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 .
Restriction/Election
Applicant’s election without traverse of Group 1, claims 1-7, 15, 23, 26, 28, 41-43, 49, and 68 in the reply filed on 29 October 2025 is acknowledged.
Claims 51 and 65-67 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 29 October 2025.
Claim Status
Claims 1, 6, 41-43, and 68 are currently amended, claims 8-14, 16-22, 24-25, 27, 29-40, 44-48, 50, and 52-64 were previously cancelled, claims 5 and 7 are newly canceled, claims 51 and 65-67 have been withdrawn, and claims 1-4, 6, 15, 23, 26, 28, 41-43, 49, and 68 have been considered on their merits.
Withdrawn Objections/Rejections
The claim objection directed to claim 68 has been withdrawn due to Applicant’s amendment to the claims.
The claim rejections under 35 U.S.C. § 112(b) of claims 42 and 43 have been withdrawn due to Applicant’s amendments to the claims.
The claim rejections under 35 U.S.C. § 102 have been withdrawn due to Applicant’s amendments to the claims.
The claim rejections under 35 U.S.C. § 103 have been withdrawn due to Applicant’s amendments to the claims.
The non-statutory rejection of the claims have been withdrawn due to Applicant’s amendments to the claims. However, upon further consideration, new rejections have been set forth below, as the reference claims still comprise the limitations of the instant claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
This is a new rejection necessitated by Applicant’s amendment to the claims.
Claim 6 recites the limitation “The nucleic acid construct of claim 5…”, however, claim 5 has been canceled. Therefore, claim 6 is not written in proper dependent form as the claim does not depend from a claim previously set forth.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 applicant regards as his invention.
Claim 6 is 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.
This is a new rejection necessitated by Applicant’s amendments to the claims.
Claim 6 recites the limitation “The nucleic acid construct of claim 5…”, however, claim 5 has been canceled. Therefore, the scope of the claim is unclear as the metes and bounds of the claim have not been set forth. The language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds". See, e.g., the following decisions: In re Hammack, 427 F 2d. 1378, 1382, 166 USPQ 204, 208 (CCPA 1970); In re Venezia 530 F 2d. 956, 958, 189 USPQ 149, 151 (CCPA 1976); In re Goffe, 526 F 2d. 1393, 1397, 188 USPQ 131, 135 (CCPA 1975); In re Watson, 517 F 2d. 465, 477, 186 USPQ 11, 20 (CCPA 1975); In re Knowlton 481 F 2d. 1357, 1366, 178 USPQ 486, 492 (CCPA 1973).
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 1-2, 6, 15, 23, 26, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski et al. (WO 01/25253 A2, published 12 April 2001, of record) in view of Colosi (WO 01/83797 A1, published 8 November 2001, of record) and Whyteside et al. (WO 2019/038544 A1, published 28 February 2019).
This is a new rejection necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claim 1, Samulski teaches nucleotide sequences encoding temperature sensitive (ts) AAV Rep78 and Rep68 proteins with missense mutations (Abstract). Samulski teaches ts AAV Rep mutants would be advantageous to provide a functional Rep protein that may be controlled or inactivated at non-permissive temperatures so that the toxicity normally associated with AAV Rep proteins may be diminished or avoided (p. 4, lines 14-17). Samulski teaches the adenovirus vector may further comprise the adenovirus sequences which provide helper functions essential for productive AAV infection, wherein, the helper functions are provided by the adenovirus early genes, which include E2A, E4orf6, and VA RNA adenovirus sequences (p. 35, lines 12-15). Samulski teaches the nucleotide sequence encoding the ts AAV Rep protein may be operably linked with any suitable expression control element (p. 26, lines 29-33). Samulski teaches the promoter/enhancer element may be constitutive or inducible (regulatable promoter), depending on the pattern of expression desired (p. 27, lines 1-5). Samulski teaches inducible expression control elements are preferred in those applications in which it is desirable to provide another level of control over expression of Rep activity (p. 27, lines 8-10). Samulski teaches exemplary inducible promoters/enhancer elements include Tet on/off elements, RU486-inducible promoters, ecdysone-inducible promoters, rapamycin-inducible promoters, and metalothionein promoters (p. 27, lines 17-23).
