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 .
1. Claims 1-24 are pending and under consideration.
Priority
2. 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. 119(e) or under 35 U.S.C. 120, 121, or 365(c) 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, Application No. 63/425,783, fails 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. Examiner has established a priority date of November 16, 203 for claims 1-24 because the claims as currently constituted recite a TIM-4 fusion protein comprising a TIM-4 extracellular domain and at least one co-stimulatory domain, wherein the TIM-4 extracellular domain comprises SEQ ID NO: 7 or a sequence having at least 95% identity to SEQ ID NO: 7 and SEQ ID NOs: 8, 3 and 5 or a sequence having at least 95% identity thereto and a review of the parent application does not reveal the claimed limitations. Applicant is invited to submit evidence pointing to the serial number, page and line where support can be found establishing an earlier priority date.
Claim Objections
3. Claim 3 is objected to because of the following informalities: the claim should have the article “a” between “comprises” and “CD3z". 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.
4. Claim 3 is 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 3 is drawn to wherein the co-stimulatory domain comprises CD3z co-stimulatory domain.
CD3z is a T-cell receptor complex protein having an ITAM containing endodomain. See Jena et al. (Blood Aug. 19, 2010 116 (7): 1035-1044), p. 1035-right col., p. 1036-right col. Fig. 1. CD3z is not a co-stimulatory molecule like CD28 or 4-1BB/CD137. See Jena p. 1037-left col. Thus it is unclear what is meant to be encompassed by a CD3z co-stimulatory domain of claim 3. Therefore, the claim is indefinite.
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.
(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.
5. Claim(s) 1, 3-12, 14-16, 18-22 and 24 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by WO 2023/010097 A1 (Corey et al. Feb. 02, 2023, filed July 28, 2022), “Corey”.
Corey teaches TIM-4 engulfment receptor CER-1250 (SEQ ID NO: 24), a Tim-4 binding mutant/CD28/TLR2/CD3z; with a mutated IgV domain with AAAA substitution to abrogate phosphatidylserine binding. See p. 54, p. 161-lines 18-25, and Fig. 49.
CER-1250 (SEQ ID NO: 24) has a 98.6% identity to SEQ ID NO: 7 and the SEQ ID NO: 7 portion of SEQ ID NOs: 3 and 5. See Appendix.
CER-1250 (SEQ ID NO: 24) has a 99.7% identity to SEQ ID NO: 8. See Appendix.
CER-1250 (SEQ ID NO: 24) comprises CD3z signaling domain, a CD28 co-stimulatory domain, a signal sequence and a transmembrane domain. See p. 54, p. 161-lines 18-25, and Fig. 49.
Corey teaches polynucleotide expression vectors with promoters for expression of the chimeric TIM-4 engulfment receptors. See pp. 59-60.
Corey teaches the expression vectors include lentiviral and retroviral vectors. See paragraph bridging pp. 32-33 and p. 64-lines 10-20.
Corey teaches T-cells comprising the chimeric Tim4 receptors of the inventions. See paragraph bridging pp. 12-13.
Corey teaches expressing CARs targeting tumor antigens with the Tim4 receptors. See paragraph bridging pp. 62-63.
Corey teaches treating cancer with the chimeric Tim4 receptors by administering to a subject (i) a therapeutically effective amount of a pharmaceutical composition including one or more chimeric Tim-4 receptors, or a population of host T cells genetically modified to express one or more chimeric Tim-4 receptors. See p. 2-lines 25-30 and p. 90-lines 13-25 and claims 15-17.
Corey teaches that the pharmaceutical compositions comprises a pharmaceutically acceptable carrier, diluent, or excipient. See paragraph bridging pp. 94-95.
Corey teaches treating melanoma, leukemia, and neuroblastoma, which are PS-associated cancers. See p. 17-lines 20-25, p. 37-lines 5-11, p. 91-lines 26-33, claims 16 and 17 and the instant specification at p. 16-lines 3-5.
