guidance of the Specification
The specification provides working examples involving oncogenic TF Sox2’s DNA binding domain, lacking its C-terminal transcriptional activation domain, fused to a combination of three epigenetic effector domains including a KRAB domain, a DNMT3A domain, and a DNMT3L domain (pg. 83, lines 26-29), and this particular ESF is referred to as SES (pg. 84, line 5). The specification discloses injections in situ of lentivirus expression this particular ESF successfully reduced tumor mass of patient-derived glioblastoma multiforme (GBM) cancer stem cells (FIG. 7f; pg. 86, lines 1-8). However, the specification also discloses that "proliferation of cell lines from prostatic, liver and pancreatic cancers were largely unaffected by SES treatment suggesting a cancer-specific SES efficacy" (FIG. 1h; pg. 84, lines 5-11). Further, the specification teaches two additional ESFs, comprising TEAD1 and c-MYC oncogenic TF DNA binding domains, also shows proliferative loss of GBM cancer stem cells (FIG. 11e-f and FIG. 13; pg. 87, lines 19-30). Accordingly, the specification demonstrates that ESFs comprising DNA-binding domains from different oncogenic or cancer-associated TFs fused to specific epigenetic repressor domains can have anti-tumor effect in GBM models. However, these results positively indicate the claimed ESF does not enable a method of treatment or treating cancer merely because the cells are cancer cells, particularly non-GBM cancer cells.
These examples do not establish that other TFs, epigenetic effector domain, target genes, or disease/conditions or cancer can be treated by merely administering an ESF. The specification does not provide a reasonable basis for predicting successful treatment across the vast number of pathologically disease/conditions or cancers encompassed by the claims, including cancers in which the selected oncogenic or cancer-associated TF is not a driver or participant of the malignant phenotype.
State of the Art
At the time of the filling, the state of the art does not demonstrate the disclosed models can be reasonably and predictably be extrapolated across the full scope of the claims. Vishnoi (Cancers, 2020, 12(2296):1-32) teaches that TF profiles are cell-specific, and in pathological conditions the expression of subsets of TFs becomes more cancer-specific (pg. 18, para. 3). Further, given the fact that all cells require transcription for survival and maintenance, modulation of TF-targeted genes may turn out to be toxic and with unavoidable side effects (pg. 18, para. 3) as TFs can be both oncogenic and tumor-suppressive in different cancers (pg. 2, para. 1). Chen (Oncogene, 2020, 39:6633-6646) also teaches that cancers depend on different transcriptional regulatory circuits, and modulation of individual TF will reduce expression of other members in the circuits (FIG. 3, pg. 6636, col. 1, para. 1). Thus, modulation of target genes via ESFs comprising other oncogenic or cancer-associated TF DNA binding domains could yield results different from that observed in the disclosed Sox2, TEAD1, or cMYC examples. Fredericks (Cancer Letters, 2001, 162: S23-S32) demonstrates ESF comprising oncogenic TF PAX3 DNA binding domain fused to a KRAB repressor domain inhibited malignant growth and tumorigenesis in PAX3-dependent alveolar rhabdomyosarcoma, but the same strategy did not yield a generalized tumorigenic growth-inhibitory effect, particularly an ESF comprising a MYB DNA binding domain fused to a KRAB domain (Table 1).
Thus, the prior art teaches the mere identification of a transcription factor as oncogenic or cancer-associated does not establish that operably linking its DNA binding domain to an epigenetic effector would therapeutically treat any disease/condition or every cancer. The therapeutic effect of an ESF depends on the particular oncogenic or cancer-associated TF’s DNA binding domain, epigenetic effector domain, endogenous target genes, the cellular pathway involved, and the cancer context.
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to determine (i) for each particular disease/condition or cancer, whether the selected oncogenic or cancer-associated TF DNA binding domain participates in causing the disease/condition or cancer, (ii) which target genes or transcriptional regulatory circuits are responsible for the malignant phenotype, (iii) whether epigenetic modulation of these target genes would be therapeutic, and (iv) whether recruitment of claimed ESF to these target genes would produce the desirable therapeutic effect.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to make and use the invention as claimed. Therefore, claims 12-13 and 19-20 are not considered to be fully enabled by the instant disclosure.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 6-11, 15-18, and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seo (Molecular and Cellular Biology, 2011, 31(22): 4593-4608; IDS received 08/28/2023, Cite No. C21).