Samulski teaches a nucleic acid sequence encoding an E4 protein, a nucleic acid sequence encoding a E2A protein, or a nucleic acid sequence encoding a VA RNA (p. 35, lines 12-15), however, is silent to the nucleic acid sequence being operatively linked to a first regulatable promoter. However, Colosi teaches the utilization of regulatable promoters for the expression of such proteins were known in the art.
Colosi teaches polynucleotides for use in recombinant adeno-associated virus virion production (Abstract). Colosi teaches methods for producing rAAV in which an AAV rep coding region and AAV vector sequences are introduced into a suitable host cell (p. 21, lines 14-15). Colosi teaches introducing an accessory function system into the host cell, said accessory function system providing accessory functions for supporting rAAV virion production in the host cell, wherein the accessory function system may comprise an adenovirus E2A 72kD coding region (p. 22, lines 1-6). Colosi teaches a construct carrying the E2A region under the control of a CMV promoter or an ecdysone-inducible promoter (p. 9, lines 13-15). Colosi teaches ecdysone-regulated E2A constructs (p. 39-40, Controlled expression of E1A and E2A genes).
Regarding the limitation directed to wherein the first and second regulatable promoters are different, Samulski and Colosi both teach regulatable (inducible) promoters for the expression of a Rep protein and a helper/accessory (E2A) protein, respectively. Samulski teaches several examples of inducible promoters/control elements which can be utilized with the expression of a Rep protein, to include Tet on/off elements, RU486-inducible promoters, rapamycin-inducible promoters, and metalothionein promoters (p. 27, lines 17-23). These promoters differ from that of Colosi, who teaches a construct carrying the E2A region under the control an ecdysone-inducible promoter (p. 9, lines 13-15).
Samulski in view of Colosi do not teach a forskolin inducible promoter or a hypoxia inducible promoter.
However, Whyteside teaches the use of a regulatory nucleic acid sequences capable of regulating gene expression in eukaryotic cells and which are responsive to the unfolded protein response (UPR) in a eukaryotic cell containing the construct, methods of using such constructs and associated vectors, cells and such like (Abstract). Whyteside teaches regulation of expression that acts at the point of translation as it relates to the use of an intron that is spliced out as a result of the unfolded protein response (UPR) in eukaryotic cells to control expression (p. 2, lines 5-7). Whyteside teaches the unfolded protein response (UPR) is a cellular coping mechanism for endoplasmic reticulum stress (p. 2, lines 9-10). Whyteside teaches the UPR inducible promoter comprises a transcription factor which drives the UPR operatively linked to a minimal promoter sequence, such as the CMV-minimal promoter (p. 14, lines 11-14).
Whyteside teaches an UPR-inducing chemical agents for use in the present invention is forskolin (p. 22, lines 14-15). Whyteside teaches other methods of inducing the unfolded protein response comprise exposing the cells to hypoxia (p. 25, lines 21-22). Whyteside teaches the inducible promoter can suitably comprise the SEQ ID NO: 22, which comprises the CMV-minimal promoter and the UPR inducible promoter sequence (p. 14, lines 1-3 and 19-29), which is 37.8% identical to instant SEQ ID NO: 2, see alignment below.