Corey also teaches administering adoptive cellular immunotherapy agent (e.g., recombinant TCR enhanced affinity TCR, CAR, TCR-CAR, scTCR fusion protein, dendritic cell vaccine) and immune checkpoint inhibitors, i.e. T cell activating immunotherapies. See p. 96-lines 10-20, p. 79-lines 5-27 and claims 19, 20, and 59-61.
Corey teaches administering the chimeric Tim-4 receptor T cell compositions intratumorally or intravenously, i.e. systemically. See p. 96-lines 7-9.
Corey teaches treating ovarian, glioma, and medulloblastoma, which are EGFR associated cancers as claimed. See p. 17-lines 20-25, p. 89-lines 9-32, p. 92-lines 20-25 and claims 15-17. .
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.
6. Claim(s) 1, 3-12, and 14-24 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2023/010097 A1 (Corey et al. Feb. 02, 2023), “Corey”.
Corey teaches as set forth above, but does not teach administering radiation and/or chemotherapy prior to administration of the T cell comprising the chimeric TIM-4 receptor.
Corey also teaches administering radiation therapy and chemotherapy. See p. 96-lines 10-20, p. 79-lines 5-27 and claims 19, 20, and 59-61.
Corey also teaches wherein the additional therapeutic agent is administered to the subject sequentially or concurrently with the chimeric Tim-4 receptor. See claim 47.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Corey and administer radiation and/or chemotherapy prior to administration of the T cell comprising the chimeric TIM-4 receptor because Corey also teaches administering radiation therapy and chemotherapy and that the additional therapeutic agents can be administered sequentially. One would have been motivated to optimize the order of addition of the receptor T cell compositions and radiation and/or chemotherapy to optimize therapeutic activity of the treatment and minimize side effects.
7. Claim(s) 13 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2023/010097 A1 (Corey et al. Feb. 02, 2023), “Corey” as applied to claims 1, 3-12, and 14-24 above, and further in view of Jiang et al. (Cancer Immunol Res. (2018) 6 (11): 1314–1326, IDS), “Jiang”.
Corey teaches as set forth above.
Corey additionally teaches using CARs targeting EGFR and EGFR VIII with the chimeric Tim-4 receptor. See p. 71-lines 9-33 and p. 97-lines 17-27.
Jiang teaches a humanized single-chain antibody, M27, with a single specificity that binds to an epitope found both on wild-type EGFR- and EGFRvIII-overexpressing tumor cells, but not EGFR-expressing normal cells, including primary keratinocytes, on which wild-type EGFR is highly expressed. M27-derived CAR T cells effectively lysed EGFRvIII- or EGFR-overexpressing tumor cells, but showed no observable toxicity on normal cells. Inclusion of the CD137 (4-1BB) costimulatory intracellular domain in the M27-28BBZ CAR provided CAR T cells with higher tumor lysis activity than when not included (as in the M27-28Z CAR). The growth of established EGFR- or EGFRvIII-overexpressing glioma xenografts was suppressed by M27-28BBZ CAR T cells as well. The growth of heterogenic xenograft tumors, created by mixing EGFR- and EGFR-overexpressing glioblastoma cells, was also effectively inhibited by M27-28BBZ CAR T cells. The survival of mice in the orthotopic models was significantly prolonged after M27-28BBZ CAR T-cell infusion. These results suggested that tumor-selective, bi-targeted anti-EGFR/EGFRvIII CAR T cells may be a promising modality for the treatment of patients with EGFR/EGFRvIII-overexpressing glioblastoma. See abstract and Figs. 1-6.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Corey and Jiang and combine the bi-targeted anti-EGFR/EGFRvIII CAR with the chimeric Tim-4 receptor of Corey in T cells for cancer treatment because Corey teaches expressing CARs targeting tumor antigens with the Tim4 receptors and teaches targeting EGFR and EGFR VIII and Jian teaches the bi-targeted anti-EGFR/EGFRvIII CAR T cells inhibited growth of heterogenetic glioblastoma xenograft tumors and improved survival of mice in the orthotopic models. One would have been motivated to combine the bi-targeted anti-EGFR/EGFRvIII CAR with the chimeric Tim-4 receptor of Corey in T cells for cancer given the effectiveness of the bi-targeted anti-EGFR/EGFRvIII CAR T cells taught by Jiang.