Regarding claim 1, Seo teaches a “chimeric” transcription factors (i.e., epigenetic silencer factor (ESF)) comprising a Sox2 domain that binds to the DNA (i.e., transcription factor DNA-binding domain) fused to a herpesvirus VP16 activation domain or the Engrailed repressor domain (i.e., epigenetic effector domain) (pg. 4595, col. 2, para. 1). As evidenced by instant specification, Sox2 is an oncogenic or cancer-associated transcription factor (pg. 3, line 25).
Regarding claims 2 and 3, Seo further teaches wherein the transcription factor is Sox2 (Fig. 1C; pg. 4595, col. 2, para. 1).
Regarding claim 4, Seo further teaches wherein the epigenetic effector domain is an Engrailed repressor (En-R) domain (Fig. 1C; pg. 4595, col. 2, para. 1).
Regarding claim 6, Seo teaches PCR products (i.e., nucleic acid sequence) encoding the chimeric molecule (i.e., ESF) are cloned into FUCRW plasmid (i.e., polynucleotide) (pg. 4594, col. 2, para. 1).
Regarding claim 7, Seo further teaches the ESF is cloned into FUCRW plasmids and refer to these plasmids as “expression Sox2 expression constructs” (pg. 4594, col. 2, para. 4). Further, expressions of these constructs are verified in Western Blots using antibodies against the C-terminal or HMG domain of Sox2 (caption for Fig. 1D). Accordingly, Seo positively teaches wherein the polynucleotide further comprises a promoter operably linked to the nucleic acid sequence encoding ESF through the demonstration of successful expression of the ESF.
Regarding claims 8, and 16-17, Seo further teaches the FUCRW plasmid is a lentiviral vector (pg. 4594, col. 1, para. 7).
Regarding claims 9 and 18, Seo further teaches “all lentiviruses were produced using 293T cells and pVSV-G, pLP1, and pLP2 as helper plasmids” which generates a lentiviral particle that functions as a nanoparticle (paragraph bridging col. 1 and col.2, pg. 4594).
Regarding claims 10 and 11, Seo further teaches “OB1-TOP cells were transduced with Sox2 expression constructs and treated with recombinant Wnt3A protein” (pg. 4594, col. 2, last paragraph). Thus, Seo teaches a cell comprising the ESF or a polynucleotide encoding thereof, as well as a composition, e.g., mixture comprising the Sox2 expression constructs and solution for transduction.
Regarding claims 15 and 21, Seo further teaches the Sox2-Engrailed chimera (i.e., ESF comprising Sox2 transcription factor and Engrailed Repressor domain) did not rescue colony-forming or self-renewal ability of osteoblasts, demonstrating that Sox2-Engrailed chimera successfully repressed transcription and/or expression of at least one target gene in a cell (pg. 4595, col. 2, para. 1; Fig. 1C and 1D). As compared to wild-type Sox2 and Sox2-VP16 chimera where the epigenetic effector domain is an activator, the colony-forming ability of osteoblasts is rescued (Fig. 1C and 1D).
Claims 1-2, 4, 6-8, 10-15, and 19-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fredericks (Molecular and Cellular Biology, 2000, 20(14): 5019-5031) (hereinafter as Fredericks 1). Claim 7 is evidenced by Fredericks (Molecular and Cellular Biology, 1995, 15(3):1522-1535) (hereinafter as Fredericks 3).
Regarding claim 1, Fredericks 1 teaches a PAX3-KRAB protein (i.e., epigenetic silencer factor (ESF)) comprising a PAX3 DNA binding domain fused to a KRAB repression module (i.e., epigenetic effector domain) (abstract, FIG. 1B, FIG. 2A). Fredericks 1 further teaches that in alveolar rhabdomyosarcoma tumors (ARMS), the PAX3 DNA binding domain is fused to an activation domain derived from the FKHR gene that functions as a dominant oncogene and this fusion is referred to as an oncogenic transcriptional activator (abstract, pg. 5019, col. 2, para. 1). Accordingly, the PAX3 DNA binding domain in the PAX3-KRAB fusion protein is an oncogenic transcription factor or a cancer-associated transcription factor.
