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 .
Application Status
Any rejection of record in the previous office actions not addressed herein is withdrawn. New grounds of rejection are presented herein that were not necessitated by applicant' s amendment of the claims since the office action mailed 08/21/2025. Therefore, this action is not final.
Priority
Applicant’s claim to priority from US provisional application 62/697,829 filed 07/13/2018 is hereby acknowledged.
This Application is a National phase entry of PCT/US19/41472 filed 07/11/2019 under U.S.C. § 371.
Election/Restrictions
Applicant's election with traverse of Group 1, drawn to claims 1-20 and Species Group A1 and B1 in the reply filed on 05/15/2024 is acknowledged. The traversal is on the ground(s) that the search and examination can be made without serious burden. This is not found persuasive because the restriction requirement is based on lack of unity, the application being a National Stage entry application under U.S.C. §371. Search burden is not an issue considered for this restriction requirement.
The requirement is still deemed proper and is therefore made FINAL
Claim Status
Amendments to claims filed 11/20/2025 are hereby acknowledged.
Claims 2, 13, 21-25 and 27-33 are cancelled.
Claims 5, 7, 12 and 26 are still withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and species, there being no allowable generic or linking claim.
Claims 1, 3-12, 14-20 and 26 are pending. Claims 1, 3-4, 6, 8-11, 14-20 are under examination in this office action.
The following are New rejections:
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 non-obviousness.
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, 3, 4, 6 and 14-20 are rejected under 35 U.S.C. §103 as being unpatentable over Fujimoto (Fujimoto, H. et al. Nucleic Acids Research, Vol. 32, No. 4 (2004), pp: 1555-1565; previously cited), in view of Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006).
Regarding claim 1(a)(i) reciting “ an R2 retrotransposon R2 polypeptide” and claim 1 (a)(ii) reciting “ an R2 retrotransposon 3’ untranslated region (UTR) and an R2 retrotransposon 5’ UTR”, Fujimoto teaches a system using R2 retrotransposon and R2 polypeptide retrotransposase from Bombyx mori.
Fujimoto teaches a first nucleic acid (plasmid pAcYM1 containing cassette AcR2[ORF]) comprising a nucleotide sequence encoding the R2 retrotransposon R2 polypeptide from Bombyx mori (R2Bm, i.e. transposase) flanked by two R2 UTRs (See page 1561, left column, “[R]escue of the frame-shifted mutation by co-infection with a helper virus” section; and figure 1, a.).
Fujimoto teaches a second nucleic acid (plasmid pAcYM1 containing cassette AcR2[600<R2Δ>30]) comprising a mutant nucleotide sequence encoding a gene product (a mutant sequence for R2Bm), wherein two R2 retrotransposon UTRs flank the mutated ORF (see Figure 1, h).
Therefore, Fujimoto teaches a gene delivery system comprising two viral vectors in the form of two recombinant AcNPVs (Autographa californica Nuclear Polyhedrosis Viruses) comprising a first virus encapsulating a first nucleic acid sequence comprising a sequence encoding an ORF for R2 from Bombyx mori (R2Bm, i.e. transposase, heterologous to the host AcNPV) and a second virus (helper virus) encapsulating a second nucleic acid comprising a nucleotide sequence encoding a mutated R2Bm ORF flanked by R2 retrotransposon terminal repeats (5’UTR and 3’UTR), a sequence also heterologous to the host AcNPV (see figure 1 and see “[A]bstract’ section, figure 4 and page 1561, “[R]escue of the frame-shifted mutation by co-infection with a helper virus” section).
Fujimoto also teaches “an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence depicted in SEQ ID NO: 37” (see page 1555, right column and page 1556, right column, line 6; and see alignment below).
Fujimoto teaches the ORF of R2 from Bombyx mori ( see “[I]ntroduction” section) that was cloned by using PCR on Bombyx mori genomic sequence; Fujimoto teaches “the” R2Bm sequence in the section “[C]loning of R2Bm” referring to a single/unique genomic sequence for this reverse transcriptase; therefore the R2 gene from Bombyx mori is the same sequence encoding for the protein described in figure 7 of instant application.
Fujimoto teaches a sequence described as GenBank accession no. AB076841. This sequence is 98.5% identical to instant’s application SEQ ID NO: 37.
See alignment below (Qy (query)= SEQ ID NO: 37, Db (database)= AB076841).
