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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-25 are the original claims filed 3/15/2024. In the preliminary amendment of 6/26/2024, Claims 1-25 are canceled and new claims 26-41 are added. Claims 26-41 are all the claims.
Priority
2. USAN 18/607,387 filed 03/15/2024, is a Continuation of 17/385,805, filed 07/26/2021, now abandoned, 17/385,805 is a Divisional of 15/525,906, filed 05/10/2017, now U.S. Patent # 11072644 and having 1 RCE-type filing therein,
15/525,906 is a National Stage entry of PCT/IB2015/058650, International Filing Date: 11/09/2015, PCT/IB2015/058650 Claims Priority from Provisional Application 62/081,960, filed 11/19/2014, PCT/IB2015/058650 Claims Priority from Provisional Application 62/078,927, filed 11/12/2014. The claimed iCAR comprising the ITIM sequences of SEQ ID NOs 1971, 1974 and 1631 are accorded an effective filing date of 11/12/2014.
Information Disclosure Statement
3. As of 9/14/2026, a total of three (3) IDS are filed: 3/15/2024; 7/23/2024; and 12/16/2024. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
4. The abstract of the disclosure is objected to because it contains legal phraseology, i.e., “said”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
5. The disclosure is objected to because of the following informalities:
a) The use of the term ATCC, glutaMAx, EnVision, Bright-Glo, lipofectamine, Millex-HV, SwissProt, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The specification contains amino acid sequences > 4 amino acids (e.g., GGGGSGGGGS, (Gly-Gly-Gly-Ser)n, p. 51, lines 4-17) in length and nucleotide sequences > 10 nucleic acids in length (e.g., GGTGGCGGAGG TTCTGGAGGTGG AGGTTCC). And for those tables before and after Table 1 to Table 10, that are not labeled and contain sequences, none of the sequence data are identified by sequence number. See 37 CFR 1.1821-1.825.
c) The specification contains numerous tables that are not identified by table number on pp. 24-28, 30-34, 36-38, 40-50, 119, and 138-151.
Appropriate correction is required.
Claim Objections
6. Claims 33-35 and 37 are objected to because of the following informalities:
a) Amend claims 33-35 to replace “said ITIM” with “[said] the ITIM”.
b) Amend claim 37 for consistency to recite:
- the antigen to which the antigen binding domain of the first CAR binds is present in tumor cells of pancreatic ductal adenocarcinoma and the antigen to which the antigen binding domain of the second CAR binds is TMPRSS1IB, CYP17A1 or ATP4B, or
- the antigen to which the antigen binding domain of the first CAR binds is present in tumor cells of kidney clear cell carcinoma and the antigen to which the antigen binding domain of the second CAR binds is GP2, MUC21, CLCA4 [and] or SLC27A6.
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.
7. Claim 39 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 39 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: the transfection/transduction of the immune cell with a DNA/RNA material encoding the CAR invention as taught at
[0341] The present invention also includes an RNA construct that can be directly transfected into a cell. A method for generating mRNA for use in transfection involves in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3′ and 5′ untranslated sequence (“UTR”), a 5′ cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length. RNA so produced can efficiently transfect different kinds of cells. In one embodiment, the template includes sequences for the N-CAR. In an embodiment, an RNA N-CAR vector is transduced into a T-cell by electroporation.”
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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.
Written Description
8. Claims 26-41 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 26-35 drawn to a CAR comprising an intracellular domain comprising an ITIM of the sequence VTYAEV (SEQ ID NO:1971), VTYAQL (SEQ ID NO:1974) or TEYSEV (SEQ ID NO: 1631).
Claims 27-41 drawn to an isolated immune cell, comprising: a first CAR and a second CAR, wherein the second CAR is a CAR according to claim 26.