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The sequence, SEQ ID NO: 22, of Whyteside was also aligned to instant SEQ ID NO: 4-5 and 146-147 and were found to possess less identity than to instant SEQ ID NO: 2. Thus, since Whyteside teaches using an UPR inducible promoter which can be induced by forskolin or hypoxia in the nucleic acid expression constructs to regulate gene expression in eukaryotic cells, Whyteside teaches a hypoxia forskolin inducible promoter that does not have the sequence of instant SEQ ID NO: 2.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the polynucleotide encoding a modified Rep protein of Samulski with the polynucleotide encoding adenovirus E2A coding region under the control of an inducible promoter of Colosi in view of Whyteside with a reasonable expectation of success because both Samulski and Colosi teach methods of viral vector production and Colosi and Whyteside teach regulatable CMV promoters. One would be motivated to utilize the polynucleotide encoding a modified Rep protein of Samulski with the polynucleotide encoding adenovirus E2A coding region under the control of an inducible promoter of Colosi in view of Whyteside because Colosi teaches the Rep coding region need not include all of the wild-type genes but may be altered, e.g., by the insertion, deletion, or substitution of nucleotides, so long as the Rep genes present provide for sufficient integration functions when expressed in a suitable recipient cell (p. 11, line 29 and p. 12, lines 1-2) Additionally, Colosi teaches the induced E2A genes provided increased virion production (Table 4) and Whyteside teaches induce expression of a therapeutic product at the desired time and/or location of location of treatment in gene therapy. Furthermore, the combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007). See MPEP 2141(I).
Regarding claim 2, Samulski teaches nucleotide sequences encoding temperature sensitive (ts) AAV Rep78 and Rep68 proteins with missense mutations (Abstract). The Rep protein comprising a missense mutation reads as a modified Rep protein.
Regarding claim 15, Samulski teaches cells containing the ts AAV Rep proteins preferably stably integrated into the genome of the cell (Abstract). Samulski teaches methods for delivering heterologous nucleic sequences into a broad range of cells, including dividing and non-dividing cells (p. 42, Gene Transfer Technology).
Regarding claim 23, Samulski teaches the nucleotide sequence may further comprise one or more heterologous nucleotide sequences of interest (p. 27, lines 28-31). Samulski teaches the heterologous nucleic acid sequence may encode a reporter (marker) peptide or protein (p. 29, lines 25-29).
Regarding claim 26, Samulski teaches targeted integration of AAV vectors into human and simian chromosomes, as well as animal models containing the targeting locus (p. 43, lines 12-14). Samulski teaches specific integration of AAV vectors into the genome may greatly reduce concerns regarding position effects and chromosome rearrangements and/or disruptions when developing gene delivery strategies (p. 43, lines 16-18). Samulski teaches the ts AAV Rep proteins offer a more reliable means of controlling Rep activity for targeted integration of AAV vectors into host cells (p. 43, lines 26-28). The integration of AAV vectors into host cells reads as stable expression of the nucleic acid construct.
Additionally, Colosi teaches AAV vectors sequences are typically introduced by transfecting packaging cells with plasmids encoding them, including AAV vector sequences in helper viruses, or by stably maintaining these sequences in the cell line, either episomally, or by integrating them into the genome (p. 42, Example 4). Colosi teaches packaging cell line strategies that integrate rep and cap and helper genes into the genome of the packaging cell may give low vector yields due to the low number of gene copies typically integrated by stable transfection procedures (p. 42, Example 5). Colosi teaches to address this problem, the genes which require high levels of expression, i.e., rep and E2A, may be provided to a host cell on an episome (p. 42, example 5). Episomal delivery of these genes read as stable expression.
Regarding claim 28, Samulski teaches the ts AAV Rep proteins offer a more reliable means of controlling Rep activity for targeted integration of AAV vectors into host cells (p. 43, lines 26-28). Samulski teaches the hybrid adenovirus vectors comprising AAV replication and packaging sequences, AAV Rep and Cap, and the adenovirus sequences which provide helper functions essential for productive AAV infection, wherein, the helper functions are provided by the adenovirus early genes, E1A, E2A, E4orf6, and VA RNA adenovirus sequences (p. 35, lines 5-15). The integration of AAV vectors into host cells reads as stable expression of the nucleic acid construct. The early gene delivery reads as a second nucleic acid construct.
