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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 18, 2025 has been entered.
Claims 9-10, 12-13 and 15-30 are pending.
The request for rejoinder of the withdrawn claims upon allowance of the claims under examination is acknowledged. However, the claims are not ready for allowance.
Claims 18-28 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 9-10, 12-13, 15-17, 29 and 30, drawn to a cell having an improved engraftment fitness comprising a first chimeric antigen receptor (CAR) comprising a particular first ligand binding domain capable of specifically binding to CD19 encoded by a nucleotide sequence of SEQ ID NO: 12 as the species; a particular second CAR comprising a second ligand binding domain capable of specifically binding to a particular tumor antigen selected from L1CAM encoded by a nucleotide of SEQ ID NO: 16 as the species; and wherein the cell has an improved engraftment fitness compared to a cell lacking the first CAR, a pharmaceutical composition comprising said cell and a pharmaceutically acceptable excipient, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 62/202,698, filed August 7, 2015, is acknowledged.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, 62/202,698, and 15/750,708, fail to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application.
The previously-filed application 62/202,698 does not disclose the human T cell, second ligand binding domain is ROR1 as in independent claim 9, conservative amino acid substitution in any sequence of SEQ ID NO: 11, 13, 26 or 17 as in claim 29 and having at least 95% sequence identity to any one of SEQ ID NO: 12, 14, 16 or 18 as per claim 30.
The previously-filed application 15/750,708 does not disclose conservative amino acid substitution in any sequence of SEQ ID NO: 11, 13, 26 or 17 as in claim 29 and having at least 95% sequence identity to any one of SEQ ID NO: 12, 14, 16 or 18 as per claim 30.
Therefore for the purposes of applying prior art, the effective filing date of claims 9-10, 12-13, 15-17 is September 12, 2022, the date that the present application was filed.
Should applicant disagree with the examiner’s factual determination above, applicant should point to evidence that shows that the invention of claims 9-10, 12-13, 15-17, 29 and 30 is in fact described in one or more of the previously-filed applications.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9-10, 12-13, 15-17, 29 and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is New Matter rejection.
Claim 9, as amended on 11/18/2025, recites: A human T cell having an improved engraftment fitness, comprising:
a first chimeric antigen receptor (CAR) comprising a first ligand binding domain which specifically binds to CD 19 or CD20, wherein the first ligand binding domain comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 11 or 13;
a second CAR comprising a second ligand binding domain which specifically binds to a tumor antigen selected from LICAM or ROR1, wherein the second ligand binding domain comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs:15 or 17; and
wherein:
the first CAR is different from the second CAR,
each CAR comprises an IgG4 spacer domain, a transmembrane domain, and an intracellular signaling domain comprising a 4-1BB domain and a CD3 zeta domain, and the cell has an improved engraftment fitness compared to a cell lacking the first CAR.
Claim 29 recites the cell of claim 9, wherein (i) the first ligand binding domain comprises an amino acid substitution, wherein the amino acid substitution of SEQ ID NOs: 11 or 13 is a conservative substitution; and (ii) the second ligand binding domain comprises an amino acid substitution, wherein the amino acid substitution of SEQ ID NOs:15 or 17 is a conservative substitution.
30. (NEW) The cell of claim 9, wherein the first ligand binding domain is encoded by a nucleotide sequence having at least 95% sequence identity with any one of SEQ ID NOs:12 or 14, and wherein the second ligand binding domain is encoded by a nucleotide sequence having at least 95% sequence identity with any one of SEQ ID NOs:16 or 18.
Applicants indicate that support for the amendment to claim 9 and new claims 29 and 30 “can be found throughout the specification as filed, for example, paragraphs [0021], [0056], [0059]” (remarks filed 11/18/25, p. 5, 1st paragraph).
However, support for “the first ligand binding domain comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 11 or 13”, and “the second ligand binding domain comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs:15 or 17” is not found in the originally filed application, except for SEQ ID NOs: 11, 13, 15, and 17 themselves, see para. [0056] to [0059].
That is, the application as originally filed does not support amino acid sequences “having at least 95% sequence identity with any one of SEQ ID NOs: 11 OR 13” and amino acid sequences “having at least 95% sequence identity with any one of SEQ ID NOs: 15 or 17”, except for the sequences set forth in SEQ ID NOs: 11, 13, 15 and 17. The application as filed does not even include any discussion of sequences differing from SEQ ID NOs: 11, 13, 15 or 17 by any level of sequence identity.
Claim 29 also recites, in line 2-3, “the amino acid substitution of SEQ ID NOs: 11 or 13 is a conservative substitution”, and in lines 4-5, “the amino acid substitution of SEQ ID NOs: 15 or 17 is a conservative substitution”. Support in the originally filed disclosure could not be found for “conservative substitution”.
However, as discussed above, support is lacking in the original disclosure for amino acid sequences having at least 95% sequence identity to SEQ ID NOs: 11, 13, 15, or 17, except for those sequences themselves. The disclosure as originally filed does not have support for amino acid substitutions of any kind, including conservative substitutions, of the sequence set forth in SEQ ID NOs: 11, 13, 15 or 17. Substitutions to the amino acid sequence of SEQ ID NOs: 11, 13, 15 or 17 is not discussed in the originally filed application.
Claim 30 recites the first ligand binding domain is encoded by a nucleotide sequence having at least 95% sequence identity with any one of SEQ ID NOs:12 or 14, and wherein the second ligand binding domain is encoded by a nucleotide sequence having at least 95% sequence identity with any one of SEQ ID NOs:16 or 18.
The application as originally filed does not have support for “nucleotide sequences having at least 90% sequence identity with SEQ ID NOs: 12 or 14”, except for SEQ ID NOs: 12 and 14 themselves, or for nucleotide sequences having at least 90% sequence identity to SEQ ID NOs: 16 or 18, other than SEQ ID NOs: 16 and 18 themselves, see para. [0056] to [0060].
The subject matter of nucleotide sequences having at least 90% sequence identity with any one of SEQ ID NOs: 12, 14, 16, or 18 first appeared in the instant application in the claim amendment filed 11/12/2022, which introduced claim 13 as a new claim. The actual filing date of the instant application is 09/12/2022.
MPEP 608.04(b) teaches that a preliminary amendment present on the filing date of the application is considered part of the original disclosure, but a preliminary amendment filed after the filing date of the application is not part of the original disclosure of the application.
Applicants indicate that support for new claims 9-28 (introduced in the amendment filed 11/22/2022) “can be found throughout the specification as filed, for example, original claims 1-8; paragraphs [0028], [0174], [0175], [0207]-[0219]; and figures 9-11” (remarks filed 11/22/2022, p. 4, 1st paragraph). However, no support could be found in the originally filed disclosure, including in the cited paragraphs, figures, and original claims, for nucleotide sequences having at least 90% sequence identity to SEQ ID NOs: 12, 14, 16, or 18 (other than SEQ ID NOs: 12, 14, 16, and 18 themselves).
In regard to claims 9 and 13, the originally filed disclosure does not discuss “human T cell”, amino acid or nucleotide sequences differing from SEQ ID NOs: 11-18 by any % sequence identity. A search of the original disclosure for terms such as ‘identity’, percent, %, homolog, homologous, substitute, conservative substitution, variant, variation, etc. did not disclose any such term in relation to any of SEQ ID NOs: 11-18.
Finally, the prior filed applications 15/750,708, PCT/US2016/045360 and 62/202,698 did not did not disclose the limitations of “human T cell”, “ROR1”, having at least 90% sequence identity with SEQ ID 12 or 14 of the first ligand binding domain and 90% sequence identity with SEQ ID 16 or 18 of the second ligand binding domain or of having at least 95% sequence identity with SEQ ID 11 or 13 of the first ligand binding domain and 95% sequence identity with SEQ ID 15 or 17 of the second ligand binding domain and conservative substitution. Matter not present on the filing date of the application in the specification, claims, or drawings that is added after the application filing is usually new matter including adding specific percentages, conservative substitution and human T cell.
For the reasons discussed above, claims 9, 10, 12-13, 15-17, 29 and 30 encompass new matter.
Applicant is required to remove any new matter in response to this Office Action.
Claim Rejections - 35 USC § 102
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.
Claims 9-10, 12-13, 15-17 and 30 are rejected under 35 U.S.C. 102 (a)(1)as being anticipated by Jensen et al (WO2017/027291, published February 16, 2017; PTO 892).
Claim 9 recites a human T cell having an improved engraftment fitness, comprising:
a first chimeric antigen receptor (CAR) comprising a first ligand binding domain which specifically binds to CD19 or CD20, wherein the first ligand binding domain comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 11 or 13;
a second CAR comprising a second ligand binding domain which specifically binds to a tumor antigen selected from L1CAM or ROR1, wherein the second ligand binding domain comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs:15 or 17; and wherein:
the first CAR is different from the second CAR, each CAR comprises an IgG4 spacer domain, a transmembrane domain, and an intracellular signaling domain comprising a 4-1BB domain and a CD3 zeta domain, and the cell has an improved engraftment fitness compared to a cell lacking the first CAR.
Regarding claims 9, 10, 12, 13, Jensen teaches dual CAR human T cells (see para. [0141]) comprising a first chimeric antigen receptor (CAR) comprising a first B cell ligand binding domain which specifically binds to CD19 or CD20 wherein the first B cell ligand comprises an amino acid sequence which specifically binds to CD19 (see para. [0145], [0157]) or CD20 (para. [0145], [0157]) and a second ligand on tumor is L1CAM or ROR1 (see para. [0158]).
