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 .
Claim Status
Applicant amended claims 3-5, 8, 12-13, 16, 18, 21-25, 27 and 39 (6/2/2025) and cancelled claims 9-11, 15, 17, 19-20, 28-32, and 34-38 (6/2/2025). No new matter was added. Thus, claims 1-8, 12-14, 16, 18, 21-27, 33, and 39-40 are under examination (6/2/2025).
Priority
Claims 1-8, 12-14, 16, 18, 21-27, 33, and 39-40 receive a priority date of 10/11/2021, the filing date of US Provisional No. 63254477.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The Information Disclosure Statement from 6/3/2025 is considered.
Specification
The disclosure is objected to because of the following informalities (see MPEP § 608.01):
The use of the terms “IDEXX BioResearch” (p.45), “ThermoFisher” (p. 45 and used throughout the Specification), “Life Technologies” (p. 45), “Gibco” (p. 45), “Sigma-Aldrich” (p. 45 and used throughout the Specification), “Empire Genomices” (p. 46), “Molecular Probes” (p. 46), “Twist Bioscience” (p. 46), “Electron Microscopy Sciences” (p. 46), “Tween20” (p. 46), “Millipore” (p. 46), “ZytoVision” (p. 47), “Olympus Corporation” (p. 48), “Triton” (p. 52), “Zymo” (p. 52), “Illumina” (p. 52 and used throughout the Specification), “New England Biolabs” (p. 52 and used throughout the Specification), Agilent” (p. 53), “Roche” (p. 53), “Oxford Nanopore” (p. 55), “Bionano Genomics” (p. 55 and used throughout the Specification), “Bio-Rad” (p. 55), “Biotium” (p. 56), “Qiagen” (p. 57), “Beckman Coulter” (p. 57), “ADDgene” (p. 59), “10X Genomics” (p. 60) which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains embedded hyperlinks and/or other forms of browser-executable codes in reference to ecSig (Paragraph 157) and E-CRISP (Paragraph 164) and NCBI Health (Paragraph 84) and Broad Institute sgRNA tool (Paragraph 193) and gTrack (Paragraph 214) and github code (Paragraph 221). 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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8, 12-14, 16, 18, 21-27, 33, and 39-40 are rejected are rejected under 35 U.S.C. 103 as being unpatentable over Bagchi et al. (WO 2021/055846 A1; published 3/25/2021) and Liu (US PGPub 2021/0254056 A1; published 8/19/2021) and further in view of Belouchi et al. (US PGPUB 20100144538 A1; published 6/10/2010).
Regarding claims 1-4, Bagchi teaches that in some embodiments, disclosed herein are vectors comprising: a nucleic acid sequence encoding a PVT1 217 splice variant micropeptide, wherein the PVT1 217 splice variant micropeptide is at least 12 amino acids in length, and comprises at least 10 contiguous amino acids that are identical to a peptide encoded by a short open reading frame (shORF) located at the junction of Exon 3 and Exon 4 of human PVT1 217 and in some embodiments, the nucleic acid sequence encoding a PVT 1 217 splice variant micropeptide has least 80% sequence identity to the sequence set forth in SEQ ID NO: 1 (Paragraph 4, lines 1-5).
Bagchi further teaches that in some embodiments, the HNB fusion polypeptides disclosed herein employ leader sequences from other species to permit the recombinant expression of a protein in a heterologous host and in some embodiments, the HNB fusion polypeptides disclosed comprise immunologically active domains, such as an antibody epitope, to facilitate purification of the HNB fusion polypeptide, where inclusion of a cleavage site at or near the fusion junction will facilitate removal of the extraneous polypeptide after purification and other useful fusions include linking of functional domains, such as active sites from enzymes such as a hydrolase, glycosylation domains, cellular targeting signals or transmembrane regions. Additional HNB fusion polypeptides as disclosed herein can comprise a cell-penetrating peptide linked to a polypeptide to promote uptake of the polypeptide by the cell (Paragraph 64, lines 1-10). Additionally, Bagchi teaches mRNAs according to the present disclosure may be synthesized according to any of a variety of known methods and for example, mRNAs according to the present disclosure may be synthesized via in vitro transcription (IVT), where briefly, IVT is typically performed with a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may include DTT and magnesium ions, and an appropriate RNA polymerase (e.g., T3, T7 or SP6 RNA polymerase), DNAse I, pyrophosphatase, and/or RNAse inhibitor. The exact conditions will vary according to the specific application (Paragraph 83, lines 1-10).
