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 Claims Claims 1-16, 19, 21, 28, and 29 are pending. Priority Claims 1-16, 19, 21, 28, and 29 are a 371 of PCT/GB 2022/05097 filed on April 114, 2022, which has priority to UNITED KINGDOM 2105581.9 filed on April 19, 2021, and to UNITED KINGDOM 2110922.8 filed on July 29, 2021, and to UNITED KINGDOM 2113603.1 filed on September 23, 2021, and to UNITED KINGDOM 2116571.7 filed on November 17, 2021. Information Disclosure Statement The information disclosure statement(s) (IDS) submitted on February 21, 2022, was filed before the mailing of the First Office Action on April 4, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner. Examiner’s Note Claim 19 recites “5’- and 3’-viral ITRs flanking a transgene”. While the meaning appears to be that the ITRs are positioned at the 5’ and the 3’ ends of the transgene . The claim would be better understood if the claim specified that the ITRs flank the transgene on at the 5’ end and the 3’ end such as “a transfer plasmid comprising a viral 5’ ITR, a transgene, and a 3’ viral ITR, arranged in a 5’ to 3’ orientation”. 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 appl icant regards as his invention. Claims 1-16, 19, and 21 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 1 recites “are operably associated in this order (5’-3’)”. “Operably associated” is unclear. What type or degree of association is required? Does this require direct physical linkage, indirect interaction, spatial proximity, a form of regulatory control? As written, a person of ordinary skill would not understand the what is meant by “operably associated”. Claim 1 recites “operably associated with one or more adenovirus Early genes”. “Operably associated” is unclear. What type or degree of association is required? Does this require direct physical linkage, indirect interaction, spatial proximity, a form of regulatory control? As written, a person of ordinary skill would not understand the what is meant by “operably associated”. Claims 2-16 are also rejected based on dependency to claim 1. Claim 5 recites “…CARE element independently comprise or consist of:”. “comprise or consist of” is unclear. The use of “comprise or consist of” renders the scope of the claim unclear given that “comprise” is an open-ended transitional phrase that permits additional elements and/or limitations, while “consist of” is a closed transitional phrase that excludes elements not expressly recited in the claim. Therefore, a person of ordinary skill would not be able to determine to scope of the claim. Claim 6 recites “…CARE element independently comprise or consist of”. “comprise or consist of” is unclear. The use of “comprise or consist of” renders the scope of the claim unclear given that “comprise” is an open-ended transitional phrase that permits additional elements and/or limitations, while “consist of” is a closed transitional phrase that excludes elements not expressly recited in the claim. Therefore, a person of ordinary skill would not be able to determine to scope of the claim. Claim 7 is also rejected based on dependency to claim 6. Claim 7 recites “…p5 promoter region independently comprises or consists of:”. “comprises or consists of” is unclear. The use of “comprise or consist of” renders the scope of the claim unclear given that “comprise” is an open-ended transitional phrase that permits additional elements and/or limitations, while “consist of” is a closed transitional phrase that excludes elements not expressly recited in the claim. Therefore, a person of ordinary skill would not be able to determine to scope of the claim. Claim 8 recites “…CARE element independently comprises or consists of”. “comprises or consists of” is unclear. The use of “comprise or consist of” renders the scope of the claim unclear given that “comprise” is an open-ended transitional phrase that permits additional elements and/or limitations, while “consist of” is a closed transitional phrase that excludes elements not expressly recited in the claim. Therefore, a person of ordinary skill would not be able to determine to scope of the claim. Claim 13 recites “…siRNA against an adenovirus Late gene mRNA”. “Against” is unclear because it lacks any objective boundary with respect to what specific relationship is between the shRNA or siRNA and the adenovirus Late gene mRNA is required. Claim 19 recites the limitation "5’- and 3’ ITRs" in Line 5. There is insufficient antecedent basis for this limitation in the claim. Claim 21 recites “…CARE element independently additionally comprise”. As written, “additionally” is unclear. Is the pre-AAV p5 promoter region completely separate from the existing CARE element, does it partially overlap, or is it present somewhere else in the element. A person of ordinary skill would not understand what the metes and bounds are for “additionally”. Claim 21 recites “operably-associated”. “Operably associated” is unclear. What type or degree of association is required? Does this require direct physical linkage, indirect interaction, spatial proximity, a form of regulatory control? As written, a person of ordinary skill would not understand the what is meant by “operably associated”. 