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
8. Claims 1, 3-15, 18-20 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 9, 14, 15, 17, 18, 23, 24, 29, 36, 38, 39, 42, 44, 48, 51 and 52 of co-pending Application No. 18/511,825 (reference application, published as US 2024/0156868 A1) evidenced by WO 2023/279095 A1 (Fecci et al Jan. 05, 2023), “Fecci”.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘825 claims are drawn to:
1. A TIM-4 fusion protein comprising a TIM-4 domain linked to a single chain variable fragment (scFv) specific for CD3, wherein the TIM-4 domain comprises SEQ ID NO: 3 or a sequence having 95% identity to SEQ ID NO: 3, and wherein the scFv specific for CD3 comprises complementarity determining regions (CDR) of SEQ ID NOs: 22-27 or sequences with at least 95% identity to SEQ ID NO: 22-27.
2. The fusion protein of claim 1, wherein the scFv specific for CD3 comprises SEQ ID NO: 5 or a sequence with at least 95% identity to SEQ ID NO: 5.
3. The fusion protein of claim 1, further comprising an N-terminal signal sequence, wherein the N-terminal signal sequence includes a signal sequence of SEQ ID NO: 2 or sequences with at least 95% identity to SEQ ID NO: 2 and wherein the TIM-4 domain is linked to the scFv specific for CD3 via a linker peptide.
7. The fusion protein of claim 1, additionally comprising a tag, wherein the tag can be used for purification, tracking or imaging the fusion protein.
9. The fusion protein of claim 1, comprising SEQ ID NO: 1 or sequences with at least 90% identity to SEQ ID NO: 1.
14. A pharmaceutical composition comprising a recombinant TIM-4 fusion protein of claim 1 and a pharmaceutically acceptable excipient, carrier and/or diluent.
15. A construct comprising a promoter operably linked to a polynucleotide sequence encoding the TIM-4 fusion protein of claim 1.
17. The construct of claim 15, additionally comprising a sequence encoding a chimeric antigen receptor (CAR), the CAR comprising an extracellular domain, a transmembrane domain, and an intracellular signaling domain wherein the CAR and the TIM-4 fusion protein are connected via a self-cleavage site.
18. The construct of claim 17, wherein the CAR comprises an extracellular domain comprising a scFv of SEQ ID NO: 10 or sequences with at least 95% identity to SEQ ID NO: 10 or a scFv of SEQ ID NO: 17 or sequences with at least 95% identity to SEQ ID NO: 17.
23. The construct of claim 15, wherein the construct is included in a lentiviral, retroviral or AAV vector.
24. A chimeric antigen receptor (CAR)-T cell comprising the construct of claim 15 wherein the construct comprises: a) a polynucleotide encoding a EGFR VIII CAR of SEQ ID NO: 10, a self-cleavage site, a signal sequence, a TIM-4 domain of SEQ ID NO: 3, a linker, and an scFv specific for CD3 of SEQ ID NO: 22-27 or wherein the construct comprises a polynucleotide encoding a polypeptide with at least 95% identity to SEQ ID NO: 10, 3, 22, 24, 25, 26 and 27; or b) a polynucleotide encoding a EGFR VIII CAR of SEQ ID NO: 10, a self-cleavage site, a signal sequence, a TIM-4 domain of SEQ ID NO: 3, a linker and an scFv specific for CD3 of SEQ ID NO: 5 or wherein the construct comprises a polynucleotide encoding a polypeptide with at least 95% identity to SEQ ID NO: 10, 3 and 5; or c) a polynucleotide encoding a D2C7 CAR of SEQ ID NO: 17, a self-cleavage site, a signal sequence, a TIM-4 domain of SEQ ID NO: 3, a linker and an scFv specific for CD3 of SEQ ID NO: 22-27 or wherein the construct comprises a polynucleotide encoding a polypeptide with at least 95% identity to SEQ ID NO 17, 3, 22, 23, 24, 25, 26 and 27; or d) a polynucleotide encoding a D2C7 CAR of SEQ ID NO: 17, a self-cleavage site, a signal sequence, a TIM-4 domain of SEQ ID NO: 3, a linker and an scFv specific for CD3 of SEQ ID NO: 5 or wherein the construct comprises a polynucleotide encoding a polypeptide with at least 95% identity to SEQ ID NO 17, 3 and 5.