Definition(s)/ Claim interpretation
“ITSM”: the motif is defined in the specification as being an aspect of an N-CAR and being regulatory for T-cell activity otherwise associated with a P-CAR as follows:
Example 1—Identification of Inhibitory Domains to be Used in N-CARs
[0393] There are several receptors, i.e. CTLA-4, PD-1, BTLA, TIM-3, LAG3 that are known to provide a negative signal to attenuate or abrogate T-cell signaling. The intracellular signaling components of PD-1 were studied to identify motifs that may be responsible for its activity. PD-1 contains both an immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) and data suggests that the ITSM domain plays a significant role in recruiting phosphatases (i.e. SHP2) that enable inactivation of upstream signaling components, like CD3zeta (see Riley J L., Immunol Rev. 2009 May; 229(1):114-25; or Yokosuka T et al., J Exp Med. 2012 Jun. 4; 209(6):1201-17). Other receptors and molecules with ITSMs were identified and analyzed to help understand the functional role of this sequence motif with the intention to utilize it in providing a negative signal that attenuates or abrogates T-cell activation caused by engagement of the P-CAR. Protein sequences were downloaded from swissprot database restricting to sequences that were annotated as being cytoplasmic. Each of these cytoplasmic sequences was searched for the patterns of interest (ITIM motif, ITSM motif or ITIM and ITSM motif).
Example 2—Design of N-CARs
[0394] N-CARs comprising at least one ITSM, alone or in combination with one or more ITIMs or other inhibitory domain such as those of TIM-3, LAG-3 or CTLA4 are prepared in an effort to generate effective NOT gates.
[0395] In particular, the following N-CARs are prepared: [0396] N-CARs comprising multiple tandems PD-1 ITIM-ITSM; [0397] N-CARs comprising multiple tandems PD-1 ITSM; [0398] N-CARs comprising single or multiple non-PD1 natural ITSM or ITIM-ITSM; [0399] N-CARs comprising synthetic ITSM or ITIM-ITSM; [0400] N-CARS comprising at least one ITSM and signaling domains from other inhibitory receptors such as TIM-3, LAG-3 or CTLA4.
“immune cell”: the specification clarifies the immune cell comprising the dual CAR system as a T cell
[0356] In some embodiments, the invention relates to an isolated immune cell comprising an N-CAR as defined herein. In some embodiments, the invention further relates to immune cells comprising an N-CAR as defined herein and a P-CAR. In some embodiments, said immune cell is a T-cell. In some embodiments, said T-cell is a human T-cell.
“antigen binding domain”: the specification clarifies the meaning of the antigen binding domain being smaller than a full antibody and comprising single variable domains and mimetic such as a recombinant fibronectin domain:
[0342] The antigen binding domain can be any domain that binds to the off-tissue antigen including but not limited to a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, and a functional fragment thereof, including but not limited to a single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain (VHH) of camelid derived nanobody, and to an alternative scaffold known in the art to function as antigen binding domain, such as a recombinant fibronectin domain, and the like. In some instances, it is beneficial for the antigen binding domain to be derived from the same species in which the N-CAR will ultimately be used in. For example, for use in humans, it may be beneficial for the antigen binding domain of the N-CAR to comprise human or humanized residues for the antigen binding domain of an antibody or antibody fragment.
[0358] The extracellular portion of a P-CAR comprising an antibody or antibody fragment thereof may exist in a variety of forms where the antigen binding domain is expressed as part of a contiguous polypeptide chain including, for example, a single domain antibody fragment (sdAb), a single chain antibody (scFv) and a humanized antibody (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, N.Y.; Houston et al, 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).
Regarding structure-function correlation for inhibitory CAR/ activatable CAR (ITSM) molecules, the specification teaches at pp. 1-2 “Given the potency of such therapeutics, the field's ability to identify novel targets for such therapy is hindered by concerns about on- target off-tissue (meaning off-tumor) activity. Such events not only mitigate efficacy but also present tremendous safety challenges as demonstrated by recent clinical events (see Morgan RA et al, Mol Ther. 2010 Apr;18(4):843-51; Morgan RA et al., J Immunother. 2013 Feb;36(2):133-51 or Linette GP et al., Blood 2013 Aug 8;122(6):863-71). Clinical approaches to mitigate these safety concerns while effective also act directly or indirectly on the infused CAR T-cell therapeutic entities.