The CD19CAR comprises the amino acid sequence set forth in SEQ ID NO: 11 as per claims 9 and 10 and is encoded by the sequence set forth in SEQ ID NO: 12 as per claim 13, see para. [0207].
The reference SEQ ID NO: 11 is 100% identical to the claimed SEQ ID NO: 11, which is at least 95% identity to SEQ ID NO: 11, see sequence alignment below:
Query Match 100.0%; Score 1285; Length 244;
Best Local Similarity 100.0%;
Matches 244; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQTTSSLSALGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQTTSSLSALGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSR 60
Qy 61 FSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEG 120
Qy 121 STKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSET 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 STKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSET 180
Qy 181 TYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSV 240
Qy 241 TVSS 244
||||
Db 241 TVSS 244
and the second CAR comprising a second ligand binding domain which specifically binds to a tumor antigen LICAM comprising SEQ ID NO: 15 as per claim 9, and is encoded by a nucleic acid sequence set forth in SEQ ID NO: 16 as per claim 13, see para. [0223].
The reference SEQ ID NO: 15 is 100% identical to the claimed SEQ ID NO: 15, , which is at least 95% identity to SEQ ID NO: 15, see sequence alignment below:
Query Match 100.0%; Score 1294; Length 242;
Best Local Similarity 100.0%;
Matches 242; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQQPGAELVKPGASVKLSCKASGYTFTGYWMHWVKQRPGHGLEWIGEINPSNGRTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQQPGAELVKPGASVKLSCKASGYTFTGYWMHWVKQRPGHGLEWIGEINPSNGRTNY 60
Qy 61 NERFKSKATLTVDKSSTTAFMQLSGLTSEDSAVYFCARDYYGTSYNFDYWGQGTTLTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NERFKSKATLTVDKSSTTAFMQLSGLTSEDSAVYFCARDYYGTSYNFDYWGQGTTLTVSS 120
Qy 121 GGGGSGGGGSGGGGSDIQMTQSSSSFSVSLGDRVTITCKANEDINNRLAWYQQTPGNSPR 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGGGSGGGGSGGGGSDIQMTQSSSSFSVSLGDRVTITCKANEDINNRLAWYQQTPGNSPR 180
Qy 181 LLISGATNLVTGVPSRFSGSGSGKDYTLTITSLQAEDFATYYCQQYWSTPFTFGSGTELE 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LLISGATNLVTGVPSRFSGSGSGKDYTLTITSLQAEDFATYYCQQYWSTPFTFGSGTELE 240
Qy 241 IK 242
||
Db 241 IK 242
Jensen further teaches CD20CAR comprises the amino acid sequence set forth in SEQ ID NO: 13 as per claim 9 and is encoded by the sequence set forth in SEQ ID NO: 14 as per claim 13, see para. [0220].
The reference SEQ ID NO: 13 is 100% identical to the claimed SEQ ID NO: 13, which is at least 95% identity to SEQ ID NO: 13, see sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 1417; Length 266;
Best Local Similarity 100.0%;
Matches 266; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 METDTLLLWVLLLWVPGSTGDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 METDTLLLWVLLLWVPGSTGDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPG 60
Qy 61 SSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGG 120
Qy 121 TKLEIKGSTSGGGSGGGSGGGGSSEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHW 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TKLEIKGSTSGGGSGGGSGGGGSSEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHW 180
Qy 181 VKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYC 240
Qy 241 ARSNYYGSSYWFFDVWGAGTTVTVSS 266
||||||||||||||||||||||||||
Db 241 ARSNYYGSSYWFFDVWGAGTTVTVSS 266
And the ROR1CAR comprises the amino acid sequence set forth in SEQ ID NO: 17 and is encoded by the sequence set forth in SEQ ID NO: 17 as per claim 9, and is encoded by a nucleotide sequence set forth in SEQ ID NO: 18 as per claim 13, see para. [0223].
The reference SEQ ID NO: 17 is 100% identical to the claimed SEQ ID NO: 17, which is at least 95% identity to SEQ ID NO: 17, see sequence alignment below:
Query Match 100.0%; Score 1326; Length 250;
Best Local Similarity 100.0%;
Matches 250; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 PQEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 PQEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTY 60
Qy 61 YATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTI 120
Qy 121 SSGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SSGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEA 180
Qy 181 PRYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 PRYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFG 240
Qy 241 GGTQLTVTGG 250
||||||||||
Db 241 GGTQLTVTGG 250
Each CAR comprises an IgG4 hinge spacer (see para. [0009], Fig. 2), a CD28 transmembrane domain (CD28tm, para. [0010], Fig. 2), an intracellular signaling domain comprising 4-1BB and a CD3 zeta domain, see Fig. 2, in particular.
PNG
media_image1.png
173
541
media_image1.png
Greyscale
Regarding claim 15, Jensen teaches that the cell is a CD4+ T cell or a CD8+ T cell, see para. [0021], [0027].
Regarding claim 16, Jensen teaches that the CD4+ T cell is a naive CD4+ T-cells, CD4+ memory T-cells, central memory CD4+ T-cells, effector memory CD4+ T-cells and bulk CD4+ T-cells or the cell is a CD8+ T cytotoxic lymphocyte cell, a CD8+ memory T-cells, central memory CD8+ T-cells, effector memory CD8+ T-cells and bulk CD8+ T-cells, see para. [0022].
Regarding claim 17, Jensen teaches a pharmaceutical composition comprising the reference chimeric antigen receptor and a pharmaceutical acceptable carrier, see para. [0159] to [0162].
Regarding claim 30, Jensen teaches FMC63 CD19CAR comprises the amino acid sequence set forth in SEQ ID NO: 11 and is encoded by the sequence set forth in SEQ ID NO: 12, see para. [0224], in particular.
The reference SEQ ID NO: 12 is 100% identical to the claimed SEQ ID NO: 12, which is at least 95% identity to SEQ ID NO: 12, see sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 735; Length 735;
Best Local Similarity 100.0%;
Matches 735; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GACATCCAGATGACCCAGACCACCTCCAGCCTGAGCGCCAGCCTGGGCGACCGGGTGACC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GACATCCAGATGACCCAGACCACCTCCAGCCTGAGCGCCAGCCTGGGCGACCGGGTGACC 60
Qy 61 ATCAGCTGCCGGGCCAGCCAGGACATCAGCAAGTACCTGAACTGGTATCAGCAGAAGCCC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ATCAGCTGCCGGGCCAGCCAGGACATCAGCAAGTACCTGAACTGGTATCAGCAGAAGCCC 120
Qy 121 GACGGCACCGTCAAGCTGCTGATCTACCACACCAGCCGGCTGCACAGCGGCGTGCCCAGC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GACGGCACCGTCAAGCTGCTGATCTACCACACCAGCCGGCTGCACAGCGGCGTGCCCAGC 180
Qy 181 CGGTTTAGCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATCTCCAACCTGGAACAG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CGGTTTAGCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATCTCCAACCTGGAACAG 240
Qy 241 GAAGATATCGCCACCTACTTTTGCCAGCAGGGCAACACACTGCCCTACACCTTTGGCGGC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GAAGATATCGCCACCTACTTTTGCCAGCAGGGCAACACACTGCCCTACACCTTTGGCGGC 300
Qy 301 GGAACAAAGCTGGAAATCACCGGCAGCACCTCCGGCAGCGGCAAGCCTGGCAGCGGCGAG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GGAACAAAGCTGGAAATCACCGGCAGCACCTCCGGCAGCGGCAAGCCTGGCAGCGGCGAG 360
Qy 361 GGCAGCACCAAGGGCGAGGTGAAGCTGCAGGAAAGCGGCCCTGGCCTGGTGGCCCCCAGC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GGCAGCACCAAGGGCGAGGTGAAGCTGCAGGAAAGCGGCCCTGGCCTGGTGGCCCCCAGC 420
Qy 421 CAGAGCCTGAGCGTGACCTGCACCGTGAGCGGCGTGAGCCTGCCCGACTACGGCGTGAGC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 CAGAGCCTGAGCGTGACCTGCACCGTGAGCGGCGTGAGCCTGCCCGACTACGGCGTGAGC 480
Qy 481 TGGATCCGGCAGCCCCCCAGGAAGGGCCTGGAATGGCTGGGCGTGATCTGGGGCAGCGAG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 TGGATCCGGCAGCCCCCCAGGAAGGGCCTGGAATGGCTGGGCGTGATCTGGGGCAGCGAG 540
Qy 541 ACCACCTACTACAACAGCGCCCTGAAGAGCCGGCTGACCATCATCAAGGACAACAGCAAG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 ACCACCTACTACAACAGCGCCCTGAAGAGCCGGCTGACCATCATCAAGGACAACAGCAAG 600
Qy 601 AGCCAGGTGTTCCTGAAGATGAACAGCCTGCAGACCGACGACACCGCCATCTACTACTGC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 AGCCAGGTGTTCCTGAAGATGAACAGCCTGCAGACCGACGACACCGCCATCTACTACTGC 660
Qy 661 GCCAAGCACTACTACTACGGCGGCAGCTACGCCATGGACTACTGGGGCCAGGGCACCAGC 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 GCCAAGCACTACTACTACGGCGGCAGCTACGCCATGGACTACTGGGGCCAGGGCACCAGC 720
Qy 721 GTGACCGTGAGCAGC 735
|||||||||||||||
Db 721 GTGACCGTGAGCAGC 735
Jensen teaches CD20CAR comprises the amino acid sequence set forth in SEQ ID NO: 13 and is encoded by the sequence set forth in SEQ ID NO: 14, see para. [0221].