29. The CAR-T cell of claim 24, wherein the self-cleavage site comprises SEQ ID NO: 11 or a sequence with at least 95% sequence identity to SEQ ID NO: 11, the signal sequence comprises SEQ ID NO: 2 or a sequence with at least 95% sequence identity to SEQ ID NO: 2 and the linker comprises SEQ ID NO: 4.
36. A CAR-T cell comprising a polynucleotide encoding SEQ ID NO: 20 or a sequence with at least 95% sequence identity to SEQ ID NO: 20 or a polynucleotide encoding SEQ ID NO: 21 or a sequence with at least 95% sequence identity to SEQ ID NO: 21.
38. A method for treating cancer, the method comprising administering a therapeutically effective amount of a recombinant TIM-4 fusion protein of claim 1 and a pharmaceutically acceptable excipient, carrier and/or diluent.
39. The method of claim 38, additionally comprising administering T lymphocytes, wherein T lymphocytes are activated upon binding to the TIM-4 fusion protein (a T cell activating immunotherapy).
42. A method for treating cancer, the method comprising administering a therapeutically effective amount of the CAR-T cell of claim 24 and a pharmaceutically acceptable excipient, carrier and/or diluent.
44. The method of claim 38, wherein the cancer is an EGFR-associated cancer or a PS-associated cancer.
48. A method of diagnosing cancer, the method comprising administering the fusion protein of claim 7, detecting the presence or accumulation of a tag in a subject suspected of having cancer, wherein the tag allows for in vivo detection of the cancer
51. A method of inducing a T-cell response in a subject suffering from cancer, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 14, wherein an antitumor response to the cancer is induced.
52. A method of inducing a T-cell response in a subject suffering from cancer, the method comprising administering to the subject a therapeutically effective amount of the CAR-T cells of claim 24, wherein an antitumor response to the cancer is induced.
SEQ ID NOs: 3, 20 and 21 of the ‘825 claims comprise SEQ ID NO: 7 of the instant claims, which is comprised by SEQ ID NOs: 3 and 5 of the instant claims. See Appendix.
SEQ ID NO: 21 of the ‘825 claims comprises the EGFRvIII D2C7 CAR and the TIM-4 domain. See p. 12 of the ‘825publication.
The D2C7 CAR binds EGFR and EGFRvIII. See Example 1 of Fecci.
The D2C7 CAR comprises a signal sequence, transmembrane domain, CD28 and 4-1BB co-stimulatory domains and a CD3z domain. See Fig. 1A of Fecci.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
9. Claims 16, 17, and 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 9, 14, 15, 17, 18, 23, 24, 29, 36, 38, 39, 42, 44, 48, 51 and 52 of co-pending Application No. 18/511,825 (reference application, published as US 2024/0156868 A1) evidenced by WO 2023/279095 A1 (Fecci et al Jan. 05, 2023), “Fecci” as applied to Claims 1, 3-15, 18-20 and 24 above in view of WO 2023/010097 A1 (Corey et al. Feb. 02, 2023), “Corey”.
The ’825 claims teach as set forth above, but do not teach the limitations of claims 16, 17, and 21-23.