Query Match 98.5%; Score 5782; DB 1; Length 1114
Best Local Similarity 98.8%;
Matches 1101; Conservative 2; Mismatches 11; Indels 0; Gaps 0;
Qy 1 MMASTALSLMGRCNPDGCTRGKHVTAAPMDGPRGPSSLAGTFGWGLAIPAGEPCGRVCSP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MMASTALSLMGRCNPDGCTRGKHVTAAPMDGPRGPSSLAGTFGWGLAIPAGEPCGRVCSP 60
Qy 61 ATVGFFPVAKKSNKENRPEASGLPLESERTGDNPTVRGSAGADPVGQDAPGWTCQFCERT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ATVGFFPVAKKSNKENRPEASGLPLESERTGDNPTVRGSAGADPVGQDAPGWTCQFCERT 120
Qy 121 FSTNRGLGVHKRRAHPVETNTDAAPMMVKRRWHGEEIDLLARTEARLLAERGQCSGGDLF 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 FSTNRGLGVHKRRAHPVETNTDAAPMMVKRRWHGEEIDLLARTEARLLAERGQCSGGDLF 180
Qy 181 GALPGFGRTLEAIKGQRRREPYRALVQAHLARFGSQPGPSSGGCSAEPDFRRASGAEEAG 240
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GALPGFGRTLEAIKGQRRREPYRALVQAHLARFGSQPGPSSGGCSAEPDFRRASGAEEAV 240
Qy 241 EERCAEDAAAYDPSAVGQMSPDAARVLSELLEGTGRRRACRAMRPKTAGRRNDLHDDRTA 300
|||||||||||||||||||||||||||||||||:||||||||||||||||||||||||||
Db 241 EERCAEDAAAYDPSAVGQMSPDAARVLSELLEGAGRRRACRAMRPKTAGRRNDLHDDRTA 300
Qy 301 SAHKTSRQKRRAVYARVQELYKKCRSRAAAEVIDGACGGVGHSLEEMETYWRPILERVSD 360
||||||||||||:|||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SAHKTSRQKRRAEYARVQELYKKCRSRAAAEVIDGACGGVGHSLEEMETYWRPILERVSD 360
Qy 361 APGPTPEALHALGRAEWHGGNRDYTQLWKPISVEETKASRFDWRTSPGPYGIRSGQWRAV 420
|||||||||||||||||||||||||||||||||||:|||||||||||||:||||||||||
Db 361 APGPTPEALHALGRAEWHGGNRDYTQLWKPISVEEIKASRFDWRTSPGPDGIRSGQWRAV 420
Qy 421 PVHLKAEMFNAWMARGEIPEVLRQCRTVFVPKVERPGGPGEYRPISIASIPLRHFHSILA 480
||||||||||||||||||||:||||||||||||||||||||||||:||||||||||||||
Db 421 PVHLKAEMFNAWMARGEIPEILRQCRTVFVPKVERPGGPGEYRPILIASIPLRHFHSILA 480
Qy 481 RRLLACCPPDARQRGFICADGTLENSAVLDAVLGDSRKKLWECHVAVLDFAKAFDTVSHE 540
||||||||||||||||||||||||||||||||||||||||:|||||||||||||||||||
Db 481 RRLLACCPPDARQRGFICADGTLENSAVLDAVLGDSRKKLRECHVAVLDFAKAFDTVSHE 540
Qy 541 ALVELLRLRGMPVQFCGYIAHLYDTASTTLAVNNEMSSPVKVGRGVRQGDPLSPILFNVV 600
||||||||||||:|||||||||||||||||||||||||||||||||||||||||||||||
Db 541 ALVELLRLRGMPEQFCGYIAHLYDTASTTLAVNNEMSSPVKVGRGVRQGDPLSPILFNVV 600
Qy 601 MDLILASLPERVGYRLEMEPVSALAYADDLVLLAGSKVGMQESISAVDCVGRQMGLRLNC 660
|||||||||||||||||||:|||||||||||||||||||||||||||||||:||||||||
Db 601 MDLILASLPERVGYRLEMELVSALAYADDLVLLAGSKVGMQESISAVDCVGKQMGLRLNC 660
Qy 661 RKSAVLSMIPGGHRKKHHYLTERTFNIGGKPLRQVSCVERWRYLGVDFEASGCVTLEHSI 720
||||||||||:|||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 RKSAVLSMIPDGHRKKHHYLTERTFNIGGKPLRQVSCVERWRYLGVDFEASGCVTLEHSI 720
Qy 721 SSALNNISRAPLKPQQRLEILRAHLIPRFQHGFVLGNISDDRLRMLDVQIRKAVGQWLRL 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 SSALNNISRAPLKPQQRLEILRAHLIPRFQHGFVLGNISDDRLRMLDVQIRKAVGQWLRL 780
Qy 781 PADVPKAYYHAAVQDGGLAIPSVRATIPDLIVRRFGGLDSSPWSVARAAAKSDKIRKKLR 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 PADVPKAYYHAAVQDGGLAIPSVRATIPDLIVRRFGGLDSSPWSVARAAAKSDKIRKKLR 840
Qy 841 WAWKQLRRFSRVDSTTQRPSVRLFWREHLHASVDGRELRESTRTPTSTKWIRERCAQITG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 WAWKQLRRFSRVDSTTQRPSVRLFWREHLHASVDGRELRESTRTPTSTKWIRERCAQITG 900