Regarding claim 2, Fredericks 1 teaches wherein the transcription factor is PAX3 (abstract).
Regarding claim 4, Fredericks 1 teaches wherein the epigenetic effector domain is a KRAB domain (abstract).
Regarding claim 6, Fredericks 1 teaches cloning nucleic acid sequences encoding each component of the ESF together to construct the PAX3-KRAB fusion protein (pg. 5022, “Expression plasmids” subsection).
Regarding claim 7, Fredericks 1 further teaches the polynucleotide was cloned into a pCDNA3 plasmid and it further comprises a CMV promoter operably linked to the nucleic acid sequence encoding the ESF, as evidenced by Fredericks 3 teaching the pCDNA3 vector comprises a T7 and CMV promoter for in vitro transcription and expression in mammalian cells, respectively (pg. 1525, col. 1, para. 1).
Regarding claim 8, Fredericks 1 further teaches the polynucleotide is cloned into a pCDNA3 plasmid (i.e., vector) (pg. 5022, “Expression plasmids” subsection).
Regarding claim 10, Fredericks 1 further teaches the “pCDNA3 PAX3-derivative expression plasmid” (i.e., polynucleotide encoding the ESF) is transfected into Rh30 cells (pg. 5022, “Transfections and reporter assays” subsection).
Regarding claim 11, Fredericks 1 further teaches transfecting Rh30 cells with calcium phosphate DNA precipitates containing a mixture of plasmids (pg. 5022, “Transfections and reporter assays” subsection). Accordingly, Fredericks teaches a composition comprising the recited vector.
Regarding claims 12-13, and 19-20, the specification discloses “in some embodiments, the treatment reduces tumour size” (pg. 81, line 28). Fredericks 1 further teaches injecting Rh30 cell suspensions into SCID mice (i.e., administering the recited vector or ESF to a subject in need thereof), and that tumorigenicity in mice is suppressed, leading to inhibition of malignant growth of Rh30 ARMS in vivo (pg. 5022, col. 1, para. 2; pg. 5023, “Tumor formation” subsection; Table 2). Accordingly, Fredericks 1 teaches this particular embodiment encompassed in the claims via inhibition of ARMS malignant growth in mice.
Regarding claims 15 and 21, Fredericks 1 further teaches introducing the vector comprising the polynucleotide encoding the ESF into a cell (pg. 5022, “Transfections and reporter assays” subsection), and the ESF expressed in the cell functions as a potent repressor that nearly abolished all the reporter’s gene activity (Fig. 4A; pg. 5024, col. 2, para. 3). Thus, Fredericks 1 teaches a method of decreasing transcription and/or expression of at least one target gene in a cell.
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 5, 9, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Fredericks (Molecular and Cellular Biology, 2000, 20(14): 5019-5031) (hereinafter as Fredericks 1) and Fredericks (Cancer Letters, 2001, 162: S23-S32) (hereinafter as Fredericks 2), in view of Chen (WO 2019/204766 A1; Pub Date: 24 Oct 2019) and Cathomen (US 2019/0024090 A1; Pub Date: 24 Jan 2019; IDS received 08/28/2023, Cite No. A3).
Regarding claim 5, Fredericks 1 teaches the ESF of claim 1, as discussed above, and is incorporated herein by reference. Fredericks 1 further teaches wherein the ESF comprises a KRAB domain (i.e., epigenetic effector domain) (abstract, FIG. 1B, FIG. 2A). Fredericks 1 also teaches the employed ESF is “a strategy designed to directly compete with the oncogenic transcriptional activator and repress PAX3 target genes with an engineered repressor”, and “[d]ominantly interfering with endogenous cellular activators using heterologous repressors is an approach which has also been successfully used in other studies” (pg. 5027, col. 1, para. 1).
