CHIMERIC ANTIGEN RECEPTORS (CAR) FOR B CELL MALIGNANCIES

§102 §103 §112

DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Election/Restrictions Applicant’s election without traverse of Group I, claims 1-16 in the reply filed on 08/10/2026 is acknowledged. Claims 17-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/10/2026. Status of Claims The amendment filed on 09/12/2024 amended claims 9-12, 15, and 16, and cancelled claim 21. Claims 1-20 are pending. Claims 17-20 are withdrawn as directed to a non-elected invention. Claims 1-16 will be examined on the merits. Priority Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Information Disclosure Statement The information disclosure statement filed 09/12/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. The references without copies are Foreign Patents WO-2013123061 and IN 202121007954, Foreign Patent References 1 and 2. Nucleotide and/or Amino Acid Sequence Disclosures REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES Items 1) and 2) provide general guidance related to requirements for sequence disclosures. 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted: In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying: the name of the ASCII text file; ii) the date of creation; and iii) the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended). When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical. Specific deficiencies and the required response to this Office Action are as follows: Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Required response – Applicant must provide: Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers; AND/OR A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter. Claim Objections Claim 6 is objected to because of the following informalities: Claim 6 recites the human CD3-zeta signaling domain as having the amino acid sequence of SEQ ID NO: 31, while claim 8 recites that SEQ ID NO: 31 encodes the co-stimulatory domain of CD. Appropriate correction is required. Sequence Alignment 1: SEQ ID NO: 31 and human CD3-zeta PNG media_image1.png 266 1220 media_image1.png Greyscale Sequence Alignment 2: SEQ ID NO: 32 and human CD3-zeta PNG media_image2.png 382 1211 media_image2.png Greyscale Claims 1, 11, and 12 are objected to because of the following informalities: claim 1 recites (f). Claims 11 and 12 recite CARs with limitations denoted by i. – iii. Consistency is requested. Appropriate correction is required. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 2, 11, and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 recites “A bispecific chimeric antigen receptor (CAR) comprising: (a) a CD19 binding domain along with CD20 or CD22…”. It is unclear if limitation (a) intends to recite a bispecific CAR comprising a CD19 binding domain and a CD20 or CD22 binding domain, or if limitation (a) intends to recite a bispecific CAR comprising a CD19 binding domain and a CD20 or CD22 protein. Appropriate clarification is required. For the purposes of examination, in light of dependent claim 2 and the examples in the specification, Examiner is interpreting claim 1(a) as intending to recite a CD19 binding domain and a CD20 or CD22 binding domain. Claim 2 recites “The…CAR as claimed in claim 1, comprising an amino acid sequence of CD 19, CD20 and CD22 binding domains as set forth in SEQ ID NOs: 21, 22 and 23, respectively.” However, claim 1 recites “a bispecific…CAR comprising: (a) a CD19 binding domain along with CD20 or CD22”, indicating the bispecific CAR can comprise a CD19 binding domain and either a CD20 or CD22 [binding domain, see above]. However, claim 2 recites that the CAR comprises all three binding domains. The terms “or” in claim 1 and “and” in claim 2 contradict each other and claim 2 is indefinite. For the purposes of examination, Examiner will be interpreting claim 2 as reciting “CD19, CD20, and/or CD22 binding domains” in light of claim 1. Claims 11 and 12 are indefinite in their recitation of limitation “ii. a combination of co-stimulatory domains selected from CD28 and 41BB, OX40 and 41BB, ICOS and OX40, ICOS and 41BB, and ICOS, OX40, and 41BB…” It is unclear if limitation ii intends for a co-stimulatory domain to be selected from each of the groupings, resulting in five co-stimulatory domains, or if the limitation intends for a group of co-stimulatory domains to be selected from out of the five groupings presented. Appropriate correction is required. For the purposes of examination, in light of the examples in the specification, the Examiner will be interpreting claims 11 and 12 as requiring one grouping of co-stimulatory domains, selected from the five groupings presented. Claim Rejections - 35 USC § 102 