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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/05/2026 has been entered.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119
(a)-(d). Acknowledgment is made of Applicants’ claim for benefit to foreign application GB2013466.4 filed 08/27/2020.
This application claims the benefit of priority to Patent Application PCT/PT2021/050028. Acknowledgement is made of Applicants’ claim for benefit to prior filed to Patent Application
Number PCT/PT2021/050028, filed on 08/25/2021.
Information Disclosure Statement
The Information Disclosure Statements filed 02/27/2023 and 05/05/2023 have been considered by the Examiner.
Status of Claims
Claims 1-4, 6-9, 11, 13-17, 19-20, 22-23, and 27 are under examination.
Claims 5, 10, 12, 18, 21, and 24-26 are cancelled.
Claim Rejections - 35 USC § 112
Rejection to claims 13-16 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inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, have been withdrawn in view of the applicant’s amendment filed 12/24/2025.
Claim Rejections - 35 USC § 102
Rejection to claims 1-4, 7, 9, 11, 18, 20, 22-23, and 27 under 35 U.S.C. 102(a)(1) as being anticipated by Gruenert (WO 2020/091958 A1) has been withdrawn in view of applicant’s amendments filed 12/24/2025.
Rejection to claims 1-4, 6-8, 17 and 20 under 35 U.S.C. 102(a)(1) as being anticipated by Kamata et al. (PLoS ONE, 2010) has been withdrawn in view of applicant’s amendments filed 08/05/2026.
Response to Argument
Applicant’s amendments, see page 6, filed 08/05/2026, with respect to claims 1-4, 6-8, 17 and 20 have been fully considered and are persuasive. The rejection to claims 1-4, 6-8, 17 and 20 over Kamata et al. (PLoS ONE, 2010) have been withdrawn in view of applicant’s amendments filed 08/05/2026.
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.
Rejection to claim 13 under 35 U.S.C. 103 as being unpatentable over Gruenert (WO2020/091958 A1) as applied to claims 1 and 11 above, and further in view of Um et al. (WO 2016/108333 Al) has been withdrawn in view of applicant’s amendments filed 12/24/2025.
Rejection to claim 14 under 35 U.S.C. 103 as being unpatentable over Gruenert (WO2020/091958 A1) as applied to claims 1 and 11 above, and further in view of Wang et al. (CN108676097-A) has been withdrawn in view of applicant’s amendments filed 12/24/2025.
Rejection to claim 15 under 35 U.S.C. 103 as being unpatentable over Gruenert (WO2020/091958 A1) as applied to claims 1 and 11 above, and further in view of Hochberg et al. (WO 03/035883 A2) has been withdrawn in view of applicant’s amendments filed 12/24/2025.
Rejection to claim 16 under 35 U.S.C. 103 as being unpatentable over Gruenert (WO2020/091958 A1) as applied to claims 1 and 11 above, and further in view of Bonny et al. (EP1661912) has been withdrawn in view of applicant’s amendments filed 12/24/2025.
Rejection to claim 19 under 35 U.S.C. 103 as being unpatentable over Gruenert (WO2020/091958 A1) as applied to claim 1, and further in view of Yan et al. (CN104017827-A) has been withdrawn in view of applicant’s amendments filed 12/24/2025.
New rejection necessitated by amendment:
Claims 1-4, 6-9, 11, 17, 20, 22-23, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Kamata et al. (PLoS ONE, 2010) in view of Gruenert et al. (WO2020/091958 A1).
Regarding claim 1, Kamata et al. teach a genetic construct comprising: (i) a ubiquitin C promoter (a constitutive promoter) operably linked to a nucleic acid sequence encoding mCherry, a reporter molecule where the construct further includes microRNA target sites miR-223, miR-155, and miR-142-3p; and (ii) a second promoter (CMV-constitutive promoter) operably linked to EGFP and an inhibitor of the first promoter which includes miR-302a/d targets which are different than the first targets (page 2, Figure 1A).
Kamata et al. do not teach the inhibitor of the first promoter is a Lac operon, wherein the second nucleic acid sequence comprises a Lac repressor and the first promoter comprises a Lac operator regulator site.