In addition, Fredericks 2 demonstrates in Figure 2 (reproduced below) that engineered ESFs could be modular comprising diverse oncogenic transcription factor targeting domains (i.e., DNA binding domain) and heterologous repression domains (i.e., epigenetic effector domain) (abstract; pg. S24, col. 2, para. 1). Fredericks 2 further teaches exemplary examples including but not limited to (i) PAX3-KRAB and PAX3-SNAG which comprises the same DNA binding domain and differ in epigenetic effector domain are both capable of inhibiting ARMS malignant growth, and (ii) MYB-KRAB that differs in DNA binding domain resulting in repression of endogenous BCL2 gene and induced apoptosis (Table 1). These results positively teach that each component of the ESF could be modified according to the desired target gene and regulatory effect.
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However, Fredericks 1 and Fredericks 2 do not teach wherein the epigenetic effector domain comprises a combination of a KRAB domain, a DNMT3A domain, and a DNMT3L domain.
Cathomen teaches a “designer epigenome modifier” (i.e., epigenetic silencer factor (ESF)) comprising a TALE DNA binding domain and at least one epigenetic effector domain including i) a KRAB domain, ii) a DNMT3A domain, and iii) a DNMT3L domain ([0013]-[0017]). The possible combinations of components are illustrated in FIG. 1A, reproduced below. Cathomen further discloses that the combination of KRAB, DNMT3A, and DNMT3L domains in the ESF achieved stable gene silencing up to two months compared to ESF comprising either one of the domains that resulted in transient silencing lasting less than two weeks ([0110]). Further, Cathomen teaches the ESF can be used in a method of decreasing transcription and/or expression of at least one target gene in a cell through silencing the targe gene (FIG. 1B, FIG. 2A), where the DNA binding domain directs the ESF to a specific target site in the promoter or any other regulatory element of the target gene leading to the methylation of neighboring histone tails, and consequently silencing the target gene ([0061]).
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In addition, Chen teaches an “all-in-one” protein (i.e., ESF) comprising a dCas9 DNA-binding domain fused to at least one epigenetic effector domain including i) a KRAB domain, ii) a DNMT3A, and iii) DNMT3L (description of FIG. 1A, claim 3) as illustrated below (FIG. 1A). Chen also teaches the ESF could be used in a method of decreasing or silencing transcription and/or expression of at least one target gene in a cell by methylating a chromatin containing the target gene and/or introducing repressive chromatin marks to the chromatin ([0010], [0083], claims 31-32).
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Thus, Cathomen positively teaches the advantage of including additional epigenetic effector domains, particularly DNMT3A and DNMT3L in combination of KRAB, to repress transcription and/or expression of a target gene, and Chen demonstrates that this combination of epigenetic effector domains could also be applied to additional ESFs comprising different DNA binding domains.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Fredericks 1’s epigenetic effector domain to include DNMT3A and DNMT3L as taught by Cathomen and Chen because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: PAX3 retains its known DNA binding function, while DMNT3A and DNMT3L retains its known function of methylating genes to silence transcription. One would have been motivated to have done so for the advantage of achieving stable gene silencing with extended duration compared to ESF comprising a KRAB domain alone as taught by Cathomen. One would have had a reasonable expectation of success in doing so because Fredericks 1 and 2 teach each component of the ESF is modular and could be modified based on the endogenous oncogenic transcription factor one desire to compete with and a well-characterized repression domain. Fredericks 1 and 2 further demonstrate engineered ESFs differing in epigenetic effector domains only are still capable of achieving the same effect, e.g., PAX3-KRAB and PAX3-SNAG (Table 1). In addition, Cathomen and Chen both demonstrate that KRAB, DNMT3A, and DNMT3L are well-characterized repressors, and their combination is commonly employed in ESFs.
Regarding claim 9 and 18, the obviousness to modify the ESF of Fredericks 1 to further comprise a DNMT3A and DNMT3L domain as taught by Cathomen and Chen is discussed above as applied to claim 5. Fredericks 1 teaches the ESF or the vector encoding the ESF is transfected into a cell as calcium phosphate DNA precipitates (pg. 5022, “Transfection and reporter assays” subsection).
However, Fredericks 1 does not teach the ESF or the vector encoding ESF is comprised in a nanoparticle.
