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 .
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.
Application Status
This Office Action is in response to Amendments and Remarks filed 07/02/2026.
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 Claims 5, 7, 12 and 26 are still withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and species, there being no allowable generic or linking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, 3-7, 9-10, 14, 17-20 and 26 are currently amended.
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 necessitated by Applicant’s amendments:
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 Fujiwara (Fujiwara, H. “ Site-specific non-LTR retrotransposons”. Microbiology Spectrum, Vol. 3, No. 2 (2015), p:MDNA3-0001-2014, pp: 1-16; cited on IDS filed 07/02/2026), in view of Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006; previously cited), and Fujimoto (Fujimoto, H. et al. Nucleic Acids Research, Vol. 32, No. 4 (2004), pp: 1555-1565; previously cited).
Regarding claims 1 and 20, Fujiwara teaches sites-specific non-LTR retrotransposons (see title). Fujiwara specifically teaches that R2 retrotransposon element is a site-specific non-LTR element, targeting 28S rDNA (see Figure 1 and Figure 7).
Fujiwara teaches integration of R2O1 ORF within the 28S rDNA locus (See Figure 7).
Fujiwara teaches that in vitro-transcribed R2O1 retrotransposes into the 28S rDNA target sequence of a zebrafish embryo with high frequency and accuracy and is transmitted to the next generation. Fujiwara teaches the use of R2O1 carrying a reporter EGFP gene in its 3’ UTR, i.e., a recombinant transgene, to produce transgenic fluorescent fish with the transgene integrated/inserted within the 28S rDNA target (see page 13, right column, second paragraph).
Fujiwara also states that the adenovirus-mediated and AcNPV-mediated R2O1 retrotransposition results in an accurate integration into the 28S target in several types of cultured human cells (same paragraph).
Fujiwara concludes that the results demonstrate that site-specific non-LTR retrotransposons, such as R2O1 could become a novel type of sequence-specific gene delivery vectors in gene therapy application (page 13, right column, second paragraph).
Examiner interprets that the first nucleic acid in Fujiwara encodes an R2O1 polypeptide sequence, and the second nucleotide sequence is the EGFP gene sequence, i.e., a “non- Bombyx mori transgene”.
Fujiwara teaches that a precise transgene integration to a specific target site is necessary to avoid unpredictable side effects, particularly in therapeutic applications for human cells (see page 13, left column, “Application of sequence specific retrotransposons as a gene delivery tool” section, lines 1-3).
Fujiwara does not teach SEQ ID NO: 37, nor an amino acid that has at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 37. Fujiwara does not teach a codon-optimization. Fujiwara is silent on the length of the EGFP transgene and does not teach a transgene of at least 200 nucleotides in length.
However, Kaminski teaches “Transposon-based vectors and methods of nucleic acid integration” (see title). Kaminski teaches in details 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 foreign 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.
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]).
Fujimoto teaches a system using R2 retrotransposon and R2 polypeptide retrotransposase from Bombyx mori, to study complementation by homologous recombination (see title).
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 also teaches a gene delivery system comprising two viral vectors in the form of two recombinant AcNPVs (Autographa californica Nuclear Polyhedrosis Viruses) to study complementation (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).
In this study, Fujimoto teaches “an amino acid sequence having at least 90% 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
Therefore, It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have codon-optimized R2 transposase gene taught by Fujiwara, for optimum eukaryotic cell transfection as taught by Kaminski. It would have been obvious to incorporate transgenes that are 200 nucleotides in length or more as taught by Kaminski. It would have been obvious to have substituted the R2O1 retrotransposon polypeptide taught by Fujiwara with a R2Bm comprising the sequence taught by Fujimoto, since both retrotransposons would be equivalent in their functionality. One with ordinary skills in the art motivated in using a R2 sequence known in the art and adapted via codon-optimization to obtain optimized and safe integration in a specific target site for use in human gene therapy, could have performed these modifications with a reasonable expectation of success and would have arrived at the claimed invention.
Regarding claims 3 and 4, Fujiwara teaches a single transgene, i.e., EGFP gene (see page 13, right column, second paragraph).
Kaminski teaches a single foreign nucleotide sequence encoding for a single foreign 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]).
The obviousness of the combination of references is discussed above.
Regarding claim 6, Fujiwara teaches insertion/integration at the 28S rDNA site, a sequence encoding R2O1 and a EGFP transgene, therefore, a first, single gene product encoded by the transgene (see page 13, right column, second paragraph).
Fujiwara does not teach a second gene product in the transgene.
