CTNF 18/707,262 CTNF 101761 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 Amendments to the claims filed 28 Jan 2026 are acknowledged. Claims 3-5, 7, 10, 12-13, 15-19, 21, 23-24, 26, 30-31, 33-34, 36-41, 45-52, 54, and 56-57 are canceled. Claims 2, 11, 20, 22, 27, 29, 32, 35, and 42 are amended. Claims 1-2, 6, 8-9, 11, 14, 20, 22, 25, 27-29, 32, 35, 42-44, 53, and 55 are pending and under consideration. Claim Objections 07-29-01 AIA Claim s 27 and 29 are objected to because of the following informalities: The first instance of any abbreviation, such as CRISPR, TALEN, and PAM, recited in the claims should be accompanied by the full, written out term, then the abbreviation may be used alone thereafter . Appropriate correction is required. 07-30-03-h AIA Claim Interpretation It is noted that the specification does not provide a definition by which the inventor or joint inventors regard as "targeted'. The specification refers to targeting cells comprising the mutation and targeting the mutation itself (p. 15), which are structurally different targets. The specification recites that "the target mutated cells include a mutation that can be targeted and that can be the basis for discriminating between target mutated cells and off-target cells" (p. 15). However, this description of "discriminating" may refer to the treatment method, identifying suitable cells or tissue for the treatment, in assessing the effect of treatment, or other uses. It is thus interpreted that targeting cells or mutations only need result in treatment of the mutated cells with less treatment applied to cells lacking the mutation. Claim Rejections - 35 USC § 112(b) 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. Claims 27 , 32 , and 44 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. 07-35-01 Claim 27 contains the trademark/trade name TALEN. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. § 112(b). See Ex parte Simpson , 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe transcription activator-like endonucleases and accordingly, the identification/description is indefinite. The phrases "Shiga toxin 1 and 2", "Phospholipases A and C", and "Streptolysin O and S" recited in claim 32 render the claim indefinite. Shiga toxin 1 and Shiga toxin 2 are known in the art as separate molecules. It is unclear whether the alternative options for the treatment molecule requires that both Shiga toxin 1 and Shiga toxin 2 must be present together or whether Shiga toxin 1 and Shiga toxin 2 are listed as separate alternatives. The phrases "Phospholipases A and C" and "Streptolysin O and S" are unclear for the same reason as Phospholipase A and Phospholipase C are known in the art as separate molecules and Streptolysin O and Streptolysin S are known in the art as separate molecules. Claim 44 is rejected under 35 U.S.C. 112(b) as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The claim pertains to a nucleic acid in a method but fails to recite an active step in which the nucleic acid is used or acted upon. Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-15 AIA Claim s 1-2, 8-9, 11, 14, 20, 25, 27-29, 35, 42-43, 53, and 55 are rejected under 35 U.S.C. § 102( a)(1 ) as being anticipated by Chen (Z.H. Chen, et al. Nat Biotech , 2017) . Chen discloses a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system for inducing a suicide gene in cancer cells (Abstract and Introduction p. 543). Regarding claims 1 and 53 , Chen discloses a system and a method for treating mice (a collection of cells) comprising treatment of xenografted PC3 prostate cancer cells comprising a TMEM135-CCDC67 fusion gene (mutated cells) in the genome (cellular DNA), which "creates a unique sequence breakpoint not present in normal tissues" (a plurality of cells lacking the first mutation) (Results pp. 543 and 546). The mice were transfected with an adenovirus (administering to the collection of cells) comprising a first nucleic acid encoding a cDNA for herpes simplex virus 1 thymidine kinase (HSV-1 tk) fused to enhanced