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claim(s) 1-8, 10-14, and 16 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2019/0083596 A1, Orentas et al., published 03/21/2019. The instant claims are drawn to bispecific CARs comprising a CD19 and CD20 or CD22 binding domain, a linker region, a hinge or spacer region, a transmembrane region, an intracellular signaling domain, and two or more intracellular co-stimulatory signaling domains selected from CD28, 41BB, OX40, and ICOS. Orentas et al. teach bispecific CARs comprising CD19 and CD20 binding domains or CD19 and CD22 binding domains in Figures 1, 2, and 5, and in paragraphs [0081]-[0082] and [0112]. Orentas et al. teach that the extracellular binding domains are CD19, CD20, and CD22 binding domains in paragraph [0137], which comprise Orentas SEQ ID NO: 28, 2, and 8, respectively, which are the same as those in instant SEQ ID NO: 21, 22, and 23, respectively, thus teaching instant claim 2 (See Sequence Alignments 3-5 below or attached). Additionally, Orentas SEQ ID NO: 24 teaches both SEQ ID NO: 21 and SEQ ID NO: 22 (see Sequence Alignments 6-7 attached). Sequence Alignment 3: SEQ ID NO: 21 and Orentas SEQ ID NO: 28 Query Match 100.0%; Score 1279; DB 1; Length 242; Best Local Similarity 100.0%; Matches 242; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS 60 Qy 61 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGG 120 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 61 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGG 120 Qy 121 GSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 180 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 121 GSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 180 Qy 181 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV 240 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 181 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV 240 Qy 241 SS 242 || Db 241 SS 242 Sequence Alignment 5: SEQ ID NO: 23 and Orentas SEQ ID NO: 8 Query Match 92.1%; Score 1291; DB 1; Length 249; Best Local Similarity 100.0%; Matches 246; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 22 QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWY 81 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWY 60 Qy 82 NDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMV 141 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 61 NDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMV 120 Qy 142 TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPG 201 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 121 TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPG 180 Qy 202 KAPNLLIYAASSLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQG 261 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 181 KAPNLLIYAASSLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQG 240 Qy 262 TKLEIK 267 |||||| Db 241 TKLEIK 246 Orentas et al. further teach that the CARs comprise (G4S)3 and (G4S)5 linkers, as seen in SEQ ID NO: 24 (see Sequence alignment 8 below), thus teaching claims 3 and 7. Sequence Alignment 8: SEQ ID NO: 24 and Orentas SEQ ID NO: 24 PNG media_image3.png 246 1208 media_image3.png Greyscale Orentas et al. also teach the hinge or space region and the transmembrane region as being in Orentas SEQ ID NO:15 from CD8 in paragraphs [0146] and [0154], aligning with SEQ ID NO: 25 and 26, thus teaching instant claims 4 and 5 (see Sequence Alignments 9 and 10 below). Sequence Alignment 9: SEQ ID NO: 25 and Orentas SEQ ID NO: 15 PNG media_image4.png 268 1257 media_image4.png Greyscale Sequence Alignment 10: SEQ ID NO: 26 and Orentas SEQ ID NO: 15 PNG media_image5.png 251 1182 media_image5.png Greyscale Orentas et al. additionally teach an intracellular signaling domain of CD3-zeta in paragraph [0162] and Orentas SEQ ID NO: 20, aligning with instant SEQ ID NO: 32, teaching instant claim 6 (See Sequence Alignment 11 below). Sequence Alignment 11: SEQ ID NO: 32 and Orentas SEQ ID NO: 20 PNG media_image6.png 391 1204 media_image6.png Greyscale Orentas et al. teach the co-stimulatory domains can include those of ICOS, OX40, 41BB, and CD28 in paragraph [0162]. Orentas et al. teach that any combination of these can be used in paragraphs [0036] and [0242], but that a combination of CD28 and 41BB is preferable in paragraph [0164]. The sequences taught by Orentas et al. align with those of SEQ ID NO: 28-31, as seen in Sequence Alignments 12-15 below, thus teaching instant claim 8. Sequence Alignment 12: SEQ ID NO: 28 and NCBI RefSeq: NP_036224.1 PNG media_image7.png 262 1192 media_image7.png Greyscale Sequence Alignment 13: SEQ ID NO: 29 and NCBI RefSeq: NP_003318.1 PNG media_image8.png 279 1174 media_image8.png Greyscale Sequence Alignment 14: SEQ ID NO: 30 and