Qy 901 RDFVQFVHTHINALPSRIRGSRGRRGGGESSLTCRAGCKVRETTAHILQQCHRTRGGRIL 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||:|||||
Db 901 RDFVQFVHTHINALPSRIRGSRGRRGGGESSLTCRAGCKVRETTAHILQQCHRTHGGRIL 960
Qy 961 RHNKIVSFVAKAMEENKWTVELEPRLRTSVGLRKPDIIASRDGVGVIVDVQVVSGQRSLD 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 RHNKIVSFVAKAMEENKWTVELEPRLRTSVGLRKPDIIASRDGVGVIVDVQVVSGQRSLD 1020
Qy 1021 ELHREKRNKYGNHGELVELVAGRLGLPKAECVRATSCTISWRGVWSLTSYKELRSIIGLR 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 ELHREKRNKYGNHGELVELVAGRLGLPKAECVRATSCTISWRGVWSLTSYKELRSIIGLR 1080
Qy 1081 EPTLQIVPILALRGSHMNWTRFNQMTSVMGGGVG 1114
||||||||||||||||||||||||||||||||||
Db 1081 EPTLQIVPILALRGSHMNWTRFNQMTSVMGGGVG 1114
Fujimoto does not teach a second nucleic acid comprising a heterologous nucleotide sequence wherein the heterologous nucleotide sequence is different than a mutant R2bm ORF and has a length of at least 200 nucleotides, nor a first nucleic encoding an R2 retrotransposon wherein the R2 polypeptide-encoding nucleotide sequence is codon-optimized for expression in a eukaryotic cell.
However, Kaminski teaches “Transposon-based vectors and methods of nucleic acid integration” (see title). Kaminski teaches compositions comprising integrating enzymes that can deliver nucleic acids to a target DNA (see abstract).
Kaminski claims in claim 1, “A composition comprising nucleic acid comprising a transgene flanked by two terminal repeats and a nucleic acid encoding an integrating enzyme under the control of a promoter element” (see claim 1, page 47). Kaminski claims in claim 7 that “The composition of claim 1, wherein the integrating enzyme can be selected from the group consisting of transposase, integrase, retrotransposase, recombinase, bacteriophage integrase, integron, terminase or retroviral integrase” (see page 47). Kaminski claims in claim 22 “The composition of claim 1, wherein the nucleic acid encoding the transgene and the nucleic acid encoding the transposase are separate nucleic acids (see page 48; see page 12, [0123]).
Kaminski teaches a first and a second nucleic acids, wherein the first nucleic acid comprises a gene encoding for a transposase polypeptide, operably linked to an enhancer/promoter (EP) (which can be also a retrotransposase, according to Kaminski’s claim 7 on page 47), and a second nucleic acid comprising “inverted terminal repeats, or the like”, e.g., 5’UTR and 3’UTR of a retrotransposon, flanking a transgene operably linked to a second enhancer/ promoter (see Figure 2 and [0013]).
Kaminski teaches that in the gene transfer system, the nucleic acid fragment, i.e., transgene or heterologous nucleotide sequence, can be a gene to provide gene therapy (see [0102]). Kaminski also teaches that “and advantage of this system is that it is not limited to a significant extent by the size of the intervening nucleic acid sequence positioned between the inverted repeats”. The size of the construct can range from 1.3 Kb to about 5 kb (see [0109]). Therefore, Kaminski teaches transgenes that can be 200 nucleotides or more.