In order to address the issues pertaining to on-target off-tissue activity of CAR T- cells, there is growing emphasis in creating logic gates to modulate T-cell signaling (see Federov VD et al., Sci Transl Med. 2013 Dec 11;5(215):215ra172 (IDS 3/15/2024)).”
Federov designed antigen-specific inhibitory chimeric antigen receptors (iCARs) to preemptively constrain T cell responses to demonstrate that CTLA-4– or PD-1–based iCARs can selectively limit cytokine secretion, cytotoxicity, and proliferation induced through the endogenous T cell receptor or an activating chimeric receptor.
“The crux of the iCAR strategy relies on three critical properties.
The first is that basal expression of the iCAR does not inhibit T cell function in the absence of antigen. Endogenous CTLA-4 or PD-1 signaling requires the presence of the respective ligands to exert their effect. Likewise, we did not find expression of the iCARs described herein to affect basal T cell functions. Other inhibitory receptors that are restricted to T cell subsets may act in concert to fine-tune the regulation of T cell responses (21, 22). Receptors such as LAG-3, 2B4, and BTLA and their combination (for example, as a single second-generation iCAR with multiple combined cytoplasmic domains) warrant further investigation.
The second key property is the maintenance of T cell functionality despite previous engagement of the iCAR. We found that iCAR-transduced T cells could still mount a response against a target antigen after a previous exposure to an inhibitory antigen. This reversibility is reminiscent of natural killer cell behavior, in which the phosphorylation state of signaling molecules rather than transcriptional changes control rapid functional responses, such as cytotoxicity (41). Anti–PD-1 and anti–CTLA-4 antibodies are able to reverse the impaired function of anergized or exhausted T cells, again arguing for the ability to temporally regulate T cell responses (22). Additionally, biochemical analyses of PD-1 and CTLA-4 effects on the TCR complex depend on phosphorylation states, downstream kinases, and motility rather than apoptosis (40, 42–44). Although both our in vitro and in vivo results demonstrate inhibition in response to off-target cells with sustained therapeutic functionality, there is still the possibility that some of the cells may be anergized over time (42). Ultimately, a T cell infusion is stochastic, with some T cells promptly encountering their target and eliminating it, whereas other T cells will first encounter the inhibitory cells. It is conceivable that T cells that repeatedly encounter off-target cells will not expand—a satisfactory outcome for the iCAR strategy, which aims to allow for therapeutic responses to proceed while diminishing the immune attack against normal tissues. The overall expansion of the infused T cell population will integrate these different paths occurring at the clonal level, with some T cells undergoing expansion while others are suppressed, possibly resulting in the disappearance of all infused T cells over time. Under our experimental conditions, enough T cells persisted over 3 weeks to eliminate the targeted tumor. Under such a circumstance, a second or third T cell infusion could be infused if needed, which may be clinically advantageous as discussed elsewhere (9). The eventual induction of anergy and clonal elimination as a means to protect off-target tissues while allowing tumor elimination to proceed should be contrasted to suicide gene strategies where adverse reactivity must manifest itself before T cell elimination is triggered, which results in terminating therapeutic responses as well.
