DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 11-14-25.
Claims 1-7, 9, 11, 15, 16, 19-22, 26, 27, 32-35, 37 and 43 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of Group I, a C terminal p53 mutation, an MDM amplified cancer, and a combination of NMD inhibitor amlexanox and SRFS inhibitor TG003 as the species election, in the reply filed on 11-14-25, is acknowledged.
Upon further consideration, all of the claims of Group I are hereby rejoined. Claims 1-7, 9, 11, 15, 16, 19-22, 26, 27, 32-35 have been examined on their merits as set forth below.
Claims 37 and 43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11-14-2025.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the drawings are of poor quality and not discernible. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected 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:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
Specific deficiency - The sequence disclosures are located in e.g., claims 2-7, the specification at e.g. pages 5-10, 31-34, and the figures.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
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 2-7 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.
Claim 2, recites “C-terminal p53 mutation” without providing any accompanying sequences.
Claim 3 recites “a nonsense mutation or missense downstream of exon 9” without providing any accompanying sequences.
Claim 4 recites “premature termination codons (PTCs) in the coding region” without providing the sequences for the PTCs.
Claim 5 recites particular residues (i.e. 331, 342, 349) with no accompanying sequences. Appropriate corrections are required.
In claim 9, the acronyms “MDM2” and MDMX” are recited without providing the full names that these acronyms represent.
Appropriate corrections/clarifications are required for all of the above.
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, 2, 4, and 15 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Bhuvanagiri et al (WO 2014/180996).
Bhuvanagiri et al (WO 2014/180996) teach the treatment of various cancers comprising the administration of the nonsense mediated RNA decay (NMD) inhibitor, 5-azacytidine. (Abstract, second para page 1, 4th para, page 2, 2nd para page 3, 2nd para, page 4, Figs. 1, 2, 5, 6, 8, 12, 1st full para page 7, first full para page 20, Conclusions on pages 42-43 ). Bhuvanagiri teaches the inhibition of UPF1 and SMG5 with indole derivatives for inhibiting NMD (last para page 14). Bhuvanagiri teaches combination therapy including 5-azacytidine (1st and second full para page 30).
Claim(s) 1, 2, 4, and 15 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Christiano, A (WO 2018/237326).
Christiano, A (WO 2018/237326) teach the treatment of cancers comprising the administration of nonsense mediated mRNA decay (NMD) inhibitors comprising amlexanox in combination with immune modulators (Abstract. para 0001-0009, Fig. 1-4, para 0015-0022, 0058-0066, 0075-0083, 0158-0162, 0189). Christiano also teaches the inhibition of UPF proteins, RENT1 and SMG1 for inhibiting NMD (para 0171).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4, 6, 7, 9, 11, 15, 16, 19-22, 26, 27, 32-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bhuvanagiri et al (WO 2014/180996), Christiano, A (WO 2018/237326), Mazloomian et al (Communications Biology, Vol. 2:165, pages 1-15 (2019)), and Cowen et al (Scientific Reports, Vol. 7:17535, pages 1-9 (2017)), the combination in view of Vassilevv et al (Science, Vol. 303, pages 844-848 (2004)), Prak et al (Biochemistry, Vol. 55, pages 608-617 (2015)), and Scheffner et al (Cell, Vol. 63, pages 1129-1136 (1990)) Scheffner et al (Cell, Vol. 63, pages 1129-1136 (1990)).
The claims are drawn to methods of treating a subject determined to have a p53-deficient cancer, comprising restoring p53 function in the subject's tumor by administering a therapeutically effective amount of an inhibitor of nonsense-mediated decay (NMD) to said subject, which p53-deficient cancer comprises a C- terminal p53 mutation, with premature termination codons (PTCs) in the coding region, wherein the p53-deficient cancer optionally comprises the p53α, p53 β, or p53y isoform. wherein the p53-deficient cancer is an MDM2 or MDMX overexpressing cancer, or wherein the p53- deficient cancer is an HPV-positive cancer, which inhibitor of NMD optionally comprises 5-azacytidine, amlexanox, or an siRNA targeting eIF4A, RENT1, or UPF3B, and which method optionally further comprises administering a serine/arginine rich splicing factor (SRFS1) inhibitor optionally comprising TG003, or an inhibitor of MDM2, which cancer is optionally lung or cervical cancer, or glioblastoma.
Bhuvanagiri et al (WO 2014/180996) teach the treatment of various cancers comprising the administration of the nonsense mediated RNA decay (NMD) inhibitor, 5-azacytidine. (Abstract, second para page 1, 4th para, page 2, 2nd para page 3, 2nd para, page 4, Figs. 1, 2, 5, 6, 8, 12, 1st full para page 7, first full para page 20, Conclusions on pages 42-43 ). Bhuvanagiri teaches the inhibition of UPF1 and SMG5 with indole derivatives for inhibiting NMD (last para page 14). Bhuvanagiri teaches combination therapy including 5-azacytidine (1st and second full para page 30).