Gruenert teaches a genetic construct comprising a first promoter operably linked to a first nucleic acid sequence encoding a transgene, the first sequence includes miRNA target sites (page 30, paragraph 0134). Gruenert teaches the genetic construct further comprises a second promoter (CMV or SV40) operably linked to a second nucleic acid sequence encoding a therapeutic transgene, where the sequence includes MBSs specific for miRs present in cancer cells (page 30, paragraph 0139). Gruenert teaches an inhibitor, a lac repressor, encoded by the second nucleic acid sequence inhibits the first promoter (page 10, paragraph 0036). Gruenert teaches the second nucleic acid contains a constitutively active promoter, a lacI gene encoding a lactose operon repressor (page 10, paragraph 0037).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Kamata et al. for a genetic construct with the teachings of Gruenert et al. for a genetic construct with an inhibitor of the first promoter a lac repressor. Gruenert et al. provide motivation by teaching that micro binding domains are specific for microRNAs present in cancer cells, the gene encoding the transcription repressor is not expressed in cancer cells but is expressed in non-cancer cells. Gruenert et al. teach the second DNA sequence of the vector system comprises one or more binding sites for a lac repressor 3' or 5' to the start codon of the transgene and the vector system comprises a DNA sequence comprising a constitutively active promoter, a lacI gene encoding the lactose operon (lac) repressor. Gruenert et al. teach the lacI gene is under the control of an MBD that is specific for microRNAs present in the cancer cells, it is expected that the lacI gene is not expressed or minimally expressed in the cancer cells (page 10, paragraphs 0036-0037). One of skill in the art would have had a reasonable expectation of success at combining Kamata et al. and Gruenert et al. because both teach vectors including microRNAs for cellular expression modulation.
Regarding claim 2, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Kamata et al. further teach the miRNA target site of the second nucleic acid are miR-302a/d targets. Kamata et al. teach the second target sites are different targets than miR-223, miR-155, and miR-142-3p the target sites of the first nucleic acid sequence (page 3, Characterization of a miRNA dependent reporter vector that distinguishes pluripotent cells from differentiated progeny).
Regarding claim 3, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Kamata et al. teach the construct includes 3 miRNA target sites which include a copies of miR-223, miR-155, miR-142-3p within the first nucleic acid sequence (page 3, Characterization of a miRNA dependent reporter vector that distinguishes pluripotent cells from differentiated progeny).
Regarding claim 4, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Kamata et al. teach the miRNA target sites present in the first nucleic acid are miR-223, miR-142-3p, and miR-155. Kamata et al. further teach miR-223, miR-142-3p, and miR-155 are enriched primarily in cells of hematopoietic origin (page 8, right column).
Regarding claim 6, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Kamata et al. teach the second nucleic acid includes 2 miRNA target sites which includes copies of miR-302a and miR-302d (miR-302 a/d) (page 3, Characterization of a miRNA dependent reporter vector that distinguishes pluripotent cells from differentiated progeny).
Regarding claim 7, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Kamata et al. teach the miR-302a and miR-302d target sites. Kamata et al. further teach miR-302 gene encodes a cluster of eight miRNAs which are preferentially expressed in embryonal carcinoma cells, which reads on diseased cell (page 9, Construction of lentiviral vector).
Regarding claim 8, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Kamata et al. teach the construct includes GFP and mCherry which are optical reporters (page 9, Construction of lentiviral vector).
Regarding claim 9, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Gruenert et al. further teaches the therapeutically active molecule is a therapeutic protein (page 1, paragraph 0003).
Regarding claim 11, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Gruenert teaches therapeutic proteins can be apoptosis inducers which reads on an apoptosis driver protein (page 12, paragraph 0043).
Regarding claim 17, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Kamata et al. further teach the second promoter is arranged in the opposite orientation in the construct to the first promoter (pages 2&3, Characterization of a miRNA dependent reporter vector that distinguishes pluripotent cells from differentiated progeny & Figure 1A).
Regarding claim 20, Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Gruenert teaches a recombinant vector (page 16, paragraph 0063) comprising the genetic construct with two sequences including miRNAs as described above (pages 2, Figure 1A).
Regarding claim 22, Gruenert teaches a method of treating or preventing cancer in a subject (page 2, paragraph 0007). Gruenert teaches the method of treating includes administering a therapeutically effective amount (page 28, paragraph 0124) of a construct or vector. Kamata et al. and Gruenert et al. make obvious the recombinant vector described above in regard to claim 20. Gruenert teaches a vector for treating or preventing cancer (pages 2, Figure 1A).
Regarding claim 23, Kamata et al. and Gruenert et al. make obvious the recombinant vector described above in regard to claim 20. Gruenert et al. teach a pharmaceutically acceptable excipient (page 44, claim 95).
Regarding claim 27, Gruenert teaches a method of diagnosing or treating cancer in a subject (page 1, paragraph 0003). Gruenert teaches the method comprises: a) obtaining a sample from the subject (page 29, paragraph 0130), b) detecting, in the sample, the reporter molecule of the genetic construct (page 16, paragraph 0064), c) diagnosing the subject with cancer when the reporter molecule is detected (page 29, paragraph 0131) and d) administering an effective amount of treatment for the cancer to the subject diagnosed with such (page 28, paragraph 0124). Kamata et al. and Gruenert et al. make obvious the recombinant vector described above in regard to claim 20.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Kamata et al. (PLoS ONE, 2010) in view of Gruenert et al. (WO2020/091958 A1) as applied to claims 1 and 11 above, and further in view of Um et al. (WO 2016/108333 Al).
Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Gruenert teaches therapeutic proteins can be apoptosis inducers which reads on an apoptosis driver protein (page 12, paragraph 0043).
Regarding claim 13, Kamata et al. and Gruenert et al. do not teach the therapeutic protein is Bax where the amino acid sequence as set forth in SEQ ID No: 16.
Um et al. teach a method for screening cancer metastasis and a pharmaceutical composition for inhibiting cancer metastasis (cover page, abstract). Um et al. teach the pharmaceutical agent facilitates formations of the Bax/complex-1 conjugate in cancer cells preventing cancer metastasis (cover page, abstract). Um et al. teach a pharmaceutical composition for inhibiting the cancer metastasis comprising a gene for Bcl-2 associated X (Bax) protein (page 35, claim 9). Um et al. teach the Bax protein having the amino acid SEQ ID NO: 3 (page 36, claim 10), which is the same as SEQ ID NO:16 of the present application. Um et al. teach administration of the pharmaceutical agent would be effective for cancer (cover page, abstract).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Kamata et al. and Gruenert et al. for a vector system with a transgene with the teachings of Um et al. for addition of the gene encoding a Bax protein. Um et al. provide motivation by teaching that a pharmaceutical vector with the gene for the Bax protein can treat/prevent cancer metastasis. One of skill in the art would have had a reasonable expectation of success at combining Kamata et al. and Gruenert et al. with Um et al. because both make obvious vectors for cancer treatment.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Kamata et al. (PLoS ONE, 2010) in view of Gruenert et al. (WO2020/091958 A1) as applied to claims 1 and 11 above, and further in view of Wang et al. (CN108676097-A).
Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Gruenert teaches therapeutic proteins can be apoptosis inducers which reads on an apoptosis driver protein (page 12, paragraph 0043).
Regarding claim 14, Kamata et al. and Gruenert et al. do not teach the therapeutic protein is Apoptin where the sequence is SEQ ID No:18.
Wang et al. teach targeting a tumor cell (cover page, abstract). Wang et al. further teach chimeric peptides or chimeric proteins are capable of targeting and killing tumor cells. Wang et al. further teach normal diploid cell are not harmed in treatment because the method is specific for cancer cells (cover page, abstract). Wang et al teach apoptin protein (SEQ ID NO.3) which specifically induces tumor cell apoptosis and necrosis without damage to the normal diploid cells. Wang et al. teach treating a tumor with apoptin which has a strong tumor cell nuclear localization signal. Wang et al. teach expression of Apoptin-iRGD chimeric peptide of an AAV virus. Wang et al. teach apoptin protein SEQ ID NO: 3 (page 4), which is the same sequence as SEQ ID NO: 18 of the present application. Wang et al. teach the applying the vector to a subject in need to facilitate a specific treatment (page 8). Wang et al. teach the treatment with apoptin does not have the toxic side effects that are common to many modern malignant solid tumor treatment methods (page 8).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Kamata et al. and Gruenert et al. for a vector system comprising a transgene, the expression of which is regulated with the teachings of Wang et al. for introduction of apoptin to a tumor. Wang et al. provide motivation by teaching that using apoptin is a specific treatment for cancer which is safer than conventional methods. One of skill in the art would have had a reasonable expectation of success at combining Kamata et al., Gruenert et al., and Wang et al. because both make obvious alternative methods of treating cancer via vector.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Kamata et al. (PLoS ONE, 2010) in view of Gruenert et al. (WO2020/091958 A1) as applied to claims 1 and 11 above, and further in view of Hochberg et al. (WO 03/035883 A2).
Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Gruenert teaches therapeutic proteins can be apoptosis inducers which reads on an apoptosis driver protein (page 12, paragraph 0043).
Regarding claim 15, Kamata et al. and Gruenert et al. do not teach the therapeutic protein is E4orf4 where the sequence is the same as SEQ ID No: 20.