Third, the iCAR approach is antigen-specific and thus requires the ability to identify tissue-specific target antigens that are absent or down-regulated on the tumor but expressed by the off-target tissues. This question has not been as broadly investigated as the search for tumor antigens, although efforts, such as the Protein Atlas database, are under way to characterize the “surfaceome” of all human tissues (45). One strategy is to use broad classes of surface antigens that are down-regulated on tumor cells. One example is represented by human leukocyte antigen (HLA) molecules, which are found in virtually all cell types, but are down-regulated on tumors as a mechanism of tumor escape from T cell immune responses (46). Thus, allogeneic T cells expressing an iCAR against a host HLA molecule that is down-regulated on the tumor may selectively promote the GVT effect. The iCAR approach may be of particular interest in the setting of DLI as a means to protect GVHD target tissues without impairing GVT responses. Another class of antigens amiable to a similar strategy includes cell surface tumor suppressor antigens, such as OPCML, HYAL2, DCC, and SMAR1 (47–49). OPCML-v1, for example, is widely expressed in all normal adult and fetal tissues but is down-regulated in lymphomas and breast and prostate cancer. Cell surface carbohydrates, lipids, and posttranslational modifications, such as mucin-type O-glycans (core 3 O-glycans) have also been found to be down-regulated by tumors (50). Another candidate target is E-cadherin, which is highly expressed in normal skin, liver, and gut—the primary targets of GVHD (51)—but down-regulated by tumor cells undergoing an epithelial to mesenchymal transition, indicating tumor progression and metastasis (52).”
Frankel (IDS 7/23/2024) further substantiates the use of iCARs consisting of an SA-binding domain, hinge and transmembrane domains, and a functional intracellular domain (ICD) derived from the cytoplasmic tails of inhibitory coreceptors containing immunoreceptor tyrosine-based inhibitory motifs (ITSM). Frankel provide proof of principle for protocols for transducing aCAR/iCAR pairs in NK cells.
Sahillioglu (IDS 7/23/2024) states that ITIM/ITSM containing inhibitory receptors generally recruit SH2 domain containing phosphatases such as SHP1/2 to counteract ITAM signaling. To design synthetic T cell activity regulators, the use of intracellular domains that are derived from proteins that are physiological inhibitors of TCR signaling forms a logical first choice. However, different immune receptors and immune receptor signaling domains can influence cell activity when introduced into other cell types, and the abundance of inhibitory signaling and SH2 domain containing proteins in diverse immune cell types raises the level of complexity for specific regulation. (p. 1030)
Regarding a representative number of species, the specification provides general disclosures on how to make and use iCAR and numerous potential ITSM motifs for a cassette aspect of an iCAR (Examples 1 and 2). In Example 3, working examples of an i(n)CAR (anti-PSMA; Table 10) /a(p)CAR (anti-CD19; Table 9) pairing in a transduced Jurkat T cell line for in vitro T-cell activation assay. Figure 5 and 10 show results for inhibition of activity by i(n)CAR for a(p)CAR-induced T cell activation. Example 4 hypothetical example of an i(n)CAR(anti-PSMA; Table 10) /a(p)CAR (anti-CD19; Table 9) pairing in a transduced primary human T cell for in vitro T-cell activation assay. Example 5 hypothetical example of an i(n)CAR(anti-PSMA; Table 10) /a(p)CAR (anti-CD19; Table 9) pairing in a xenograft animal model that has yet to be shown to be operative for the limited species of iCAR/aCAR of the specification much less the tumors to be treated.
A) Table 10 lists the intracellular domains comprising natural or engineered ITIM for tested N-CARs comprising the sequence of SEQ ID NO: 1999 (scfv) from anti-PSAM antibody clone J591, a PD-1 hinge and transmembrane domain, and an intracellular domain selected from the sequences (p 130, lines 2-5). The extent of testing is in T-cell activation assays with results depicted in Figures 1-10. The extent of testing the instant claimed ITIM of SEQ ID NOs: 1971, 1974 and 1631 in the IT domains for the N-CAR is follows:
N-CAR Name/ Intracellular domain (sequence to sequence alignment (ABSS))
PD1 (SEQ ID NO: 2000): none of SEQ ID NOs 1971, 1974 and 1631.
BTLA (SEQ ID NO: 2001): none of SEQ ID NOs 1971, 1974 and 1631.
