DETAILED ACTION
Notice of Pre-AIA or AIA Status
The text of those sections of Title 35, U.S. Code not included in this action can
be found in a prior Office action.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is in response to the papers filed on 07/09/2026. Claims 1, 4, 16, 27, 30, 31, 42, 45, 47, 48, and 50 are currently pending as per claims filed on 07/09/2026. Claims 2, 14, 28, 29, 40, 41, 49, 51, and 52 are cancelled and Claim 1, 4, 16, 27, 30, 31, 42, 45, 47, 48, and 50 have been amended by Applicants’ amendment filed on 07/09/2026. No new claims were added.
Therefore, claims 1, 4, 16, 27, 30, 31, 42, 45, 47, 48, and 50 are under examination to which the following grounds of rejection are applicable. Claims 1 and 27 are independent claims.
Priority
The instant application is a continuation of 17/902,255 filed 09/02/2022 (abandoned) which is a continuation of PCT/US21/20874 filed on 03/04/2021 which claims benefit of provisional 62/985,876 filed on 03/05/2020. Thus, the earliest possible priority for the instant application is 03/05/2020.
Withdrawn objections/rejection in response to Applicants’ arguments or
Amendment
Claim Rejections - 35 USC § 112(b)
In view of Applicants’ amendment of claim 1, 2, 4, 14, 16, and 27-31 removing the phrase “activated” and “activatable”, “capable of regulating the expression of the target polynucleotide”, “expressing a system in a cell”, and “adapter moiety”, the claim rejections under 35 U.S.C. 112(b) has been withdrawn.
Applicants’ arguments are moot in view of the withdrawn rejection.
Claim Rejections - 35 USC § 112(a)
In view of Applicants’ amendment of claim 1, 2, 4, 14, 16, and 27-31 which narrow the claims to the disclosed and experimentally tested species (now drawn to a human primary T cell comprising an endogenous TCR/CD3 complex wherein the system expressed in the human primary T cell comprises LAT linked through TEV protease recognition to a cCas9KRAB, a protease chimeric polypeptide comprising ZAP70 or BRB2 fused to a TEV protease and a gRNA targeting PD-1), the claim rejections under 35 U.S.C. 112(a) has been withdrawn.
Applicants’ arguments are moot in view of the withdrawn rejection.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment of claim 1, 2, 4, 14, 16, and 27-31 which narrow the claims to the disclosed and experimentally tested species (now drawn to a human primary T cell comprising an endogenous TCR/CD3 complex wherein the system expressed in the human primary T cell comprises LAT linked through TEV protease recognition to a cCas9KRAB, a protease chimeric polypeptide comprising ZAP70 or BRB2 fused to a TEV protease and a gRNA targeting PD-1), the rejection of claim(s) 1, 2, 4, 14, 16, 27-31, 40-42, 45, 47-50, 51 and 52 under 35 U.S.C. 103 as being unpatentable over Chung et al (US Patent Application No. 2019/0256833 A1) and further in view of Qi et al (US Patent Application No. 2020/0071729 A1) and Wang et al (WO 2019/014390 A1) has been withdrawn.
A response to Applicant’s arguments with regard to a withdrawn rejection is moot.
New objections/rejection in response to Applicants’ arguments or
Amendment
Claim Rejections - 35 USC § 103
Claim 1, 4, 16, 27, 30, 31, 42, 45, 47, 48, and 50 are newly rejected under 35 U.S.C. 103 as being unpatentable over Qi et al (US 20180346543 A1) and further in view of Garber (Nature Bio. 2018, pages 215-219) and Ahmadi (Blood. 2011, pages 3528-3537). This is a new rejection necessitated by amendment of the claims in the response filed 07/09/2026.
Regarding claims 1 and 27, Qi teaches systems and methods for decreasing the transcription of a target nucleic acid in a human primary T cell, where the target nucleic acid is PD-1 (Example 15). Qi teaches the method comprises:
expressing a system in a T cell wherein the system comprises (para 0006):
- a chimeric transmembrane receptor (i.e. a chimeric antigen receptor (CAR)) polypeptide comprising:
(i) an extracellular region comprising an antigen interacting domain that binds an antigen and
(ii) an intracellular region comprising an immune cell signaling domain comprising a primary signaling domain which can be LAT and is linked to an actuator moiety which can be dCas9-KRAB via a TEV protease cleavage site (para 0033)
a chimeric adaptor polypeptide comprising ZAP70 (para 0036) linked to a cleavage moiety which can be a TEV protease (para 0055, 0064),
wherein the TEV protease is capable of cleaving the TEV-protease cleavage site on the receptor when the LAT protein binds the ZAP70 of the chimeric adaptor polypeptide,
and, upon contacting T cell with a target cell, the chimeric adaptor polypeptide is recruited to the receptor and releases the dCas9-KRAB from immune cell signaling domain via cleavage by TEV protease at the TEV protease cleavage site, wherein the dCas9-KRAB in turn decreases expression of programmed cell death protein 1 (PD-1) (para 0066, para 0255).
Qi teaches the system comprises a guide RNA to repress the transcription of target DNA PD-1 (para 0215, example 15).
See below for Figure 3B of Qi (left) as compared to Figure 3A of the instant application (right) showing the expression systems comprising LAT, ZAP70, TEV, and dCas9-KRAB in both applications:
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410
327
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457
356
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Qi does not teach that the human primary cell comprises an endogenous T cell receptor/CD3 complex wherein upon the contacting of the human primary T cell by a ligand that binds specifically the ligand binding domain of the TCR.
