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 .
Claims Status
Claims 1-10 are pending in the claims filed 05/25/2023.
Claims 7-8 are currently amended.
Claims 1-10 are examined herein.
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.
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) in view of Miller et al (Mol. Cell. Biol. (1986) 6 (8), 2895-2902; hereafter cited as Miller(1986)).
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.
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 dissed 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 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.
Claim 4 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 Dronadula et al (Gene Ther. (2011) 18:5;1-22).
Regarding claim 4: The claim recites optional elements which are not considered to limit the claim in any way.
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.
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).
Conclusion
No claims are allowed.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631