CD224 (SEQ ID NO: 2002): none of SEQ ID NOs 1971, 1974 and 1631.
PD1-CTLA4 (SEQ ID NO: 2003): none of SEQ ID NOs 1971, 1974 and 1631.
PD1-LAG3 (SEQ ID NO: 2004): none of SEQ ID NOs 1971, 1974 and 1631.
PD1-PD1 (SEQ ID NO: 2005): none of SEQ ID NOs 1971, 1974 and 1631.
PD1-TIM3 (SEQ ID NO: 2006): none of SEQ ID NOs 1971, 1974 and 1631.
CD300LF (SEQ ID NO: 2007): none of SEQ ID NOs 1971, 1974 and 1631.
LY9 (SEQ ID NO: 2008): none of SEQ ID NOs 1971, 1974 and 1631.
PECAM (SEQ ID NO: 2009): none of SEQ ID NOs 1971, 1974 and 1631.
SIGLEC9 (SEQ ID NO: 2010): none of SEQ ID NOs 1971, 1974 and 1631.
SIRPA (SEQ ID NO: 2011): none of SEQ ID NOs 1971, 1974 and 1631.
PD1-L2-ITSM (SEQ ID NO: 2012): none of SEQ ID NOs 1971, 1974 and 1631.
PD1-L2-ITSM-L2-ITSM (SEQ ID NO: 2013): none of SEQ ID NOs 1971, 1974 and 1631.
PD1 (ITSM mut 1) (SEQ ID NO: 2014): none of SEQ ID NOs 1971, 1974 and 1631.
PD1 (ITSM mut 2) (SEQ ID NO: 2015): none of SEQ ID NOs 1971, 1974 and 1631.
PD1 (ITSM mut 3) (SEQ ID NO: 2016): none of SEQ ID NOs 1971, 1974 and 1631.
PD1-KIRDL2 (SEQ ID NO: 2017): none of SEQ ID NOs 1971, 1974 and 1631.
Accordingly, the specification does not describe any of the claimed ITIM species falling within a universal intracellular domain much less that any of the species of intracellular domains defined in Table 10 comprise the specific ITMs of the instant claimed. The instant claims read on a universe of iCAR or N-CAR defined only by the ITIM structure. The POSA could reasonably conclude that Applicants are not in possession of the claimed invention to satisfy the structure/function correlation under the written description requirements.
MPEP 2163 (II)(3)(a)
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004)
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.
9. Claims 26-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12 and 15-21 of U.S. Patent No. 11072644 B2.
Claims 26-41 the interpretation of the claims is discussed herein above.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed inhibitory CAR (iCAR) comprising an antigen binding domain, a transmembrane domain, and an intracellular domain comprising the ITIM sequence for TEYSEV and an engineered immune cell comprising the iCAR is common and shared between both claim sets.
Ref 1. A chimeric antigen receptor (CAR) comprising an extracellular domain comprising an antigen binding domain, a transmembrane domain, and an intracellular domain, wherein: (a) the intracellular domain comprises an Immunoreceptor Tyrosine-based Switch Motif (ITSM), wherein said ITSM is a sequence of amino acids TX1YX2X3X4 (SEQ ID NO: 2049), wherein X1 is E; X2 is A or S; X3 is S or E; and X4 is V or I; and (b) the intracellular domain has at least 95% amino acid sequence identity with SEQ ID NO: 2016.
The instant claimed ITIM of SEQ ID NO: 1631 for TEYSEV is encompassed within the formula of generic ref claim 1.
Ref 2. The CAR according to claim 1, wherein said ITSM is selected from the group consisting of TEYASI (SEQ ID NO: 936), TEYSEI (SEQ ID NO: 940), and TEYSEV (SEQ ID NO: 941).
Ref 3. TheCAR according to claim 1, wherein the antigen binding domain is a single chain variable fragment (scFv).