Hochberg et al. teach replicative viral vectors that are capable of selectively replicating in cancer and/or hyperproliferative cells (page 4, Summary of the Invention). Hochberg et al. teach a method of treating cancer or a hyperproliferative disorder in a subject a conditionally replicative viral vector, wherein at least one of the viral nucleic acids encoding a product essential for its replication is operably linked to an H19 regulatory sequence (page 31, claim 1). Hochberg et al. teach the conditionally replicative virus is an adenovirus (page 10, 5.2 Conditionally Replicative Viral Vectors and Essential Gene Products). Hochberg et al. teach inclusion of the amino acid sequence for E4 protein (SEQ ID NO:15) a gene product of adenovirus 2 (page 7, figure 9), which is the same as SEQ ID NO: 20 of the present application. Hochberg et al. teach the method includes at least one nucleic acid encoding a product essential for the virus replication which can be the E4 gene of the adenovirus (page 33, claim 13).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Kamata et al. and Gruenert et al. for a vector system with a transgene with the teachings of Hochberg et al. for inclusion of the amino acid sequence for E4 protein for replication. Hochberg et al. provide motivation by teaching that inclusion of at least one nucleic acid encoding a product is essential for the virus replication. One of skill in the art would have had a reasonable expectation of success at combining Kamata et al. and Gruenert et al. with Hochberg et al. because they both make obvious viral vectors for cancer treatment.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Kamata et al. (PLoS ONE, 2010) in view of Gruenert et al. (WO2020/091958 A1) as applied to claims 1 and 11 above, and further in view of Bonny et al. (EP1661912).
Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Gruenert teaches therapeutic proteins can be apoptosis inducers which reads on an apoptosis driver protein (page 12, paragraph 0043).
Regarding claim 16, Kamata et al. and Gruenert et al. do not teach the therapeutic protein is Bim and further the sequence of which as set forth in SEQ ID No:25 or a biologically active fragment thereof.
Bonny et al. teach pharmaceutical compositions containing fusion proteins (cover page, abstract). Bonny et al. teach treatment and/or prophylaxis of diseases caused by defective apoptosis, cancer (page 35, claim 13). Bonny et al. teach the amino acid sequence of D-TAT-Bim SEQ ID NO: 13 (page 14, line 4), which is the same as SEQ ID NO:25 of the present application. Bonny et al. teach apoptosis as an essential modulator of the size and health of the cellular community (page 2, paragraph 0002). Bonny et al. further teach mutations of proteins, that prevent this normal programmed cell death, play an essential role in many diseases including cancer (page 2, paragraph 0002). Bonny et al. teach cancerous cell growth often results from defective control of cell death(page 2, paragraph 0002). Bonny et al. further teach resistance to apoptosis is a key characteristic of malignant cells enabling them to increase in number and survive(page 2, paragraph 0002).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Kamata et al. and Gruenert et al. for a vector system comprising a transgene and regulation with the teachings of Bonny et al. for a Bim fusion protein. Bonny et al. provide motivation by teaching that mutations of proteins in the apoptotic pathway inhibits proper cell turnover and introduction of the Bim fusion protein would promote apoptosis. One of skill in the art would have had a reasonable expectation of success at combining Kamata et al. and Gruenert et al. with Bonny et al. because both teach vectors for cancer treatments.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Kamata et al. (PLoS ONE, 2010) in view of Gruenert et al. (WO2020/091958 A1) as applied to claim 1, and further in view of Yan et al. (CN104017827-A).
Kamata et al. and Gruenert et al. make obvious a genetic construct as described above regarding claim 1. Gruenert teaches therapeutic proteins can be apoptosis inducers which reads on an apoptosis driver protein (page 12, paragraph 0043).
Regarding claim 19, Kamata et al. and Gruenert et al. do not teach the sequence of the genetic construct or the nucleic acid sequence as set out in any one of SEQ ID Nos: 5, 22 to 24, 27, or 78 to 82, or a fragment or variant thereof.
Yan et al. teach construction of a slow virus plasmid expression vector which can be used for diagnostic and detection of disease (cover page, abstract). Yan et al. teach an artificial sequence SEQ ID NO:2 (claim 1) which is 52.2% match to SEQ ID NO:5 of the present application. SEQ ID NO:2 of Yan et al. reads on a fragment or variant of SEQ ID NO: 5 as set forth by the definition on page 76 of the present application. Yan et al. teach the lentiviral plasmid has high sensitivity, is cost effective, and improves quality of life for the patient (cover page, abstract).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Kamata et al. and Gruenert et al. for a transgene regulated by an inducible promoter for use in cancer cells with the teachings of Yan et al. for a slow virus plasmid expression vector which can be used for diagnostic and disease detection purposes (cover page, abstract). Yan et al. provide motivation by teaching the lentiviral plasmid has high sensitivity, is cost effective, and improves quality of life for the patient (cover page, abstract). One of skill in the art would have had a reasonable expectation of success at combining Kamata et al. and Gruenert et al. with Yan et al. because both make obvious methods related to optical disease detection.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.L.M./Examiner, Art Unit 1638
/ANNA SKIBINSKY/Primary Examiner, Art Unit 1635