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. Claims 1 - 4, 6, 9 -16, 19, 21, 28, and 29 are rejected under 35 U.S.C. §103 as being unpatentable over Murphy et al. [Adeno-associated virus type 2 p5 promoter: a rep-regulated DNA switch element functioning in transcription, replication, and site-specific integration, ASM Journals, Journal of Virology , 2007], in view of Musatov et al. [A cis-acting element that directs circular adeno-associated virus replication and packaging, J Virol ., 2002], in view of Aponte-Ubillis et al. (Hereinafter Ubillis) [Molecular design for recombination adeno-associated virus (rAAV) vector production, Applied Microbiology and Biotechnology , 2018], in view of Wang and Srivastava (Hereinafter Wang) [Rescue and autonomous replication of adeno-associated virus type 2 genomes containing rep-binding site mutations in the viral p5 promoter, J Virol ., 1998], in view of Fry et al. [Promoter orientation within an AAV-CRISPR vector affects Cas9 expression and gene editing efficiency, The CRISPR Journal , 2020], in view of Eckstein et al. [Inhibition of adenovirus infections by siRNA-mediated silencing of early and late adenoviral gene functions, Antiviral Research , 2010] . With respect to claim 1, Ubillus discloses a host cell, i.e. HEK293 cell line, used for culture for the production of AAV vectors where the vector genome construct contains one or more additional nucleic acid molecules that encode viral components [Fig. 3]. Ubillus further discloses that the nucleotide sequence is “operably associated” with regulatory elements [Id.]. Ubillus further discloses the use of multiple p5 promoter elements with one p5 promoter element being upstream of the Rep and another p5 promoter that is downstream of the Cap [Adenovirus complementation system ¶ 3]. Lastly, Ubillus discloses that regulatory elements such as promoters are modular and can be duplicated, rearranged, and/or optimized in order to improve vector production and function [Fig. 1, Fig. 2]. However, Ubillus does not teach the replication function of p5 or that p5 is cis-acting or orientation considerations. With respect to claim 1’s limitations regarding p5 replication function and cis-acting, Musatov et al. discloses that p5 has been found to be involved in amplification of integrated Rep-Cap sequences in HeLa cells [Rep p5 promoter is another origin of cAAV replication ¶ 1]. Musatov et al. further discloses that at least one cis-acting replication element outside the ITR that is mapped to the p5 promoter of the rep gene [Discussion ¶ 1]. This shows that these elements are capable of directing replication in linked nucleotide sequences. Lastly, Murphy et al. teaches that the p5 promoter comprises a Re-binding site and can function as a Rep-dependent DNA replication element that is capable of mediating the replication of those nucleic acid sequences that are present [Abstract]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Ubillus with the additional teachings of Murphy et al. and Musatov et al. given that Ubillus teaches a recombinant AAV production system comprising nucleic acid constructs that include promoter elements, such as p5 promoters, where these regulatory elements can be duplicated, rearranged, and optimized within vector constructs. Murphy et al. further teaches that the AAV p5 promoter is capable of functioning as a Rep-dependent DNA replication element that can mediate replication of associated nucleic acid sequences, while Musatov et al. teaches that p5 promoter regions can function as cis-acting replication elements capable of directing replication and/or amplification of nucleic acid molecules. Because of this, there is a reasonable expectation of success that combining these references, a person of ordinary skill in the art would be able to incorporate multiple p5 promoter elements into a nucleic acid construct, including arranging these elements where they flank a nucleotide sequence of interest and in a selected orientation, e.g. 5’-3’, so as to promote or regulate replication and/or amplification. For claim 2 where prior to step (a) of claim 1, the method includes introducing the first nucleic acid molecule into a host cell, Ubillus discloses the multiple nucleic acids are introduced into HEK293 cells, i.e. host cells [Fig. 3]. For claim 3 where the AAV p5 promoter contains a TATA box, AAV Rep bi nd ing site, and a trs-like element, Wang, discussing Rep-binding mutations in p5 promoters, discloses the presence of the TATA box [Introduction ¶ 1], an AAV Rep-binding site [Abstract], and a trs-like element [Introduction ¶ 1]. For claim 4 where the p5 promoter further comprises a MLTF/USP1 binding site, a YY1 -60 binding site, and a YY1+1 binding site, Murphy et al. teaches a MLTF binding site along with a YY1-60 binding site and a YY1+1 initiator [Promoter sequence elements surround the RBE contribute to p5IEE function ¶ 1]. For claim 6 where the first or second CARE element comprises a pre-AAV p5 promoter region, Murphy et al. discloses a Rep-binding element where this region extends beyond the promoter core where is located “upstream”, i.e. 5’ of the core p5 promoter region [Abstract]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of claimed invention to modify the systems and methods of Murphy et al. with the additional teachings of Wang where an artisan would have recognized the upstream regulatory/replication sequence as being a pre-p5 region . For claim 9 where the first and/or second CARE element comprises a 5’ portion of the Reg gene found in AAV, again, Murphy et al. discloses a Rep-binding element where the region extends beyond the promoter core where it is located “upstream”, i.e. 5’, of the core p5 promoter region [Abstract]. For claim 10 where the first nucleotide sequence encodes a therapeutic polypeptide, a CRISPR enzyme or viral gene, Fry et al. teaches that adeno-associated virus vector delivery of CRISPR is one approach to gene editing [Abstract] . For claim 11 where the first nucleotide sequence encodes a recombinant AAV genome, Ubillus discloses that recombinant AAV vectors are increasingly popular tools for gene therapy applications, and that certain productivity yields can produce various ranges of vector genomes [Abstract]. For claim 12 where the method of claim 1 where the first nucleotide contains sequences for AAV rep gene, AAV cap gene, or both, and a cap gene and a transgene, and is