Kaminski also teaches that for the case of a Transposase TnsD, “The DNA sequence recognition domain of TnsD is altered to optimize recognition of the cognate human target sequence” (see page 33, [0332] and [0334]).
Examiner interprets this modification of TnsD DNA sequence as a codon-optimization for human gene targeting, therefore for a eukaryotic cell.
Therefore, It would have been obvious to one with ordinary skills in the art, before the effective filing date, to have substituted the second heterologous nucleic acid sequence flanked by R2 retrotransposon 3’ and 5’ UTRs elements taught by Fujimoto with the transgene as taught by Kaminski. It would also have been obvious to substitute the retrotransposase gene taught by Kaminski in claim 7, with the R2bm transposase gene taught by Fujimoto in the first nucleic acid construct and codon-optimized the R2bm transposase DNA sequence for eukaryotic cell transfection as taught by Kaminski. Both retrotransposons would be equivalent in their functionality. Fujimoto also teaches the advantages of their system, for rapidity and facility to manipulate and to determine the integration mechanism, and suggests that it can be applied to analyze the insertion of other retrotransposons (see page 1556, left column, first paragraph). Therefore, one motivated in performing this substitution and test for equivalency could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claims 3 and 4, Kaminski teaches a single heterologous nucleotide sequence encoding for a single heterologous gene product, i.e. a reporter gene such as luciferase, GFP, an oncogenes or anti-oncogene, or a gene for gene therapy, or an antigen (see [0129]-[0134]).
Fujimoto also teaches a heterologous nucleotide sequence (heterologous to the host AcNPV) that encodes an R2Bm ORF comprising a frame-shift mutation (see figure 6). Fujimoto teaches that the single open reading frame encodes for a protein (a polypeptide) (see “[I]ntroduction” section).
The obviousness of the combination of references is discussed above.
Regarding claim 6, Kaminski teaches that the nucleic acid fragment can comprise at least a portion of an open reading frame to produce a functional amino-acid containing product. In a preferred embodiment, the nucleic acid sequence encodes at least one active or functional peptide, polypeptide, or protein” (see [0097]). Therefore, Examiner interprets this teaching as potentially including more than one polypeptide.
Regarding claim 14, Kaminski teaches a heterologous nucleotide sequence encoding a gene product that is operably linked to a transcriptional control element, i.e. EP (see figure 1 and 2; [0154]), which can be a SV40 or cytomegalovirus promoter (see [0156]-[0161]).
Regarding claim 15, Kaminski teaches regulatable promoter, e.g. inducible promoter such as ABA inducible promoter ([0161], and page 47, claims 5- 6).
Regarding claim 16, Kaminski teaches constitutive promoters (see [0159], [0161]).
Regarding claims 17-19, Kaminski teaches that in the gene transfer system, the nucleic acid fragment, i.e., transgene or heterologous nucleotide sequence, can be a gene to provide gene therapy (see [0102]). Kaminski also teaches that “an advantage of this system is that it is not limited to a significant extent by the size of the intervening nucleic acid sequence positioned between the inverted repeats”. The size of the construct can range from 1.3 Kb to about 5 kb. Kaminski also teaches that a transposase such as Mariner can transpose a construct up to 13 kb (see [0109]).
Therefore, the heterologous nucleotide can be more than 200 nucleotides in length and up to 13Kb. This teachings suggests that there is no significant limitation in length for the heterologous nucleotide sequence.
Regarding claim 20, Kaminski teaches kits comprising the gene delivery system comprising a first and second nucleic acids vectors, as claimed in Kaminski’s claims 1, 7 and 22 on pages 47-48, and reagents that can be used to practice the methods of delivering nucleic acids to target a DNA using nucleic acid integration (see [0246]).
The obviousness of combining the references Fujimoto and Kaminski is described above. In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability”. KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Claim 8 is rejected under 35 U.S.C. §103 as being unpatentable over Fujimoto (Fujimoto, H. et al. Nucleic Acids Research, Vol. 32, No. 4 (2004), pp: 1555-1565; previously cited) in view of Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006), as applied to claims 1, 3 and 4 above, and in further view of McIvor (McIvor, R.S. et al. US 2017/0233452 A1, published August 17, 2017).
The rejections of claims 1, 3 and 4 are discussed above. The elements of claims 1, 3 and 4 are rendered obvious by the combination of references Fujimoto and Kaminski.
