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 .
The rejection under section 112(a), lack of written description of SLP-76 polypeptides is withdrawn in view of the amendments including SLP-76 SEQ ID NOs.
The rejection under section 112(b) is withdrawn in view of amendments deleting terms of relative degree.
The rejection under section 112(d) is withdrawn in view of amendments reforming claim 57 as an independent claim.
The following rejections are maintained:
The rejection under section 112(a), lack of written description of percent sequence identities of SLP-76 SEQ ID NOs is maintained below. Inclusion of other claims in the rejection was necessitated by Applicant’s amendments.
Claim Rejections - 35 USC § 112
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.
Claims 46-50, 52, 54-57, 59-61, 63-65 remain 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.
The rejected claims recite percent identities of SLP-76 peptides.
A PHOSITA could envision sequences that met the percent identity requirement. Moreover, by using conservative substitutions, a PHOSITA could likely envision sequences having the same tertiary structure as the SLP-76 peptide.
However, there is no teaching that the conservation of structure (whether in the DNA or encoded polypeptide) would be a surrogate for conservation of SLP-76 function. Specifically, there is no teaching as to which residues of the recited peptides could be altered while still conserving the function of the encoded polypeptide.
The specification demonstrated the recited function for the polypeptides encoded by SEQ ID NO’s, but offered no teaching as to what regions of the recited protein were critical for conservation of the recited function and which regions could be modified. Rather, the specification leaves it to others to discover the nature and scope of substitutions, deletions, and insertions that can be made to arrive at the recited sequence identity that additionally allows for SLP-76 activity.
Applicants may attempt to use BLAST homology data to argue that a PHOSITA would be able to address the issue, but the evidence is accorded little weight and characterized as an invitation to experiment.
Even though the DNA/polypeptides that could be envisioned by the PHOSTIA could be easily tested as set forth in the specification for conservation of the recited function, this was not enough to describe the structure so that a PHOSITA could determine beforehand whether or not a particular structure meets the functional requirements. Here, since SLP-76 variants are claimed by percent identity and function of the expressed protein. However, a PHOSITA cannot determine if the peptides with the recited percent identities produce a protein that accomplished the recited function from the specification itself in order to meet the written description requirement.
Adequate written description of the SLP-76 polypeptides covered by the recited percent identities, requires that one of ordinary skill must be able to determine beforehand whether or not a particular structure meets the functional requirements. Here, Applicant has not demonstrated which residues of the recited SLP-76 peptides could be altered while still conserving the function of the encoded polypeptide. Therefore, the rejection is maintained.
The rejection of claims 46-50, 52, 54-57, 60, 61, 63-65 under section 103 is withdrawn since the applied references fail to teach or suggest cells expressing two separate polypeptides: a first polypeptide comprising a SLP-76 peptide bound to a cell membrane, wherein the SLP-76 polypeptide has a sequence of at least 90% sequence identity to any one of SEQ ID NOs: 1, 7, 14, 16, 18, 19, 40, 59 or 60, and a second polypeptide comprising a CAR polypeptide having a binding affinity for a target antigen or for an adaptor molecule specifically recognizing the target antigen.
Claim 59 remains rejected under these grounds of rejection:
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.
Claim 59 remains rejected under 35 U.S.C. 103 as being unpatentable over Shim et al., J lmmunol, 1 March 2011, Vol 186 No 5 Pages 2926-2935 (Shim), in view of Linder et al., Sci Adv. 20 May 2020, Vol 6, No 21, (pp 1-8) (Linder) and WO 2020190771 (WO 771)
Shim teaches the role of SLP-76 and LAT in the PI3K signaling pathway in activated T cells. Shim examines the role of the association of these two molecules on the activation of PI3K signaling cascade. Experiments were done to determine the role of SLP-76, either wild-type, tyrosine mutants, or membrane-targeted forms of various SLP-76 constructs, on the membrane localization and phosphorylation of Akt, which is an event downstream of PI3K activation. Reconstitution studies with these various SLP-76 constructs in a Jurkat variant cell line that lacks SLP-76 or linker for activation of T cells (LAT) show that the activation of PI3K pathway following TCR ligation requires both SLP-76 and LAT adaptor proteins. The results suggest that SLP-76 associates with p85 after T cell activation and that LAT recruits this complex to the membrane, leading to Akt activation.
Specifically, Shim discloses a composition comprising an isolated recombinant cell modified to overexpress and/or contain elevated levels of a SLP-76 polypeptide (pg 2930 col 2 para 3; "To examine whether SLP-76 association with LAT or membrane targeting of SLP-76 is required for the Pl3K signaling after TCR ligation, SLP-76--deficient J14 cells were reconstituted with SLP-G2 (Gads binding domain mutant of SLP-76; consequently not associated with LAT) or TM-SLP-G2 (SLPG2 fused to LAT TM; consequently membrane-targeted). Expression of SLP-76 Wt and TM-SLP-G2 constructs, but not the SLP-G2 construct alone, reconstituted the TCR- and TCR/CD28-induced PI3K signaling pathways in J14 cells"; pg 2927 col 1 para 3; 'The plasmids carrying Wt SLP-76 and its various tyrosine mutants cloned into a modified pEF-Bos vector with an N-terminal sequence encoding the flag epitope were provided"), wherein the recombinant cell is capable of being activated by a target antigen expressed at a low density (Pg 2927 col 1 para 1; "Results from the study not only show that TCR-induced Pl3K/Akt activation is dependent on membrane translocation and tyrosine phosphorylation of SLP-76, but that LAT is also required for the localization of SLP-76 to the membrane. Collectively, these results suggest distinct roles of two adaptor molecules in the activation of Pl3K signaling pathway following TCR ligation: SLP-76 for membrane translocation of p85 and LAT for membrane translocation of SLP-76").