Orentas SEQ ID NO: 84 PNG media_image9.png 255 1207 media_image9.png Greyscale Sequence Alignment 15: SEQ ID NO: 31 and Orentas SEQ ID NO: 86 PNG media_image10.png 241 1202 media_image10.png Greyscale Finally, as Orentas et al. teach that CD19 and CD20 extracellular binding domains and CD19 and CD22 extracellular binding domains can be used in the bispecific CARs of Orentas et al. in figure 2, that they can be connected by a GS linker in SEQ ID NO: 24, and that intracellular signaling domains CD3-zeta, 41BB, and CD28 can be used in paragraph [0164], Orentas et al. teach instant claims 10 and 11. Orentas et al. also teach nucleic acids encoding these CARs, teaching instant claim 12, in paragraph [0042], a lentiviral vector comprising the nucleic acids encoding the CARs, teaching instant claims 13 and 14, in paragraph [0014] and a host T cell comprising the lentiviral vector and a carrier (or excipient), teaching claims 16, in paragraph [0297]. Therefore, Orentas et al. teach instant claims 1-8, 10-14, and 16. Claim Rejections - 35 USC § 103 The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claim(s) 1-14 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0083596 A1, Orentas et al., in view of Weinkove et al. The instant claims are drawn to bispecific CARs comprising a CD19 and CD20 or CD22 binding domain, a linker region, a hinge or spacer region, a transmembrane region, an intracellular signaling domain, and two or more intracellular co-stimulatory signaling domains selected from CD28, 41BB, OX40, and ICOS. Orentas et al. teach bispecific CARs comprising CD19 and CD20 binding domains or CD19 and CD22 binding domains in Figures 1, 2, and 5, and in paragraphs [0081]-[0082] and [0112]. Orentas et al. teach that the extracellular binding domains are CD19, CD20, and CD22 binding domains in paragraph [0137], which comprise Orentas SEQ ID NO: 28, 2, and 8, respectively, which are the same as those in instant SEQ ID NO: 21, 22, and 23, respectively, thus teaching instant claim 2 (See Sequence Alignments 3-5 above and attached). Additionally, Orentas SEQ ID NO: 24 teaches both SEQ ID NO: 21 and SEQ ID NO: 22 (see Sequence Alignments 6-7 attached). Orentas et al. further teach that the CARs comprise (G4S)3 and (G4S)5 linkers, as seen in SEQ ID NO: 24 (see Sequence alignment 8 above), thus teaching claims 3 and 7. Orentas et al. also teach the hinge or space region and the transmembrane region as being in Orentas SEQ ID NO:15 from CD8 in paragraphs [0146] and [0154], aligning with SEQ ID NO: 25 and 26, thus teaching instant claims 4 and 5 (see Sequence Alignments 9 and 10 above). Orentas et al. additionally teach an intracellular signaling domain of CD3-zeta in paragraph [0162] and Orentas SEQ ID NO: 20, aligning with instant SEQ ID NO: 32, teaching instant claim 6 (See Sequence Alignment 11 above). Orentas et al. teach the co-stimulatory domains can include those of ICOS, OX40, 41BB, and CD28 in paragraph [0162]. Orentas et al. teach that any combination of these can be used in paragraphs [0036] and [0242], but that a combination of CD28 and 41BB is preferable in paragraph [0164]. The sequences taught by Orentas et al. align with those of SEQ ID NO: 28-31, as seen in Sequence Alignments 12-15 above, thus teaching instant claim 8. Finally, as Orentas et al. teach that CD19 and CD20 extracellular binding domains and CD19 and CD22 extracellular binding domains can be used in the bispecific CARs of Orentas et al. in figure 2, that they can be connected by a GS linker in SEQ ID NO: 24, and that intracellular signaling domains CD3-zeta, 41BB, and CD28 can be used in paragraph [0164], Orentas et al. teach instant claims 10 and 11. Orentas et al. also teach nucleic acids encoding these CARs, teaching instant claim 12, in paragraph [0042], a lentiviral vector comprising the nucleic acids encoding the CARs, teaching instant claims 13 and 14, in paragraph [0014] and a host T cell comprising the lentiviral vector and a carrier (or excipient), teaching claims 16, in paragraph [0297]. Orentas et al. do not explicitly teach CARs with sequences identical to SEQ ID NOs: 11-20. However, the CARs that Orentas et al. teach, such as SEQ ID NO: 26, has 91% sequence identity with SEQ ID NO: 12, for example, and is essentially the same as those of SEQ ID NOs: 11-20, comprising the same components, as seen in the labeled alignment below. The differences are in the leader peptide, the linkers used in the CD19 scFv, and Orentas SEQ ID NO: 24 does not contain a second co-stimulatory domain. Annotated Sequence Alignment 16: SEQ ID NO: 12 and Orentas SEQ ID NO: 26 PNG media_image11.png 362 1132 media_image11.png Greyscale PNG media_image12.png 696 891 media_image12.png Greyscale PNG