Additionally, Colosi teaches episomal E2A and rep/cap genes (p. 42, Example 5). Colosi teaches the episome would encode the rep and cap sequences without the p5 promoter, and ecdysone inducible E2A gene, ori P, the SV40 origin and a selectable marker (p. 43, Example 5, lines 4-5 and Fig. 6). This also reads as two nucleic acid constructs and the episomal delivery reads as at least two nucleic acid constructs are stably expressed.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal: Applicant’s arguments, see pages 8-9 of the response, filed 22 April 2026, with respect to the rejection of claim 1 under 103 have been fully considered and are persuasive. Specifically, the amendment to the claims to include specific inducible promoters and SEQ ID NOs which were not present in the previously presented claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Whyteside. Whyteside teaches the hypoxia inducible promoters and forskolin inducible promoters as required by amended claim 1.
Additionally, Applicant presented results regarding the improved protein expression while utilizing a hypoxia inducible promoter or a forskolin inducible promoter. These results are not commensurate in scope with the claims as the composition claims are directed to a nucleic acid construct and does not require increased protein expression.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Samulski et al. (WO 01/25253 A2, published 12 April 2001, of record) in view of Colosi (WO 01/83797 A1, published 8 November 2001, of record) and Whyteside et al. (WO 2019/038544 A1, published 28 February 2019) as applied to claims 1-2, 5-7, 15, 23, 26, and 28 above, and further in view of Weger et al. (Virology 330 (2004), IDS ref., of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. Applicant did not present any traversal directed to previous rejections of these claims.
Regarding claim 3, Samulski in view of Colosi and Whyteside are silent to the specific lysine to arginine mutation at amino acid 84 (K84R) Rep protein mutation, however, this mutation and its advantages were known in the art.
Weger teaches the large Rep proteins Rep78 and Rep68 of the helper-dependent adeno associated virus type 2 (AAV-2) are essential for both site-specific integration of AAV DNA in the absence of helpervirus and productive AAV replication in the presence of helpervirus (Abstract). Weger teaches modification the largely sumolation-deficient Rep78 lysine to arginine point mutation, at amino acid position 84 (K84R), showed a strongly reduced half-life as compared to the wild-type protein (Abstract and p. 289, 1st column). Weger teaches this finding implicates the role for small ubiquitin-related polypeptide (SUMO-1) in the regulation of Rep78 protein stability which is critical for the establishment and maintenance of AAV latency (Abstract and p. 289, Discussion).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the K84R mutation taught by Weger teaches with the nucleotide sequence encoding the modified Rep protein of Samulski teaches with a reasonable expectation of success because both Samulski and Weger teaches Rep protein mutations to provide a level of expression control. One would be motivated to utilize the K84R mutation taught by Weger with the nucleotide sequence encoding the modified Rep protein of Samulski because Samulski teaches the nucleotide sequence encoding the ts Rep protein may encode other mutations and/or modifications to the Rep protein in addition to the mutation conferring a ts phenotype (p. 26, lines 22-24).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Samulski et al. (WO 01/25253 A2, published 12 April 2001, of record) in view of Colosi (WO 01/83797 A1, published 8 November 2001, of record) and Whyteside et al. (WO 2019/038544 A1, published 28 February 2019) as applied to claims 1-2, 5-7, 15, 23, 26, and 28 above, and further in view of Samanta et al. (Nucleic Acids Research, Vol. 46, No. 17, published 13 June 2018, of record).
This is a new rejection necessitated by Applicant’s amendments to the claims. Applicant did not present any traversal directed to previous rejections of these claims.
Regarding claim 4, Samulski teaches the nucleic acid of interest may encode an antisense nucleic acid, a ribozyme, RNA effecting spliceosome-mediated trans-splicing, or other non-translated RNAs, such as guide RNAs (p. 29, lines 30-34 and p. 30, lines 1-3).
Samulski is silent to position of the ribozyme relative to the nucleic acid encoding the Rep protein.
However, Samanta teaches a polymerase ribozyme can be utilized to label the 3’ end of RNA or DNA molecules by incorporating a variety of functionalized nucleotide analogs (Abstract and Fig. 1).