Chen teaches a vector comprising a polynucleotide that includes a nucleic acid sequence encoding the ESF ([0008]), and that the vector is comprised in a nanoparticle for non-viral transfection ([0073]), pg. 22, line 21).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the calcium phosphate transfection strategy used by Fredericks 1 to a nanoparticle as taught by Chen because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. Both calcium phosphate transfection and nanoparticle encapsulation are non-viral transfections as taught by Chen ([0073]). Thus, the substitution is merely swapping similar features that serve the same function. One would have had a reasonable expectation of success in doing so because Chen teaches non-viral transfections of the ESF into a cell, particularly via nanoparticle encapsulation of the nucleic acids encoding the ESF.
Regarding claims 16-17, the obviousness to modify the ESF of Fredericks 1 to further comprise a DNMT3A and DNMT3L domain as taught by Cathomen and Chen is discussed above as applied to claim 5. Fredericks 1 teaches the vector encoding the ESF is pCDNA3, a nonviral vector (pg. 5022, “Expression plasmids” subsection).
However, Fredericks 1 does not teach wherein the vector is a viral vector, specifically a lentiviral vector or adeno-associated viral (AAV) vector.
Chen teaches a vector comprising a polynucleotide that includes a nucleic acid sequence encoding the ESF ([0008]), and that the vector is a lentiviral or AAV vector ([0073]).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the transfection strategy used by Fredericks 1 to viral transfection as taught by Chen because it would have merely amounted to a simple substitution as discussed above and as applied to claims 9 and 18. One would have had a reasonable expectation of success in doing so because Chen teaches viral transfections of the ESF into a cell, particularly via viral vectors including but not limited to lentiviral and AAV vectors encoding the ESF.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Fredericks (Molecular and Cellular Biology, 2000, 20(14): 5019-5031) (hereinafter as Fredericks 1), in view of Fredericks (Cancer Letters, 2001, 162: S23-S32) (hereinafter as Fredericks 2) and Seo (Molecular and Cellular Biology, 2011, 31(22): 4593-4608).
Regarding claim 3, Fredericks 1 teaches the ESF of claim 1, as discussed above, and is incorporated herein by reference. The teachings of Fredericks 1 and 2 are discussed above as applied to claim 5 and are incorporated herein by reference. In summary, Fredericks 1 and 2 teach each component of the ESF is modular and could be modified based on the endogenous oncogenic transcription factor one desire to compete with and a well-characterized repression domain, including but not limited to KRAB, Engrailed repressor, and SNAG (Table 1; Fig. 2).
However, Fredericks 1 and 2 do not teach wherein the DNA binding domain is Sox2.
Seo’s teachings are discussed above as applied to claim 2 and are incorporated herein reference. In summary, Seo teaches a “chimeric” transcription factor (i.e., ESF) comprising a Sox2 DNA binding domain fused to an Engrailed repressor domain (i.e., epigenetic effector domain) (pg. 4595, col. 2, para. 1). As evidenced by instant specification, Sox2 is an oncogenic or cancer-associated transcription factor (pg. 3, line 25). Seo further teaches Sox2 targets endogenous FoxP1 and BMI-1 genes (abstract) and the ESF comprising Sox2 and Engrailed repressor inhibited transcription and/or expression of at least one target gene in osteoblasts, resulting in loss of their self-renewal ability (pg. 4595, col. 2, para. 1; Fig. 1C and 1D).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the Fredericks 1 and 2 DNA binding domain to Sox2 as taught by Seo because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. The substituted components and their functions are known in the art. Fredericks 1 and 2’s PAX3 or MYB oncogenic transcription factors target PAX3 or MYB-specific genes while Seo’s Sox2 is another oncogenic transcription factor that targets Sox2 specific genes. Accordingly, the substitution is merely swapping similar features that serve the same purpose, which is selecting from one oncogenic transcription factor to another that one desires to compete with the endogenous oncogenic transcriptional activator and repress that endogenous transcription factor’s target genes. One would have done so for the advantage of using the ESF to identify Sox2 target genes critical for self-renewal in osteoblasts. One would have had a reasonable expectation of success in doing so because Fredericks 1 and 2 teach the DNA binding domain of the ESF is modular (FIG 2A) and demonstrates successful repression of endogenous target genes based on the selection of the DNA binding domain (Table 1).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1-13, and 15-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-4, 6-7, 12, 14-15, 17, 19, and 22-23 of U.S. Patent No. 12,152,240 in view of Fredericks (Molecular and Cellular Biology, 2000, 20(14): 5019-5031) (hereinafter as Fredericks 1), Fredericks (Cancer Letters, 2001, 162: S23-S32) (hereinafter as Fredericks 2), Seo (Molecular and Cellular Biology, 2011, 31(22): 4593-4608), and Chen (WO 2019/204766 A1; Pub Date: 24 Oct 2019).