The reference SEQ ID NO: 14 is 100% identical to the claimed SEQ ID NO: 14, which is at least 95% identity to SEQ ID NO: 14, see para. [0221], sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 798; Length 798;
Best Local Similarity 100.0%;
Matches 798; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGGAGACAGACACACTCCTGCTATGGGTGCTGCTGCTCTGGGTTCCAGGTTCCACAGGT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ATGGAGACAGACACACTCCTGCTATGGGTGCTGCTGCTCTGGGTTCCAGGTTCCACAGGT 60
Qy 61 GACATTGTGCTGACCCAATCTCCAGCTATCCTGTCTGCATCTCCAGGGGAGAAGGTCACA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GACATTGTGCTGACCCAATCTCCAGCTATCCTGTCTGCATCTCCAGGGGAGAAGGTCACA 120
Qy 121 ATGACTTGCAGGGCCAGCTCAAGTGTAAATTACATGGACTGGTACCAGAAGAAGCCAGGA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ATGACTTGCAGGGCCAGCTCAAGTGTAAATTACATGGACTGGTACCAGAAGAAGCCAGGA 180
Qy 181 TCCTCCCCCAAACCCTGGATTTATGCCACATCCAACCTGGCTTCTGGAGTCCCTGCTCGC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TCCTCCCCCAAACCCTGGATTTATGCCACATCCAACCTGGCTTCTGGAGTCCCTGCTCGC 240
Qy 241 TTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGAGTGGAGGCTGAA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGAGTGGAGGCTGAA 300
Qy 301 GATGCTGCCACTTATTACTGCCAGCAGTGGAGTTTTAATCCACCCACGTTCGGAGGGGGG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GATGCTGCCACTTATTACTGCCAGCAGTGGAGTTTTAATCCACCCACGTTCGGAGGGGGG 360
Qy 361 ACCAAGCTGGAAATAAAAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 ACCAAGCTGGAAATAAAAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGG 420
Qy 421 GGCGGCAGCAGCGAGGTGCAGCTGCAGCAGTCTGGGGCTGAGCTGGTGAAGCCTGGGGCC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GGCGGCAGCAGCGAGGTGCAGCTGCAGCAGTCTGGGGCTGAGCTGGTGAAGCCTGGGGCC 480
Qy 481 TCAGTGAAGATGTCCTGCAAGGCTTCTGGCTACACATTTACCAGTTACAATATGCACTGG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 TCAGTGAAGATGTCCTGCAAGGCTTCTGGCTACACATTTACCAGTTACAATATGCACTGG 540
Qy 541 GTAAAGCAGACACCTGGACAGGGCCTGGAATGGATTGGAGCTATTTATCCAGGAAATGGT 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 GTAAAGCAGACACCTGGACAGGGCCTGGAATGGATTGGAGCTATTTATCCAGGAAATGGT 600
Qy 601 GATACTTCCTACAATCAGAAGTTCAAAGGCAAGGCCACATTGACTGCAGACAAATCCTCC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 GATACTTCCTACAATCAGAAGTTCAAAGGCAAGGCCACATTGACTGCAGACAAATCCTCC 660
Qy 661 AGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGACTATTACTGT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGACTATTACTGT 720
Qy 721 GCAAGATCTAATTATTACGGTAGTAGCTACTGGTTCTTCGATGTCTGGGGCGCAGGGACC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 GCAAGATCTAATTATTACGGTAGTAGCTACTGGTTCTTCGATGTCTGGGGCGCAGGGACC 780
Qy 781 ACGGTCACCGTCTCCTCA 798
||||||||||||||||||
Db 781 ACGGTCACCGTCTCCTCA 798
Jensen teaches that the second ligand binding domain of L1CAM CAR comprises the amino acid sequence set forth in SEQ ID NO: 15 and is encoded by the sequence set forth in SEQ ID NO: 16, see para. [0224], in particular.
The reference SEQ ID NO: 16 is 100% identical to the claimed SEQ ID NO: 16, which is at least 95% identity to SEQ ID NO: 16, see sequence alignment below:
Query Match 100.0%; Score 726; Length 726;
Best Local Similarity 100.0%;
Matches 726; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGGTGCAGCTGCAGCAGCCTGGCGCCGAGCTGGTGAAGCCAGGCGCCAGCGTGAAGCTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CAGGTGCAGCTGCAGCAGCCTGGCGCCGAGCTGGTGAAGCCAGGCGCCAGCGTGAAGCTG 60
Qy 61 TCCTGCAAGGCCAGCGGCTACACCTTCACCGGCTACTGGATGCACTGGGTGAAGCAGAGA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TCCTGCAAGGCCAGCGGCTACACCTTCACCGGCTACTGGATGCACTGGGTGAAGCAGAGA 120
Qy 121 CCCGGCCACGGCCTGGAATGGATCGGCGAGATCAACCCCAGCAACGGCCGGACCAACTAC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CCCGGCCACGGCCTGGAATGGATCGGCGAGATCAACCCCAGCAACGGCCGGACCAACTAC 180
Qy 181 AACGAGCGGTTCAAGAGCAAGGCCACCCTGACCGTGGACAAGAGCAGCACCACCGCCTTC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AACGAGCGGTTCAAGAGCAAGGCCACCCTGACCGTGGACAAGAGCAGCACCACCGCCTTC 240
Qy 241 ATGCAGCTGTCCGGCCTGACCAGCGAGGACAGCGCCGTGTACTTCTGCGCCAGGGACTAC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ATGCAGCTGTCCGGCCTGACCAGCGAGGACAGCGCCGTGTACTTCTGCGCCAGGGACTAC 300
Qy 301 TACGGCACCAGCTACAACTTCGACTACTGGGGCCAGGGCACCACACTGACCGTGAGCAGC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 TACGGCACCAGCTACAACTTCGACTACTGGGGCCAGGGCACCACACTGACCGTGAGCAGC 360
Qy 361 GGCGGAGGGGGCTCTGGCGGCGGAGGATCTGGGGGAGGGGGCAGCGACATCCAGATGACC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GGCGGAGGGGGCTCTGGCGGCGGAGGATCTGGGGGAGGGGGCAGCGACATCCAGATGACC 420
Qy 421 CAGAGCAGCAGCAGCTTCAGCGTGAGCCTGGGCGACCGGGTGACCATCACCTGTAAGGCC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 CAGAGCAGCAGCAGCTTCAGCGTGAGCCTGGGCGACCGGGTGACCATCACCTGTAAGGCC 480
Qy 481 AACGAGGACATCAACAACCGGCTGGCCTGGTATCAGCAGACCCCCGGCAACAGCCCCAGG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 AACGAGGACATCAACAACCGGCTGGCCTGGTATCAGCAGACCCCCGGCAACAGCCCCAGG 540
Qy 541 CTGCTGATCAGCGGCGCCACCAACCTGGTGACCGGCGTGCCCAGCCGGTTTAGCGGCAGC 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 CTGCTGATCAGCGGCGCCACCAACCTGGTGACCGGCGTGCCCAGCCGGTTTAGCGGCAGC 600
Qy 601 GGCTCCGGCAAGGACTACACCCTGACCATCACAAGCCTGCAGGCCGAGGACTTCGCCACC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 GGCTCCGGCAAGGACTACACCCTGACCATCACAAGCCTGCAGGCCGAGGACTTCGCCACC 660
Qy 661 TACTACTGCCAGCAGTACTGGTCCACCCCCTTCACCTTCGGCAGCGGCACCGAGCTGGAA 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 TACTACTGCCAGCAGTACTGGTCCACCCCCTTCACCTTCGGCAGCGGCACCGAGCTGGAA 720
Qy 721 ATCAAA 726
||||||
Db 721 ATCAAA 726
Jensen teaches that the second ligand binding domain of ROR1 CAR comprises the amino acid sequence set forth in SEQ ID NO: 17 and is encoded by the sequence set forth in SEQ ID NO: 18, see para. [0224], in particular.