green fluorescent protein (EGFP) (EGFP-tk) that provides synthetic lethality for targeted cancer cells (first nucleic acid encoding a treatment molecule) (Results p. 544). The adenovirus additionally comprises a second nucleic acid comprising Cas9 D10A nickase that cleaves DNA specifically within the TMEM135-CCDC67 fusion gene and two short guide RNAs (sgRNA) complementary to one of the regions flanking the chromosomal break point, which allows for insertion of the EGFP-1 tk sequence ((ii) a second nucleic acid encoding a gene editor that targets the first mutation and cleaves the cellular DNA at a target integration site and targets the first mutation and (b) integrating the first nucleic acid encoding the treatment molecule into the target integration site) (Results p. 544 and Fig. 1). The first and second nucleic acids are delivered together to treat the target mutated cancer cell (system for targeting mutations in cancer, claim 53 ) (Fig. 1). Regarding claim 2 , the adenovirus disclosed by Chen comprises a Cas9 D10A nickase that cleaves (cuts or nicks) to allow for integration of the first nucleic acid encoding a treatment (Results p. 544). Regarding claim 8 , the first nucleic acid is targeted to the TMEM135-CCDC67 fusion gene is found within the genomic DNA on chromosome 11 (Results p. 543). Regarding claim 9 , the expression of EGFP-tk is controlled by the endogenous TMEM135 promoter (inducible promoter) after insertion into the target site (Fig. 1). Regarding claim 11 , the target mutated cell is a PC3 prostate cancer cell line (cancer or neoplastic cell) (Results p. 544). Regarding claim 14 , the mice used for xenografting cancer cells have a SCID background, which does not comprise the TMEM135-CCDC67 fusion gene (Results p. 546 and Methods p. 552). Regarding claim 20 , the first nucleic acid lacks a promoter (Results p. 544). Regarding claim 25 , the first nucleic acid comprises a splice acceptor sequence (5' flanking region) and a splice donor sequence (3' flanking region) flanking EGFP-tk that are homologous to exon 14 of TMEM135 (target integration site) (Results p. 544 and Fig. 1). Furthermore, the first nucleic acid lacks a promoter (Fig. 1 legend). Regarding claim 27 , the gene editor is a Cas9 D10A nickase for gene editing using a CRISPR system (Introduction p. 543). Regarding claim 28 , the TMEM135-CCDC67 fusion gene is associated with cancer and provides "a unique target in cancer cells for therapeutic intervention" (Results p. 543). Regarding claim 29 , the targeted mutation is a TMEM135-CCDC67 fusion gene (nucleic acid encoding a protein fusion) (Introduction p. 543). Regarding claim 35 , the method comprises expression of HSV-1 tk in target cells, which results in death of the target mutated cell in the presence of the metabolite ganciclovir (Introduction p. 543 and Fig. 1). Regarding claim 42 , the first nucleic acid targets the mutation using splice acceptor/donor sequences and the second nucleic acid targets the mutation using two sgRNAs (Results p. 544 and Fig. 1). Regarding claim 43 , the second nucleic acid encodes Cas9 D10A (peptide) (Results p. 544). Chen notes that a D10A mutation falls within the catalytic domain and converts Cas9 into a nickase and that nicking genomic DNA (producing single-stranded breaks at the target DNA) rather introducing double-stranded breaks directs repair toward homology-directed repair (repressing non-homologous recombination) (Introduction p. 543). Regarding claim 55 , the nucleic acid constructs are delivered via pAD5 adenovirus (viral vector) (Results p. 544) . 