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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-8, 10, 13-16, 19-20, and 22-24 in the reply filed on 15 October 2025 is acknowledged.
Claims 25-26, 37, 39, and 41-46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 15 October 2025.
Applicant has canceled claim 6 in the response filed 11 March 2026, Group I now consists of claims 1-5, 7-8, 10, 13-16, 19-20, and 22-24.
Claim Status
Claims 9, 11-12, 17-18, 21, 27-36, 38, and 40 were previously canceled, claim 6 is newly canceled, claims 1 and 13 have been amended, claims 25-26, 37, 39, and 41-46 stand withdrawn, claims 1-5, 7-8, 10, 13-16, 19-20, 22-24 have been considered on their merits.
Withdrawn Rejections
The rejections under 35 USC § 102 have been withdrawn due to Applicant’s amendments to the claims. However, upon further consideration a new rejection has been made in view of the same references of record.
The rejections under 35 USC § 103 have been withdrawn due to Applicant’s amendments to the claims. However, upon further consideration a new rejection has been made in view of the same references of record.
The provisionally nonstatutory double patenting rejections have been withdrawn due to Applicant’s amendments to the claims. However, upon further consideration a new rejection has been made in view of the same references of record.
Claim Objections
Claims 2-3, 5, 8, 14-15, and 20 are objected to because of the following informalities: the claim status indicators read as “Original” when they should read “Previously Presented”. Appropriate correction is required.
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 applicant regards as his invention.
Claim 5 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 amendment to the claims.
Claim 5, which depends from claim 4 and ultimately depends from claim 1, recites the phrase “wherein the inducible promoter”. It is unclear to what inducible promoter this phrase refers as claim 1 requires two inducible promoters.
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.
Claims 4-5 are 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 4, which depends from claim 1, requires the limitation “wherein at least one promoter is an inducible promoter”, however, claim 1 already requires two inducible promoters. Therefore, claim 4 does not further limit claim 1.
Claim 5, which ultimately depends from claim 1, requires the limitation “wherein the inducible promoter comprises a doxycycline-inducible promoter, a mifepristone-inducible promoter, or a cumate-inducible promoter”, however claim 1 already requires two inducible promoters comprising a doxycycline-inducible promoter, a mifepristone-inducible promoter, or a cumate-inducible promoter. Therefore, claim 5 does not further limit claim 1.
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.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 7-8, 10, 13-16, 19-20, and 23-24 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Chanas et al. (WO 2020/078953, published 23 April 2020, of record) as evidenced by Gonçalves (Virology Journal 2005, published 06 May 2005, IDS ref., of record).
This is a new rejection made in response to Applicant's amendments to the claims that is substantially similar to a previous rejection of record. Any aspect of Applicant's traversal relevant to the new rejection of record is addressed below.
Regarding claim 1, Chanas teaches methods for producing the AAV vector producer cell lines (Abstract). Chanas teaches AAV vector producer cell line wherein all of the nucleic acid sequences encoding the viral genes (AAV and helper virus) and transgene essential for recombinant AAV production are integrated together at a single locus within the AAV vector producer cell genome and in which expression of the Rep proteins may be regulated to allow efficient manipulation of the producer cell line (p. 2, lines 20-24). Chanas teaches all of the
genes incorporated in the vector will integrate at one locus within the endogenous mammalian host cell genome (p. 3, lines 22-23). Chanas teaches the term “producer cell” refers to a cell line with AAV packaging genes, the helper virus genes, and a DNA genome of the recombinant AAV vector, stably integrated into the host genome (p. 6, lines 10-13). The producer cell of Chanas reads as a stable mammalian cell line.
Regarding the limitations directed to the first polynucleotide, Chanas teaches the expression of Rep is controlled by using an expression control system in which all the rep transcripts from both the rep promoters, P5 and P19, are prematurely terminated until a time point wherein expression of Rep is desired (p. 2, lines 25-27). Chanas teaches the rep gene will generally encode at least one large Rep protein (i.e., Rep78/68) (p. 12, lines 8-9). Chanas teaches inducible expression systems are advantageous in applications in which it is desirable to provide regulation over expression of specific nucleic acid sequences (p. 20, Inducible Promoters). Chanas teaches exogenous control over recombinase regulated Rep expression is obtained by operably linking an inducible promoter to the nucleic acid sequences encoding the recombinase gene (p. 20, Inducible Promoters). Chanas teaches the inducible promoter is a Tet responsive promoter (Ptet promoter), wherein the Tet responsive promoter comprises at least one Tet operon (Tetracycline-Controlled Transcriptional Activation) which is turned on or off in the presence of tetracycline or one of its derivatives (pp. 20-21). Therefore, the inducible expression system of Chanas reads as the first polynucleotide operably linked to a first inducible promoter comprising a doxycycline-inducible promoter, as the addition of doxycycline would result in Rep expression.
Regarding the limitations directed to the second and third polynucleotides, Chanas teaches the helper virus genes comprise an E4 ORF6 coding region, an adenovirus E2A 72 kD coding region (coding region for the DNA-binding protein), and a VA gene (p. 15, lines 2-5). Chanas teaches a CMV-TO2 promoter is operably linked to E2A gene and E4 gene (p. 15, lines 17-18). The helper virus genes read as a second and third polynucleotide encoding Ad E4orf6 and Ad DBP operably linked to promoters. Chanas teaches a first and second inducible promoter in CMV-TO2, a doxycycline-inducible promoter, in both the E2A and E4 polynucleotides, which are operably linked to said promoters (Fig. 5).
Regarding claims 2 and 3, Chanas teaches a CMV-TO2 promoter is operably linked to E2A gene and E4 gene (p. 15, lines 17-18). The CMV promoter reads as at least one promoter is an exogenous (claim 2) and a non-AAV promoter (claim 3).
Regarding claims 4 and 5, Chanas teaches exogenous control over expression of the helper virus genes is also obtained by a transcriptional control element operably linked to one or more of the helper virus genes (p. 20, lines 29-30). Chanas teaches the transcriptional control element may be an inducible promoter (claim 4) where a native promoter is to be used (p. 20, lines 31-32). Chanas teaches the inducible promoter is a Tet responsive promoter, wherein transcription is reversibly turned on or off in the presence of the antibiotic tetracycline or one of its derivatives, doxycycline (DOX) (claim 5) (p. 20, lines 35-37 and p. 21, lines 1-2). Chanas teaches the promoter is pCMV-TO2, a Pol II promoter, containing a CMV enhancer and promoter upstream of 2x Tet operon sequences (p. 22, lines 1-2).
Regarding claim 7, Chanas teaches the AAV vector producer cell of the present invention comprises a dual splicing switch within the rep gene for controlling expression of Rep proteins. The dual splicing switch is an intron comprising an excisable transcription termination sequence (''terminating intron'') (p. 16, lines 5-7). Chanas teaches the terminating intron is positioned within the Rep coding region (p. 16, line 12). Chanas teaches, in one embodiment, the terminating intron is positioned within Rep coding region downstream of the p19 promoter, therefore, the terminating intron is positioned within a reading frame shared by all four Rep proteins, such that expression of all four rep gene products can be simultaneously controlled (p. 16, lines 21-24). Chanas teaches the termination intron comprises 3 polyA signal sequences in tandem (p. 16, lines 34-35). The polyA signal sequences read as a tag in the first polynucleotide and the dual splicing switch reads as a destabilization domain. Alternatively, Chanas teaches a cell line with the rep gene under control of the dual splicing switch, in one embodiment, the gene of the transcription terminating sequence is a selectable marker, such as, without limitation, hygromycin, puromycin or blasticidin S resistance genes (p. 17, lines 5-8). The selectable marker also reads as a tag for the destabilization domain.
Regarding claim 8, Chanas teaches the rep gene is activated in the presence of a recombinase enzyme (recombinase) as the terminating intron is removed from the rep gene (p. 17, lines 9-10). Recombinase reads as a ligand, therefore, the dual splicing switch of Chanas read as a ligand-responsive destabilization domain. Additionally, Chanas teaches, in a further embodiment, the recombinase control system comprises a mutated steroid hormone receptor ligand-binding domain operably linked to the recombinase gene (p. 19, lines 34-35).
Regarding claim 10, Chanas teaches the term "producer cell" refers to a cell line with AAV packaging genes (rep and cap genes), the helper virus genes as required and a DNA genome of the recombinant AAV vector, (e.g. a transgene of interest flanked by the two AAV inverted terminal repeats (ITRs)), stably integrated into the host cell genome (p. 6, lines 10-13). Chanas teaches the AAV ITRs will be at the 5’ and 3’ ends of the vector genome and flank the transgene (p. 12, lines 20-23). The promoter is operably linked to the transgene, as can be seen in the figure above, indicated by the black arrow with a right angle bend (Fig. 5).
Regarding claim 13, Chanas teaches the expression of Rep is controlled by using an expression control system in which all the rep transcripts from both the rep promoters, P5 and P19, are prematurely terminated until a time point wherein expression of Rep is desired (p. 2, lines 25-27). Chanas teaches the rep gene will generally encode at least one large Rep protein (i.e., Rep78/68) and one small Rep protein (i.e., Rep52/40) (p. 12, lines 8-10). This reads as the first polynucleotide encoding a large Rep protein operably linked to a promoter and the fifth polynucleotide encoding an AAV small Rep protein operably linked to a promoter.
Chanas teaches the helper virus genes comprise an E4 ORF6 coding region, an adenovirus E2A 72 kD coding region (coding region for the DNA-binding protein), and a VA gene (p. 15, lines 2-5). Chanas teaches a CMV-TO2 promoter is operably linked to E2A gene and E4 gene (p. 15, lines 17-18). Chanas teaches by integrating the helper virus genes required for AAV vector production into the host cell genome does not require co-infection with a wild-type helper virus (p. 15, lines 20-22). The helper virus genes read as a second and third polynucleotide encoding Ad E4orf6 and Ad DBP operably linked to promoters.
Chanas teaches the AAV capsid (cap) gene encodes the structural proteins that form a
functional AAV capsid, wherein, in one embodiment, the Cap proteins comprise VP1, VP2 and/or VP3 (p. 12, lines 16-19). Chanas teaches the skilled person will understand that the cap gene is transcribed from the p40 promoter (p. 24, lines 19-20). This reads as the fourth polynucleotide encoding AAV capsid protein operably linked to a promoter.
Chanas teaches the polynucleotide encoding the Cap protein (fourth polynucleotide) are transcribed from the p40 promoter and the polynucleotide encoding the Rep protein (first polynucleotide) are transcribed by rep promoters, P5 and P19. This reads as the first and fourth polynucleotide are operably linked to different promoters.
Therefore, Chanas teaches the limitations of claim 13.
Regarding claims 14-16, Chanas teaches a CMV-TO2 promoter is operably linked to E2A gene and E4 gene (p. 15, lines 17-18). The CMV promoter reads as at least one promoter is an exogenous (claim 14) and a non-AAV promoter (claim 15). Chanas teaches exogenous control over expression of the helper virus genes is also obtained by a transcriptional control element operably linked to one or more of the helper virus genes (p. 20, lines 29-30). Chanas teaches the transcriptional control element may be an inducible promoter (claim 16) where a native promoter is to be used (p. 20, lines 31-32). Chanas teaches the inducible promoter is a Tet responsive promoter, wherein transcription is reversibly turned on or off in the presence of the antibiotic tetracycline or one of its derivatives, doxycycline (DOX) (p. 20, lines 35-37 and p. 21, lines 1-2).
Regarding claim 19, Chanas teaches The AAV vector producer cell of the present invention comprises a dual splicing switch within the rep gene for controlling expression of Rep proteins. The dual splicing switch is an intron comprising an excisable transcription termination sequence (''terminating intron'') (p. 16, lines 5-7). Chanas teaches the terminating intron is positioned within the Rep coding region (p. 16, line 12). Chanas teaches, in one embodiment, the terminating intron is positioned within Rep coding region downstream of the p19 promoter, therefore, the terminating intron is positioned within a reading frame shared by all four Rep proteins, such that expression of all four rep gene products can be simultaneously controlled (p. 16, lines 21-24). Chanas teaches the termination intron comprises 3 polyA signal sequences in tandem (p. 16, lines 34-35). The polyA signal sequences read as a tag in the first polynucleotide and the dual splicing switch reads as a destabilization domain. Alternatively, Chanas teaches a cell line with the rep gene under control of the dual splicing switch, in one embodiment, the gene of the transcription terminating sequence is a selectable marker, such as, without limitation, hygromycin, puromycin or blasticidin S resistance genes (p. 17, lines 5-8). The selectable marker also reads as a tag for the destabilization domain.
Regarding claim 20, Chanas teaches the rep gene is activated in the presence of a recombinase enzyme (recombinase) as the terminating intron is removed from the rep gene (p. 17, lines 9-10). Recombinase reads as a ligand, therefore, the dual splicing switch of Chanas read as a ligand-responsive destabilization domain. Additionally, Chanas teaches, in a further embodiment, the recombinase control system comprises a mutated steroid hormone receptor ligand-binding domain operably linked to the recombinase gene (p. 19, lines 34-35).
Regarding claim 23, “inefficient” is considered a relative term, however, an inefficient start codon is a term of art, and is considered any non-AUG start codons. The fourth polynucleotide has been engineered, therefore, any inefficient start codon reads as an engineered inefficient translation start codon as none of the claimed polynucleotides would have occurred in the mammalian cell.
Chanas teaches the AAV capsid (cap) gene encodes the structural proteins that form a functional AAV capsid, wherein, in one embodiment, the Cap proteins comprise VP1, VP2 and/or VP3 (p. 12, lines 16-19). Chanas teaches the skilled person will understand that the cap gene is transcribed from the p40 promoter (p. 24, lines 19-20). The p40 promoter is known in the art to utilize alternative splicing in order to produce the capsid proteins, specifically, VP2 utilizes an inefficient start codon, as evidenced by Gonçalves in order to achieve the appropriate capsid ratios. Gonçalves teach the cap gene is transcribed from a single promoter at map position 40 (p40) and alternative splicing at two acceptor sites originates two transcripts (p. 2, 2nd column). Gonçalves teach the larger transcript encodes VP1 and the shorter mRNA possesses a noncanonical start codon (ACG) (ineffective translation start codon), which is utilized to generate VP2, and a downstream conventional initiation codon (AUG) directing the synthesis of VP3 (p. 2, 2nd column). Therefore, the polynucleotide encoding the AAV capsid protein taught by Chanas read as comprising an engineered inefficient translation start codon.
Regarding claim 24, Chanas teaches the term "producer cell" refers to a cell line with AAV packaging genes (rep and cap genes), the helper virus genes as required and a DNA genome of the recombinant AAV vector, (e.g. a transgene of interest flanked by the two AAV inverted terminal repeats (ITRs)), stably integrated into the host cell genome (p. 6, lines 10-13). Chanas teaches the AAV ITRs will be at the 5’ and 3’ ends of the vector genome and flank the transgene (p. 12, lines 20-23). The promoter is operably linked to the transgene, as can be seen in the figure above, indicated by the black arrow with a right angle bend (Fig. 5).
Thus, the reference anticipates the subject matter of claims 1-5, 7-8, 10, 13-16, 19-20, and 23-24.
Response to Traversal
Applicant's arguments filed 11 March 2026 have been fully considered but they are not persuasive.
Applicant’s traversal has been fully considered but is considered moot in light of the new rejection as the reference of record teaches the new limitations.
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.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Chanas et al. (WO 2020/078953, published 23 April 2020, of record) as applied to claims 1-5, 7-8, 10, 13-16, 19-20, and 23-24 above, and further in view of Becerra et al. (Journal of Virology, Aug. 1988, of record).
This is a new rejection made in response to Applicant’s amendment to the claims that is substantially similar to the previous rejection of record. Any aspect of Applicant’s traversal relevant to the new rejection is addressed below.
Chanas et al. anticipate the subject matter of claims 1-5, 7-8, 10, 13-16, 19-20, and 23-24, and thus, also render them obvious.
Regarding claim 22, Chanas is silent to the polynucleotide, encoding an mRNA for the capsid protein, missing at least one native intron, however, doing so would have been obvious in view of Becerra.
It is believed that Becerra, when discussing the capsid protein is utilizing a different nomenclature for the individual proteins which make up the capsid, protein A, B, and C. Therefore, these proteins have been interpreted utilizing the modern nomenclature, VP1, VP2, and VP3.
Becerra teaches methods for synthesis of AAV structural proteins and analyzed the in vitro translation of AAV capsid proteins from synthetic transcripts and the in vivo expression of AAV mRNA and capsid proteins in 293 cells transfected with AAV DNA constructs (Abstract). Becerra teaches in vitro synthesis of AAV RNA transcripts, specifically, 5’-end deletion constructs, pE, pAha, and pX, which yielded RNA transcripts with successively shorter leader sequences (p. 2474, Results). Becerra teaches the pAha-derived RNA, the AAV sequence starts at the AhaIII site, downstream from the origin of AAV sequences in pM-derived RNA, which yields an RNA resembling the natural unspliced p40 transcript (p. 2474, Results). Becerra teaches pAha was constructed to yield a transcript with most of the natural intron deleted, except for a terminal segment of only 34 bases (p. 2474, Results). Becerra teaches the pAha-derived RNA efficiently translated protein A (VP1), even though the template used to prepare this to transcript contained only a small portion of the intervening sequences (i.e., the last 34 bases of the intron) (p. 2748, 2nd column). Becerra teaches these results demonstrate that translation of VP1 is greatly enhanced by removal of upstream intervening sequences (introns) in the 5' leader of the synthetic equivalent of the unspliced p40 transcript (p. 2748, 2nd column).
Therefore, it would have been obvious to construct the fourth polynucleotide with at least one missing native intron with a reasonable expectation of success because Becerra teaches that translation of VP1 is greatly enhanced by removal of native introns. Thus, one would be motivated to construct the polynucleotide encoding the AAV capsid protein of Chanas in view of the teachings of Becerra because doing so would provide improved efficiency in the production of the capsid protein and Chanas teaches methods for producing the AAV vector producer cell lines which would benefit from efficient production of the structural proteins. Additionally, the absence of introns ensures the gene can be expressed without relying on the host cell's splicing machinery, or avoids potential issues like alternative splicing, which can produce different protein variants, as seen with AAV capsid proteins, or nonsense-mediated decay if splicing is inefficient.
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 filed 11 March 2026 have been fully considered but they are not persuasive.
Applicant’s traversal has been fully considered but is considered moot in light of the new rejection as the reference of record teaches the new limitations.
Applicant argues Becerra fails to cure the deficiencies of Chanas, this argument is not persuasive because Chanas was not found to be deficient.
In response to applicant's argument that Becerra fails to teach or suggest a stable mammalian cell line comprising a first polynucleotide encoding an AAV large Rep protein and that the fourth polynucleotide encoding an AAV capsid protein, wherein the first polynucleotide and the fourth polynucleotide are operably linked to two different promoters, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
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 1-5, 7-8, 10, 13-16, 19-20, and 22-24, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of copending Application No. 18/990,358 (reference application) in view of Chanas et al. (WO 2020/078953, published 23 April 2020) and Becerra et al. (Journal of Virology, Aug. 1988) as evidenced by Gonçalves (Virology Journal 2005, published 06 May 2005, IDS ref.).
This is a new rejection made in response to Applicant’s amendment to the claims that is substantially similar to the previous rejection of record. Any aspect of Applicant’s traversal relevant to the new rejection is addressed below.
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims render obvious the instant claims.
Regarding claims 1-5, 10, 13-16, reference claims 1-8 recite a stable mammalian cell line comprising a polynucleotide encoding one or more, AAV REP, AAV CAP , Ad E4orf6, and Ad E2-DNA binding protein (E2DBP). The E2DBP reads as an Ad DBP. Reference claim 1B teach a polynucleotide sequence integrated in the genome of the stable mammalian cell encoding a polypeptide of interest (gene of interest) flanked by ITR, (claim 10 and 24). Reference claim 8 teach inducibly and constitutively expressed polynucleotides are operably linked to different promoters. The reference claims do not specify which Rep proteins are expressed, however, absent evidence to the contrary, this is interpreted as encoding all Rep proteins which include both large and small proteins (claim 13).
The reference claims are silent to the inducible promoters comprising a doxycycline-inducible promoter, a mifepristone-inducible promoter, or a cumate-inducible promoter.
However, Chanas teaches inducible expression systems are advantageous in applications in which it is desirable to provide regulation over expression of specific nucleic acid sequences (p. 20, Inducible Promoters). Chanas teaches the inducible promoter is a Tet responsive promoter (Ptet promoter), wherein the Tet responsive promoter comprises at least one Tet operon (Tetracycline-Controlled Transcriptional Activation) which is turned on or off in the presence of tetracycline or one of its derivatives, i.e., doxycycline (pp. 20-21).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the doxycycline-inducible promoter of Chanas with a reasonable expectation of success because doxycycline inducible promoters are well known in the art. One would have been motivated to utilize the doxycycline-inducible promoter of Chanas because doxycycline-inducible promoters are known to be a useful tool for regulating expression of nucleic acids in a controlled manner.
The reference claims are silent to the polynucleotides being operably linked to a promoter. However, the use of a promoter to express polynucleotides is obvious.
Chanas teaches methods for producing the AAV vector producer cell lines (Abstract). Chanas teaches the expression of Rep is controlled by using an expression control system in which all the rep transcripts from both the rep promoters, P5 and P19, are prematurely terminated until a time point wherein expression of Rep is desired (p. 2, lines 25-27). Chanas teaches the helper virus genes comprise an E4 ORF6 coding region, an adenovirus E2A 72 kD coding region (coding region for the DNA-binding protein), and a VA gene (p. 15, lines 2-5). Chanas teaches a CMV-TO2 promoter (exogenous promoter) is operably linked (claims 1-3 and 14-15) to E2A gene and E4 gene (p. 15, lines 17-18). Chanas teaches the transcriptional control element may be an inducible promoter (claims 4 and 16) where a native promoter is to be used (p. 20, lines 31-32). Chanas teaches the inducible promoter is a Tet responsive promoter, wherein transcription is reversibly turned on or off in the presence of the antibiotic tetracycline or one of its derivatives, doxycycline (DOX) (claim 5) (p. 20, lines 35-37 and p. 21, lines 1-2). Chanas teaches a first and second inducible promoter in CMV TO2, a doxycycline-inducible promoter, in both the E2A and E4 polynucleotides, which are operably linked to said promoters (claim 6). See Chanas Figure 5 below, wherein, all of the individual expression cassettes possess operably linked promoters:
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Regarding claim 23, “inefficient” is considered a relative term, however, an inefficient start codon is a term of art, and is considered any non-AUG start codons. The fourth polynucleotide has been engineered, therefore, any inefficient start codon reads as an engineered inefficient translation start codon as none of the claimed polynucleotides would have occurred in the mammalian cell.
Chanas teaches the AAV capsid (cap) gene encodes the structural proteins that form a functional AAV capsid, wherein, in one embodiment, the Cap proteins comprise VP1, VP2 and/or VP3 (p. 12, lines 16-19). Chanas teaches the skilled person will understand that the cap gene is transcribed from the p40 promoter (p. 24, lines 19-20). The p40 promoter is known in the art to utilize alternative splicing in order to produce the capsid proteins, specifically, VP2 utilizes an inefficient start codon, as evidenced by Gonçalves in order to achieve the appropriate capsid ratios. Gonçalves teach the cap gene is transcribed from a single promoter at map position 40 (p40) and alternative splicing at two acceptor sites originates two transcripts (p. 2, 2nd column). Gonçalves teach the larger transcript encodes VP1 and the shorter mRNA possesses a noncanonical start codon (ACG) (ineffective translation start codon), which is utilized to generate VP2, and a downstream conventional initiation codon (AUG) directing the synthesis of VP3 (p. 2, 2nd column). Therefore, the polynucleotide encoding the AAV capsid protein taught by Chanas read as comprising an engineered inefficient translation start codon.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize operably linked promoters to express polynucleotides expressing AAV helper and viral genes as it is well-known in the art and without a promoter, only a very low, non-meaningful level of background expression may occur, which is significantly lower than that achieved with a proper promoter.
Regarding claims 7-8 and 19-20, reference claims do not teach a ligand-responsive destabilization domain.
However, Chanas teaches the AAV vector producer cell of the present invention comprises a dual splicing switch within the rep gene for controlling expression of Rep proteins. The dual splicing switch is an intron comprising an excisable transcription termination sequence (''terminating intron'') (p. 16, lines 5-7). Chanas teaches the terminating intron is positioned within the Rep coding region (p. 16, line 12). Chanas teaches, in one embodiment, the terminating intron is positioned within Rep coding region downstream of the p19 promoter, therefore, the terminating intron is positioned within a reading frame shared by all four Rep proteins, such that expression of all four rep gene products can be simultaneously controlled (p. 16, lines 21-24). Chanas teaches the termination intron comprises 3 polyA signal sequences in tandem (p. 16, lines 34-35). The polyA signal sequences read as a tag in the first polynucleotide and the dual splicing switch reads as a destabilization domain (claims 7 and 19). Alternatively, Chanas teaches a cell line with the rep gene under control of the dual splicing switch, in one embodiment, the gene of the transcription terminating sequence is a selectable marker, such as, without limitation, hygromycin, puromycin or blasticidin S resistance genes (p. 17, lines 5-8). The selectable marker also reads as a tag for the destabilization domain. Chanas teaches the rep gene is activated in the presence of a recombinase enzyme (recombinase) as the terminating intron is removed from the rep gene (p. 17, lines 9-10). Recombinase reads as a ligand, therefore, the dual splicing switch of Chanas read as a ligand-responsive destabilization domain (claims 8 and 20). Additionally, Chanas teaches, in a further embodiment, the recombinase control system comprises a mutated steroid hormone receptor ligand-binding domain operably linked to the recombinase gene (p. 19, lines 34-35).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize ligand-responsive destabilization domains as it is well-known in the art and a ligand-responsive destabilization domain is a useful tool for conditionally and reversibly control the abundance and function of a specific protein within a cell. It provides a mechanism for regulating the end-product of polynucleotide expression at the post-translational level.
Regarding claim 22, the reference claims in view of Chanas are silent to the polynucleotide, encoding an mRNA for the capsid protein, missing at least one native intron, however, doing so would have been obvious in view of Becerra.
It is believed that Becerra, when discussing the capsid protein is utilizing a different nomenclature for the individual proteins which make up the capsid, protein A, B, and C. Therefore, these proteins have been interpreted utilizing the modern nomenclature, VP1, VP2, and VP3.
Becerra teaches methods for synthesis of AAV structural proteins and analyzed the in vitro translation of AAV capsid proteins from synthetic transcripts and the in vivo expression of AAV mRNA and capsid proteins in 293 cells transfected with AAV DNA constructs (Abstract). Becerra teaches in vitro synthesis of AAV RNA transcripts, specifically, 5’-end deletion constructs, pE, pAha, and pX, which yielded RNA transcripts with successively shorter leader sequences (p. 2474, Results). Becerra teaches the pAha-derived RNA, the AAV sequence starts at the AhaIII site, downstream from the origin of AAV sequences in pM-derived RNA, which yields an RNA resembling the natural unspliced p40 transcript (p. 2474, Results). Becerra teaches pAha was constructed to yield a transcript with most of the natural intron deleted, except for a terminal segment of only 34 bases (p. 2474, Results). Becerra teaches the pAha-derived RNA efficiently translated protein A (VP1), even though the template used to prepare this to transcript contained only a small portion of the intervening sequences (i.e., the last 34 bases of the intron) (p. 2748, 2nd column). Becerra teaches these results demonstrate that translation of VP1 is greatly enhanced by removal of upstream intervening sequences (introns) in the 5' leader of the synthetic equivalent of the unspliced p40 transcript (p. 2748, 2nd column).
Therefore, it would have been obvious to construct the fourth polynucleotide with at least one missing native intron because Becerra teaches that translation of VP1 is greatly enhanced by removal of native introns and doing so would provide improved efficiency in the production of the capsid protein. and Chanas teaches methods for producing the AAV vector producer cell lines which would benefit from efficient production of the structural proteins. Additionally, the absence of introns ensures the gene can be expressed without relying on the host cell's splicing machinery, or avoids potential issues like alternative splicing, which can produce different protein variants, as seen with AAV capsid proteins, or nonsense-mediated decay if splicing is inefficient.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Traversal
Applicant did not present any arguments pertaining to this rejection.
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Mullick et al. (BMC Biotechnology 2006, 6:43)
Mullick teaches a number of expression systems have been developed where transgene expression can be regulated, wherein, some applications require the regulation of several genes, there is a need for a variety of independent yet compatible systems. Mullick teaches the ability to regulate both the level and the duration of expression allows the study of proteins whose constitutive expression might not be tolerated by the cell. Mullick teaches the tetracycline resistance operon is utilized for gene regulation in mammalian cells. Mullick teaches the Tet switch is the most widely used inducible system in mammalian cells. Mullick teaches there is a need for additional systems for the control of gene expression in mammalian cells in order to control multiple simultaneously and independently control several genes. Mullick teaches controlling gene expression by utilizing a cumate-inducible promoter.
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
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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