The reference SEQ ID NO: 18 is 100% identical to the claimed SEQ ID NO: 18, which is at least 95% identity to SEQ ID NO: 18, see sequence alignment below:
Query Match 100.0%; Score 745; Length 745;
Best Local Similarity 100.0%;
Matches 745; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CCAGGAACAGCTCGTCGAAAGCGGCGGCAGACTGGTGACACCTGGCGGCAGCCTGACCCT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CCAGGAACAGCTCGTCGAAAGCGGCGGCAGACTGGTGACACCTGGCGGCAGCCTGACCCT 60
Qy 61 GAGCTGCAAGGCCAGCGGCTTCGACTTCAGCGCCTACTACATGAGCTGGGTCCGCCAGGC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GAGCTGCAAGGCCAGCGGCTTCGACTTCAGCGCCTACTACATGAGCTGGGTCCGCCAGGC 120
Qy 121 CCCTGGCAAGGGACTGGAATGGATCGCCACCATCTACCCCAGCAGCGGCAAGACCTACTA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CCCTGGCAAGGGACTGGAATGGATCGCCACCATCTACCCCAGCAGCGGCAAGACCTACTA 180
Qy 181 CGCCACCTGGGTGAACGGACGGTTCACCATCTCCAGCGACAACGCCCAGAACACCGTGGA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CGCCACCTGGGTGAACGGACGGTTCACCATCTCCAGCGACAACGCCCAGAACACCGTGGA 240
Qy 241 CCTGCAGATGAACAGCCTGACAGCCGCCGACCGGGCCACCTACTTTTGCGCCAGAGACAG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 CCTGCAGATGAACAGCCTGACAGCCGCCGACCGGGCCACCTACTTTTGCGCCAGAGACAG 300
Qy 301 CTACGCCGACGACGGCGCCCTGTTCAACATCTGGGGCCCTGGCACCCTGGTGACAATCTC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CTACGCCGACGACGGCGCCCTGTTCAACATCTGGGGCCCTGGCACCCTGGTGACAATCTC 360
Qy 361 TAGCGGCGGAGGCGGATCTGGTGGCGGAGGAAGTGGCGGCGGAGGATCTGAGCTGGTGCT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 TAGCGGCGGAGGCGGATCTGGTGGCGGAGGAAGTGGCGGCGGAGGATCTGAGCTGGTGCT 420
Qy 421 GACCCAGAGCCCCTCTGTGTCTGCTGCCCTGGGAAGCCCTGCCAAGATCACCTGTACCCT 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GACCCAGAGCCCCTCTGTGTCTGCTGCCCTGGGAAGCCCTGCCAAGATCACCTGTACCCT 480
Qy 481 GAGCAGCGCCCACAAGACCGACACCATCGACTGGTATCAGCAGCTGCAGGGCGAGGCCCC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GAGCAGCGCCCACAAGACCGACACCATCGACTGGTATCAGCAGCTGCAGGGCGAGGCCCC 540
Qy 541 CAGATACCTGATGCAGGTGCAGAGCGACGGCAGCTACACCAAGAGGCCAGGCGTGCCCGA 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 CAGATACCTGATGCAGGTGCAGAGCGACGGCAGCTACACCAAGAGGCCAGGCGTGCCCGA 600
Qy 601 CCGGTTCAGCGGATCTAGCTCTGGCGCCGACCGCTACCTGATCATCCCCAGCGTGCAGGC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 CCGGTTCAGCGGATCTAGCTCTGGCGCCGACCGCTACCTGATCATCCCCAGCGTGCAGGC 660
Qy 661 CGATGACGAGGCCGATTACTACTGTGGCGCCGACTACATCGGCGGCTACGTGTTCGGCGG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 CGATGACGAGGCCGATTACTACTGTGGCGCCGACTACATCGGCGGCTACGTGTTCGGCGG 720
Qy 721 AGGCACCCAGCTGACCGTGACCGGC 745
|||||||||||||||||||||||||
Db 721 AGGCACCCAGCTGACCGTGACCGGC 745
Products of identical chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims, e.g., improved engraftment are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01.
Thus, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 9 and 29 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Jensen et al (WO2017/027291, published February 16, 2017; PTO 892) in view of Bitter et al (US20160362472, published December 15, 2016; PTO 892) and/or Fry et al (WO2016/149578, published September 22, 2016; PTO 892.
Claim 29 recites the cell of claim 9, wherein (i) the first ligand binding domain comprises an amino acid substitution, wherein the amino acid substitution of SEQ ID NOs: 11 or 13 is a conservative substitution; and (ii) the second ligand binding domain comprises an amino acid substitution, wherein the amino acid substitution of SEQ ID NOs:15 or 17 is a conservative substitution.
The teachings of Jensen have been discussed supra.
Jensen further teaches the ligand binding domain can be a conserved sequence in a structure, see para. [0070].
Jensen does not teach the first ligand binding domain is a conservative substitution in SEQ ID NO: 11 or 13 and the second ligand binding domain is a conservative substitution in SEQ ID NO: 15 or 17.
However, Bitter teaches various chimeric antigen receptor such as CD19 chimeric antigen receptor (aka CD19 CART, para. [0443], reference claims) in combination with CAR molecules directed to CD20, see abstract, para. [0006], [0014], in particular. Bitter further teaches that the amino acid sequence of the antigen binding domain (e.g., antigen-binding domain that binds one or more CD19, CD20, ROR1) can be modified, e.g., conservative substitution. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine), see para. [0645].
Likewise, Fry teaches dual specific chimeric antigen receptor that binds to CD19 and CD22. Fry further teaches that the parent CAR with at least one conservative amino acid substitution, see para. [0044]. Conservative amino acid substitutions are known in the art, and include amino acid substitutions in which one amino acid having certain physical and/or chemical properties is exchanged for another amino acid that has the same or similar chemical or WO 2016/149578 13 PCT/US2016/023055 physical properties. For instance, the conservative amino acid substitution can be an acidic/negatively charged polar amino acid substituted for another acidic/negatively charged polar amino acid (e.g., Asp or Glu), an amino acid with a nonpolar side chain substituted for another amino acid with a nonpolar side chain (e.g., Ala, Gly, Val, Ile, Leu, Met, Phe, Pro, Trp, Cys, Val, etc.), a basic/positively charged polar amino acid substituted for another basic/positively charged polar amino acid (e.g. Lys, His, Arg, etc.), an uncharged amino acid with a polar side chain substituted for another uncharged amino acid with a polar side chain (e.g., Asn, Gln, Ser, Thr, Tyr, etc.), an amino acid with a beta-branched side-chain substituted for another amino acid with a beta-branched side-chain (e.g., Ile, Thr, and Val), an amino acid with an aromatic side-chain substituted for another amino acid with an aromatic side chain (e.g., His, Phe, Trp, and Tyr), etc., see para. [0045].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to include conservative substitutions as taught by Bitter or Fry in the first ligand binding domain is a conservative substitution in SEQ ID NO: 11 or 13 and the second ligand binding domain is a conservative substitution in SEQ ID NO: 15 or 17 of Jensen to arrive at the claimed invention with a reasonable expectation success, e.g., the variants having the same chemical or physical properties.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to modify Jensen’s CAR in view of Bitter or Fry because Fry teaches amino acid substitutions are known in the art, see para. [0045].
One of ordinary skill in the art would have been motivated to do so because Fry teaches that such conservative substitution of one or more amino acid residues within a CAR with other amino acid residues from the same side chain family having the same physiochemical properties is not likely to change and function of the CAR, see para. [0045].
One of ordinary skill in the art would have been motivated to do so because Bitter teaches that
such conservative substitution of amino acids within the CAR having similar side chains have been defined in the art, and such substitutions are not likely to change the shape and function of such CAR, see para. [0645].
A person of ordinary skill in the art is always motivated to pursue the known options within her or his technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 9-10, 12-13, 15-17, 29 and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,458,167 in view of Fry et al (WO2016/149578, published September 22, 2016; PTO 892.
In the interest of compact prosecution, and although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘167 patent issued from the application which served as the parent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
The subject matter claimed in the instant application is fully disclosed in the ‘167 patent.
Issued claim 1 recites a T cell comprising a first chimeric antigen receptor (CAR) encoded by a first polynucleotide, and a second CAR encoded by a second polynucleotide, wherein the first CAR is different from the second CAR, and the first CAR and the second CAR each comprise a 4-1BB signaling domain, a CD3-zeta signaling domain, a transmembrane domain, and an extracellular spacer comprising an IgG hinge spacer, and wherein: the first polynucleotide comprises: a first nucleic acid encoding a leader sequence, and a second nucleic acid 3′ of the first nucleic acid, wherein the second nucleic acid encodes a first ligand binding domain which specifically binds to a B cell specific cell surface molecule; and the second polynucleotide comprises: a third nucleic acid encoding a leader sequence, and a fourth nucleic acid 3′ of the third nucleic acid, wherein the nucleic acid encodes a second ligand binding domain which specifically binds to a cell surface tumor specific molecule; wherein: (i) the B cell specific cell surface molecule is selected from CD19 or CD20, and wherein the first ligand binding domain is encoded by a nucleotide sequence having at least 95% identity with any one of SEQ ID NOs: 12 or 14; and (ii) the cell surface tumor specific molecule is EGFR, and wherein the second ligand binding domain comprises the amino acid sequence of SEQ ID NO:19 (species). The issued patent also teaches chimeric antigen receptor that binds to L1CAM comprising the amino acid sequence of SEQ ID NO: 15, which is identical to instant SEQ ID NO: 15. The issued patent also teaches chimeric antigen receptor that binds to ROR1 comprising the amino acid sequence of SEQ ID NO: 17, which is identical to instant SEQ ID NO: 157.
Issued claim 2 recites the T cell of claim 1, wherein the first polynucleotide or the second polynucleotide, further comprises: an inducible promoter, wherein the inducible promoter is 5′ of the first nucleic acid or the third nucleic acid; or a suicide gene system.
Issued claim 3 recites the T cell of claim 1, wherein the T cell is selected from: a CD8+ T cytotoxic lymphocyte cell selected from a naive CD8+ T-cell, a CD8+ memory T-cell, a central memory CD8+ T-cell, a regulatory CD8+ T-cell, an IPS derived CD8+ T-cell, an effector memory CD8+ T-cell, or a bulk CD8+ T-cell; or a CD4+ T helper lymphocyte cell selected from a naive CD4+ T-cell, a CD4+ memory T-cell, a central memory CD4+ T-cell, a regulatory CD4+ T-cell, an IPS derived CD4+ T-cell, an effector memory CD4+ T-cell, or a bulk CD4+ T-cell, which corresponds to instant claim 16.
Issued claim 4 recites the T cell of claim 1, wherein the B cell specific cell surface molecule is CD20, and the first ligand binding domain comprises the amino acid sequence of SEQ ID NO:13, which corresponds to instant claim 9.