07-15 AIA Claim s 1, 2, 6, 8-9, 11, 14, 22, 27-29, 32, 35, 42, 53, and 55 are rejected under 35 U.S.C. § 102( a)(1 ) as being anticipated by Peng (W. Peng, et al., Gene Therapy , 2005), as evidenced by Bose (A. Bose, et al., J Clin Invest , 2025), Shiota (M. Shiota, et al., Endocrin Cancer , 2022), and Shapira (A. Shapira and I. Banhar, Toxins , 2010 . Peng discloses a system and a method for treating prostate cancer by induced expression of diphtheria toxin in prostate-specific antigen (PSA)-expressing cells. Regarding claims 1 and 53 , Peng discloses a method of treating mice (a collection of cells) comprising LNCaP xenografts by administering to the mice adenovirus comprising a gene encoding diphtheria toxin A (DT-A) (first nucleic acid encoding a treatment molecule) and Flp recombinase (a second nucleic acid encoding a gene editor) (Results pp. 1574 and 1576). LNCaP cells are a prostate cancer cell line comprising a T878A mutation within the ligand binding domain within androgen receptor (AR) that alters its function relative to wild-type AR (target mutated cell including a first mutation in cellular DNA) (Shiota p. R144 and Table 1). LNCaP were injected into nu / nu mice, which lack the T878A AR mutation (plurality of cells lacking the first mutation) (Materials and Method p. 1579). The nucleic acid encoding DT-A is integrated into a target integration site downstream of Flp recombinase target (FRT) sequences and is delivered to the LNCaP cells by adenovirus (step (b), integrating the first nucleic acid into the target integration site of the cellular DNA of the target mutated cell) (Results p. 1574 and Fig. 1). Expression of DT-A results in results in death of the mutation-bearing cells (step (c), expressing the first nucleic acid encoding the treatment molecule after integration, wherein the treatment molecule treats the target mutated cell) (Results p. 1576 and Fig. 4). Expression of the Flp recombinase is driven by a chimeric prostate specific antigen (PSA) promoter, limiting expression of DT-A to cells with high PSA expression, a targetable feature in prostate cancer (Results p. 15744, Fig. 1, and Discussion p. 1577). Regarding claim 2 , the first nucleic acid is spontaneously uptaken by prostate cells (integrated spontaneously into the cellular DNA) in mice (Results p. 1576 and Fig. 5). Regarding claim 6 , LNCaP cells comprise a plurality of mutations (Bose Fig. 1E). Regarding claim 8 , the nucleic acid comprising the treatment molecule DT-A is delivered by adenovirus (viral DNA) (Results p. 1574). Regarding claim 9 , expression of DT-A is induced by androgen activation of a recombinant PSA promoter that drives expression of Flp recombinase, whereafter the Flp recombinase removes a region of DNA flanked by FRT sequences that lies between an RSV promoter and the DT-A sequence, thereafter allowing for constitutive activation of DT-A (Results p. 1574 and Fig. 1). This system limits expression of DT-A to PSA-expressing cells (Results p. 1574). Regarding claim 11 , the target mutated LNCaP cells are cancerous neoplastic human (animal) cells (Shiota p. R144 and Table 1). Regarding claim 14 , nu / nu mice (plurality of cells lacking the first mutation) comprise wild-type AR (Materials and Method p. 1579). Regarding claim 22 , the first nucleic acid comprising the DT-A gene has a sequence between the RSV promoter and the DT-A sequence that prevents expression (expression inhibitor) in non-PSA-expressing cells that is removed by Flp recombinase in PSA-expressing cells to allow expression of DT-A (that if removed induces expression of the first nucleic acid) (Results p. 1574). Regarding claim 27 , Flp recombinase is a restriction enzyme. Regarding claim 28 , LNCaP cells express mutated AR, AR T878A, which is associated with prostate cancer (Shiota pp. R144-47 and Tables 1 and 2). Regarding claim 29 , AR T878A is a point mutation (Shiota p. R144 and Table 1). Regarding claim 32 , DT-A is an AB toxin (Shapira p. 2525). Regarding claim 35 , expression of the toxin DT-A results in death of the target mutated LNCaP cells (Results pp. 1574-1576 and Fig. 4-6). Regarding claim 42 , expression of the Flp recombinase is driven by a chimeric prostate specific antigen (PSA) promoter, limiting expression of DT-A to cells with high PSA expression, a targetable feature in prostate cancer (Results p. 15744, Fig. 1, and Discussion p. 1577). Regarding claim 55 , the nucleic acids are housed in an adenoviral vector, serotype 5 (Results p. 