Christiano, A (WO 2018/237326) teach the treatment of cancers comprising the administration of nonsense mediated mRNA decay (NMD) inhibitors comprising amlexanox in combination with immune modulators (Abstract. para 0001-0009, Fig. 1-4, para 0015-0022, 0058-0066, 0075-0083, 0158-0162, 0189). Christiano also teaches the inhibition of UPF proteins, RENT1 and SMG1 for inhibiting NMD (para 0171).
Mazloomian et al (Communications Biology, Vol. 2:165, pages 1-15 (2019)) teach that the RNA helicase, EIF4A3, regulates the exon junction complex and nonsense mediated mRNA decay (NMD) functions in RNA transcript processing (Abstract). NMD is triggered if the premature stop codon is at least 50-55 nucleotides upstream of the final exon-exon junction. Mazloomian teaches novel specific and potent chemical inhibitors of EIF4A3, a core component of the exon junction complex (EJC), results in class specific splicing defects and monotonic increase of NMD prone transcripts of genes involved in the cell cycle and apoptosis (text, left column, page 2). Alternative spliced events are modulated by EIF4A3 inhibition (Fig. 2, page 4, Fig. 4, page 6). Biological processes affected most by EIF4A3 inhibition include, but are not limited to transcription regulation in response to stress (Fig. 5 on page 7). Mazloomian teaches that, in addition to the known roles of EIF4A3 in NMD, EIF4A3 is also involved in cell cycle and stress granule pathways. (text on page 10).
Cowen et al (Scientific Reports, Vol. 7:17535, pages 1-9 (2017)) (See IDS filed 1-12-24) teach the nonsense mediated mRNA decay (NMD) pathway is a diverse regulatory network for mRNA cellular fate throughout development and in response to cellular stressors, and critical for maintaining mRNA homeostasis. The disruption of the NMD pathway is linked with numerous genetic diseases and cancers, likely a result of dysregulation of tumor suppressors and oncogenes. NMD involves a complex of RNA binding proteins, including regulator of nonsense transcripts 1 (RENT1) protein, recruited upon the detection of a premature termination codon, which leads also to recruitment of SMG7. (text, first para page 2). The loss of SMG7 results in NMD deficiency and upregulation of p53β but not p53y (Fig. 1 on page 3, Fig. 2 on page 4).
The primary references do not teach inhibitors of MDM2, cdc like kinases, or the relationship between HPV and NMD.
Vassilevv et al (Science, Vol. 303, pages 844-848 (2004)) (See IDS filed 1-12-24) teaches the identification of potent and selective small molecule antagonists of MDM2, activating the p53 pathway in cancer cells and providing cell cycle arrest, apoptosis and growth inhibition of tumors in vivo. (Abstract). Overexpression of MDM2 is found in many human tumors. (Abstract) Vassilevy screened a diverse library of synthetic chemicals, including cis-imidazoline compounds with chiral purity, one imidazoline compound is Nutlin. (Text on page 845, Fig. 1 on page 845 Fig. 3 on page 847).
Prak et al (Biochemistry, Vol. 55, pages 608-617 (2015)) teach the screening of small molecules and the identification of potent inhibitors of cdc like kinases (CLK2). Abstract. Prak identified structural elements within a novel chemical scaffold structure, benzobisthiazoles providing CLK2 inhibition. (Fig.2 on page 611). One potent inhibitor of CLK2 is TG003 (Table 2 on page 612).
Scheffner et al (Cell, Vol. 63, pages 1129-1136 (1990)) (See IDS filed 1-12-24) teach that wild type p53 gene has tumor suppressor properties and is a target for several oncoproteins encoded by tumor viruses. E6 proteins of human papillomavirus (HPV) promote the degradation of p53 (Abstract, Fig. 1 on page 1130, Fig. 4 on page 1132).
It would have been obvious to treat the various forms of cancer instantly claimed by administering inhibitors of nonsense mediated decay because the role of p53 in NMD was well known in the art prior to the effective filing date of the instant invention. The various inhibitors of NMD were well known in the art and used for treating multiple forms of cancer, as disclosed in the teachings of Christiano, Bhuvanagiri and Mazloomian. Furthermore, the administration of additional modulators, including the CLK2 inhibitor, TG003 was also routinely used for treating cancers, as taught by Prak. Combination therapy with NMD inhibitors and immune modulators, and the inhibition of UPF proteins, RENT1 and SMG1 for inhibiting NMD was also well known in the art, as disclosed by Christiano.
One of ordinary skill in the art before the effective filing date of the instant invention would have been motivated to treat cancers using the various modulators claimed, and in the combinations claimed because cancer treatment involving inhibition of NMD coupled with CLK2 inhibitors or immune modulators was routinely used in the prior art, as set forth above.
For these and the aforementioned reasons, the instant invention would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
8-31-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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