Issued claim 5 recites the T cell of claim 1, wherein the B cell specific cell surface molecule is CD19, and the first ligand binding domain comprises the amino acid sequence of SEQ ID NO:11, which corresponds to instant claim 9.
Issued claim 6 recites the T cell of claim 1, wherein: the first polynucleotide comprises: a fifth nucleic acid encoding a linker, wherein the fifth nucleic acid is 3′ of the nucleic acid encoding the first CAR, and a sixth nucleic acid encoding a marker domain, wherein the sixth nucleic acid sequence is 3′ of the fifth nucleic acid; and the second polynucleotide comprises: a seventh nucleic acid encoding a linker, wherein the seventh nucleic acid is 3′ of the nucleic acid encoding the second CAR, and an eighth nucleic acid encoding a marker domain, wherein the eighth nucleic acid is 3′ of the seventh nucleic acid sequence.
Issued claim 7 recites the T cell of claim 6, wherein: the leader sequence of the first polynucleotide or the second polynucleotide comprises a granulocyte-macrophage colony-stimulating factor signal sequence; the linker of the first polynucleotide or the second polynucleotide comprises a ribosome skip sequence or an internal ribosome entry sequence (IRES); and the marker domain of the first polynucleotide or the second polynucleotide comprises a truncated HER2 polypeptide (Her2tG) or a truncated EGFR polypeptide (EGFRt).
Issued claim 8 recites the T cell of claim 7, wherein: the leader sequence of the first polynucleotide or the second polynucleotide comprises the amino acid sequence of SEQ ID NO:29 or SEQ ID NO:31; the extracellular spacer of the first CAR or the second CAR comprises the amino acid sequence selected from SEQ ID NO:01, SEQ ID NO:03, or SEQ ID NO:39; the 4-1BB signaling domain comprises the amino acid sequence of SEQ ID NO:07, and the CD3-zeta signaling domain comprises the amino acid sequence of SEQ ID NO:09; the linker of the first polynucleotide or the second polynucleotide comprises the nucleotide sequence of SEQ ID NO:34; and the marker domain of the first polynucleotide or the second polynucleotide comprises the amino acid sequence of SEQ ID NO:35 or SEQ ID NO:37.
Issued claim 9 recites a pharmaceutical composition comprising the T cell of claim 1 and a pharmaceutically acceptable excipient, which corresponds to instant claim 17.
Issued claim 10 recites a T cell comprising: a first chimeric antigen receptor (CAR) comprising a first ligand biding domain capable of specifically binding to a B cell specific cell surface molecule; and a second CAR comprising a second ligand biding domain capable of specifically binding to a cell surface tumor specific molecule, wherein the first CAR is different from the second CAR, and wherein the first CAR and the second CAR each comprise a 41-BB signaling domain, CD3-zeta signaling domain, a transmembrane domain, and an extracellular spacer comprising an IgG hinge spacer; and wherein: (i) the B cell specific cell surface molecule is selected from CD19 or CD20, and wherein the first ligand binding domain is encoded by a nucleotide sequence having at least 95% identity with any one of SEQ ID NOs: 12 or 14, which corresponds to new claim 30, and (ii) the cell surface tumor specific molecule is EGFR, and wherein the second ligand binding domain comprises the amino acid sequence of SEQ ID NO:19, which corresponds to instant claims 9 and 13.
Issued claim 11 recites the T cell of claim 10, wherein the B cell specific cell surface molecule is CD20, and the first ligand binding domain comprises the amino acid sequence of SEQ ID NO:13, which corresponds to instant claims 9 and 13.
Issued claim 12 recites T cell of claim 11, wherein the B cell specific cell surface molecule is CD19, and the first ligand binding domain comprises the amino acid sequence of SEQ ID NO:11, which corresponds to instant claims 9 and 13.
Issued claim 13 recites the T cell of claim 10, wherein the T cell is a CD4+ T cell, which corresponds to instant claims 14-16.
Issued claim 14 recites the T cell of claim 10, wherein the T cell is a CD8+ T cell, which corresponds to instant claims 14-16.
The claims and the disclosure of ‘167 patent further teaches:
Patent No.:
Rejected over Patent claims:
First anti-CD19 CAR (SEQ NO: 11) explicitly in the claims:
First anti-CD20 CAR (SEQ NO: 13) explicitly in the claims:
Second anti-L1CAM CAR (SEQ ID NO: 15)
Second anti-ROR1 CAR (SEQ ID NO: 17)
11458167
1-14
1, 5, 9, 12
1, 4, 9, 11
Col. 7, lines 12-21
Col. 7, lines 21-27
17/931,258
9, 10, 30
9,
9
9
The reference SEQ ID NO: 11 is 100% identical to the claimed SEQ ID NO: 11, which is at least 95% identity to SEQ ID NO: 11, see reference claim 12, sequence alignment below:
Query Match 100.0%; Score 1285; Length 244;
Best Local Similarity 100.0%;
Matches 244; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQTTSSLSALGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQTTSSLSALGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSR 60
Qy 61 FSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEG 120
Qy 121 STKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSET 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 STKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSET 180
Qy 181 TYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSV 240
Qy 241 TVSS 244
||||
Db 241 TVSS 244
and the second CAR comprising a second ligand binding domain which specifically binds to a tumor antigen LICAM comprising SEQ ID NO: 15 as per claim 9, and is encoded by a nucleic acid sequence set forth in SEQ ID NO: 16 as per claim 13, see reference SEQ ID NO: 15 and 16, respectively.
The reference SEQ ID NO: 15 is 100% identical to the claimed SEQ ID NO: 15, , which is at least 95% identity to SEQ ID NO: 15, see sequence alignment below:
Query Match 100.0%; Score 1294; Length 242;
Best Local Similarity 100.0%;
Matches 242; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQQPGAELVKPGASVKLSCKASGYTFTGYWMHWVKQRPGHGLEWIGEINPSNGRTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQQPGAELVKPGASVKLSCKASGYTFTGYWMHWVKQRPGHGLEWIGEINPSNGRTNY 60
Qy 61 NERFKSKATLTVDKSSTTAFMQLSGLTSEDSAVYFCARDYYGTSYNFDYWGQGTTLTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NERFKSKATLTVDKSSTTAFMQLSGLTSEDSAVYFCARDYYGTSYNFDYWGQGTTLTVSS 120
Qy 121 GGGGSGGGGSGGGGSDIQMTQSSSSFSVSLGDRVTITCKANEDINNRLAWYQQTPGNSPR 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGGGSGGGGSGGGGSDIQMTQSSSSFSVSLGDRVTITCKANEDINNRLAWYQQTPGNSPR 180
Qy 181 LLISGATNLVTGVPSRFSGSGSGKDYTLTITSLQAEDFATYYCQQYWSTPFTFGSGTELE 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LLISGATNLVTGVPSRFSGSGSGKDYTLTITSLQAEDFATYYCQQYWSTPFTFGSGTELE 240
Qy 241 IK 242
||
Db 241 IK 242
The ‘167 patent further teaches CD20CAR comprises the amino acid sequence set forth in SEQ ID NO: 13 as per claim 9 and is encoded by the sequence set forth in SEQ ID NO: 14 as per claim 13, see reference claims 11 and 10.
The reference SEQ ID NO: 13 is 100% identical to the claimed SEQ ID NO: 13, which is at least 95% identity to SEQ ID NO: 13, see sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 1417; Length 266;
Best Local Similarity 100.0%;
Matches 266; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 METDTLLLWVLLLWVPGSTGDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 METDTLLLWVLLLWVPGSTGDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPG 60
Qy 61 SSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGG 120
Qy 121 TKLEIKGSTSGGGSGGGSGGGGSSEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHW 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TKLEIKGSTSGGGSGGGSGGGGSSEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHW 180
Qy 181 VKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYC 240
Qy 241 ARSNYYGSSYWFFDVWGAGTTVTVSS 266
||||||||||||||||||||||||||
Db 241 ARSNYYGSSYWFFDVWGAGTTVTVSS 266
And the ROR1CAR comprises the amino acid sequence set forth in SEQ ID NO: 17 and is encoded by the sequence set forth in SEQ ID NO: 17 as per claim 9, and is encoded by a nucleotide sequence set forth in SEQ ID NO: 18 as per claim 13, see reference SEQ ID NO: 17 and 18, respectively.
The reference SEQ ID NO: 17 is 100% identical to the claimed SEQ ID NO: 17, which is at least 95% identity to SEQ ID NO: 17, see sequence alignment below:
Query Match 100.0%; Score 1326; Length 250;
Best Local Similarity 100.0%;
Matches 250; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 PQEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 PQEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTY 60
Qy 61 YATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTI 120
Qy 121 SSGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SSGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEA 180
Qy 181 PRYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 PRYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFG 240
Qy 241 GGTQLTVTGG 250
||||||||||
Db 241 GGTQLTVTGG 250
Each CAR comprises an IgG4 hinge spacer (see para. [0009], Fig. 2), a CD28 transmembrane domain (CD28tm, para. [0010], Fig. 2), an intracellular signaling domain comprising 4-1BB and a CD3 zeta domain, see Fig. 2, in particular.
PNG
media_image1.png
173
541
media_image1.png
Greyscale
Regarding claim 15, the ‘167 patent teaches that the cell is a CD4+ T cell or a CD8+ T cell, see reference claim 3.