Corey teaches a set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ’825 and Corey and treat with the methods of claims 16, 17, and 21-23 because Corey teaches or suggests treating with said methods using a Tim-4 chimeric receptor comprising T cell. One would have been motivated to optimize the treatments of the ’825 claims using the Tim-4 chimeric receptor T cells method of Corey .
This is a provisional nonstatutory double patenting rejection.
Conclusion
10. Claims 1 and 3-24 are rejected. Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
11. No claims allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Greg Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
Alignment of SEQ ID NO: 7 with SEQ ID NO: 24 of Corey
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 1477 97.5 641 1 US-18-292-782-24 CHIMERIC TIM4 RECE
ALIGNMENTS
RESULT 1
US-18-292-782-24
Query Match 97.5%; Score 1477; DB 1; Length 641;
Best Local Similarity 98.6%;
Matches 286; Conservative 0; Mismatches 4; Indels 0; Gaps 0;
Qy 1 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 25 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 84
Qy 61 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTHRTATT 120
|||||||||||||||||||||||||||||||||| ||||||||||||||||||||||
Db 85 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGAAAAVKINVRLNLQRASTTTHRTATT 144
Qy 121 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 145 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 204
Qy 181 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 205 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 264
Qy 241 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 290
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 265 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 314
Alignment of SEQ ID NO: 8 with SEQ ID NO: 24 of Corey
RESULT 4
BMJ96472
ID BMJ96472 standard; protein; 641 AA.
XX
AC BMJ96472;
XX
DT 16-MAR-2023 (first entry)
XX
DE Tim4-CD28-TLR2 TIR-CD3 zeta fusion (CER-1250), SEQ ID 24.
XX
KW CAR-T cell; CD3 zeta protein; T cell surface glycoprotein CD28;
KW T-cell CD3 glycoprotein zeta chain; T-cell immunoglobulin and mucin 4;
KW T-cell immunoglobulin and mucin domain containing-4;
KW T-cell immunoglobulin mucin protein 4; TLR-2; Tim4 protein;
KW TimD4 protein; cancer; chimeric antigen receptor-T cell;
KW chimeric protein; cluster of differentiation 3 zeta; cytostatic;
KW fusion protein; immunotherapy; phosphatidylserine receptor; t-lymphocyte;
KW therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Peptide 1..24
FT /note= "Signal peptide"
XX
CC PN WO2023010097-A1.
XX
CC PD 02-FEB-2023.
XX
CC PF 28-JUL-2022; 2022WO-US074281.
XX
PR 28-JUL-2021; 2021US-0226643P.
PR 28-JUL-2021; 2021US-0226712P.
PR 28-JUL-2021; 2021US-0226736P.
PR 13-AUG-2021; 2021WO-US046014.
PR 13-AUG-2021; 2021WO-US046041.
PR 13-AUG-2021; 2021WO-US046043.
PR 16-FEB-2022; 2022US-0311016P.
PR 16-FEB-2022; 2022US-0311042P.
PR 16-FEB-2022; 2022US-0311043P.
PR 16-FEB-2022; 2022US-0311045P.
PR 29-APR-2022; 2022US-0336972P.
PR 29-APR-2022; 2022US-0336980P.
PR 13-MAY-2022; 2022US-0341999P.
PR 13-MAY-2022; 2022US-0342031P.
XX
CC PA (CERO-) CERO THERAPEUTICS INC.
CC PA (CORE/) COREY D M.
CC PA (CIEN/) CIENIEWICZ B.
CC PA (THOM/) THOMAS S.
XX
CC PI Corey DM, Cieniewicz B, Thomas S;
XX
DR WPI; 2023-155062/016.
XX
CC PT Chimeric T-cell immunoglobulin and mucin 4 receptor useful for treating
CC PT cancer comprises single chain chimeric protein comprising extracellular
CC PT domain, intracellular signaling domain and CD28 transmembrane domain.
XX
CC PS Example 5; SEQ ID NO 24; 265pp; English.