Regarding instant claim 1, patented claims 2, 15 and 22 of ‘240 recite an artificial transcription repressor (ATRs) (i.e., epigenetic silencer factor) comprising a DNA-binding domain and at least one epigenetic effector domain selected from the group consisting of a KRAB domain, a DNMT3A domain, and a DNMT3L domain. Further ‘240 recites wherein the DNA binding domain is selected from the group consisting of a TALE DNA-binding domain, a zinc finger domain, a tetracycline-controlled repressor DNA-binding domain, a meganuclease or CRISPR/Cas system (claim 2). Accordingly, ‘240 demonstrates that the DNA binding domain is modular and could be modified.
However, ‘240 does not recite wherein the DNA binding domain is an oncogenic or cancer-associated transcription factor DNA binding domain.
Fredericks 1 teaches a PAX3-KRAB protein (i.e., ESF) comprising a PAX3 DNA binding domain fused to a KRAB domain (abstract, FIG. 1B, FIG. 2A). Fredericks 1 further teaches the PAX3 DNA binding domain is referred to as an oncogenic transcription factor (abstract, pg. 5019, col. 2, para. 1). Fredericks 1 discloses this employed ESF is “a strategy designed to directly compete with the oncogenic transcriptional activator and repress PAX3 target genes with an engineered repressor”, and “[d]ominantly interfering with endogenous cellular activators using heterologous repressors is an approach which has also been successfully used in other studies” (pg. 5027, col. 1, para. 1). Further, the PAX3-KRAB ESF successfully inhibited alveolar rhabdomyosarcoma tumors malignant growth in mice (pg. 5022, col. 1, para. 2; Table 2).
In addition, Fredericks 2 teaches ESFs comprising the same epigenetic effector domain, KRAB, and differing in DNA binding domain can effectively inhibit transcription of specific endogenous target genes, particularly the ESFs of MYB-KRAB and PAX3-KRAB (Table 1). Fredericks 2 further demonstrates (Fig. 2) that each component of the ESF could be modular and modified according to the desired target gene, similar to the teachings of ‘240.
Thus, it would have been obvious to one of ordinary skill in the art to have modified ‘240’s DNA binding domain to an oncogenic or cancer-associated transcription factor DNA binding domain as taught by Fredericks 1 and 2 because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: PAX3 retains its known DNA binding function, while KRAB retains its repression ability. One would have been motivated to have done so for the advantage of repressing PAX3 or other endogenous oncogenic transcription factor target genes required for tumorigenesis as taught by Fredericks 1. One would have had a reasonable expectation of success in doing so because ‘240 demonstrates the DNA binding domain in the ESF is modular to target specific genes, and Fredericks 1 and 2 teaches the DNA binding domain in an engineered ESF can be substituted to an oncogenic transcription factor to compete with endogenous oncogenic transcription factors when pairing with a well-characterizes repression domain.
Regarding instant claim 2, the obviousness to modify ‘240’s ESF to an oncogenic transcription factor DNA binding domain, particularly PAX3 is discussed above as applied to claim 1.
Regarding instant claim 3, patented claims of ‘240 recites an ESF comprising a DNA binding domain and at least one epigenetic effector domain as discussed above as applied to instant claim 1. The teachings of Fredericks 1 and 2 are also discussed above as applied to instant claim 1.
However, ‘240 does not recite wherein the transcription factor is Sox2.
Seo teaches a “chimeric” transcription factor (i.e., ESF) comprising a Sox2 DNA binding domain fused to an Engrailed repressor domain (i.e., epigenetic effector domain) (pg. 4595, col. 2, para. 1). As evidenced by instant specification, Sox2 is an oncogenic or cancer-associated transcription factor (pg. 3, line 25). Seo further teaches Sox2 targets endogenous FoxP1 and BMI-1 genes (abstract) and the ESF comprising Sox2 and Engrailed repressor inhibited transcription and/or expression of at least one target gene in osteoblasts, resulting in loss of their self-renewal ability (pg. 4595, col. 2, para. 1; Fig. 1C-D).