Regarding claim 16, the ‘167 patent teaches that the CD4+ T cell is a naive CD4+ T-cells, CD4+ memory T-cells, central memory CD4+ T-cells, effector memory CD4+ T-cells and bulk CD4+ T-cells or the cell is a CD8+ T cytotoxic lymphocyte cell, a CD8+ memory T-cells, central memory CD8+ T-cells, effector memory CD8+ T-cells and bulk CD8+ T-cells, see reference claim 3.
Regarding claim 17, the ‘167 patent teaches a pharmaceutical composition comprising the reference chimeric antigen receptor and a pharmaceutical acceptable carrier, see reference claim 9.
Regarding claim 30, the ‘167 patent teaches FMC63 CD19CAR comprises the amino acid sequence set forth in SEQ ID NO: 11 and is encoded by the sequence set forth in SEQ ID NO: 12, see reference claims 5 and 10, in particular.
The reference SEQ ID NO: 12 is 100% identical to the claimed SEQ ID NO: 12, which is at least 95% identity to SEQ ID NO: 12, see sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 735; Length 735;
Best Local Similarity 100.0%;
Matches 735; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GACATCCAGATGACCCAGACCACCTCCAGCCTGAGCGCCAGCCTGGGCGACCGGGTGACC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GACATCCAGATGACCCAGACCACCTCCAGCCTGAGCGCCAGCCTGGGCGACCGGGTGACC 60
Qy 61 ATCAGCTGCCGGGCCAGCCAGGACATCAGCAAGTACCTGAACTGGTATCAGCAGAAGCCC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ATCAGCTGCCGGGCCAGCCAGGACATCAGCAAGTACCTGAACTGGTATCAGCAGAAGCCC 120
Qy 121 GACGGCACCGTCAAGCTGCTGATCTACCACACCAGCCGGCTGCACAGCGGCGTGCCCAGC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GACGGCACCGTCAAGCTGCTGATCTACCACACCAGCCGGCTGCACAGCGGCGTGCCCAGC 180
Qy 181 CGGTTTAGCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATCTCCAACCTGGAACAG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CGGTTTAGCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATCTCCAACCTGGAACAG 240
Qy 241 GAAGATATCGCCACCTACTTTTGCCAGCAGGGCAACACACTGCCCTACACCTTTGGCGGC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GAAGATATCGCCACCTACTTTTGCCAGCAGGGCAACACACTGCCCTACACCTTTGGCGGC 300
Qy 301 GGAACAAAGCTGGAAATCACCGGCAGCACCTCCGGCAGCGGCAAGCCTGGCAGCGGCGAG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GGAACAAAGCTGGAAATCACCGGCAGCACCTCCGGCAGCGGCAAGCCTGGCAGCGGCGAG 360
Qy 361 GGCAGCACCAAGGGCGAGGTGAAGCTGCAGGAAAGCGGCCCTGGCCTGGTGGCCCCCAGC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GGCAGCACCAAGGGCGAGGTGAAGCTGCAGGAAAGCGGCCCTGGCCTGGTGGCCCCCAGC 420
Qy 421 CAGAGCCTGAGCGTGACCTGCACCGTGAGCGGCGTGAGCCTGCCCGACTACGGCGTGAGC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 CAGAGCCTGAGCGTGACCTGCACCGTGAGCGGCGTGAGCCTGCCCGACTACGGCGTGAGC 480
Qy 481 TGGATCCGGCAGCCCCCCAGGAAGGGCCTGGAATGGCTGGGCGTGATCTGGGGCAGCGAG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 TGGATCCGGCAGCCCCCCAGGAAGGGCCTGGAATGGCTGGGCGTGATCTGGGGCAGCGAG 540
Qy 541 ACCACCTACTACAACAGCGCCCTGAAGAGCCGGCTGACCATCATCAAGGACAACAGCAAG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 ACCACCTACTACAACAGCGCCCTGAAGAGCCGGCTGACCATCATCAAGGACAACAGCAAG 600
Qy 601 AGCCAGGTGTTCCTGAAGATGAACAGCCTGCAGACCGACGACACCGCCATCTACTACTGC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 AGCCAGGTGTTCCTGAAGATGAACAGCCTGCAGACCGACGACACCGCCATCTACTACTGC 660
Qy 661 GCCAAGCACTACTACTACGGCGGCAGCTACGCCATGGACTACTGGGGCCAGGGCACCAGC 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 GCCAAGCACTACTACTACGGCGGCAGCTACGCCATGGACTACTGGGGCCAGGGCACCAGC 720
Qy 721 GTGACCGTGAGCAGC 735
|||||||||||||||
Db 721 GTGACCGTGAGCAGC 735
The ‘167 patent teaches CD20CAR comprises the amino acid sequence set forth in SEQ ID NO: 13 (reference claim 11) and is encoded by the sequence set forth in SEQ ID NO: 14.
The reference SEQ ID NO: 14 is 100% identical to the claimed SEQ ID NO: 14, which is at least 95% identity to SEQ ID NO: 14, see para. [0221], sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 798; Length 798;
Best Local Similarity 100.0%;
Matches 798; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGGAGACAGACACACTCCTGCTATGGGTGCTGCTGCTCTGGGTTCCAGGTTCCACAGGT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ATGGAGACAGACACACTCCTGCTATGGGTGCTGCTGCTCTGGGTTCCAGGTTCCACAGGT 60
Qy 61 GACATTGTGCTGACCCAATCTCCAGCTATCCTGTCTGCATCTCCAGGGGAGAAGGTCACA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GACATTGTGCTGACCCAATCTCCAGCTATCCTGTCTGCATCTCCAGGGGAGAAGGTCACA 120
Qy 121 ATGACTTGCAGGGCCAGCTCAAGTGTAAATTACATGGACTGGTACCAGAAGAAGCCAGGA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ATGACTTGCAGGGCCAGCTCAAGTGTAAATTACATGGACTGGTACCAGAAGAAGCCAGGA 180
Qy 181 TCCTCCCCCAAACCCTGGATTTATGCCACATCCAACCTGGCTTCTGGAGTCCCTGCTCGC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TCCTCCCCCAAACCCTGGATTTATGCCACATCCAACCTGGCTTCTGGAGTCCCTGCTCGC 240
Qy 241 TTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGAGTGGAGGCTGAA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGAGTGGAGGCTGAA 300
Qy 301 GATGCTGCCACTTATTACTGCCAGCAGTGGAGTTTTAATCCACCCACGTTCGGAGGGGGG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GATGCTGCCACTTATTACTGCCAGCAGTGGAGTTTTAATCCACCCACGTTCGGAGGGGGG 360
Qy 361 ACCAAGCTGGAAATAAAAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 ACCAAGCTGGAAATAAAAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGG 420
Qy 421 GGCGGCAGCAGCGAGGTGCAGCTGCAGCAGTCTGGGGCTGAGCTGGTGAAGCCTGGGGCC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GGCGGCAGCAGCGAGGTGCAGCTGCAGCAGTCTGGGGCTGAGCTGGTGAAGCCTGGGGCC 480
Qy 481 TCAGTGAAGATGTCCTGCAAGGCTTCTGGCTACACATTTACCAGTTACAATATGCACTGG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 TCAGTGAAGATGTCCTGCAAGGCTTCTGGCTACACATTTACCAGTTACAATATGCACTGG 540
Qy 541 GTAAAGCAGACACCTGGACAGGGCCTGGAATGGATTGGAGCTATTTATCCAGGAAATGGT 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 GTAAAGCAGACACCTGGACAGGGCCTGGAATGGATTGGAGCTATTTATCCAGGAAATGGT 600
Qy 601 GATACTTCCTACAATCAGAAGTTCAAAGGCAAGGCCACATTGACTGCAGACAAATCCTCC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 GATACTTCCTACAATCAGAAGTTCAAAGGCAAGGCCACATTGACTGCAGACAAATCCTCC 660
Qy 661 AGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGACTATTACTGT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGACTATTACTGT 720
Qy 721 GCAAGATCTAATTATTACGGTAGTAGCTACTGGTTCTTCGATGTCTGGGGCGCAGGGACC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 GCAAGATCTAATTATTACGGTAGTAGCTACTGGTTCTTCGATGTCTGGGGCGCAGGGACC 780
Qy 781 ACGGTCACCGTCTCCTCA 798
||||||||||||||||||
Db 781 ACGGTCACCGTCTCCTCA 798
The ‘167 patent teaches that the second ligand binding domain of L1CAM CAR comprises the amino acid sequence set forth in SEQ ID NO: 15 and is encoded by the sequence set forth in SEQ ID NO: 16.