Therefore, it would have been obvious to one of ordinary skill in the art to have incorporated the ribozyme of Samulski at the 3’ end of the nucleic acid construct encoding the Rep protein with a reasonable expectation of success because Samanta teach a ribozyme can be utilized at the 3’ end of RNA or DNA molecules. One would be motivated to have incorporated the ribozyme of Samulski at the 3’ end of the nucleic acid construct encoding the Rep protein because Samanta teaches a highly efficient polymerase ribozyme can be used to install a wide variety of functionalized nucleotide analogs onto the 3’ end of a target nucleic acid molecule (p. 5, Discussion).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 68 is rejected under 35 U.S.C. 103 as being unpatentable over Samulski et al. (WO 01/25253 A2, published 12 April 2001, of record) in view of Colosi (WO 01/83797 A1, published 8 November 2001, of record) and Whyteside et al. (WO 2019/038544 A1, published 28 February 2019) as applied to claims 1-2, 5-7, 15, 23, 26, and 28 above, and further in view of Beerli et al. (The Journal of Biological Chemistry, Vol. 275, No. 42, published 20 October 2000, of record).
This is a new rejection necessitated by Applicant’s amendments to the claims. Applicant did not present any traversal directed to previous rejections of these claims.
Regarding claim 68, Samulski teaches it will be understood by those skilled in the art that the heterologous nucleotide sequence(s) of interest may be operably associated with appropriate transcription/translation control signals and polyadenylation signals (p. 31, lines 11-14). Samulski teaches the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced (p. 31, lines 18-20).
However, Samulski in view of Colosi and Whyteside are silent to the nucleic acid sequence encoding a Rep protein under the control of a heterologous transcriptional activator, wherein the transcriptional activator is a zinc finger transcriptional activator (ZF-TA).
Beerli teaches ligand-dependent transcriptional regulators were generated by fusion of designed Cys2-His2 zinc finger proteins (Abstract). The zinc finger transcription regulator reads as a zinc finger transcriptional activator (ZF-TA). Beerli teaches together with optimized minimal promoters, these regulators provide 4-hydroxytamoxifen- or RU486-inducible expression systems with induction ratios of up to 3 orders of magnitude (Abstract). Beerli teach these inducible expression systems are functionally independent, and each can be selectively switched on within the same cell (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the ZF-TA taught by Beerli with the nucleic acid construct encoding Rep protein of Samulski with a reasonable expectation of success because Samulski teaches RU486-inducible promoters are one of several inducible promoters used in the expression of the Rep protein (p. 27, lines 17-23), and Beerli teaches the ZF-TA is part of an expression system utilizing the RU486-inducible promoter. One would be motivated to utilize the ZF-TA taught by Beerli with the nucleic acid construct encoding Rep protein of Samulski because Beerli teaches the ability to engineer DNA binding specificities of zinc finger proteins enables the construction of ligand dependent transcriptional regulators with potential for the regulation of virtually any desired artificial or natural promoter (Abstract). Additionally, Beerli teaches the chemically regulated gene switches would be advantageous for utilization in the specific modulation of gene expression (Abstract).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 41 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski et al. (WO 01/25253 A2, published 12 April 2001, of record) in view of Fisher et al. (eLife 2017, published 17 February 2017, of record), Colosi (WO 01/83797 A1, published 8 November 2001, of record), and Whyteside et al. (WO 2019/038544 A1, published 28 February 2019).
This is a new rejection necessitated by Applicant’s amendment to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claim 41, Samulski teaches nucleotide sequences encoding temperature sensitive (ts) AAV Rep78 and Rep68 proteins with missense mutations (Abstract). Samulski teaches ts AAV Rep mutants would be advantageous to provide a functional Rep protein that may be controlled or inactivated at non-permissive temperatures so that the toxicity normally associated with AAV Rep proteins may be diminished or avoided (p. 4, lines 14-17). Samulski teaches the adenovirus vector may further comprise the adenovirus sequences which provide helper functions essential for productive AAV infection, wherein, the helper functions are provided by the adenovirus early genes, which include E2A, E4orf6, and VA RNA adenovirus sequences (p. 35, lines 12-15). Samulski teaches the nucleotide sequence encoding the ts AAV Rep protein may be operably linked with any suitable expression control element (p. 26, lines 29-33). Samulski teaches the promoter/enhancer element may be constitutive or inducible, depending on the pattern of expression desired (p. 27, lines 1-5). Samulski teaches inducible expression control elements are preferred in those applications in which it is desirable to provide another level of control over expression of Rep activity (p. 27, lines 8-10). Samulski teaches exemplary inducible promoters/enhancer elements include Tet on/off elements, RU486-inducible promoters, ecdysone-inducible promoters, rapamycin-inducible promoters, and metalothionein promoters (p. 27, lines 17-23). Therefore, Samulski teaches a first nucleic acid construct comprising a promoter operatively linked to the nucleic acid encoding a Rep protein and a second nucleic acid construct comprising a promoter operatively linked to the nucleic acid encoding a E2A.
