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 .
Status of Claims / Response to Amendments
The Amendments and Remarks filed 12/29/2025 in response to the Office Action of 07/29/2025 are acknowledged and have been entered.
Claims 1-11, 13, 15-18 and 20 have been amended by Applicant.
Claims 1-11, 13 and 15-20 are currently pending and under examination in the instant Office Action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This Office Action contains New Rejections Necessitated by Amendments.
Claim Objections -Withdrawn
Applicant has amended claims 1, 10, 13 and 15 and canceled claims 12 and 14. As such, the objection has been withdrawn.
Claim Rejections – Withdrawn
The rejection of claims 5, 7-9, 11, 13, 16-18, 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph has been withdrawn.
The rejection of claims 9 and 21 under 112(d), fourth paragraph has been withdrawn.
The written description rejection of claim 3 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
The enablement rejection of claims 1, 9, 10-15, and 20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
The rejection of claims 1-5 and 7-10 under 35 U.S.C. 102 as being anticipated by Zhang (Oncotarget. 2017 Oct 6;8(52):90215–90224) and Torigoe (CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761034Orig1s000 CHEMISTRY REVIEWS), Quality Assessment BLA 761034 Atezolizumab, 2016) has been withdrawn.
The rejection of claims 1-5, 7-10, 12 and 14-21 under 35 U.S.C. 103 as being unpatentable over Bachmann (WO2016030414A1 Date Published 2015-08-26) in view of Zhang (Oncotarget. 2017 Oct 6;8(52):90215–90224) and Torigoe (CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761034Orig1s000 CHEMISTRY REVIEWS) has been withdrawn.
The rejection of claims 1-10, 12 and 14-21 under 35 U.S.C. 103 as being unpatentable over Bachmann (WO2016030414A1 Date Published 2015-08-26) in view of Zhang (Oncotarget. 2017 Oct 6;8(52):90215–90224), Torigoe (CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761034Orig1s000 CHEMISTRY REVIEWS) and further in view of Altintas (WO2018162749A1 Date Published 2018-03-09) has been withdrawn.
The rejection of claims 1-21 under 35 U.S.C. 103 as being unpatentable over Bachmann (WO2016030414A1 Date Published 2015-08-26) in view of Zhang (Oncotarget. 2017 Oct 6;8(52):90215–90224), Torigoe (CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761034Orig1s000 CHEMISTRY REVIEWS), Altintas (WO2018162749A1 Date Published 2018-03-09) and further in view of Das (Biotechnol. J. 2016, 11, 71–79) and Wing (Journal of Immunotoxicology, 5:1, 11-15, 2008) has been withdrawn.
The provisional nonstatutory double patenting rejection of claims 1-21 as being unpatentable over claims 23, 30 and 42 of copending Application No. US 17/251,447 in view of Bachmann (WO2016030414A1 Date Published 2015-08-26), Zhang (Oncotarget. 2017 Oct 6;8(52):90215–90224), Torigoe (CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761034Orig1s000 CHEMISTRY REVIEWS), Altintas (WO2018162749A1 Date Published 2018-03-09), Das (Biotechnol. J. 2016, 11, 71–79) and Wing (Journal of Immunotoxicology, 5:1, 11-15, 2008). has been withdrawn.
Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103 (first) – Necessitated by Amendments
Claims 1-5, 8-10, and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bachmann (WO2016030414A1 Date Published 2015-08-26) in view of Zhang (Oncotarget. 2017 Oct 6;8(52):90215–90224) and Torigoe (CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761034Orig1s000 CHEMISTRY REVIEWS).