However, 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.
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have modified the gene delivery system as taught by Fujiwara modified by Kaminski and Fujimoto and added more than one nucleic acid in the transgene. One with ordinary skills in the art motivated in co-expressing subunits of a therapeutic molecule could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Regarding claim 14, Kaminski teaches a foreign 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 foreign 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 foreign nucleotide can be more than 200 nucleotides in length and up to 13Kb. This teaching suggests that the size of the transgene can multiple kilobases in length.
The obviousness of combining the references Fujiwara, Kaminski and Fujimoto 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 Fujiwara (Fujiwara, H. “ Site-specific non-LTR retrotransposons”. Microbiology Spectrum, Vol. 3, No. 2 (2015), p:MDNA3-0001-2014, pp: 1-16; cited on IDS filed 07/02/2026), in view of Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006; previously cited), and Fujimoto (Fujimoto, H. et al. Nucleic Acids Research, Vol. 32, No. 4 (2004), pp: 1555-1565; previously cited), 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; previously cited).
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 Fujiwara, Kaminski and Fujimoto.
The combination of Fujiwara, Kaminski and Fujimoto does not render obvious elements of claim 8, i.e., a foreign gene product that is a foreign 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, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have modified the gene delivery system as taught by Fujimoto/Kaminski and introduced a foreign 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 Fujiwara (Fujiwara, H. “ Site-specific non-LTR retrotransposons”. Microbiology Spectrum, Vol. 3, No. 2 (2015), p:MDNA3-0001-2014, pp: 1-16; cited on IDS filed 07/02/2026), in view of Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006; previously cited), and Fujimoto (Fujimoto, H. et al. Nucleic Acids Research, Vol. 32, No. 4 (2004), pp: 1555-1565; previously cited), 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 Fujiwara, Kaminski and Fujimoto.
However, the combination of references does not render obvious elements of claims 9 and 10, i.e., a first foreign gene product that is a first foreign polypeptide and a second foreign gene product that is a second foreign polypeptide (claim 9). The combination of references does not render obvious a gene delivery vehicle system wherein the foreign nucleotide sequence comprises in order from 5’ to 3’ a nucleotide sequence encoding the first foreign polypeptide, an IRES or a nucleotide sequence encoding a self-cleaving polypeptide, and a nucleotide sequence encoding the second foreign 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 foreign 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 foreign 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 foreign 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 of the claimed invention to have modified the constructs as taught by Fujiwara modified by Kaminski and Fujimoto 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 of the claimed invention to have further modified the construct of Fujiwara/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 Fujiwara (Fujiwara, H. “ Site-specific non-LTR retrotransposons”. Microbiology Spectrum, Vol. 3, No. 2 (2015), p:MDNA3-0001-2014, pp: 1-16; cited on IDS filed 07/02/2026), in view of Kaminski (Kaminski, J.M. US 2006/0210977 A1 published September 21, 2006; previously cited), Fujimoto (Fujimoto, H. et al. Nucleic Acids Research, Vol. 32, No. 4 (2004), pp: 1555-1565; previously cited), 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; previously cited).
The rejection of claim 9 is discussed above. The combination of references Fujiwara, Kaminski, Fujimoto and Minshull renders elements of claim 9 obvious. However, the combination of references 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 Fujiwara/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 of the claimed invention to have further modified Fujiwara/Fujimoto/Kaminski and Minshull to introduce a foreign 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 07/02/2026, 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 but are moot because the new ground of rejections do not rely on the same combination of references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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).
In this case, Fujiwara teaches the elements of claims 1 and 20 except for SEQ ID NO: 37, codon-optimization and the length of the transgene. Fujiwara does not teach kits either. However, the combination of Fujiwara, Kaminski, and Fujimoto renders all the elements obvious. Kaminski teaches compositions and methods, and kits for modifying a genome using transposases. Kaminski teaches different lengths for transgenes. Kaminski also teaches optimizing sequences for human cells’ expression. Fujimoto’s teaching in the new set of rejections is used solely to teach SEQ ID NO: 37, and its use in the art.
Applicant is claiming a gene delivery system for specific targeting/integration in 28S rDNA locus, a safe and controlled alternative that has been made obvious by Fujiwara. Fujiwara effectively and stably integrated a transgene, EGFP gene, and a nucleic acid encoding R2O1 within the 28S rDNA site, before the effective filing date of the claimed invention. The dependent claims are generic, building on otherwise already reported therapeutic systems.
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).
Conclusion
No claim is 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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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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