The combination of Fujimoto and Kaminski does not render obvious elements of claim 8, i.e., a heterologous gene product that is a heterologous polypeptide, and a chimeric antigen receptor.
However, McIvor teaches a vector comprising the nucleic acid sequence of a chimeric antigen receptor (CAR) (see [0082] and [0091]).
As for Kaminski, McIvor teaches the use of transposon constructs to deliver a CAR for cancer gene therapy though adoptive cell transfer of a genetically modified T cell or NK cell (see [0014]).
Therefore, one with ordinary skills in the art, before the effective filing date, could have modified the gene delivery system as taught by Fujimoto/Kaminski and introduced a heterologous nucleic acid sequence encoding for a CAR as transgene as taught by McIvor. One with ordinary skills in the art, motivated in counteracting tumor immune escape could have performed this modification for delivering therapeutic CAR to the cancer patient. One with ordinary skills in the art could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Claims 9 and 10 are rejected under 35 U.S.C. §103 as being unpatentable over Fujimoto (Fujimoto, H. et al. Nucleic Acids Research, Vol. 32, No. 4 (2004), pp: 1555-1565; previously cited) in view of Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006), as applied to claims 1 and 6 above, and in further view of Minshull (Minshull, J. et al. US 2017/0101647_ A1; published April 13, 2017, previously cited).
The rejections of claims 1 and 6 are discussed above. The elements of claims 1 and 6 are rendered obvious by the combination of references Fujimoto and Kaminski.
However, the combination of Fujimoto and Kaminski does not render obvious elements of claims 9 and 10, i.e., a first heterologous gene product that is a first heterologous polypeptide and a second heterologous gene product that is a second heterologous polypeptide (claim 9). The combination of Fujimoto and Kaminski does not render obvious a gene delivery vehicle system wherein the heterologous nucleotide sequence comprises in order from 5’ to 3’ a nucleotide sequence encoding the first heterologous polypeptide, an IRES or a nucleotide sequence encoding a self-cleaving polypeptide, and a nucleotide sequence encoding the second heterologous polypeptide (claim 10).
However, regarding claims 9 and 10, Minshull teaches a gene delivery system in the form of transfer vectors (see [0051]-[0054]), comprising a first nucleic acid encoding a transposase (see [0054]) and a second nucleic acid encoding a heterologous polynucleotide sequence flanked by a 5’UTR and a 3’UTR, in the form of inverted terminal repeats (two transposon ends) (see [0054], [0049]-[0050] and [0080]), as taught by Kaminski.
Regarding claim 9, Minshull teaches that the expression polypeptide and a selectable polypeptide may be included on the same gene transfer polynucleotide (see [0133]), i.e. a first and a second heterologous nucleotide sequences separated by genetic insulators, introns, separate promoter and enhancer sequences (see [0128]-[0130], [0133], [0188] and Table 13). Therefore, the expression cassette can have two different heterologous nucleic acid sequences expressing two different polypeptides.
Regarding claim 10, Minshull teaches that two genes operably linked to a single promoter preceding the first gene (i) and a second gene (iii), where the two genes were operably linked by an IRES sequence or a CHYSEL sequence (ii) (see [0128], [0191]). Minshull teaches that coupling the translation of two open reading frames through IRES produced very high levels of expression (see [0193]).
It would have been obvious to one with ordinary skills in the art, before the effective filing date, to have modified the constructs as taught by Fujimoto modified by Kaminski and inserted a first and second polynucleotide flanked by the R2 retrotransposons 3’ and 5’ UTRs as taught by Minshull. One with ordinary skills in the art, motivated in expressing more than one polypeptide could have performed this modification with a reasonable expectation of success as demonstrated by Minshull. One with ordinary skills in the art could have performed this modification and arrived at the claimed invention before the effective filing date.
It would also have been obvious to one with ordinary skills in the art, before the effective filing date, to have further modified the construct of Fujimoto/Kaminski modified by Minshull, and inserted a “coupling” element or a translational “coupling” element as taught by Minshull to allow the expression of a first polypeptide to be linked to the expression of a second polypeptide, and inserted an IRES element or a nucleotide sequence encoding a self-cleaving polypeptide such as CHYSEL sequence between both polypeptides encoding sequences as taught by Minshull (see [0023], [0037], and [0193]).One with ordinary skills in the art, motivated in ensuring the coupled expression of both polypeptides, at a high level of expression, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Claim 11 is rejected under 35 U.S.C. §103 as being unpatentable over Fujimoto (Fujimoto, H. et al. Nucleic Acids Research, Vol. 32, No. 4 (2004), pp: 1555-1565; previously cited), in view of Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006) and Minshull (Minshull, J. et al. US 2017/0101647_ A1; published April 13, 2017; previously cited), as applied to claim 9 above, and in further view of McIvor (McIvor, R.S. et al. US 2017/0233452 A1, published August 17, 2017).