However, Samulski does not teach a stop nucleic acid sequence flanked by a first pair of recombinase recognition sequences (RRS) in between the promoter and the nucleic acid encoding a Rep protein or the nucleic acid sequence encoding a E2A.
Fisher teaches FlpStop is a generalized transgenic tool for conditional, cell type-specific disruption of gene function (p. 3, Results). Fisher teaches FlpStop, a small construct for conditional gene disruption capable of integrating into MiMIC insertions (Fig. 1b). Fisher teaches h there are two parallel strategies to disrupt gene expression; first, the construct acts on transcription using the SV40 and Tubα1 transcriptional terminators and second, the construct acts on translation by incorporating the MHC intron 18 splice acceptor followed by stop codons in all three reading frames (p. 3, Results). Fisher teaches disruptive elements, called SA-STOP, are flanked by two pairs of Flp recombinase target (FRT) (RRS) sites that form a FLEx-switch, making the DNA region invertible and thus conditional (p. 3, Results).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the FlpStop taught by Fisher with the nucleic acid constructs taught by Samulski with a reasonable expectation of success because both the FlpStop and the regulatable promoters of Samulski are used as expression control elements. One would be motivated to utilize the FlpStop taught by Fisher with the nucleic acid constructs taught by Samulski because Fisher teaches FlpStop is a generalized transgenic tool for conditional, cell type-specific disruption of gene function, thus, demonstrating the ability of FlpStop to add another layer of regulation to the nucleic acid constructs.
Regarding the limitation regarding the 5’ to 3’ direction, Samulski in view of Fisher do not teach the position of the FlpStop is after the promoter and before the nucleic acid encoding a Rep protein and E2A. However, as a generalized tool for conditional transgenic control, it would have been obvious to one of ordinary skill to position the conditional stop nucleic acids after the promoter with a reasonable expectation of success because placing the stop signal before the nucleic acid to be translated would effectively stop translation of the protein in question. One would be motivated to position the conditional stop nucleic acids after the promoter because this would further aid in the regulation of the nucleic acid constructs.
Samulski in view of Fisher do not teach wherein the promoter of the second nucleic acid construct is a forskolin inducible promoter or a hypoxia inducible promoter, wherein the promoters do not have a sequence of SEQ ID NO: 2, 4, 5, or 146-147.
However, Colosi teaches polynucleotides for use in recombinant adeno-associated virus virion production (Abstract). Colosi teaches methods for producing rAAV in which an AAV rep coding region and AAV vector sequences are introduced into a suitable host cell (p. 21, lines 14-15). Colosi teaches introducing an accessory function system into the host cell, said accessory function system providing accessory functions for supporting rAAV virion production in the host cell, wherein the accessory function system may comprise an adenovirus E2A 72kD coding region (p. 22, lines 1-6). Colosi teaches a construct carrying the E2A region under the control of a CMV promoter or an ecdysone-inducible promoter (p. 9, lines 13-15). Colosi teaches ecdysone-regulated E2A constructs (p. 39-40, Controlled expression of E1A and E2A genes).