XX
CC The present invention relates to a novel chimeric T-cell immunoglobulin
CC and mucin 4 (Tim4/T-cell immunoglobulin and mucin domain containing-
CC 4/TimD4/phosphatidylserine receptor) receptor, useful for treating
CC disease in a subject. The chimeric Tim4 receptor comprises a single chain
CC chimeric protein, where the single chain chimeric protein comprises: (a)
CC an extracellular domain comprising a Tim4 binding domain comprising the
CC amino acid sequence of SEQ ID NO: 6 (see BMJ96454); (b) an intracellular
CC signaling domain, where the intracellular signaling domain comprises a
CC primary CD28 intracellular signaling domain of SEQ ID NO: 12 (see
CC BMJ96460), a secondary TLR2 TIR intracellular signaling domain of SEQ ID
CC NO: 17 (see BMJ96465), and a tertiary CD3 zeta intracellular signaling
CC domain of SEQ ID NO: 14 (see BMJ96462), or a primary CD28 intracellular
CC signaling domain of SEQ ID NO: 12 (see BMJ96460), a secondary CD3 zeta
CC intracellular signaling domain of SEQ ID NO: 14 (see BMJ96462), and a
CC tertiary TLR2 TIR intracellular signaling domain of SEQ ID NO: 17 (see
CC BMJ96465); and (c) a CD28 transmembrane domain of SEQ ID NO: 11 (see
CC BMJ96459) positioned between and connecting the extracellular domain and
CC the CD28 intracellular signaling domain. The invention further relates
CC to: (1) a polynucleotide encoding the chimeric Tim4 receptor; (2) an
CC expression vector comprising the polynucleotide; (3) an engineered cell
CC (e.g., a T cell) comprising the chimeric Tim4 receptor, the
CC polynucleotide, or the expression vector; (4) a composition comprising
CC the chimeric Tim4 receptor, the polynucleotide, the vector, or the
CC engineered cell; (5) a method for treating disease in a subject; (6) a
CC method for enhancing an effector response or anti-tumor efficacy in a
CC subject; (7) a method for enhancing CCR7+ expressing T cells in a subject
CC having cancer; and (8) a method for enhancing CD4/CD8 T cell ratio in a
CC subject having cancer. The novel chimeric Tim4 receptor of the invention
CC can be used for treating disease in a subject, where the disease is
CC cancer such as breast cancer, prostate cancer, ovarian cancer, cervical
CC cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer,
CC liver cancer, brain cancer, lymphoma, leukemia, or lung cancer,
CC adenocarcinoma of the breast, prostate, and colon, all forms of
CC bronchogenic carcinoma of the lung, myeloid leukemia, melanoma, hepatoma,
CC neuroblastoma, papilloma, apudoma, choristoma, branchioma, malignant
CC carcinoid syndrome, carcinoid heart disease, and carcinoma, histiocytic
CC disorders, malignant histiocytosis, leukemia, Hodgkin's disease, immune
CC proliferative small, non-Hodgkin's lymphoma, plasmacytoma, multiple
CC myeloma, chronic myeloid leukemia (CML), plasmacytoma,
CC reticuloendotheliosis, melanoma, chondroblastoma, chondroma,
CC chondrosarcoma, fibroma, fibrosarcoma, giant cell tumors, histiocytoma,
CC lipoma, liposarcoma, mesothelioma, myxoma, myxosarcoma, osteoma,
CC osteosarcoma, chordoma, craniopharyngioma, dysgerminoma, hamartoma,
CC mesenchymoma, mesonephroma, myosarcoma, ameloblastoma, cementoma,
CC odontoma, teratoma, thymoma, trophoblastic tumor, adenoma, cholangioma,
CC cholesteatoma, cyclindroma, cystadenocarcinoma, cystadenoma, granulosa
CC cell tumor, gynandroblastoma, hepatoma, hidradenoma, islet cell tumor,
CC Leydig cell tumor, papilloma, sertoli cell tumor, theca cell tumor,
CC leimyoma, leiomyosarcoma, myoblastoma, myomma, myosarcoma, rhabdomyoma,
CC rhabdomyosarcoma, ependymoma, ganglioneuroma, glioma, medulloblastoma,
CC meningioma, neurilemmoma, neuroblastoma, neuroepithelioma, neurofibroma,
CC neuroma, paraganglioma, paraganglioma nonchromaffin, angiokeratoma,
CC angiolymphoid hyperplasia with eosinophilia, angioma sclerosing,
CC angiomatosis, glomangioma, hemangioendothelioma, hemangioma,
CC hemangiopericytoma, hemangiosarcoma, lymphangioma, lymphangiomyoma,
CC lymphangiosarcoma, pinealoma, carcinosarcoma, chondrosarcoma,
CC cystosarcoma phyllodes, fibrosarcoma, hemangiosarcoma, leiomyosarcoma,
CC leukosarcoma, liposarcoma, lymphangiosarcoma, myosarcoma, myxosarcoma,