The reference SEQ ID NO: 16 is 100% identical to the claimed SEQ ID NO: 16, which is at least 95% identity to SEQ ID NO: 16, see sequence alignment below:
Query Match 100.0%; Score 726; Length 726;
Best Local Similarity 100.0%;
Matches 726; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGGTGCAGCTGCAGCAGCCTGGCGCCGAGCTGGTGAAGCCAGGCGCCAGCGTGAAGCTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CAGGTGCAGCTGCAGCAGCCTGGCGCCGAGCTGGTGAAGCCAGGCGCCAGCGTGAAGCTG 60
Qy 61 TCCTGCAAGGCCAGCGGCTACACCTTCACCGGCTACTGGATGCACTGGGTGAAGCAGAGA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TCCTGCAAGGCCAGCGGCTACACCTTCACCGGCTACTGGATGCACTGGGTGAAGCAGAGA 120
Qy 121 CCCGGCCACGGCCTGGAATGGATCGGCGAGATCAACCCCAGCAACGGCCGGACCAACTAC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CCCGGCCACGGCCTGGAATGGATCGGCGAGATCAACCCCAGCAACGGCCGGACCAACTAC 180
Qy 181 AACGAGCGGTTCAAGAGCAAGGCCACCCTGACCGTGGACAAGAGCAGCACCACCGCCTTC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AACGAGCGGTTCAAGAGCAAGGCCACCCTGACCGTGGACAAGAGCAGCACCACCGCCTTC 240
Qy 241 ATGCAGCTGTCCGGCCTGACCAGCGAGGACAGCGCCGTGTACTTCTGCGCCAGGGACTAC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ATGCAGCTGTCCGGCCTGACCAGCGAGGACAGCGCCGTGTACTTCTGCGCCAGGGACTAC 300
Qy 301 TACGGCACCAGCTACAACTTCGACTACTGGGGCCAGGGCACCACACTGACCGTGAGCAGC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 TACGGCACCAGCTACAACTTCGACTACTGGGGCCAGGGCACCACACTGACCGTGAGCAGC 360
Qy 361 GGCGGAGGGGGCTCTGGCGGCGGAGGATCTGGGGGAGGGGGCAGCGACATCCAGATGACC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GGCGGAGGGGGCTCTGGCGGCGGAGGATCTGGGGGAGGGGGCAGCGACATCCAGATGACC 420
Qy 421 CAGAGCAGCAGCAGCTTCAGCGTGAGCCTGGGCGACCGGGTGACCATCACCTGTAAGGCC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 CAGAGCAGCAGCAGCTTCAGCGTGAGCCTGGGCGACCGGGTGACCATCACCTGTAAGGCC 480
Qy 481 AACGAGGACATCAACAACCGGCTGGCCTGGTATCAGCAGACCCCCGGCAACAGCCCCAGG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 AACGAGGACATCAACAACCGGCTGGCCTGGTATCAGCAGACCCCCGGCAACAGCCCCAGG 540
Qy 541 CTGCTGATCAGCGGCGCCACCAACCTGGTGACCGGCGTGCCCAGCCGGTTTAGCGGCAGC 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 CTGCTGATCAGCGGCGCCACCAACCTGGTGACCGGCGTGCCCAGCCGGTTTAGCGGCAGC 600
Qy 601 GGCTCCGGCAAGGACTACACCCTGACCATCACAAGCCTGCAGGCCGAGGACTTCGCCACC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 GGCTCCGGCAAGGACTACACCCTGACCATCACAAGCCTGCAGGCCGAGGACTTCGCCACC 660
Qy 661 TACTACTGCCAGCAGTACTGGTCCACCCCCTTCACCTTCGGCAGCGGCACCGAGCTGGAA 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 TACTACTGCCAGCAGTACTGGTCCACCCCCTTCACCTTCGGCAGCGGCACCGAGCTGGAA 720
Qy 721 ATCAAA 726
||||||
Db 721 ATCAAA 726
The ‘167 patent teaches that the second ligand binding domain of ROR1 CAR comprises the amino acid sequence set forth in SEQ ID NO: 17 and is encoded by the sequence set forth in SEQ ID NO: 18.
The reference SEQ ID NO: 18 is 100% identical to the claimed SEQ ID NO: 18, which is at least 95% identity to SEQ ID NO: 18, see sequence alignment below:
Query Match 100.0%; Score 745; Length 745;
Best Local Similarity 100.0%;
Matches 745; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CCAGGAACAGCTCGTCGAAAGCGGCGGCAGACTGGTGACACCTGGCGGCAGCCTGACCCT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CCAGGAACAGCTCGTCGAAAGCGGCGGCAGACTGGTGACACCTGGCGGCAGCCTGACCCT 60
Qy 61 GAGCTGCAAGGCCAGCGGCTTCGACTTCAGCGCCTACTACATGAGCTGGGTCCGCCAGGC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GAGCTGCAAGGCCAGCGGCTTCGACTTCAGCGCCTACTACATGAGCTGGGTCCGCCAGGC 120
Qy 121 CCCTGGCAAGGGACTGGAATGGATCGCCACCATCTACCCCAGCAGCGGCAAGACCTACTA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CCCTGGCAAGGGACTGGAATGGATCGCCACCATCTACCCCAGCAGCGGCAAGACCTACTA 180
Qy 181 CGCCACCTGGGTGAACGGACGGTTCACCATCTCCAGCGACAACGCCCAGAACACCGTGGA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CGCCACCTGGGTGAACGGACGGTTCACCATCTCCAGCGACAACGCCCAGAACACCGTGGA 240
Qy 241 CCTGCAGATGAACAGCCTGACAGCCGCCGACCGGGCCACCTACTTTTGCGCCAGAGACAG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 CCTGCAGATGAACAGCCTGACAGCCGCCGACCGGGCCACCTACTTTTGCGCCAGAGACAG 300
Qy 301 CTACGCCGACGACGGCGCCCTGTTCAACATCTGGGGCCCTGGCACCCTGGTGACAATCTC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CTACGCCGACGACGGCGCCCTGTTCAACATCTGGGGCCCTGGCACCCTGGTGACAATCTC 360
Qy 361 TAGCGGCGGAGGCGGATCTGGTGGCGGAGGAAGTGGCGGCGGAGGATCTGAGCTGGTGCT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 TAGCGGCGGAGGCGGATCTGGTGGCGGAGGAAGTGGCGGCGGAGGATCTGAGCTGGTGCT 420
Qy 421 GACCCAGAGCCCCTCTGTGTCTGCTGCCCTGGGAAGCCCTGCCAAGATCACCTGTACCCT 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GACCCAGAGCCCCTCTGTGTCTGCTGCCCTGGGAAGCCCTGCCAAGATCACCTGTACCCT 480
Qy 481 GAGCAGCGCCCACAAGACCGACACCATCGACTGGTATCAGCAGCTGCAGGGCGAGGCCCC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GAGCAGCGCCCACAAGACCGACACCATCGACTGGTATCAGCAGCTGCAGGGCGAGGCCCC 540
Qy 541 CAGATACCTGATGCAGGTGCAGAGCGACGGCAGCTACACCAAGAGGCCAGGCGTGCCCGA 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 CAGATACCTGATGCAGGTGCAGAGCGACGGCAGCTACACCAAGAGGCCAGGCGTGCCCGA 600
Qy 601 CCGGTTCAGCGGATCTAGCTCTGGCGCCGACCGCTACCTGATCATCCCCAGCGTGCAGGC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 CCGGTTCAGCGGATCTAGCTCTGGCGCCGACCGCTACCTGATCATCCCCAGCGTGCAGGC 660
Qy 661 CGATGACGAGGCCGATTACTACTGTGGCGCCGACTACATCGGCGGCTACGTGTTCGGCGG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 CGATGACGAGGCCGATTACTACTGTGGCGCCGACTACATCGGCGGCTACGTGTTCGGCGG 720
Qy 721 AGGCACCCAGCTGACCGTGACCGGC 745
|||||||||||||||||||||||||
Db 721 AGGCACCCAGCTGACCGTGACCGGC 745
The ‘167 patent also teaches that the human T cell wherein each CAR comprises an IgG4 hinge, a transmembrane domain, a 4-1BB domain, and a CD3 zeta domain, see reference claims 1, 9, Fig. 2.
The ‘167 patent does not teach the first ligand binding domain is a conservative substitution in SEQ ID NO: 11 or 13 and the second ligand binding domain is a conservative substitution in SEQ ID NO: 15 or 17 as per claim 29.
However, Fry teaches dual specific chimeric antigen receptor that binds to CD19 and CD22. Fry further teaches that the parent CAR with at least one conservative amino acid substitution, see para. [0044]. Conservative amino acid substitutions are known in the art, and include amino acid substitutions in which one amino acid having certain physical and/or chemical properties is exchanged for another amino acid that has the same or similar chemical or physical properties. For instance, the conservative amino acid substitution can be an acidic/negatively charged polar amino acid substituted for another acidic/negatively charged polar amino acid (e.g., Asp or Glu), an amino acid with a nonpolar side chain substituted for another amino acid with a nonpolar side chain (e.g., Ala, Gly, Val, Ile, Leu, Met, Phe, Pro, Trp, Cys, Val, etc.), a basic/positively charged polar amino acid substituted for another basic/positively charged polar amino acid (e.g. Lys, His, Arg, etc.), an uncharged amino acid with a polar side chain substituted for another uncharged amino acid with a polar side chain (e.g., Asn, Gln, Ser, Thr, Tyr, etc.), an amino acid with a beta-branched side-chain substituted for another amino acid with a beta-branched side-chain (e.g., Ile, Thr, and Val), an amino acid with an aromatic side-chain substituted for another amino acid with an aromatic side chain (e.g., His, Phe, Trp, and Tyr), etc, see para. [0045].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to include conservative substitutions as taught by Fry in the first ligand binding domain is a conservative substitution in SEQ ID NO: 11 or 13 and the second ligand binding domain is a conservative substitution in SEQ ID NO: 15 or 17 of the ‘167 patent to arrive at the claimed invention with a reasonable expectation success, e.g., the variants having the same chemical or physical properties.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to modify Jensen’s CAR in view of Bitter or Fry because Fry teaches amino acid substitutions are known in the art, see para. [0045].
One of ordinary skill in the art would have been motivated to do so because Fry teaches that such conservative substitution of one or more amino acid residues within a CAR with other amino acid residues from the same side chain family having the same physiochemical properties is not likely to change and function of the CAR, see para. [0045].