Additionally, Whyteside teaches the use of a regulatory nucleic acid sequences capable of regulating gene expression in eukaryotic cells and which are responsive to the unfolded protein response (UPR) in a eukaryotic cell containing the construct, methods of using such constructs and associated vectors, cells and such like (Abstract). Whyteside teaches regulation of expression that acts at the point of translation as it relates to the use of an intron that is spliced out as a result of the unfolded protein response (UPR) in eukaryotic cells to control expression (p. 2, lines 5-7). Whyteside teaches the unfolded protein response (UPR) is a cellular coping mechanism for endoplasmic reticulum stress (p. 2, lines 9-10). Whyteside teaches the UPR inducible promoter comprises a transcription factor which drives the UPR operatively linked to a minimal promoter sequence, such as the CMV-minimal promoter (p. 14, lines 11-14).
Whyteside teaches an UPR-inducing chemical agents for use in the present invention is forskolin (p. 22, lines 14-15). Whyteside teaches other methods of inducing the unfolded protein response comprise exposing the cells to hypoxia (p. 25, lines 21-22). Whyteside teaches the inducible promoter can suitably comprise the SEQ ID NO: 22, which comprises the CMV-minimal promoter and the UPR inducible promoter sequence (p. 14, lines 1-3 and 19-29), which is 37.8% identical to instant SEQ ID NO: 2, see alignment below.
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The sequence, SEQ ID NO: 22, of Whyteside was also aligned to instant SEQ ID NO: 4-5 and 146-147 and were found to possess less identity than to instant SEQ ID NO: 2. Thus, since Whyteside teaches using an UPR inducible promoter which can be induced by forskolin or hypoxia in the nucleic acid expression constructs to regulate gene expression in eukaryotic cells, Whyteside teaches a hypoxia forskolin inducible promoter that does not have the sequence of instant SEQ ID NO: 2.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the polynucleotide encoding a Rep protein of Samulski in view of Fisher with the polynucleotide encoding adenovirus E2A coding region under the control of an inducible promoter of Colosi in view of Whyteside with a reasonable expectation of success because both Samulski and Colosi teach methods of viral vector production and Colosi and Whyteside teach regulatable CMV promoters. One would be motivated to utilize the polynucleotide encoding a Rep protein of Samulski in view of Fisher with the polynucleotide encoding adenovirus E2A coding region under the control of an inducible promoter of Colosi in view of Whyteside because Colosi teaches the Rep coding region need not include all of the wild-type genes but may be altered, e.g., by the insertion, deletion, or substitution of nucleotides, so long as the Rep genes present provide for sufficient integration functions when expressed in a suitable recipient cell (p. 11, line 29 and p. 12, lines 1-2) Additionally, Colosi teaches the induced E2A genes provided increased virion production (Table 4) and Whyteside teaches induce expression of a therapeutic product at the desired time and/or location of location of treatment in gene therapy. Furthermore, the combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007). See MPEP 2141(I).
Regarding claim 49, Samulski teaches cells containing the ts AAV Rep proteins preferably stably integrated into the genome of the cell (Abstract). Samulski teaches methods for delivering heterologous nucleic sequences into a broad range of cells, including dividing and non-dividing cells (p. 42, Gene Transfer Technology).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal: Applicant’s arguments, see pages 8-9 of the response, filed 22 April 2026, with respect to the rejection of claim 41 under 103 have been fully considered and are persuasive. Specifically, the amendment to the claims to include specific inducible promoters and SEQ ID NOs which were not present in the previously presented claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Whyteside. Whyteside teaches the hypoxia inducible promoters and forskolin inducible promoters as required by amended claim 41.
Claims 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski et al. (WO 01/25253 A2, published 12 April 2001, of record) in view of Fisher et al. (eLife 2017, published 17 February 2017, of record), Colosi (WO 01/83797 A1, published 8 November 2001, of record), and Whyteside et al. (WO 2019/038544 A1, published 28 February 2019) as applied to claim 41 and 49 above, and further in view of Raymond et al. (PLoS ONE 2(1), published 17 January 2007, of record).
This is a new rejection necessitated by Applicant’s amendment to the claims. Applicant did not present any traversal directed to previous rejections of these claims.