The obviousness to modify ‘240’s ESF to an oncogenic transcription factor DNA binding domain as taught by Fredericks 1 and 2 is discussed above as applied to claim 1. Applying the same obviousness rationale here, it would have also been obvious to one of ordinary skill in the art to have modified the ‘240’s DNA binding domain to Sox2 as taught by Seo because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. The substituted components and their functions are known in the art. The substitution is merely swapping similar features that serve the same purpose, which is selecting from one oncogenic transcription factor to another that one desires to compete with the endogenous oncogenic transcriptional activator and repress that endogenous transcription factor’s target genes. One would have done so for the advantage of using the ESF to identify Sox2 target genes critical for self-renewal in osteoblasts. One would have had a reasonable expectation of success in doing so because ‘240 teaches the DNA binding domain of the ESF can be modified (claims 2, 15, and 22), and Fredericks 2 demonstrates successful repression of endogenous target genes based on the selection of the DNA binding domain (Table 1).
Regarding instant claims 4-5, patented claim 19 of ‘240 recites wherein the epigenetic effector domain comprises a KRAB domain, a DNMT3A domain, and a DNMT3L domain.
Regarding instant claims 6 and 8, patented claim 3 of ‘240 recites a single or separate vectors comprising the polynucleotide encoding the ESF.
Regarding instant claims 7, 9, and 16-17 ‘240 does not recite the instant limitations.
Chen teaches an ESF comprising a CRISPR/dCas9 DNA binding domain fused to at least one epigenetic effector domain including i) a KRAB domain, ii) a DNMT3A, and iii) DNMT3L (description of FIG. 1A, claim 3). Chen teaches wherein the ESF is encoded in a polynucleotide comprising a doxycycline-inducible promoter operably linked to the nucleic acid sequence encoding the ESF ([0024]), and wherein the polynucleotide is in a vector that could either be a nonviral vector comprised in a nanoparticle or a lentiviral vector for delivery into a cell ([0073]).
Thus, it would have also been obvious to one of ordinary skill in the art to have modified the polynucleotide of ‘240 that encodes the ESF to comprise instantly recited limitations as taught by Chen because it would have merely amounted to a simple combination of prior art elements. Each combined element performs the same function as they do separately. One would have been motivated to have done so for the advantage of expressing ESF under a promoter capable of expressing additional ESFs, and delivering the ESF into a cell using known methods. One would have had a reasonable expectation of success in doing so because Chen teaches successful delivery of ESF into a cell using nonviral or viral vectors, and expression of ESF using suitable promoters.
Regarding instant claim 10, ‘240 recites a cell comprising the ESF (claims 7, 17, and 23).
Regarding instant claim 11, ‘240 recites a composition comprising the ESF (claim 6).
Regarding instant claims 12 and 19, ‘240 recites a method of gene therapy (i.e., treatment) comprising administering the ESF or polynucleotide encoding the ESF (claims 4 and 12).
Regarding instant claims 13 and 20, ‘240 recites a method of gene therapy (claims 4 and 12) and a method of silencing a target gene (claim 14) but it does not recite a method of treating cancer.
Fredericks 1 teaches injecting Rh30 cell suspensions into SCID mice (i.e., administering the recited vector or ESF to a subject in need thereof), and that tumorigenicity in mice is suppressed, leading to inhibition of malignant growth of Rh30 ARMS in vivo (pg. 5022, col. 1, para. 2; pg. 5023, “Tumor formation” subsection; Table 2). Accordingly, Fredericks 1 teaches a method of treating alveolar rhabdomyosarcoma via inhibition of ARMS malignant growth in mice.
Following the obviousness to modify ‘240’s ESF to an oncogenic transcription factor DNA binding domain, particularly PAX3 as discussed above and as applied to claim 1, it would have been obvious for one ordinary skill in the art to have modified the recited method of gene therapy to specifically inhibit endogenous oncogenes as taught by Fredericks 1 because it would have merely amounted to a simple substitution from one known target gene to another. One would have done so for the advantage of repressing oncogenes and consequently inhibiting malignant growth of tumors as taught by Fredericks 1. One would have had a reasonable expectation of success in doing so because ‘240 teaches a method of broadly silencing a gene while Fredericks 1 and 2 teaches a method of silencing a particular oncogene as a method to treat cancer by selecting appropriate oncogenic transcription factors DNA binding domains.
