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 .
Status of the Claims/Application
Claims 1-3 and 10-22 are currently pending and are herein under examination on the merits.
Withdrawn Objections
Applicant’s arguments, see remarks, filed on 12/15/2025, with respect to claims 1-3 and 10-22 have been fully considered and are persuasive. Therefore, the rejections under 35 USC 103 of claims 1-3 and 10- 22 has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of new found prior art references.
New Rejections Under 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.
Claim 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bai et al.,Overcoming resistance to mitochondrial apoptosis by BZML-induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells. Cell Prolif. 2018 Aug;51(4):e12450, herein further referred to as Bai.
Regarding claims 1-3, Bai teaches a method for identifying an anti-cancer agent 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) (Bai Abstract) comprising
a) Providing a cell population A549/Taxol that is resistant to anti-mitotic drug (Bai pg. 3 Sec. 3.1)
b) Contacting the A526/Taxol cell population with BZML
c) Determining if the test agent reduces mitotic slippage (Bai pg. 2 Sec. 2.6)
d) Identifying if the test agent reduces mitotic slippage compared to the control test (Bai pg.3-4 Sec. 3.2 and Fig. 1).
Additionally, regarding the limitation that the cell is a Cdc20 variant, wherein the variant is a truncation in the N-terminus of Cdc20, the specification teaches that A549 cells are missing the N-terminus of Cdc20 (see legend for Figure 6). While applicant has identified cancer cell lines that comprise an N-terminal truncation of Cdc20, this identification does not make the screening method with a particular set of cells of claim 1 novel. MPEP 2112 I indicates that something which is old does not become patentable upon discovery of a new property. As such, screening methods using taxol-treated A549 cells and a second drug is not novel.
Claims 10-12 are rejected under 35 USC 102 as being anticipated by Chi of 892 of 08/13/2025.
Regarding claims 10-12, Chi teaches that when MDA-MB-435 eb Taxol-resistant cell line is treated with either paclitaxel (anti-mitotic) or paclitaxel and CP5V (a PROTAC that degrades Cdc20), cells treated only with paclitaxel showed 92% survival, while the combination resulted in Taxol-cytotoxic response (Chi, page 49, 1st col., 2nd parag).
Regarding the limitation that the cell is a “Cdc20 variant,” (claim 10), Chi et al. do not specifically indicate what type of Cdc20 mutation MDA-MD-435 cells have. However, Chi et al. discuss MDA-MD-435 as a cancer cell that exhibits Taxol slippage and indicates that CP5V, which degrades Cdc20 that results in cell death is indicative that MDA-MD-435’s insensitivity to Taxol results from either a mutation in Cdc20 or overexpression of Cdc20 (Chi pg. 47 col. 2 para. 4). Either type of mutation would address “Cdc20 variant.” MPEP 2112 (I) indicates that something which is old does not become patentable upon discovery of a new property. As such, screening methods using taxol-treated A549 cells and a second drug is not novel.
New Rejections Under 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.
Claims 10-12 are rejected under 35 USC 103 as being obvious over Chi of 892 of 08/13/2025, as evidenced by Wong et al., Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment. Cell Death Discovery 4, 109 (2018), herein referred to as Wong.
Regarding claims 10-12, and as indicated in to 102 rejection above, Chi et al. teach MDA-MD-435 cells treated with Taxol and CP5V. However, they do not teach a cancer cell that expresses Cdc20 that comprises an N-terminal truncation. Chi teaches that when U2OS cells are treated with CP5V (Chi et al., page 47, 2nd col., 4th parag.)
Therefore, it would have been obvious before the effective filing date for an artisan to modify the teachings of Chi to substitute the MDA-MD-435 cells of Chi’s method with the U2OS cells in order to arrive at a therapy comprising Taxol and CP5V. As indicated by Wong, U2OS is a cell line that exhibits slippage (see for example, Wong, page 2, 2nd col. Under “Results”). A skilled artisan would have had a reasonable expectation of success in treating U2OS cells with Taxol and CP5V as Wong teaches that U2OS cells exhibit slippage when treated with nocodazole (anti-mitotic) and Chi teach that an anti-mitotic and CP5V can both be used to treat cancer cells wherein the CP5V will inhibit the expression or the activity of the CDC20 variant that is overexpressed in the U2OS cell line is indicated by Chi (Chi pg. 47 col. 2 para 4).
Regarding the limitation that the cell is a “Cdc20 variant,” (claim 10) wherein the variant is a truncation in the N-terminus of Cdc20, the specification teaches that U2OS cells are missing the N-terminus of Cdc20 (see legend for Figure 6). While applicant has identified cancer cell lines that comprise an N-terminal truncation of Cdc20, this identification does not make the method of reducing the expression or activity of Cdc20 novel. MPEP 2112 I indicates that something which is old does not become patentable upon discovery of a new property. As such, screening methods using taxol-treated A549 cells and a second drug is not novel.
Claims 10-17, 22 are rejected under 103 as being obvious over Fujita et al., Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation. Aging Cell. 2020 Nov;19(11):e13251 in view of Chu et al., Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat Biotechnol 33, 543–548 (2015), herein further referred to as Fujita and Chu respectively.
Regarding claims 10-17 and 22, Fujita teach a patient with a missense mutation (R286S) in Cdc20 (Fujita, Abstract), that when knocked-in, the mutant induced SAC failure and random aneuploidy in cultured cells, indicating a pathogenicity caused by the mutant via an imbalance between APC/C-CDC20 complex (Fujita, Abstract). While Fujita et al. do not specifically teach that the patient’s cells were cancerous and were anti-mitotic insensitive, they do teach that the patient’s Cdc20 sequence variant was knocked into HCT116 cells and the knocked-in cells demonstrated slippage when treated with nocodazole (Fujita et al., page 3, 1st col.).