Regarding claim 42, Samulski teaches the nucleotide sequence may further comprise one or more heterologous nucleotide sequences of interest (p. 27, lines 28-31). Samulski teaches the heterologous nucleic acid sequence may encode a reporter (marker) peptide or protein and reporter proteins are known in the art (p. 29, lines 25-29).
However, Samulski in view of Fisher, Colosi, and Whyteside are silent to the nucleic acid construct further comprising a selection marker flanked between a third pair of RRSs.
Raymond teaches a reporter assay utilizing the PGK neo 4x pA cassette flanked by either a pair of loxP, FRT, or attB/attP in the same orientation with respect to each other (fig. 1A). PGK neo 4x pA refers to a genetic construct specifically a DNA cassette featuring the Phosphoglycerate Kinase (PGK) promoter, the neomycin resistance (neo) gene, and four polyadenylation (4x pA) signals, used as a selectable marker for gene targeting or insertion in mammalian cells.
Therefore, it would have been obvious to one of ordinary skill in the art to include nucleic acid construct further comprising a selection marker flanked between a third pair of RRSs with the nucleic acid construct of claim 41 with a reasonable expectation of success because using selectable markers are well known molecular biology technique known in the art. One would be motivated to include a selectable marker flanked by RRSs operatively linked to a promoter for a Rep protein and/or E2A because this would enable the ability to select cells which have effectively translated the protein in question, i.e., Rep protein and/or E2A.
Regarding claim 43, Raymond teaches the RRSs for the selectable marker cassette (the third pair of RRSs) can be FRT, a flipase-responsive RRS.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
Regarding claim 6, Samulski in view of Whyteside are the closest prior art references. Samulski teaches exemplary inducible promoters/enhancer elements include Tet on/off elements, RU486-inducible promoters, ecdysone-inducible promoters, rapamycin-inducible promoters, and metalothionein promoters (p. 27, lines 17-23). Whyteside teaches hypoxia and forskolin inducible promoters as. However, Samulski and Whyteside do not teach a promoter selected from SEQ ID NO: 1, 3, 6-9, 144-145, or 197-202.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6, 15, 23, 26, 28, 41-43, 49, and 68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 15, 24, 26, 28, 41-43, 49, and 68 of copending Application No. 17/907,232 (reference application).
This is a new rejection necessitated by Applicant’s amendments to the claims. Applicant requests the nonstatutory double patenting rejection be held in abeyance until allowable subject matter can be identified, in the response filed 22 April 2026.
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
Regarding claim 1, reference claim 1 disclose all of the limitations of the claim to include the forskolin inducible promoter not having the sequence of SEQ ID NO: 146-147 and the hypoxia forskolin inducible promoter not having the sequence of SEQ ID NO: 4 and 5.
Regarding claims 2-4, reference claims 2-4 disclose all of the limitations of instant claims 2-4.
Regarding claim 6, reference claim 6 discloses nucleic acid construct comprising the forskolin inducible promoter SEQ ID NO: 6 and the hypoxia forskolin inducible promoter SEQ ID NO: 1 and 3.
Regarding claim 15, reference claim 15 discloses the nucleic acid construct of claim 1 in a cell.
Regarding claim 23, reference claim 24 discloses the cell of claim 15 further comprising a nucleic acid sequence encoding a marker protein. The other limitations of the instant claim are presented in the alternative, therefore, the instant claim reads as the cell of claim 15, further comprising a nucleic acid sequence encoding a marker protein.
Regarding claims 26 and 28, reference claims 26 and 28 are identical to the instant claim respectively.
Regarding claim 41, reference claim 41 discloses all of the limitations of instant claim 41 to include the forskolin inducible promoter not having the sequence of SEQ ID NO: 146-147 and the hypoxia forskolin inducible promoter not having the sequence of SEQ ID NO: 4 and 5.
Regarding claims 42 and 43, reference claims 42 and 43 are identical to instant claims 42 and 43.
Regarding claim 49, reference claim 49 discloses a cell comprising the nucleic acid construct of claim 41.
Regarding claim 68, reference claim 68 is identical to instant claim 68.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/N.A.H./Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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