CC ovarian carcinoma, rhabdomyosarcoma, sarcoma, neoplasms,
CC neurofibromatosis, cervical dysplasia, and peritoneal cancer, B-cell
CC cancers, including B-cell lymphomas and myelomas, small lymphocytic
CC lymphoma, small lymphocytic leukemia, Waldenstrom macroglobulinemia, B-
CC cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, nodal marginal
CC zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse
CC large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma,
CC intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitf
CC lymphoma/leukemia, B-cell proliferations of uncertain malignant
CC potential, lymphomatoid granulomatosis, or post-transplant
CC lymphoproliferative disorder, or mantle cell lymphoma, triple negative
CC breast cancer, advanced ovarian cancer, advanced prostate cancer, non-
CC small cell lung cancer, common acute lymphocytic leukemias, Null-acute
CC lymphoblastic leukemias, and Hodgkin lymphoma in a subject, where the
CC subject has a refractory B cell malignancy.
XX
SQ Sequence 641 AA;
Query Match 99.5%; Score 1496; Length 641;
Best Local Similarity 99.7%;
Matches 289; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 25 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 84
Qy 61 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGAAADVKINVRLNLQRASTTTHRTATT 120
||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||
Db 85 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGAAAAVKINVRLNLQRASTTTHRTATT 144
Qy 121 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 145 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 204
Qy 181 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 205 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 264
Qy 241 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 290
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 265 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 314
Alignment of SEQ ID NO: 7 with SEQ ID NO: 3 of 18/511,825
Title: US-18-511-817-7
Perfect score: 1515
Sequence: 1 ETVVTEVLGHRVTLPCLYSS..........KTGQMDGIPMSMKNEMPISQ 290
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 291 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 50 summaries
Database : US-18-511-825A-3.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 1515 100.0 291 1 US-18-511-825A-3 RECOMBINANT TIM-4
ALIGNMENTS
RESULT 1
US-18-511-825A-3
Query Match 100.0%; Score 1515; DB 1; Length 291;
Best Local Similarity 100.0%;
Matches 290; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 60
Qy 61 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTHRTATT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTHRTATT 120
Qy 121 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 180
Qy 181 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 240
Qy 241 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 290
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 290
Alignment of SEQ ID NO: 7 with SEQ ID NO: 21 of 18/511,825
Title: US-18-511-817-7
Perfect score: 1515
Sequence: 1 ETVVTEVLGHRVTLPCLYSS..........KTGQMDGIPMSMKNEMPISQ 290
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 1126 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 50 summaries
Database : US-18-511-825A-21.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 1515 100.0 1126 1 US-18-511-825A-21 RECOMBINANT TIM-4
ALIGNMENTS
RESULT 1
US-18-511-825A-21
Query Match 100.0%; Score 1515; DB 1; Length 1126;
Best Local Similarity 100.0%;
Matches 290; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 590 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 649
Qy 61 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTHRTATT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 650 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTHRTATT 709
Qy 121 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 710 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 769
Qy 181 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 770 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 829
Qy 241 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 290
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 830 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 879
Prosecution Insights