One of ordinary skill in the art would have been motivated to do so because Bitter teaches that
such conservative substitution of amino acids within the CAR having similar side chains have been defined in the art, and such substitutions are not likely to change the shape and function of such CAR, see para. [0645].
Applicant's arguments filed November 18, 2025 have been fully considered but they are not persuasive.
Applicant’s position is that independent Claims 1 and 10 of the '167 Patent each relate to cell containing (i) an anti-CD19 CAR or an anti-CD20 CAR, and (ii) an anti-EGFR CAR. In contrast to the claims of the '167 Patent, instant Claim 9 relates to a cell containing (i) an anti-CD19 CAR or an anti-CD20 CAR, and (ii) an anti-L1CAM CAR or anti-ROR1 CAR. Thus, the subject matter of the claims of the '167 Patent and of the instant claims is non- overlapping.
In addition, to modify the claims of the '167 Patent to provide a cell within the scope of the instant claims would require a substantive design change (changing the ligand binding domain) and such a change would both substantively alter the principle of operation of the prior art and would make it unsuitable for the intended purpose of the prior art, which cannot support the obviousness of the claims. "If the proposed modification or combination of the prior art would change the principle of operation of the prior art invention being modified, then the teachings of the references are not sufficient to render the claims prima facie obvious. In re Ratti, 270 F.2d 810, 813, 123 USPQ 349, 352 (CCPA 1959)" See M.P.E.P. § 2142.VI. Similarly, "[i]f a proposed modification would render the prior art invention being modified unsatisfactory for its intended purpose, then there is no suggestion or motivation to make the proposed modification. In re Gordon, 733 F.2d 900, 221 USPQ 1125 (Fed. Cir. 1984)". See M.P.E.P. § 2142.VI. For example, substituting the anti-EGFR CAR of the cell of Claim 1 of the '167 with an anti-L1CAM CAR or anti-ROR1 CAR of the instant claims would no longer be capable of specifically binding cells expressing EGFR. Therefore, for at least the foregoing reasons, Applicant respectfully submits that the instant claims are patentably distinct and non-obvious over the claims of the '167 Patent.
To argue how the instant claims are not patentably distinct from the claims of the '167, and in reply to Applicant's prior remarks, the Office Action states:
"A person of skill in the art, reading the claims of the '167 patent, would look to the patent and follow the '167 patent's express instruction on how to make the product within the patent, e.g., Method of making a cell having bispecific chimeric antigen receptor (see Fig. 2, Fig. 10A-B, D, Fig. 11A-E, col. 126, 131 to 132, thereby arriving at the binding molecule of the examined claims." See Office Action at
page 9.
Here, the Office Action argues that the instant claims are not patentably distinct from the claims of the '167 Patent because of instructions in the specification of the '167 Patent. However, when considering whether the invention defined in a claim of an application would have been anticipated by or is an obvious variation of the invention defined in the claim of a patent or co-pending application, no part of the reference patent or application may be used as if it were prior art. General Foods Corp. v. Studiengesellschaft Kohle mbH, 972 F.2d 1272, 1281, 23 USPQ2d 1839, 1846 (Fed. Cir. 1992). See M.P.E.P. § 804.II.B1. Thus, the Office Action's use of the specification of the '167 Patent to argue how the instant claims are not patentably distinct from the claims of the '167 is improper. Therefore, Applicant respectfully submits that the Office Action has not established that the instant claims are not patentably distinct from the claims of the '167 Patent.
Accordingly, for at least the foregoing reason Applicant kindly requests that this rejection for alleged nonstatutory double patenting over Claims 1-14 of U.S. Pat. No. 11,458,167 be withdrawn.
In response, this application is a continuation of the parent application 15/750,708 (now 11,458,167), NOT a divisional application. A continuation application filed under Section 120, is not entitled to the benefit of the safe harbor provision protections afforded by § 121’s safe harbor.” Amgen v. Roche, 580 F.3d 1340, 1354 (Fed. Cir. 2009). Thus, a continuation application drawn to subject matter that is separately patentable from the subject matter of the parent patent is vulnerable to an obviousness-type double patenting rejection from the USPTO and later patent challenge.
The subject matter claimed in the instant application is fully disclosed in the ‘167 patent as set forth above and incorporates here by reference.
The ‘167 patent does not teach the first ligand binding domain is a conservative substitution in SEQ ID NO: 11 or 13 and the second ligand binding domain is a conservative substitution in SEQ ID NO: 15 or 17 as per claim 29.
However, Bitter teaches various chimeric antigen receptor such as CD19 chimeric antigen receptor (aka CD19 CART, para. [0443], reference claims) in combination with CAR molecules directed to CD20, see abstract, para. [0006], [0014], in particular. Bitter further teaches that the amino acid sequence of the antigen binding domain (e.g., antigen-binding domain that binds one or more CD19, CD20, ROR1) can be modified, e.g., conservative substitution. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine), see para. [0645].
Likewise, Fry teaches dual specific chimeric antigen receptor that binds to CD19 and CD22. Fry further teaches that the parent CAR with at least one conservative amino acid substitution, see para. [0044]. Conservative amino acid substitutions are known in the art, and include amino acid substitutions in which one amino acid having certain physical and/or chemical properties is exchanged for another amino acid that has the same or similar chemical or WO 2016/149578 13 PCT/US2016/023055 physical properties. For instance, the conservative amino acid substitution can be an acidic/negatively charged polar amino acid substituted for another acidic/negatively charged polar amino acid (e.g., Asp or Glu), an amino acid with a nonpolar side chain substituted for another amino acid with a nonpolar side chain (e.g., Ala, Gly, Val, Ile, Leu, Met, Phe, Pro, Trp, Cys, Val, etc.), a basic/positively charged polar amino acid substituted for another basic/positively charged polar amino acid (e.g. Lys, His, Arg, etc.), an uncharged amino acid with a polar side chain substituted for another uncharged amino acid with a polar side chain (e.g., Asn, Gln, Ser, Thr, Tyr, etc.), an amino acid with a beta-branched side-chain substituted for another amino acid with a beta-branched side-chain (e.g., Ile, Thr, and Val), an amino acid with an aromatic side-chain substituted for another amino acid with an aromatic side chain (e.g., His, Phe, Trp, and Tyr), etc, see para. [0045].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to include conservative substitutions as taught by Bitter or Fry in the first ligand binding domain is a conservative substitution in SEQ ID NO: 11 or 13 and the second ligand binding domain is a conservative substitution in SEQ ID NO: 15 or 17 of the ‘167 patent to arrive at the claimed invention with a reasonable expectation success, e.g., the variants having the same chemical or physical properties.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to modify Jensen’s CAR in view of Bitter or Fry because Fry teaches amino acid substitutions are known in the art, see para. [0045].
One of ordinary skill in the art would have been motivated to do so because Fry teaches that such conservative substitution of one or more amino acid residues within a CAR with other amino acid residues from the same side chain family having the same physiochemical properties is not likely to change and function of the CAR, see para. [0045].
One of ordinary skill in the art would have been motivated to do so because Bitter teaches that
such conservative substitution of amino acids within the CAR having similar side chains have been defined in the art, and such substitutions are not likely to change the shape and function of such CAR, see para. [0645].
Thus, a person of skill in the art, reading the claims of the ‘167 patent in view of Fry, would know how to make the product thereby arriving at the cells of the examined claims.
In response to the argument that substituting the anti-EGFR CAR of the cell of Claim 1 of the '167 with an anti-L1CAM CAR or anti-ROR1 CAR of the instant claims would no longer be capable of specifically binding cells expressing EGFR, the ‘167 patent having teaches the cell express first B cell ligand, e.g., scFv that binds to CD19 or CD20 and the second ligand binding domain that binds to tumor cell, e.g., L1CAM or ROR1, see col. 11, lines 6 to 43, col. 14, line 8 to col. 15, line 6, in particular.
The submission of a terminal disclaimer in compliance with 37 CFR 1.321(b) is required to overcome a double patenting rejection because it seeks to prevent the possibility of multiple suits against an accused infringer by different assignees of patents claiming patentably indistinct variations of the same invention. In re Van Ornum, 686 F.2d 937, 944-48, 214 USPQ 761, 767-70 (CCPA 1982) and to prevent
unjustified timewise extension of patent term based on a judicially created doctrine grounded in public policy. “Fundamental to this doctrine is the policy that: ‘[t]he public should … be able to act on the assumption upon the expiration of the patent it will be free to use not only the invention claimed in the patent but also modifications or variants which would have been obvious to those of ordinary skill in the art at the time the invention was made.’” In re Longi, 892-3, citing In re Zickendraht, 319 F.2d 225, 232 (CCPA 1963) (Rich, J., concurring), emphasis in original. See also Singer Mfg. Co. v. June Mfg. Co., 163 U.S. 169, 185 (1896). Without the protection of the safe harbor provision, these public policy concerns apply to all continuation applications and patents filed from a parent patent. See MPEP 1504.06.
A terminal disclaimer over the parent patent can be avoided by satisfying the requirements of a divisional application, where the divisional application is filed from a parent application with claims structured to trigger a restriction requirement. Alternatively, the Applicant can file separate applications to the different inventions where the separate applications do not share a priority claim, thus minimizing the risk of ODP. But in the absence of a restriction requirement and subsequent divisional application, a continuation application filed from a parent patent is an implicit admission that ODP applies to the resulting continuation patent.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
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) Form at https://www.uspto.gov/patents/uspto-automated-interview-request-air-form.
/PHUONG HUYNH/ Primary Examiner, Art Unit 1641