Fujita et al. do not teach that the patient’s cells were genetically modified to correct the mutation.
Chu et al. teach a method that increases the efficiency of homology-directed repair (Chu et al., Figure 1). One would have adapted Chu et al.’s teaching and obtained the genomic sequence of Cdc20 that would correct the patient’s Cdc20 mutation at position 286.
Therefore, it would have been obvious before the effective filing date for an artisan to modify the teaching of Fujita in view of Chu with a reasonable high degree of predictable success to use the method of Chu wherein the cells are contacted with an appropriate CRISPR/Cas9 and sgRNA that will correct/modify the point mutation in a patient’s genomic Cdc20, wherein the correction would inhibit the expression of CDC20 R286S mutant and thereby preventing the mutant from binding to APC/C (as indicated in claim 11). Also, an artisan would have been able to apply Chu’s method to modify the CDC20 R286S mutant with the proper amino acid at position 286 as it occurs in the wild type of in a variant not resistant to anti-mitotic, thereby increasing the expression of the wild type or a variant not resistant to the anti-mitotic drug. There would have been reasonable expectation of success as Chu et al. teach a method of using homology-directed repair to make a specific modification in the genome.
Allowable Subject Matter
Claims 18-21 are allowable. The claims are drawn the modification of one or more CDC20 alternate translational start site using Cas9 nuclease and one or more sgRNA where in the start site is at positions 127-129 or positions 262-264 of SEQ ID NO: 1 of a CDC20 variant wherein the modification will increase the translation from the wild type start site or increase the translation of the full length wild-wild type protein.
The closest prior art that teaches a cell population with N-terminal truncation and resistant to anti-mitotic drug is a the CdC20ΔN60 construct of Ji (Ji et al., (2017) A sequential multi-target Mps1 phosphorylation cascade promotes spindle checkpoint signaling eLife 6:e22513). Ji further teaches that Mps1-mediated phosphorylation of Mad1 at T716 promotes Cdc20 binding and that Mps1 and Mad1E-Mad2 only stimulated APC/CCdc20 inhibitory activity of the MCC mixture containing CdC20 wild type, but not that of the mixture containing CdC20ΔN60 (N-terminal truncation construct in HeLa Cells) which suggest that Mps1-phosphorylated Mad1 might bind to the N-terminal tail of Cdc20, which contains the two conserved basic motif (BM1 – RWQRK and BM2) required for inhibiting Cdc20 binding to APC/C (Ji pg. 13 para. 1 Fig. 5-6). Ji further teaches that the Hela cells comprising the Cdc20 with N-terminal truncated construct where resistant to anti-mitotic drug such as nocodozole or taxol (Ji pg. 16 para. 5-pg. 6 para1).
The closest prior art that teaches the use of Cas9 nuclease and sgRNA to modify the expression of a protein mutant that causes resistance to anti-mitotic drug is Saber et al., CRISPR/Cas9 for overcoming drug resistance in solid tumors. Daru. 2020 Jun;28(1):295-304. Saber further teaches a mechanism for targeting genes of interest for modification to reduce or eliminates the expression of the unwanted mutant(s) by using CRISPR/Cas9 and a sgRNA, thereby resensitizing the cells to treatment (Saber pg. 296 col. 2 para. 2-4 and Fig. 1). Saber also teaches that depending on the effect of a protein causing resistance, restoration or deletion of that specific protein could be beneficial for overcoming resistance (Saber pg. 300 col. 1 para 2). Saber also teaches that tumors usually contain one or more dominant clones and several minor subclones, and the resistant clones may outgrow the dominant clones leading to resistance to specific drug treatment, and that using Cas9/sgRNA targeting the resistant related gene is an option to tackle the problem (Saber pg. 302 col. 1 para. 3). Saber does not teach a cell population with N-terminal truncation or a mutant at the N-terminal causing resistance to anti-mitotic drugs.
The closest prior art that teaches modification at alternate start site is Chen etal., CRISPR Start-Loss: A Novel and Practical Alternative for Gene Silencing through Base-Editing-Induced Start Codon Mutations. Mol Ther Nucleic Acids. 2020 Sep 4;21:1062-1073. Chen teaches a method referred to as CRISPR Start-Loss which eliminates gene expression by utilizing both adenine base editors (ADE) and cytidine base editors (CDE) to disrupt the initiation codon ATG (Abstract) to GTG, ACG or ATA (Chen pg. 1063 Fig. 1).
Also, the closest prior art that teaches about a method to treat cancer cells expressing Cdc20 that are resistant to antimitotic drugs is Chi. Chi uses a C5PV (a PROTAC) rather than modifying the alternate translation start site of a Cdc20 variant, and does not specifically teach if the cells used in their method is a Cdc20 variant with N-terminal truncation.
Finally, neither Ji, Saber, Chen or Chi teach or suggest that a modification using Cas9 nuclease and sgRNA at a Cdc20 variant alternate translational start site inhibit the expression of the N-terminal truncated Cdc20 variant that is overexpressed in the cancer cells and causing the resistance to anti-mitotic drugs. Therefore, a skilled artisan would not have been motivated to make this modification at the alternate start sites of the Cdc20 variant.
Conclusion
Claims 18-21 are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMMANUEL LED YOUTCHOM PENDIE whose telephone number is (571)272-6313. The examiner can normally be reached Mon - Fri: 8AM - 5PM CST.
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/EMMANUEL LED YOUTCHOM PENDIE/ Examiner, Art Unit 1647
/JOANNE HAMA/ Supervisory Patent Examiner, Art Unit 1647
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