However, one of ordinary skill in the art would have considered the teachings of
Garber and Ahmadi as these references are analogous prior art pertaining to the use of TCRs over CARs in immunotherapy treatments and the importance of CD3 inclusion when expressing TCRs in T cells when using TCR gene therapy.
Garber teaches that use of TCRs in immunotherapy is more beneficial than using CARs as TCRs can target a much larger target pool since they can recognize any peptide presented by a major histocompatibility complex (MHC) on a cell’s surface, whereas CARs are limited in their recognition ability since they are engineered to display antigen-binding fragments of a specific antibody (page 215, right col, para 1). Thus “Because CARs employ an antibody’s antigen-recognition machinery, they only recognize protein antigens expressed on the cell surface. TCRs, on the other hand, can recognize intracellular proteins expressed as peptides on MHC class I molecules” giving TCR the benefit of treating solid tumors (page 216, legend Fig 1) .
Ahmadi teaches that when engineering T cells to express a TCR, inclusion of CD3 is a key regulator for proper expression of the TCR in the T cells and the increase in TCR expression was associated with increased T-cell avidity leading to improved recognition of low concentration of peptide antigen (abstract, page 3528; Introduction, page 3528, right col, para 1).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a method for decreasing expression of PD-1 in a human primary T cell by expressing a system comprising a chimeric transmembrane receptor (i.e. CAR) polypeptide via the LAT/ZAP70 system taught by Qi as described above, to instead use an endogenous TCR/CD3 complex having a ligand binding domain as that binds to a specific ligand since Garber teaches that TCRs are more beneficial in immunotherapy as they can target a larger pool of ligands including intracellular proteins expressed as peptides on MHC class I molecules compared to CARs and including CD3 in the expression system leads activation of TCR/CD3 complex by a large pool of ligands on T cells and enhanced activity as taught by Ahmadi. One would be motivated to do so to widen the applicability of the T cell therapy to more ligands including intracellular proteins than what CARs can detect as well as better detection of antigens of interest. Since use of TCRs in T cell engineering and the components of the CAR system utilizing LAT, ZAP70, TEV, dCas9-KRAB, and a sgRNA to target PD-1 have been shown in the art, one would have a reasonable expectation of success
Regarding claim 31, the teachings of Qi, Garber, and Ahmadi render obvious claim 27. Moreover, Qi teaches that the receptor binding moiety on the chimeric adaptor polypeptide comprises ZAP70 (0017) which binds to the immune cell signaling domain of the receptor polypeptide which comprises LAT (para 0013), rendering obvious ZAP70 or GRB2 of the protease chimeric polypeptide is recruited to the LAT of the gene-modulating chimeric polypeptide.
Regarding claim 45, the teachings of Qi, Garber, and Ahmadi render obvious claim 27. Moreover, Ahmadi teaches TCR α and β chains form a complex with 4 invariant CD3 chains and this complex formation is required for the TCR to be expressed on the cell surface (page 3528, right col, para 1), and for signal transduction on antigen recognition, rendering obvious wherein the endogenous TCR/CD3 complex comprises a TCR and CD3.
Regarding claim 47, the teachings of Qi, Garber, and Ahmadi render obvious claim 27. Moreover, Qi teaches the primary signaling domain of the immune cell signaling domain of the receptor comprises an immunoreceptor tyrosine-based activation motif (ITAM) of CD3 ζ (para 0013), rendering obvious the endogenous TCR/CD3 complex comprises at least one immunoreceptor tyrosine- based activation motif (ITAM).
Regarding claims 48 and 50, the teachings of Qi, Garber, and Ahmadi render obvious claim 27. Moreover, Qi teaches a chimeric adaptor polypeptide (i.e. a protease chimeric polypeptide) comprising ZAP70 (para 0036) and a chimeric transmembrane receptor polypeptide (i.e. a gene-modulating chimeric polypeptide) comprising an intracellular region comprising an immune cell signaling domain comprising LAT (para 0013).
With regard to claims 4 and 30 , wherein LAT of the gene-modulating chimeric polypeptide is recruited to TCR/CD3 complex upon activation, and wherein the ZAP70 or GRB2 of the protease chimeric polypeptide is recruited to (i) LAT of the gene-modulating chimeric polypeptide, (ii) the downstream signaling moiety, or (iii) a second downstream signaling moiety of the endogenous receptor TRR/ CD3 complex, it is noted that the claim is directed to an inherent result based on the methodology of the contacting of the human primary T cell by the ligand that binds the ligand binding domain of the TCR. Because Qi, Garber, and Ahmadi combine to disclose the methodology and system as claimed the effect of the methodology is rendered obvious by the combination of references, absent evidence to the contrary.
With regard to claims 16 and 42, wherein the gene-modulating chimeric polypeptide and the protease chimeric polypeptide are recruited upon the contacting step (b) to form a signaling complex of the endogenous TCR/CD3 complex, it is noted that the claim is directed to an inherent result based on the methodology of the contacting of the human primary T cell by the ligand that binds the ligand binding domain of the TCR. Because Qi, Garber, and Ahmadi combine to disclose the methodology and system as claimed the effect of the methodology is rendered obvious by the combination of references, absent evidence to the contrary.
Conclusion
Claims 1, 4, 16, 27, 30, 31, 42, 45, 47, 48, and 50 are rejected.
THIS ACTION IS MADE FINAL. 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.
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/JULIANA IRENE CANDELARIA/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
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