media_image13.png 502 898 media_image13.png Greyscale The leader peptide sequences and linker sequences are known structural features in the art and do not contribute to the inventive concept of the CAR. The inclusion of the CD28 signaling domain is obvious in view of Weinkove et al. Page 7, right column, of Weinkove et al. discusses combinations of co-stimulatory domains in CARs, and recites that CD28 costimulation enhances tumoricidal activity of CAR T cells, and 41BB costimulation enhances persistence of CAR T cells, and clincal evidence supports using both costimulatory domains in CAR T cell treatment to lead to enhanced proliferation and persistence of CAR T cell therapy. Therefore, it would be obvious to one of ordinary skill in the art to include both the CD28 and 41BB costimulatory domains in a bispecific CAR such as the one of Orentas et al. SEQ ID NO: 26. One would have motivation to do so to promote proliferation and persistence in the CAR cells. One would have reasonable expectation of success because other CD19 CARs have had better T cell expansion compared to those with only one costimulatory domain (See Weinkove et al. page 8 left column). Therefore, as adding the extra costimulatory domain to the bispecific CAR of Orentas et al. is obvious, and the remaining differences between the CAR of Orentas et al. and the CAR of instant SEQ ID NO: 12 do not add any functional difference to the CAR, as they are simply linker peptides known in the art and leader peptides without a specific function. Therefore, claims 1-14 and 16 are obvious over Orentas et al. in view of Weinkove et al. Claim(s) 1-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Orentas et al. in view of Weinkove et al. as applied to claims 1-14 and 16 above, and further in view of Delenda, J. Gene Med., (2004) 6: S125-S138, the Addgene® pLenti-puro product page and Guan et al., Cancer Res., (2011) 71(21):6718-27. The teachings of Orentas et al. in view of Weinkove et al. regarding claims 1-14 and 16 are disclosed above. Orentas et al. does not explicitly teach a vector with all of the limitations of claim 15, including a CMV promoter, a Psi packaging signal, a cPPT/CTS, an EF1a promoter, a linker/hinge, a WPRE, an f1 origin, and a promoter for ampicillin resistance. However, Orentas et al. do disclose that any lentiviral vector can be applied, including any known in the art, in paragraph [0255]. Orentas et al. disclose a CMV promoter (paragraph [0261]), ampicillin resistance (paragraph [0260]), and an EF1a promoter (Table 1). Orentas et al. do not explicitly disclose a Psi packaging signal, a cPPT/CTS, a WPRE, or a f1 origin. However, Delenda discloses that addition of a WPRE increases expression of a peptide of interest from a lentiviral vector, with a WPRE inducing stronger expression than its counterparts (page S128, right column). Delenda also teaches lentiviral vectors inherently contain psi packaging signals on page S128, left column, last paragraph, and that cPPT/CTS elements are included in many lentiviral vectors to improve gene transfer efficiency (by enhancing nuclear translocation). Therefore, the psi packaging signal, cPPT/CTS, and WPRE are all commonly known in the art, and one would be motivated to include them on a vector in order to improve gene transfer and expression. Finally, these elements are all included in lentiviral vectors commercially sold for gene transfer, such as the pLenti-puro vector from Addgene®, first published in 2011 by Guan et al. The vector map an f1 origin of replication, ampicillin resistance cassette and promoter, an HIV-1 psi packaging signal, and a CMV promoter. Therefore, it would be obvious to one of ordinary skill in the art to start with a commercially available vector, such as the pLenti-puro vector, and add additional elements known in the art to promote gene transfer and expression, such as a cPPT/CTS and a WPRE, as disclosed by Delenda., and add the CAR gene of interest prefixed by an EF1a promoter, as disclosed in Orentas et al. Table 1. One would have reasonable expectation of success as these elements are all well understood, routine, and conventional in the art, as evidenced by Delenda et al. Therefore, instant claim 15 is obvious over Orentas et al. in view of Weinkove et al. and further in view of Delenda, the Addgene product page for pLenti-puro, and Guan et al. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amelia Stephens whose telephone number is (571)272-1006. The examiner can normally be reached M-F 8-5 EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571) 272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /AMELIA STEPHENS/ Examiner, Art Unit 1645 /ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683