Bachmann teaches immune cell-based anti-cancer therapeutics and methods of using the therapeutics in the treatment of cancer (Abstract). Bachmann also teaches a method for stimulating a universal chimeric antigen receptor-mediated immune response in a mammal, the method comprising: administering to a mammal an effective amount of an effector cell genetically modified to express a universal chimeric antigen receptor, wherein the universal chimeric antigen receptor comprises three domains, wherein the first domain is a tag-binding domain, the second domain is an extracellular hinge and a transmembrane domain and the third domain is a signal transduction domain, wherein tag-binding domain binds to a tag derived from any human nuclear protein and administering a target module composed of a binding moiety specific for a certain human cell surface protein or protein complex and a tag, wherein the tag is derived from any human nuclear protein, wherein the target modules are administered to a subject prior to, or concurrent with, or after administration of the universal chimeric antigen receptor-expressing effector cells (Pg 12 lines 14-26).
Bachmann teaches a target module that is composed of a binding moiety specific for a tag that is a short linear epitope from the human nuclear La protein (E5B9; SEQ ID NO: 14), and against which the tag-binding domain of a CAR is directed and wherein the tag-binding domain can be an antibody or an antibody-derived antigen-binding fragment, such as a scFv, that binds to the La epitope (5B9) tag (Pg. 3 Paragraph, third, Pg. 9 Paragraph, third and Pg. 25-26). It is noted that the SEQ ID NO: 14 of Bachmann is a nucleotide sequence that translates into a 10-amino acid peptide of “KPLPEVTDEY”. They also teach that binding moieties of target modules may comprise single antigen specificity (monospecific), two, three or more antigen specificities (bi- and multispecific) (Pg. 11 Paragraph, second). They further teach that the binding moieties of the targeting modules can be anti-PSCA scFv, anti-PSMA scFv, anti-CD33 scFv or anti-CD123 scFv (Pg. 25-26). They also further teach isolated nucleic acid encoding a target module wherein the isolated nucleic is provided as cDNA (Pg. 3 Paragraph, fourth and claim 13).
Bachmann also teaches a cell comprising a nucleic acid encoding a CAR comprising three domains, wherein the first domain is a tag-binding domain (as described above), the second domain is a linking peptide chain including an extracellular hinge and a transmembrane domain and the third domain is a signal transduction domain (Pg. 3-4 Paragraph, spanning and claim 1). Bachmann further teaches in claim 4 that the hinge and transmembrane region is selected from hinge and transmembrane regions of human CD28 molecule, CD8a chain, NK cell receptors, preferably natural killer group NKG2D, or parts of the constant region of an antibody as well as combinations of different hinge and transmembrane domains thereof. They also teach in claim 5 that the signal transduction domain is selected from cytoplasmic regions of CD28, CD137 (41 BB), CD134 (OX40), DAP10 and CD27, programmed cell death-1 (PD-1 ), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and cytoplasmic regions CD3 chains, DAP12 and T cell activation inducing Fc receptors.
Bachmann teaches that lentiviral gene transfer may be applied for stable expression of CARs in immune cells by first constructing a lentiviral vector encoding for a selected universal chimeric antigen receptor (UniCAR; Pg. 13 Paragraph, first). Bachmann also teaches cells comprising a nucleic acid encoding a universal chimeric antigen receptor and target modules (Pg. 4 Paragraph, fourth). They also teach a pharmaceutical composition that contain cells and target modules with a pharmaceutically acceptable dilution agent or carrier (Pg. 4 Paragraph, fourth). Bachmann further teaches a kit comprising a vector comprising a nucleic acid sequence encoding a UniCAR and a target module and/or a vector encoding an isolated nucleic acid sequence encoding a target module (Pg. 4 Paragraphs, third).
Bachmann further provides an illustration of how the target module and UniCAR system functions against cancer in Figure 2. A T cell expresses the CAR, the scFv of which binds the target module (TM1) of the tag derived from the human nuclear protein (Pg. 9 Paragraph, third, and claim 15). The scFv of the TM1 will then bind the tumor cell, crosslinking the T cell and tumor cell (Pg. 9-10 Paragraph, spanning), leading to lysis of said tumor cell (Figure 2 and associated legend on Pg. 6). They teach in Fig. 8 concentration-response curves for UniCAR genetically modified human T cells in the presence of target modules binding to various antigens on the surface of tumor cells of different origins (PSCA, PSMA, CD33 or CD123) (Figure 8 and Pg.21 Paragraph, first).
Bachmann does not specifically teach the targeting module comprises at least one PD-L1 and/or PD-L2 binding domain.
However, these deficiencies are made up in the teachings of Zhang and Torigoe.
Zhang teaches that Atezolizumab is the first PD-L1 monoclonal antibody approved by US FDA for cancer therapy (Abstract). They teach that Atezolizumab Fab fragment was expressed in a transient HEK293 expression system by transfecting expression plasmids coding the heavy chain and light chain of the Fab fragment of atezolizumab into HEK 293 suspension cells (Pg. 90222 Column, first, Paragraph, third to Column, second, Paragraph, first). They teach that several other anti-PD-L1 antibodies including avelumab and durvalumab are also in intensive clinical trials (Pg. 90216 Column, first, Paragraph, first).
Torigoe teaches that Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy chains (448 amino acids) and two light chains (214 amino acids) (Pg. 2, S.1 General Information).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of stimulating a chimeric antigen receptor mediated immune response in a mammal comprising administering to the mammal: a) a first targeting module comprising, I) at least one tumor antigen binding domain such as PSCA, PSMA, CD33 or CD123, and II) a tag that can be a short liner epitope from the human nuclear La protein (E5B9), and b) an isolated cell comprising a nucleotide sequence encoding a universal chimeric antigen receptor (UniCAR) comprising, (I) a tag-binding domain that can be a scFv that binds to the short liner epitope from the human nuclear La protein (E5B9), (II) an extracellular hinge and a transmembrane domain, and (III) a signal transduction domain, wherein the tag of the targeting module binds to the tag-binding domain of the UniCAR as taught by Bachmann wherein the tumor antigen binding domain of the first target module of Bachmann is substituted with the PD-L1-binding Fab domain of atezolizumab as taught by Zhang and Torigoe, because Zhang teaches that PD-L1 (which atezolizumab binds) is upregulated in solid tumors which causes inhibition of PD-1+ tumor-infiltrating CD4+ and CD8+ T cells, thus blockade of PD-L1 binding to PD-1, such as by using atezolizumab, is an attractive strategy for both targeting PD-L1 expressing tumors and restoring tumor-specific T-cell immunity and anti-PD-L1 therapies in patients with several forms of cancer have seen favorable tumor responses in several on-going trials (Pg. 90215 Paragraph spanning Columns first and second and Pg. 90216 Column first Paragraph spanning) and, like the target module of Bachmann et al. (anti-PSCA scFv, anti-PSMA scFv, anti-CD33 scFv or anti-CD123 scFv), PD-L1 is targetable on tumor cells. Further, the motivation to perform the combined method would be to generate a method that can stimulate a CAR mediated immune response in a “controlled” manner by directly lysing PD-L1 expressing tumors that minimizes off-target responses while simultaneously blocking the inhibitory PD-L1 signals that can inhibit tumor-infiltrating T cells and which also causes CAR-T cell exhaustion, thereby enhancing cytotoxic function, reducing exhaustion, and fostering a robust immune response against solid tumors.
In particular regards to instant claim 10, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the first targeting module is administered by being expressed and secreted by the administered cells comprising the UniCAR of the combined method that further comprise an expression vector comprising polynucleotides encoding the first targeting module linked to a signal peptide for secretion because expression and secretion of the targeting module by the administered cells comprising the UniCAR would have the benefit of locating and/or localizing the targeting module near the cells for interaction with the tag binding domains of the UniCAR and this is facilitated by the teachings of Bachmann that teaches signal peptides for secretion of expressed proteins (second full paragraph on page 10 of Bachmann).
This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to instant claim 8, since it is well known in the art that a scFv fragment has a length of between 240-260 amino acids, and Bachmann teaches that the tag of the targeting module that is a short linear epitope from the human nuclear La protein E5B9 is 10 amino acid residues in length (KPLPEVTDEY), it would therefore be obvious to arrive at a targeting module that comprises an anti-PD-L1-binding domain such as atezolizumab as taught by Zhang and Torigoe that is in the format of an scFv fragment that is commonly used in cancer immunotherapeutics fused to the 10-amino acid peptide epitope of “KPLPEVTDEY” as taught by Bachmann, which as a fusion protein is in the range of 20 to 1600 amino acids
With regards to instant claim 9, since Bachmann teaches targeting modules that comprise a target cell binding domain that is an scFv that binds to PSCA, PSMA, CD33 or CD123, and a La 5B9 epitope, it would be obvious to perform the combined method of stimulating a chimeric antigen receptor mediated immune response further comprising administering to the mammal, a second targeting module comprising (I) at least one target cell binding domain, and (II) a tag identical to the first targeting module, wherein the at least one target cell binding domain is a scFv antigen-binding fragment that binds to PSCA, PSMA, CD33 or CD123 as taught by Bachmann. This would result in a method that combines targeting more than one tumor antigen for directed and enhanced tumor cell killing by the UniCAR for increasing the effectiveness of a cancer therapeutic.
With regards to instant claims 15-20, all reagents of a method are a “kit”. Further, generating a “kit” for a given method provides two services: 1) a variety of different reagents have been assembled and pre-mixed specifically for a defined set of experiments. Thus, one need not purchase gram quantities of numerous different reagents when each of which may be needed in only microgram amounts, when beginning a series of experiments. When one considers all of the unused chemicals that typically accumulate in weighing rooms, desiccators, and freezers, one quickly realizes that it is actually far more expensive for a small number of users to prepare most buffer solutions from the basic reagents. In actuality, a kit format saves money and resources for everyone by dramatically reducing waste; 2) the other service provided in a kit is quality control. Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to combine the reagents of a method into a kit format since a kit provides a quality control, saves money, and saves resources.
Response to Arguments
In the response of 12/29/2025, Applicant argues that PD-L1 and PD-L2 fundamentally differ from other tumor-associated antigens (such as those described in Bachmann) in both their biological roles and therapeutic implications. Most tumor-associated antigens are aberrantly expressed or mutated in cancer cells and may thereby serve as direct targets for immune effector cell recognition and destruction. In contrast, PD-L1 and PD-L2 are immune checkpoint ligands that modulate immune responses by binding to PD-1 on effector cells (e.g., T cells), inhibiting effector cell activation, and promoting immune tolerance in the tumor microenvironment. In view of these fundamental differences, Applicant submits that it would not be obvious to a PHOSITA that replacing the tumor binding domain in the targeting module taught by Bachmann with a PD-L1 and/or PD-L2 binding domain would result in the same therapeutic effect as other tumor-associated antigens, particularly when used in the context of activating effector cells expressing a UniCAR.
Examiner’s Response: The arguments found in the Reply of 12/29/2025 have been carefully considered but are not deemed persuasive. This is because not only is PD-L1 expressed on immune cells, but it is also aberrantly expressed on solid tumor cell surfaces as confirmed by Zhang (Pg. 90215 Paragraph spanning Columns first and second). Therefore, the substitution of the tumor binding domain on the targeting module that binds to PSCA, PSMA, CD33 or CD123 expressed on tumor cells as taught by Bachmann for the PD-L1 binding domain as taught by Zhang and Torigoe is in fact a substitution of binding to one tumor surface antigen (PSCA, PSMA, CD33 or CD123) for another (PD-L1). Further, it is acknowledged that the targeting module comprising a PD-L1 binding domain can also predictably bind to PD-L1 on natural immune cells in the tumor microenvironment, thereby having the benefit of stimulating said cells to effect cytotoxic killing of surrounding tumor cells.
Further in the response of 12/29/2025, Applicant also argues that based on the teachings of Zhang, Applicant respectfully submits that it would not be obvious to a PHOSITA that replacing the tumor binding domain in the targeting module taught by Bachmann with the anti-PD-L1 Fab antibody fragment of Atezolizumab would result in a reasonable expectation of success. Zhang teaches that "...some of these antibodies are in either IgG1 form (avelumab, durvalumab, atezolizumab [sic]) or IgG4 isoforms (BMS-936559). These differences will result in [sic] differences in the orientations of these antibodies when bound on PD-L1 on the cell membrane and affect subsequent binding of Fc receptors, which will lead to differences in antitumor activities or selectivity towards different types of cancers. Obviously extensive clinical tests are required to make full use of these antibodies for the benefits of cancer patients" (see p. 90218; emphasis added). Given the uncertainty of the effect of anti-PD-L1 antibodies on binding to Fc receptors and their anti-tumor activities and selectivity, and the requirement for "extensive clinical tests," it would not be obvious to a PHOSITA that incorporating an anti-PD-L1 binding domain into a targeting module as described in Bachmann would be able to facilitate a structural orientation when bound to PD-L1 that allows binding to a switchable chimeric antigen receptor, and/or elicits anti-tumor activity when bound. Torigoe does not remedy this deficiency.
Examiner’s Response: The arguments found in the Reply of 12/29/2025 have been carefully considered but are not deemed persuasive. This is because the targeting module that can comprise atezolizumab in the format of a scFv as taught by Bachmann, or in the format of a Fab as taught by Zhang, wherein both of these formats do not include incorporation of the Fc domain into the targeting module. As such, the targeting module would not be expected to bind Fc receptors which in turn would not lead to different antitumor activities or selectivity towards different types of cancers.
Claim Rejections - 35 USC § 103 (second) – Necessitated by Amendments
Claims 1-10 and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bachmann (WO2016030414A1 Date Published 2015-08-26), Zhang (Oncotarget. 2017 Oct 6;8(52):90215–90224) and Torigoe (CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761034Orig1s000 CHEMISTRY REVIEWS) as applied to claims 1-5, 8-10 and 15-20 above, and further in view of Altintas (WO2018162749A1 Date Published 2018-03-09).
The combined teachings of Bachmann, Zhang and Torigoe render obvious instant claims 1-5, 8-10 and 15-20 as discussed above in the first 103 which is incorporated here in its entirety.
However, Bachmann, Zhang and Torigoe do not specifically teach the method wherein the targeting module further comprises an effector cell binding domain, wherein the effector cell binding domain specifically binds an epitope on a human CD3 chain, a human T cell receptor (TCR) or human CD 16; or wherein the effector cell binding domain comprises a humanized amino acid sequence.
However, these deficiencies are made up by the teachings of Altintas.
Altintas teaches bispecific antibodies capable of binding human PD-L1 and capable of binding human CD3 (Abstract). They teach humanized CD3 antibodies (denoted as huCD3) for the generation of CD3xPDL1 bispecific antibodies (Example 3; Pg. 94 lines 13-17). Altintas also teaches the in vitro induction of cytotoxicity of CD3xPD-L1 bispecific antibodies in MDA-MB-231 cells in Figure 8 (Pg. 4 Paragraph, fourth).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of stimulating a chimeric antigen receptor mediated immune response in a mammal, wherein the tumor antigen binding domain of the target module of the combined method with the PD-L1-binding Fab domain of atezolizumab further comprises a CD3-binding domain of the human CD3 binding antibody that is humanized as taught by Altintas because Altintas teaches effective induction of cytotoxicity of CD3xPD-L1 bispecific antibodies in tumor cell lines. The motivation for the said combined method would be to provide the advantage of binding PD-L1 expressing tumor cells required by the target module of the combined method and to further utilize the CD3-binding region to bind T cells, thus bringing T cells in close proximity to tumor cells, thereby facilitating enhanced tumor cell killing through this pathway of T cells recruitment. These recruited T cells would include both CAR-T cells and natural T cells of the body, facilitating tumor clearance through multiple mechanisms. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (third) – Necessitated by Amendments
Claims 1-5, 8-11, 13 and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bachmann (WO2016030414A1 Date Published 2015-08-26), Zhang (Oncotarget. 2017 Oct 6;8(52):90215–90224) and Torigoe (CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761034Orig1s000 CHEMISTRY REVIEWS) as applied to claims 1-5, 8-10 and 15-20 above, and further in view of Das (Biotechnol. J. 2016, 11, 71–79).
The combined teachings of Bachmann, Zhang and Torigoe render obvious instant claims 1-5, 8-10 and 15-20 as discussed above in the first 103 which is incorporated here in its entirety.
However, Bachmann, Zhang and Torigoe do not specifically teach the method according to instant claim 10, wherein the expression vector comprising polynucleotides encoding the first targeting module linked to a signal peptide for secretion further comprises an inducible expression system that induces the transcription of the nucleotide sequence encoding the targeting module.
They also do not specifically teach a method of stimulating a chimeric antigen receptor mediated immune response in a mammal comprising administering to the mammal an isolated vector, or an isolated cell comprising: a) an inducible expression system that induces the transcription of a nucleotide sequence encoding a chimeric antigen receptor and/or a nucleotide sequence encoding a targeting module, b) the nucleotide sequence encoding the switchable chimeric antigen receptor comprising, (I) a tag-binding domain, (II) an extracellular hinge and a transmembrane domain, and (III) a signal transduction domain, and c) the nucleotide sequence encoding the targeting module comprising, (I) at least one PD-L1 binding domain, and (II) a tag, wherein the tag of the targeting module binds to the tag-binding domain of the switchable chimeric antigen receptor.
However, these deficiencies are made up by the teachings of Das and Wing.
Das teaches that the doxycycline (dox)-inducible Tet-On system is widely used to control gene expression in mammalian cells (Abstract). Das also teaches that this system is based on the bacterial Tet operon, which has been modified and improved for its function in eukaryotic cells (Abstract), and that gene expression is switched on by dox administration (Pg. 72, Column, first, Paragraph, spanning). They further teach that to identify the optimal system for different applications, they compared Tet-On variants in frequently used cell types that were either transiently transfected with the relevant plasmids or stably transduced with an “all-in-one” lentiviral vector (Abstract).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of stimulating a chimeric antigen receptor mediated immune response in a mammal, wherein the expression vector comprising polynucleotides encoding the first targeting module linked to a signal peptide for secretion is an inducible expression system that comprises the doxycycline (dox)-inducible Tet-On system as taught by Das which is able to induce the transcription of the nucleotide sequence encoding the targeting module as taught by Bachmann, Zhang and Torigoe. Or similarly, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of stimulating a chimeric antigen receptor mediated immune response in a mammal comprising administering to the mammal an isolated cell comprising an isolated nucleotide sequence encoding the UniCAR of the combined method which also comprises a polynucleotide expression vector encoding the targeting module and a signal peptide of the combined method described in the first 103 rejection above, wherein the nucleotide sequence encoding the UniCAR and/or the polynucleotide expression vector encoding the target module and signal peptide are expressed using an inducible expression system that is the doxycycline (dox)-inducible Tet-On system as taught by Das in order to control when the administered cells express the UniCAR and/or the targeting module and signal peptide. The combined method would have the advantage of having a “switch” to turn on or turn off the expression of the target module and/or the UniCAR based on whether expression of said molecules is required at the appropriate time. For example, the Tet-On system can be used to control precise timing of the expression of (1) the targeting module comprising the PD-L1 binding domain of the combined method and/or (2) the CAR of the combined method, after a reasonable time has been provided to allow for sufficient accumulation in the solid tumors of said administered cells, so as to decrease cytokine release syndrome that could arise from the administration of CAR expressing cells due to off target toxicities as taught by Bachmann. This “switchable control” is facilitated through administration or withdrawal of doxycycline for the “on” or“off” expression of molecules of interest as taught by Dax. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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.
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/YIE-CHIA LEE (TONYA)/
Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642