Regarding instant claims 15 and 21, ‘240 recites a method of silencing a target gene (i.e., decreasing transcription and/or expression of at least one target gene) comprising administering the ESF or polynucleotide encoding the ESF into a cell (claim 14).
Claims 1-13, and 15-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 45-47, 49-50, 55-57, and 59 of copending Application No. 17/963,631 (claims filed 04/14/2026) in view of Fredericks 1, Fredericks 2, Seo, and Chen (all cited supra).
Regarding instant claims 1-13, and 15-21, copending claims 45-46 and 55 of ‘631 recite an artificial transcription repressor (i.e., ESF) comprising (i) a DNA binding domain selected from the group consisting of a TALE DNA-binding domain, a zinc finger domain, a tetracycline-controlled repressor DNA-binding domain, a meganuclease or CRISPR/Cas system, and (ii) at least one epigenetic effector domain selected from the consisting of a KRAB domain, a DNMT3A domain, and a DNMT3L domain. Copending claims of ‘631 also recite wherein the epigenetic effector domain comprises a combination of a KRAB domain, a DNMT3A domain, and a DNMT3L domain (claim 59), wherein the ESF is encoded in a polynucleotide comprised in a vector (claims 47 and 56), and wherein the ESF is in a composition (claims 49) and a cell (claims 50 and 57). Copending claims 45 and 55 of ‘631 further recites a method comprising administering the ESF or polynucleotide encoding the ESF to a subject in need thereof.
All instant limitations are addressed because they are either recited in copending claims or are render obvious by prior art in view of Fredericks 1 and 2, Seo and Chen to make the same modification based on the obviousness rationale as discussed above as applied to patented claims of U.S. Patent No. 12,152,240.
This is a provisional nonstatutory double patenting rejection.
Claims 1-13, and 15-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-19, 21, 26, and 30-36 of copending Application No. 18/880,876 (claims filed 08/25/2025) in view of Fredericks 1 and Fredericks 2 (all cited supra).
For compact prosecution, the following table outlines the copending claims of ‘876 that anticipates the instant claims.
Instant claims
1
2, 3
4
5
6
7
8-11
12, 19
13, 20
16
17
18
Copending claims
17, 33
18
19
21
17
26
30, 35
36
17
31
32
34
Regarding instant claims 15 and 21, All instant limitations are addressed because they are either recited in copending claims or are render obvious by prior art in view of Fredericks 1 and 2, Seo and Chen to make the same modification based on the obviousness rationale as discussed above as applied to patented claims of U.S. Patent No. 12,152,240.
This is a provisional nonstatutory double patenting rejection.
Claims 1-13, and 15-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 45, 47, 52, 57-59, 61, and 63 of copending Application No. 18/920,508 (claims filed 04/11/2025) in view of Fredericks 1, Fredericks 2, Seo, and Chen (all cited supra).
Regarding instant claims 1-13, and 15-21, copending claims 45 and 47 recite an artificial transcription repressor (i.e., ESF) comprising (i) a DNA binding domain selected from the group consisting of a TALE DNA-binding domain, a zinc finger domain or CRISPR/Cas system, and (ii) at least one epigenetic effector domain selected from the consisting of a KRAB domain, a DNMT3A domain, and a DNMT3L domain. Copending claims of ‘508 also recite wherein the epigenetic effector domain comprises a combination of a KRAB domain, a DNMT3A domain, and a DNMT3L domain (claim 63), wherein the ESF is encoded in a polynucleotide (claim 52), and wherein the ESF is in a cell (claim 61). Copending claims 57-59 further recites a method of silencing a target gene and gene therapy comprising administering the ESF or polynucleotide encoding the ESF.
All instant limitations are addressed because they are either recited in copending claims or are render obvious by prior art in view of Fredericks 1 and 2, Seo and Chen to make the same modification based on the obviousness rationale as discussed above as applied to patented claims of U.S. Patent No. 12,152,240.
Conclusion
No claims are allowable.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights