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 .
Detailed Action
Election/Restrictions
A restriction of the claims was not required.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/CN2021/100014, filed 06/15/2021.
Applicant' s claim for the benefit of a prior-filed parent application CN202011343883.8, filed on 11/25/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is 11/25/2020.
Claims Status
Claim 4 is canceled and claims 1-3 and 5-10 have been considered on the merits. All arguments have been considered.
Withdrawn Objections & Rejections
Applicant's response filed 04/13/2026 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 01/13/2026 are hereby withdrawn.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application.
Claim Rejections - 35 USC § 103 (New)
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 rejection is essentially identical to the rejection in the previous action, however has been modified to address the limitations that have been incorporated from claim 4 into claim 1.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Volkova et al (The Journal of Biological Chemistry (2014) 289:29;1-12; previously cited) in view of Miller et al (Mol. Cell. Biol. (1986) 6 (8), 2895-2902; hereafter cited as Miller(1986); previously cited) and Dronadula et al (Gene Ther. (2011) 18:5;1-22; previously cited).
Regarding claim 1: The claim recites “self-inactivating vector”. The instant specification is silent on an explicit definition of the term.
Volkova teach retroviral vectors with deleted enhancer/promoter sequences in the U3 region of the 3’ LTR are self-inactivating vectors (p2 col2 ¶2). The claims are interpreted with the definition of “self-inactivating vector” as “retroviral vectors with deleted enhancer/promoter sequences in the U3 region of the 3’ LTR”, as taught by Volkova et al.
The claims are examined with the interpretation as discussed supra.
Volkova teach self-inactivating Moloney retroviral vectors in which the enhancer/promoter sequences in the U3 region of the 3’ LTR are deleted (p2 col2 ¶2). Volkova further teach replacing the U3 region in the 5’ LTR with CMV enhancer/promoter sequence (p2 col1 ¶2). Volkova also teach introduction of a poly(a) site (p2 col1 ¶3).
Volkova teach use of restriction enzyme sites for deletions in the U3 including XbaI/SacI and NheI and SacI (p3 col2 ¶3). Volkova do not teach using the restriction enzyme site PVU II.
Miller(1986) teach packaging cell lines for generation of retrovirus vectors in the absence of helper virus (abstract). Miller further teach a packaging cells line based on the Moloney murine leukemia virus (p5 col1 ¶1). Miller(1986) also teach use of the restriction site PvuII to modify the viral vector (Fig 2).
It would have been obvious to one of ordinary skill in the art to modify the MMLV vector taught by Volkova with the teaching of Miller, use of the PvuII restriction site to modify the viral vector.
One would have been motivated to use a PvuII restriction site to modify the viral vector because one of ordinary skill in the art would understand that using a blunt restriction site like PvuII allows use of a DNA insertion without requiring additional nucleotides in the insert sequence that would be required if cloning with a restriction enzyme that required a compatible overhang sequence.
One would have had a reasonable expectation of success because MMLV comprises multiple PvuII sites and one of ordinary skill in the art would understand how to utilize such sites using standard molecular biology methods.
The teachings of Volkova are discussed supra. Volkova are silent on post translational regulatory elements.
Dronadula teach that the success of gene therapy requires adequate transgene expression (abstract). Dronadula further teach many gene-therapy vectors include virus-derived transcriptional elements to ensure high transgene expression (abstract).
Dronadula teach the addition of the oPRE (optimal Post-transcriptional Regulatory Element) to a gene expression vector, increases expression of the transgene 2-fold (p5 ¶4).
It would have been obvious for one of ordinary skill in the art at the time of the invention to modify the MMLV vector taught by Volkova with the oPRE taught by Dronadula. One would have been motivated to do so because Dronadula teach the addition of oPRE increases the expression of the transgene, and thus increases the potential success of a gene therapy vector. One would have had a reasonable expectation of success because both inventions are drawn to viral vectors designed to deliver a transgene.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Volkova et al (The Journal of Biological Chemistry (2014) 289:29;1-12) in view of Miller et al (Mol. Cell. Biol. (1986) 6 (8), 2895-2902; hereafter cited as Miller(1986)) as applied to claim 1, and further in view of Micklem et al (GenBank EU753858.1; 2009) and Rakhmawati et al (Makara Journal of Science (2018)22:3 p1-8).
Regarding claim 2: The teachings of Volkova and Miller are discussed supra. Neither Volkova nor Miller teach a specific sequence for the 5’ and 3’ LTR.
Seq ID NO: 1 of the instant invention is a nucleotide sequence comprising 688 bp, as shown below. The underlined and bolded sequence corresponds to the LTR sequence found in both the 5’ and 3’ LTRS taught by Seq ID NOs:1 and 2 of the instant invention. The sequence that is not underlined corresponds to the CMV enhancer/promoter sequence.
Seq ID No 1:
tccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcGtgtacggtgggaggtctatataagcagagctcaataaaagagcccacaacccctcactcggcgcgccagtcctccgattgactgagtcgcccgggtacccgtgtatccaataaaccctcttgcagttgcatccgacttgtggtctcgctgttccttgggagggtctcctctgagtgattgactacccgtcagcgggggtctttcatt
Micklem et al (GenBank EU753858.1) teach the nucleic acid sequence of the retroviral expression vector L149 which shares 99.85% sequence identity with Seq ID No: 1 of the instant invention. The sequences of Micklem and the instant Seq ID NO: 1 are identical except for the nucleotide at position 474 of Seq ID NO:1 (capital bolded in the sequence above) which is “G” in the instant invention and “A” in the disclosure of Micklem.
It would have been obvious, however, to modify the MMLV vector taught by Miller, to use a CMV to modify the CMV enhancer/promoter sequence as taught by vector L149, modified to comprise a “G” at position 149 (of Seq ID NO:1) because a CMV enhancer/promoter sequences with a “G” at that position are well known in the art and commonly used in many common mammalian expression vectors such as pcDNA3.1.
Rakhmawati teach pcDNA3 and its derivatives (such as pcDNA3.1) are among the most commonly used commercial mammalian expression systems (p4 col1 ¶3).
Thus, one would have been motivated to use CMV enhancer/promoter sequence derived from one of the most commonly used mammalian expression systems in the disclosure of Miller because the CMV enhancer/promoter it is well characterized in the art. One would have a reasonable expectation of success because it is a functional sequence from one of the most commonly used expression systems and furthermore, one of ordinary skill in the art would understand that doing so uses standard molecular biology methods.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Volkova et al (The Journal of Biological Chemistry (2014) 289:29;1-12) in view of Miller et al (Mol. Cell. Biol. (1986) 6 (8), 2895-2902; hereafter cited as Miller(1986)) as applied to claim 1, and further in view of Liu et al (Nucleic Acids Research (2018) 46:18; 9864-9874).
Regarding claim 3: The teachings of Volkova are discussed supra. Volkova also teach the use of an SV40 poly(a) site increases viral titer (p2 col1 ¶2), and additional poly(A) signal in SIN vectors results in up to a 2-fold increase in viral titer (p10 col1 ¶4). Volkova do not teach that the polyadenylation sequence is the nucleotide sequence set forth in Seq ID No:3.
Liu teach the pYL1 expression vector (GenBank Accession: MH594278) which comprises a polyadenylation signal with 100% sequence identity with Seq ID NO: 3 of the instant invention.
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to substitute the SV40 poly(A) taught by Volkova with the SV40 poly(A) sequence disclosed by Liu because both inventions are drawn to the SV40 poly(A) sequences used for the expression transgenes in a mammalian expression system. There would have been a reasonable expectation that the SV40 poly(A) sequence of Liu would work equivalently to the SV40 poly(A) sequence in the invention of Volkova because changing known components, one for the other, is a common technique in molecular biology, and the results would have been predictable.
Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Volkova et al (The Journal of Biological Chemistry (2014) 289:29;1-12) in view of Miller et al (Mol. Cell. Biol. (1986) 6 (8), 2895-2902; hereafter cited as Miller(1986)) as applied to claim 1, and further in view of Micklem et al (L149 Vector 2018 [online]. NovoPro [retrieved on 12/17/2025]. Retrieved from the Internet: <URL: https://www.novoprolabs.com/vector/Vgi3dsna).
Regarding claims 5-7: The teachings of Volkova are discussed supra. Volkova also teach the vector comprises the reporter gene GFP (Fig 2c).
Volkova teach the vectors comprise a neomycin resistance gene (fig1), however Volkova do not teach that the antibiotic resistance gene confers resistance to ampicillin. Volkova are silent on the origin of replication for the MMLV vector.
Micklem teach the L149 vector, an MMLV vector comprising a resistance gene as a marker (AmpR) and a replication origin pUC (ori) (p2 map, p6 “rep-origin”, p).
It would have been prima facie obvious to substitute the antibiotic resistance gene and replication origin in the invention of Volkova for the antibiotic resistance gene and origin of replication as taught by Micklem because both inventions are drawn to MMLV vectors for expression of a transgene. There would have been a reasonable expectation that the antibiotic resistance gene and origin of replication taught by Micklem would work equivalently those in the invention of Volkova because changing known components, one for the other, is a common technique in molecular biology, and the results would have been predictable.
Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Volkova et al (The Journal of Biological Chemistry (2014) 289:29;1-12) in view of Miller et al (Mol. Cell. Biol. (1986) 6 (8), 2895-2902; here after cited as Miller(1986)) as applied to claim 1, and as evidenced by Markowitz et al (Virology (1988)167:2;400-6).
Regarding claims 8-9: Claim 8 recites “target gene”. The instant specification is silent on an explicit definition of the term. One of ordinary skill in the art would understand that a target gene of a retroviral vector is an exogenous gene that is delivered by the vector.
The claims are examined with the definitions as discussed supra.
The teachings of Volkova are discussed supra. Volkova also teach producer cell lines are generated by methods described by Markowitz, in which helper plasmids (a first plasmid) are introduced to the cells (Markowitz abstract). Volkova further teach cells to produce retroviral vectors are established by transfection of producer cells with vector plasmids (a second plasmid) (p2 col2 ¶5).
Volkova also teach advantages of retroviral vectors (such as MMLV) includes highly efficient gene delivery, integration into the host cell genome, and high levels of gene expression (p1 col1/2 ¶1/1). Furthermore, Volkova teach expression of GFP delivered by the viral vector (Fig 2). Thus Volkova teach the self-inactivating vector comprises a target gene per the claim interpretation discussed supra.
Volkova teach cell lines are transfected with plasmids to generate virus (viral titers) (p2 col2 ¶5). Volkova further teach RNA is isolated from virus particles (p2 col1 ¶3). Thus Volkova teach a viral particle generated by a retrovirus packaging system.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Volkova et al (The Journal of Biological Chemistry (2014) 289:29;1-12) in view of Miller et al (Mol. Cell. Biol. (1986) 6 (8), 2895-2902; here after cited as Miller(1986)) as applied to claim 1, and further in view of Blesch et al (Methods (2003) 33;1-9).
Regarding claim 10: The teachings of Volkova are discussed supra. Volkova also teach retroviral vectors are useful tools for delivering therapeutic genes to primary cells in vitro and have been used in gene therapy trials in humans (p1 col1 ¶1). Volkova does not explicitly teach a viral particle and a pharmaceutically acceptable excipient.
Blesch teach MLV based vectors for in vivo gene transfer in which therapeutic genes can be delivered to a selective target organ (title, p1 col1 ¶1). Delivery of therapeutic genes to a selective target organ requires a gene therapy drug comprising a viral particle and a pharmaceutically acceptable excipient.
It would have been obvious for one of ordinary skill in the art to modify the vector taught by Volkova with the teaching of Blesch, delivery of the vector in vivo, which would necessarily comprise gene therapy drug comprising a viral particle and a pharmaceutical carrier. One would have been motivated to modify the teaching of Volkova to comprise a gene therapy drug for the delivery of therapeutic genes to a selective target organ. One would have had a reasonable expectation of success because Blesch teach retroviral vectors are powerful tools for in vivo gene transfer (p8 col1 ¶5).
Response to Arguments
The responses are directed to the Arguments filed 04/13/2026, all arguments have been considered.
Regarding Arguments directed to 35 USC § 103:
The amendments to claim 1 overcome the rejection as written because the amendment import limitations that were not addressed in claim 1 previously and the rejection is withdrawn.
A new rejection is entered above which is essentially the same as the previous rejection, however is modified to address the limitations that have been incorporated from claim 4 into claim 1.
The relevant arguments are addressed below:
Applicant argues that Volkova teaches away from the claimed invention because the vector taught by Volkova with the largest deletion is defective in nuclear-cytoplasmic transport unless the defect is complemented (p10 col2 ¶1).
MPEP 2123 reads “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments”.
Volkova do not teach away from deletions in the U3 region of the 3’ LTR. Volkova teach deleting the enhancer/promoter sequences in the U3 region of the 3’ long terminal repeat is an improvement in retroviral vector design and safety (p1 col2 ¶2). Furthermore, Volkova teach multiple embodiments in which the U3 region of the 3’ LTR is deleted (XbaI/SacI; positions -147 to -34; NheI/Xba; positions -414 to -152) NheI/SacI; positions -414 to -34). While the embodiment comprising the NheI/SacI deletion taught by Volkova requires complementation, a Moloney murine leukemia virus-based self-inactivating vector which requires complementation is not excluded by the claim language and the structure taught by Volkova is considered to read on the structure of the claimed composition.
The argument is unpersuasive.
Applicant also argues that Volkova do not teach the use of oPRE in a MMLV vector and that Miller do not teach deletion of U3 in the 3’ LTR or the use of oPRE in a viral vector. It is noted that neither Volkova nor Miller are relied upon to teach the oPRE and deletion of U3 in the 3’ LTR or use of oPRE in a viral vector, respectively.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that virus-derived elements that work in one type of vector may not also work in another type of vector and argues that the teachings of Dronadula would require undue experimentation and therefore one of ordinary skill in the art would not have a reasonable expectation of success for using the oPRE taught in the adenoviral system of Dronadula in the Moloney Viral system of Volkova.
In response to applicant's argument that Dronadula is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor' s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992).
In this case, Dronadula teach an transgene expression system for gene delivery in mammalian cells which comprises functional components for transgene gene expression including the oPRE which confers improved transgene expression when compared to the identical vector without the oPRE.
This is pertinent to the disclosure of Volkova which is also drawn to a transgene expression system for gene delivery in mammalian cells. While the viral transgene expression systems are based upon different virus (adenovirus and retrovirus), both systems are drawn to expression of a transgene in mammalian cells. One of ordinary skill in the art could reasonably expect that components which improve transgene expression in one viral transgene expression system would also have a reasonable likelihood of improving transgene expression in the other.
The argument is unpersuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631
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