Ref 4. The CAR according to claim 1, wherein the intracellular domain is selected from the group consisting of SEQ ID NO: 2014, SEQ ID NO: 2015, and SEQ ID NO: 2016.
Ref 5. The CAR according to claim 1, wherein the antigen binding domain binds to PSMA, ITGAX, CD1E, CD34, CD1C, CD123, CD141, ZP2, GABRA6, CRTAM, GRM4, MDGA1, ZP2, GABRA6, CRTAM, GRM4, MDGA1, SFTPC, ROS1, SLC6A4, AGTR2, LRRC26, HTR3A, TMEM211, MRGPRX3, MEP1B, TMIGD1, CEACAM20, ALPI, TMPRSS11B, CYP17A1, ATP4B, GP2, MUC21, CLCA4 or SLC27A6.
Ref 6. The CAR according to claim 1, wherein the transmembrane domain comprises the transmembrane region(s) of the alpha, beta or zeta chain of the T-cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154.
Ref 7. The CAR according to claim 1, wherein the transmembrane domain comprises the transmembrane region of PD-1 or CD8 alpha.
Ref 8. The CAR according to claim 1, wherein the transmembrane domain is attached to the extracellular domain of the CAR via a hinge.
Ref 9. The CAR according to claim 8, wherein the hinge is an IgG4 hinge, a CD8 alpha hinge or a PD-1 hinge.
Ref 12. The CAR according to claim 1, wherein said ITSM is TEYSEV (SEQ ID NO: 941).
Ref 15. The CAR according to claim 12, wherein the intracellular domain is PD1 (ITSM mut2) (SEQ ID NO: 2015).
Ref 16. An isolated immune cell, comprising: a first CAR comprising an extracellular domain comprising an antigen binding domain, a transmembrane domain, and an intracellular domain; and a second CAR, wherein the second CAR is a CAR according to claim 1.
Ref 17. The immune cell according to claim 16, wherein:
the antigen to which the antigen binding domain of the first CAR binds is CD33 and the antigen to which the antigen binding domain of the second CAR binds is ITGAX, CD1E, CD34, CD1C, CD123, or CD141, or,
the antigen to which the antigen binding domain of the first CAR binds is FLT3 and the antigen to which the antigen binding domain of the second CAR binds is ZP2, GABRA6, CRTAM, GRM4 or MDGA1, or,
the antigen to which the antigen binding domain of the first CAR binds is MSLN and the antigen to which the antigen binding domain of the second CAR binds is SFTPC, ROS1, SLC6A4 or AGTR2, or,
the antigen to which the antigen binding domain of the first CAR binds is MUC16 and the antigen to which the antigen binding domain of the second CAR binds is LRRC26, HTR3A, TMEM211 or MRGPRX3, or,
the antigen to which the antigen binding domain of the first CAR binds is MUC17 and the antigen to which the antigen binding domain of the second CAR binds is MEP1B, TMIGD1, CEACAM20 or ALPI, or,
the antigen to which the antigen binding domain of the first CAR binds is present in tumor cells of pancreatic ductal adenocarcinoma and the antigen to which the antigen binding domain of the second CAR binds is TMPRSS11B, CYP17A1 or ATP4B,
the antigen to which the antigen binding domain of the first CAR binds is present in tumor cells of kidney clear cell carcinoma and the antigen to which the antigen binding domain of the second CAR binds is GP2, MUC21, CLCA4 and SLC27A6.
Ref 18. The immune cell according to claim 16, wherein the immune cell is a human T-cell.
Ref 19. A method of engineering an immune cell according to claim 16 comprising: (a) providing an immune cell; and (b) expressing the second CAR and the first CAR at the surface of said cells.
Ref 20. A polynucleotide comprising a nucleic acid sequence encoding a CAR according to claim 1.
Ref 21. A vector comprising a polynucleotide according to claim 20
Conclusion
10. No claims are allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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