Regarding claims 5-8, Bagchi teaches that the term “gene,” as used herein, refers to a segment of nucleic acid that encodes an individual protein or RNA (also referred to as a “coding sequence” or “coding region”), optionally together with associated regulatory regions such as promoters, operators, terminators and the like, which may be located upstream or downstream of the coding sequence and as used herein, the term “polypeptide” encompasses amino acid molecule sequences comprising at least one of the 20 common amino acids in naturally synthesized proteins, or at least one modified or unusual amino acid, including but not limited to chemically modified amino acids such as amino acid analogs, naturally occurring non-proteogenic amino acids such as norleucine, and chemically synthesized compounds having properties known in the art to be characteristic of an amino acid (Paragraph 47, lines 1-10). Further, Bagchi teaches that in some embodiments, the HNB fusion polypeptides disclosed herein employ leader sequences from other species to permit the recombinant expression of a protein in a heterologous host and in some embodiments, the HNB fusion polypeptides disclosed comprise immunologically active domains, such as an antibody epitope, to facilitate purification of the HNB fusion polypeptide, where inclusion of a cleavage site at or near the fusion junction will facilitate removal of the extraneous polypeptide after purification and other useful fusions include linking of functional domains, such as active sites from enzymes such as a hydrolase, glycosylation domains, cellular targeting signals or transmembrane regions, where additional HNB fusion polypeptides as disclosed herein can comprise a cell-penetrating peptide linked to a polypeptide to promote uptake of the polypeptide by the cell (Paragraph 64, lines 1-15).
Regarding claims 12-14, and 16, Bagchi teaches to determine the function of the HNB, the Hi-and Lo- Myc cell lines were transfected with lentiviral vectors expressing GFP, HNB or HNB where the start site has been mutated (HNB(ATG>TGA)), where all of the 8 cell lines where HNB is overexpressed (but not the ones which are transfected with GFP or HNB(ATG>TGA)) failed to proliferate, suggesting a role for HNB as a tumor suppressor (FIG. 7A and 7B) (Paragraph 110, lines 1-5). Further, Bagchi teaches that in addition, an inducible lentiviral system was developed, in which the transgene could be expressed under a Doxycycline inducible promoter and the system was verified by inserting eGFP as the transgene and by flow analysis of GFP.sup.+ cells in absence and presence of doxycycline as shown in FIG. 8 where two stable cell lines MSTO-211H-GFP.sup.1 and U20S-GFP.sup.1 were created where a GFP transgene was placed under the regulation of a Dox inducible promoter showed robust expression of GFP following treatment of lug/ml of Doxycycline within 24 hours and the same system was used to clone HNB under the regulation of a Doxycycline inducible promoter and generate the cell lines MSTO-21 lH-HNB.sup.1 and U20S- HNB.sup.1 and following Doxycycline treatment, both the cell lines exhibited significant reduction in their proliferation rates, thus confirming that HNB can affect growth and proliferation of cancer cells (FIG. 9A and FIG. 9B) (Paragraph 111, lines 1-10). Further, Bagchi teaches that western blot analysis was performed of Myc protein in Hi-Myc cell line MSTO-21 lH-HNB.sup.1 and Myc protein expression was decreased following the induction of doxycycline in this cell line, indicating that HNB is a potential regulator of Myc protein (FIG. 9C) (Paragraph 111, lines 10-15).
Regarding claims 18 and 21-27, Bagchi teaches that in some embodiments, the synthetic nucleic acid sequence encoding a PVT1 217 splice variant micropeptide is comprised in a vector and in some embodiments, the vector is a mammalian expression vector. In some embodiments, the vector is a lentiviral expression vector and further in some embodiments, the vector comprises a promoter and further in some embodiments, the promoter is inducible and in some embodiments, the pharmaceutical compositions disclosed herein further comprise a cancer cell targeting moiety (Paragraph 5, lines 20-25). Further, Bagchi teaches that FIG. 20A and 20B depicts mapping and validation of the PVT1 junction points in the ecDNA from COLO-320DM and D458 (Paragraph 42). For example, Bagchi teaches that Plasmacytoma variant translocation 1 (PVT1) is a Tong non-coding RNA’ transcribed from adjacent to the oncogene c-MYC, and has been shown to co-operate with c-Myc by stabilizing its protein product in 8q24 gain cancers (Paragraph 55, lines 1-3).
Regarding claim 33, Bagchi teaches the previously described method as applied to Example 1. Bagchi specifically teaches Identification of a tumor suppressor splice variant PVT1 217 and a previously undescribed PVT1 splice variant that can regulate Myc protein was identified and using the ENSEMBL database, PVT1 splice variants were analyzed. siRNAs were designed to target specific PVT1 splice variants and tested on MSTO-211H cell line for alteration in Myc expression levels, where it was found that the siRNA dubbed Ex9 (si_Ex9) increased the expression of Myc protein in the MSTO-211H cell line compared to control siRNA (si ctrl) or compared to si_C2 (an siRNA specific for CircPVTl, where CircPVTl is a splice variant previously reported to upregulate Myc expression) (FIG. 1). si_E9 knocked down the expression of a PVT1 splice variant, PVT1 217, indicating a role for PVT1 217 in regulating Myc levels (Paragraph 106).