optionally flanked by ITRs (inverted terminal repeats), Ubillus teaches a nucleotide sequence that includes a rep gene, a cap gene where the transgene is flanked by two ITRs [Fig. 1 and Fig. 3, Abstract]. For claim 13 where the nucleotide sequence further encodes a shRNA or siRNA, Eckstein et al. discloses the inclusion of a siRNA for the purpose of gene silencing by RNA interference as an optional therapeutic option for certain therapies [Abstract]. Based on this, it there is a reasonable expectation of success that a person of ordinary skill would recognize the teachings of Eckstein et al. in order to control and/or regulate gene expression through the use of RNA mediated inhibition using small interfering RNA particles that are capable of targeting adenoviral genes. For claim 14 where the host cell is one which expresses the adenovirus E1A protein, and the first nucleotide sequence comprises a rep gene and the p5 promoter in the CARE element is modified to prevent rep gene expression or the rep-gene is operably-associated with a heterologous inducible or repressible promoter, Murphy et al. discloses that the AAV5 promoter regulates expression of the Rep gene and functions as a Rep-responsive DNA element involved in transcription and replication [Abstract]. Murphy et al. further discloses that the p5 promoter contains specific sequences that are required for Rep binding and activity and that transcriptional activity of the p5 promoter region can be altered through modification of its sequence [Abstract]. For claim 15 , Murphy et al. teaches that an AAV p5 promoter regulates rep gene expression and serves as a rep-responsive DNA switch element controlling both transcription and replication [Abstract]. Additionally, AAV rep and cap genes can be supplied in host cells using adenoviral helper functions and replication can occur in the presence of adenoviral proteins, including E1A, provided in trans rather than expressed from the host cell genome. Murphy et al. further discloses that modulation of the p5 promoter can enhance or prevent transcription of rep [Discussion ¶ 5]. For claim 16 where the first nucleotide sequence does not encode either a functional Rep protein or a functional Cap protein, Murphy et al. discloses that rep and cap genes are essential for AAV replication and packaging, and further disclose that these genes can be supplied in a host cell in a modular fashion that includes controlled expression or inactivated version of rep and cap [Id]. Here, it would have been prima facie obvious to a person of ordinary skill prior to the filing of the claimed invention to modify the systems and methods of Murphy et al. that discloses modulation of the p5 promoter where it is capable of altering rep transcription while retaining replication function with Musatove et al. where it was demonstrated that the p5 region functions as a cis-acting replication element that is independent of its transcriptional role and Ubillus where they teach modular rAAV production systems in host cells expressing adenoviral helper proteins, including E1A proteins, where the rep and cap genes can be provided in trans. Based on this, there is a reasonable expectation of success that a person of ordinary skill in the art would combine the teachings of Murphy et al. with the additional teachings of Musatov et al. and Ubillis to modify promoter activity, provide helper functions in trans, and control rep/cap functionality. For claim 19 the production of recombinant viral particles includes a transgene, culturing a host cell with a transfer plasmid containing ITRs flanking the transgene, a first nucleic acid molecule of claim 1, rep and cap genes, sufficient helper genes, and harvesting packaged particles from the host cell, Ubillus teaches a transgene being introduced into a host cell via a transfer plasmid where the transgene is flanked by ITRs and contains rep and cap genes along with sufficient helper genes [Fig. 1]. With respect to including the nucleotide sequence found in claim 1, see claim 1 analysis. For claim 21, see claim 1 analysis. For claim 28 a host cell comprising a nucleic acid molecule found in claim 21, Ubillus describes using HEK293 host cells [Adenovirus complementation system ¶ 2]. For claim 29 where a modified host cell is produced by introducing the nucleic acid molecule as claimed in claim 21 in a host cell, Ubillus describes components can be delivered to HEK293 cells with wither transfection or viral infection [Fig. 1]. It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of taught by Murphy et al. and Musatov et al. with the additional teachings of Ubillus where a nucleic acid molecule would be introduced into a host cell where the nucleic acid molecule contained a modified p5 promoter capable of preventing or permitting rep expression with non - functional rep and/or cap sequences, into a host cell such as a HEK293 cell given that the use of HEK293 and other cell lines are well known in the art. Therefore, a person of ordinary skill would have a reasonable expectation of success for producing rAAV particles with the above characteristics given the routine nature of either transfection or viral infection using known methods to introduce modified vector systems into host cells. The Supreme court has acknowledged: When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability …if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions… … the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc ., 82 USPQ2d 1385 U.S. 2007) emphasis added. In KSR Int'l Co. v. Teleflex Inc. , 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc ., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton."). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary. Conclusion No claims allowed. 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