1574) . Claim Rejections - 35 USC § 103 07-20-aia AIA 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. Claims 1-2, 8-9, 11, 14, 20, 22, 25, 27-29, 35, 42-44, 53, and 55 are rejected under 35 U.S.C. § 103 as unpatentable over Chen (Z.H. Chen, et al. Nat Biotech , 2017) in view of Li (Q. Li, et al. Mol Ther Methods Clin Dev, Feb 2021). Chen teaches a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 method of treating mice comprising cells comprising a TMEM135-CCDC67 fusion gene mutation by administering adenovirus comprising a first nucleic acid encoding a suicide gene and a second nucleic acid encoding a modified Cas9 gene editor molecule as discussed in the rejection of claims 1-2 , 8-9 , 11 , 14 , 20 , 25 , 27-29 , 35 , 42-43 , 53 , and 55 under 35 U.S.C. § 102 above. Chen does not teach a degradation signal or expression inhibitor of the treatment molecule as required by claim 22 or an in-frame self-cleaving peptide as required by claim 44 . However, Li teaches a self-cleavage system to restrict Cas9 expression (Abstract). The self-cleavage taught by Li comprises inclusion of a self-inactivation site within transfected nucleic acid constructs, wherein both the target genomic locus and the self-inactivation site are targeted and cleaved by Cas9 (Abstract). Cas9 in this system acts a self-cleaving peptide by cleaving the nucleic acid encoding Cas9 (claim 44 ) (Li Abstract and Fig. 1). Cleavage at the self-inactivation sequence results in degradation of the nucleic acid encoding the treatment molecule after integration of the nucleic acid into the cell (integration into the cellular DNA, claim 22 ), thereby limiting expression of Cas9 (Li Abstract and Fig. 1). Li teaches that "long-term expression of Cas9 in target cells can pose a safety concern such as cytotoxicity, off-target risk, and immune responses in vivo " (Introduction p. 652). Li further teaches that inclusion of a self-inactivation sequence reduces Cas9 expression by about 60% and reduces viral copy number by 70% (Results p. 654 and Fig. 3A-3B). Li further teaches that self-limited Cas9 expression resulted in 20-fold reduction in off-target activity (Results p. 654 and Fig. 3C). Li further teaches that self-limited Cas9 expression did not reduce on-target gene editing (Results p. 654 and Fig. 2A-2B). Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the method of treating a collection of cells using a CRISPR/Cas9 system as taught by Chen with a self-cleavage system to restrict Cas9 expression as taught by Li to arrive at the claimed invention. One would be motivated to make such a combination as Li teaches that long term expression of Cas9 in target cells poses safety concerns in vivo . One would have a reasonable expectation of success in making the combination as Li teaches that inclusion a self-cleavage system reduces expression of Cas9 and copy number of the nucleic acid encoding Cas9 and reduces frequency off-target mutations without compromising on-target gene editing activity. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric B Wright whose telephone number is (571) 272-2607. The examiner can normally be reached Mo - Fr, 09:00 a.m. - 05:00 p.m. Eastern. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant may use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /Eric B Wright/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632 Application/Control Number: 18/707,262 Page 2 Art Unit: 1632 Application/Control Number: 18/707,262 Page 3 Art Unit: 1632 Application/Control Number: 18/707,262 Page 4 Art Unit: 1632 Application/Control Number: 18/707,262 Page 5 Art Unit: 1632 Application/Control Number: 18/707,262 Page 6 Art Unit: 1632 Application/Control Number: 18/707,262 Page 7 Art Unit: 1632 Application/Control Number: 18/707,262 Page 8 Art Unit: 1632 Application/Control Number: 18/707,262 Page 9 Art Unit: 1632 Application/Control Number: 18/707,262 Page 10 Art Unit: 1632 Application/Control Number: 18/707,262 Page 11 Art Unit: 1632
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