Regarding claims 39-40, Bagchi teaches that in some embodiments, the synthetic nucleic acid sequence encoding a PVT1 217 splice variant micropeptide is comprised in a vector and in some embodiments, the vector is a mammalian expression vector. In some embodiments, the vector is a lentiviral expression vector and further in some embodiments, the vector comprises a promoter and further in some embodiments, the promoter is inducible and in some embodiments, the pharmaceutical compositions disclosed herein further comprise a cancer cell targeting moiety (Paragraph 5, lines 20-25). Further, Bagchi teaches that FIG. 20A and 20B depicts mapping and validation of the PVT1 junction points in the ecDNA from COLO-320DM and D458 (Paragraph 42). For example, Bagchi teaches that Plasmacytoma variant translocation 1 (PVT1) is a Tong non-coding RNA’ transcribed from adjacent to the oncogene c-MYC, and has been shown to co-operate with c-Myc by stabilizing its protein product in 8q24 gain cancers (Paragraph 55, lines 1-3).
Bagchi does not teach or suggest a sequence of at least 70% identity set forth in SEQ ID NO: 1. Bagchi also does not teach or suggest the use of the nucleic acid molecule comprising a PVT1 encoding a cytotoxic protein or inducing an immune response. Further, Bagchi does not teach or suggest that the nucleic acid molecule encodes a viral protein that is selected from an adenovirus.
Liu teaches that the present invention comprises a method of creating new genomic signaling centers in a genome, the method comprising altering a CTCF site to disrupt an enhancer-promoter interaction of a first insulated neighborhood, wherein the enhancer is available for interaction with a different promoter to form a new genomic signaling center. In some embodiments, the CTCF site is altered using a CRISPR/Cas9 enzyme (Paragraph 23, lines 1-5). Further, Liu teaches that a stimulus that perturbs a GSC may be selected from a gene and cell therapy selected from 5- flourouracil , ACT-GRO-777, Ad35-GRIN, adenovirus gene therapy, etc, and that it should be understood that it is not intended that no connection ever be made between canonical pathways and GSNs; in fact, the opposite is the case and in order to bridge the two signaling paradigms for further scientific insights, it will be instructive to compare the canonical signaling pathway paradigm with the GSNs of the present invention (Paragraph 142 and 153, lines 1-5). Specifically, Liu teaches that canonical pathways which may be altered according to the present invention include, natural killer cell mediated cytotoxicity pathway, as well as multiple T-cell antigen pathways (Paragraph 154, lines 1-50). Additionally, Liu teaches that in certain embodiments, modulating GSCs or Ins associated with at least one gene (Tables 1-9) may be used for treating different forms of cancer, adenovirus, etc. (Paragraph 190, lines 1-50).
Belouchi teaches a wide selection of a set of polymorphism markers for use in genome wide association studies based on linkage disequilibrium mapping (Abstract). As shown in Figure 1 below, SEQ ID NO: 5474 has 100% similarity to SEQ ID NO: 1.
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[AltContent: textbox (Figure 1: Belouchi’s homo sapiens SEQ ID NO: 5474 has 100% similarity to SEQ ID NO: 1. )]
It would have been obvious to one of ordinary skill in the art at the effective filing date to modify the PVT1-based constructs of Bagchi in view of Liu and Belouchi to arrive at the claimed nucleic acid molecules and their therapeutic uses. Bagchi establishes the close relationship between PVT1 and ecDNA/MYC-driven cancer, teaches PVT1-containing expression vectors, promoter-controlled heterologous transgene expression, and demonstrates that expression of a heterologous PVT1-associated tumor-suppressive product reduces cancer cell proliferation. Although Bagchi does not expressly place the claimed heterologous therapeutic sequence under control of the PVT1 promoter, its teachings provide reason to employ the PVT1 regulatory region in the disclosed expression architecture to exploit the known association of PVT1 with ecDNA-containing cancer cells.
Further, although Bagchi’s immunologically active domains are described primarily in connection with purification and do not themselves establish the claimed cytotoxic anti-cancer immune response/T-regulatory cell inhibition, Liu teaches manipulation of cancer-associated signaling pathways, including natural-killer-cell mediated cytotoxicity and T-cell antigen pathways, as well as gene/cell therapy and adenoviral therapy for treating cancer. Thus, a skilled artisan would have had a reason to employ known cytotoxic, immunomodulatory, or viral therapeutic payloads in Bagchi’s promoter-controlled expression system to provide a therapeutic output directed against cancer cells. Belouchi’s disclosure of a sequence corresponding to SEQ ID NO: 1 further supplies the claimed PVT1 sequence limitation.
The motivation to combine arises from the three references’ complementary teachings directed to PVT1-associated cancer biology, promoter-controlled expression of heterologous products, and therapeutic manipulation of cancer cells. A skilled artisan would have reasonably expected success because Bagchi expressly demonstrates successful vector-mediated, promoter-controlled transgene expression in cancer cells and a resulting reduction in cancer cell proliferation, while Liu establishes that the recited cytotoxic/immune and viral pathways were known therapeutic approaches for cancer. Accordingly, employing the claimed VT1 sequence/promoter to control a known therapeutic heterologous payload would have represented the predictable use of known elements according to their established functions to obtain targeted anti-cancer expression.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH ROSE LAFAVE whose telephone number is (703)756-4747. The examiner can normally be reached Compressed Bi-Week: M-F 7:30-4:30.
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/ELIZABETH ROSE LAFAVE/Examiner, Art Unit 1684
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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