The rejection of claim 9 is discussed above. The combination of references Fujimoto, Kaminski and Minshull renders elements of claim 9 obvious. However, the combination does not render elements of claim 11 obvious, i.e., a first and second polypeptides forming a heterodimeric chimeric antigen receptor together.
Regarding claim 11, the claim recites “wherein the first polypeptide and the second polypeptide together form a heterodimeric chimeric antigen receptor”.
The combination of Fujimoto/Kaminski and Minshull does not specifically teach a
first and second polypeptide together forming a heterodimeric chimeric antigen receptor.
However, McIvor teaches a heterodimer chimeric antigen receptor, encoded by
nucleic acid sequences within the construct wherein the nucleic acid sequences of the first and second polynucleotide are flanked by Sleeping Beauty® T2 transposon UTRs (see figures 1A and 1B).
McIvor teaches a dimerizable anti-α Vβ 6 integrin hinge portion-encoding nucleic acid and a second polypeptide encoded by a nucleic acid comprising IgG4 hinge, CD28, 4-1BB and CD3ζ nucleic acid sequences within the same construct (see Figures 1A and 1B and [0017]).
McIvor teaches that Integrin α Vβ 6 constitutes a potentially effective target for T-cell-based cancer therapy, as it is overexpressed in several types of carcinomas ([0030]). McIvor also teaches that the majority of tumors do not express any co-stimulatory molecules and therefore co-stimulatory domains must be incorporated into the CAR molecule for efficient T cell activation. Second generation of CARs have incorporated a co-stimulatory domain in addition to CD3 activation domain. The addition of such domain allows for dimerization with signaling domain from CD28 that augments the ability of receptors to stimulate cytokine secretion and enhance antitumor activity (see [0028] and see Figures 1A and 1B).
It would have been obvious to one of ordinary skills, before the effective filing date, to have further modified Fujimoto/Kaminski and Minshull to introduce a heterologous nucleotide sequence comprising two nucleic sequences encoding CAR polypeptides capable of forming a heterodimer once expressed in the cells, as taught by McIvor (see Figure 1B). One with ordinary skills in the art, motivated in constructing a gene delivery systems using R2 transposon system comprising nucleotides encoding dimerization partners in a CAR capable of recruiting co-stimulatory molecules, and able to target specifically tumor cells and trigger signaling pathways involved in the release of cytokines in a more effective way as taught by McIvor, could have performed these modifications before the effective filing date, with a reasonable expectation of success.
Response to Arguments
Applicant’s arguments, see Remarks, pages 6-9, filed 11/20/2025, with respect to the rejection(s) of claim(s) 1, 3-4, 6, 8-11, and 14-20 under 35 U.S.C. §103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Fujimoto, Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006), Minshull and McIvor.
Applicant’s arguments with respect to the rejections under 35 U.S.C § 103 of claims 1, 3-4, 6, 8-11 and 14-20 have been considered but are moot because the new ground of rejections do not rely on the same combination of references applied in the prior rejections of record for any teaching or matter specifically challenged in the argument.
As noted by Applicant, see Remarks, page 7, Fujimoto disclosed a system that comprises two nucleic acids wherein a first nucleic acid encodes the R2 retrotransposon R2 polypeptide. However, Fujimoto does not disclose a second nucleic acid that has a heterologous nucleotide sequence, a transgene, heterologous to both the host and Bombyx mori. Therefore, Fujimoto discloses a system that does not comprise both nucleic acids as claimed. However, Kaminski resolves this deficiency. Kaminski discloses two nucleic acid sequences, one vector comprising a nucleic acid encoding a retrotransposase, and a second vector comprising nucleic acid sequence encoding a heterologous sequence flanked by inverted repeats or the like. The combination of Fujimoto and Kaminski renders obvious all the elements of claim 1.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA G DACE DENITO whose telephone number is (703)756-4752. The examiner can normally be reached Monday-Friday, 8:30-5:00EST.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636