Shim discloses that recombinant cell modified to overexpress and/or contain elevated levels of a SLP-76 polypeptide (pg 2930 col 2 para 3).
Shim does not explicitly disclose the isolated recombinant cell further comprises a T cell receptor (TCR) polypeptide wherein the TCR polypeptide has a binding affinity for the target antigen.
However, Lindner discloses that the isolated recombinant cell further comprises a T cell receptor (TCR) polypeptide wherein the TCR polypeptide has a binding affinity for the target antigen (pg 2 col 2 para 2; "Endogenous TCRs recognize peptide:major histocompatibility complex (MHC) antigen through a highly complex and interconnected process involving receptor components as well as intracellular kinases, substrates, and coreceptors").
Lindner further discloses that isolated recombinant cell comprises a TCR polypeptide, and wherein the target antigen is expressed by a target cell and presented to the TCR polypeptide by an antigen-presenting cell (APC) (pg 2 col 2 para 2).
Lindner further discloses that the isolated recombinant cell comprises an endogenous TCR polypeptide (pg 2 col 2 para 2; "Endogenous TCRs recognize peptide:major histocompatibility complex (MHC) antigen").
Lindner further discloses that the isolated recombinant cell comprises a CAR polypeptide, and wherein the target antigen is expressed by a target cell (pg 1 col 1 para 1; "solid tumor-targeted CART cells").
Lindner further discloses that the target cell is a cell correlated to a proliferative disease, a hematological malignancy (pg 1 col 1 para 1; "hematologic malignancy-targeted CART cells").
Lindner further discloses that the target cell is a cancer cell (pg 1 col 1 para 1; "solid tumor-targeted CART cells").
An artisan of ordinary skill in the art would have recognized that target antigen-MHC complex interaction with endogenous TCRS were the standard means by which a TCR recognized an antigen.
Consequently, it would have been obvious for one of ordinary skill in the art to combine intracellular signaling pathway components, such as SLP-76, as disclosed by Shim, with the isolated recombinant cell further comprises a T cell receptor (TCR) polypeptide wherein the TCR polypeptide has a binding affinity for the target antigen, as disclosed by Lindner, because it would have enabled an antigen-dependent pathway of TCR stimulation and intracellular signaling.
See also WO 771 teaching SLP-76 containing CART cells. WO 771 teaches chimeric polypeptides including (a) an extracellular targeting domain; (b) a transmembrane domain; (c) an intracellular linker for activation of T cells (LAT) domain or SLP-76 domain; and (d) an intracellular ZAP70 domain, wherein (a)-(d) are in N-terminal to C-terminal order are provided. Chimeric polypeptides including (a) an extracellular targeting domain; (b) a transmembrane domain; and (c) an intracellular ZAP70 domain, wherein (a)-(c) are in N-terminal to C-terminal order are also provided. In some embodiments, the chimeric polypeptide further includes a hinge domain and/or a signal sequence domain.
WO 771 also teaches nucleic acid molecules encoding the chimeric polypeptides and expression vectors including the nucleic acids. Isolated cells (such as T cells or natural killer cells) expressing the chimeric polypeptides and methods of treating a subject with cancer with the isolated cells are taught.
In this way, those of ordinary skill could have applied an intracellular signaling pathway components, such as SLP-76, as disclosed by Shim, with the isolated recombinant cell further comprises a CAR in the manner required and in a predictable fashion for the purposes of obtaining the instant recombinant cells. As outlined above, Shim teaches the role of SLP-76 in signaling pathway in activated T cells. The secondary references are added for the proposition that CART cells are applicable to this process of SLP-76 mediate T cell activation. Specifically, the secondary references teach that the particular known technique of antigen-dependent pathway of T cell stimulation and intracellular signaling was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to SLP-76 mediate T cell activation, as taught by Shim, would have yielded predictable results. Accordingly, using SLP-76 intracellular signaling pathway components with an isolated recombinant cell further comprising a CAR would have been prima facie obvious.
It is noted that SEQ ID NO:1 represents native SLP-76, as contemplated by the references.
The claims also recite effects of SLP-76 overexpression or recombinant cell activation, e.g., claims 50, 55, or enhancing activation of the isolated recombinant cell (claim 57), or enhancing activity of at least one T cell (claim 64). However, these effects would have been an invariable aspect of the SLP-76 expressing CAR cells as disclosed by the combination of references, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). 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 are necessarily present. Id.”).
The polynucleotides and expression systems in claim 59 do not necessarily provide gene products of two separate polypeptides, but can cover a single T cell receptor polypeptide, which is taught by the applied references. Therefore, the rejection is maintained.
Information Disclosure Statement
The information disclosure statement filed 6/8/2026 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
The IDS does not provide a copy of JP 2024507875.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at telephone number 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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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
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