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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 23 December 2025 has been entered.
Response to Amendment
The amendment filed 23 December 2025 is acknowledged. Claims 1, 17, 19, 28, 31, 32, 35, 39, 41, 44, 47-49, 55, 56, 58, 59, 61, 65, 69-72 were previously pending. Claims 73 and 74 are new. Claims 1 and 69 are amended.
Claim Status
Claims 1, 17, 19, 28, 31, 32, 35, 39, 41, 44, 47-49, 55, 56, 58, 59, 61, 65, and 69-74 are pending and under examination in the instant office action.
Withdrawal of Rejections
The rejection of claim 69 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendment to the claims.
Claim Rejections - 35 USC § 103- Maintained/Modified
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 17, 19, 28, 31-32, 35, 39, 41, 65, 69, 73, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over ESCARPE (WO2016073649; cited on the IDS filed on 03/19/2024) in view of SAHIN 2017 (US 20170015720 published 19 January 2017; PTO-892 2/11/2025).
Regarding claims 1 and 69, ESCARPE discloses a CAR comprising a CLDN antigen binding domain, a transmembrane domain, and an intracellular domain that comprises a 4-1BB costimulatory domain and a CD3-zeta signaling domain (see Fig. 5 and claims 1, 2, 5, and 8-9; where the anti-CLDN6 CARs, “SCT1-h27.108” and “SCT1-h27.207”, comprise anti-CLDN6 binding domains, and thus, read on “a CLDN6 antigen binding domain” in instant claim 1). ESCARPE teaches that “SCT1-h27.108”, the anti-CLDN6 CAR, comprises SEQ ID NO: 9 (Fig. 6B). ESCARPE teaches that the 27.108 CAR induces IL-2 (Fig. 9B) and IFNγ (Fig. 12A-B) upon exposure to CLDN6 expressing cells. SEQ ID NO: 9 comprises a transmembrane domain comprising the amino acid sequence identical to instant SEQ ID NO: 28, a hinge domain connecting the CLDN6 antigen binding domain to the transmembrane domain identical to instant SEQ ID NO: 27, and an intracellular domain comprising a 4-1BB costimulatory domain and a CD3-zeta signaling domain, where the 4-1BB costimulatory domain comprises an amino acid sequence identical to SEQ ID NO: 30 and the CD3-zeta signaling domain comprises an amino acid sequence identical to SEQ ID NO: 31. Additionally, ESCARPE teaches “signaling through CD137/4-1 BB has been shown enhance native T-cell proliferation, and may contribute to longer persistence of CAR-T in vivo” (p. 22 lines 27-30) and that “Several second generation CAR-T cells directed to the CD19 antigen have been shown to have strong antitumor effects, as well as substantial persistence, in patience with hematological malignancies […] With respect to the instant invention it has surprisingly been discovered that anti-CLDN binding domains may be advantageously integrated with each of the aforementioned chimeric antigen receptors and adoptive immunotherapies to provide effective antineoplastic treatments that overcome some of the previous limitations” (p. 23 lines 4-9).
Regarding claim 17, ESCARPE discloses a polynucleotide encoding the CAR molecule (see claim 10; Figs. 6A and 6C; SEQ ID NOs: 8 and 10; and p. 51-56 "CAR nucleic acids and vectors" section).
Regarding claim 19, ESCARPE discloses a vector comprising the polynucleotide encoding the CAR molecule (see claim 11; and p. 51-56 "CAR nucleic acids and vectors" section).
Regarding claim 28, ESCARPE discloses CLDN sensitized lymphocytes comprising the CAR molecule, wherein the CLDN sensitized lymphocyte is a T cell, specifically a CD8+ T cell, or an NK cell (see claims 15-22; and p. 56-60 "Host Cells" section; reads on “a population of immune effector cells comprising multiple immune effector cells comprising the CAR molecule of” in instant claim 28, where T/CD8+ T/NK cells are defined as an immune effector cells, see instant specification p. 55 last paragraph).
Regarding claim 65, ESCARPE discloses a pharmaceutical composition comprising the CLDN6 CAR cells (see claim 15; where “pharmaceutical composition” reads on “kit” in instant claim 65).
ESCARPE does not teach a CLDN6 antigen binding domain comprising the amino acid sequence according to SEQ ID NO: 35 or an amino acid having at least 95% identity to SEQ ID NO: 35 and comprising all three CDR sequences of SEQ ID NO: 5 and all three CDR sequences of SEQ ID NO: 24. SAHIN 2017 partially resolves this deficiency and does not teach that the CLDN6 CAR comprises SEQ ID NO: 36 or an amino acid sequence having at least 95% identity to SEQ ID NO: 36.
SAHIN 2017 discloses Claudin-6-specific immunoreceptors specifically “artificial T cell receptors (chimeric antigen receptors; CARs) and T cell epitopes which are useful for immunotherapy” (Abstract). Specifically, SAHIN 2017 teaches a T cell receptor comprising the amino acid sequence according to SEQ ID NO: 46 which binds to the tumor-associated antigen, CLDN6 [0070-0076]. SEQ ID NO: 46 comprises an antigen-binding fragment 100% identical to instant SEQ ID NO: 35 (see Result 3 from Published_Applications_AA, .rapbm) and comprises a VH and VL of instant SEQ ID NO: 5 and 24 and the peptide linker of SEQ ID NO: 26, as in claim 73. SAHIN 2017 also discloses an anti-CLDN6 CAR-28ζ that is effective at killing tumor cells in vitro (Fig. 13, Fig. 17) and in vivo (Fig. 21). Regarding the effectiveness of the antigen binding domain, SAHIN 2017 teaches that the antigen binding domain is very high affinity and that “Even extremely little amounts of CLDN6 RNA (0.001 μg) resulted in significant lysis of target cells mediated by all CAR constructs” (Example 5, [0046]).
SAHIN 2017 teaches that “An in vitro proliferation assay was performed using CAR-transfected CD8+ T cells together with CLDN6 or control RNA-transfected autologous iDCs (Fig. 14). The mTCR.sub.CD8-CLDN6 #18 mediated best proliferation in response to CLDN-6 transfected cells (73%). The CLDN6-CAR-28 also resulted in a significant proportion of proliferation cells (44%), while the CLDN6-CAR/Cɑ failed to induce proliferation probably due to a lack of CD28-mediated costimulation. As induction of proliferation is a prerequisite for successful antitumoral activity, we decided to use CAR-28 format for further lead structure selection”.
SAHIN 2017 further teaches “The co-stimulation domain serves to enhance the proliferation and survival of the cytotoxic lymphocytes upon binding of the CAR to a targeted moiety. The identity of the co-stimulation domain is limited only in that it has the ability to enhance cellular proliferation and survival upon binding of the targeted moiety by the CAR. Suitable co-stimulation domains include CD28, CD137 (4-1 BB), a member of the tumor necrosis factor (TNF) receptor family, CD134 (OX40), a member of the TNFR-superfamily of receptors, and CD278 (ICOS), a CD28-superfamily co-stimulatory molecule expressed on activated T cells. The skilled person will understand that sequence variants of these noted co-stimulation domains can be used without adversely impacting the invention, where the variants have the same or similar activity as the domain on which they are modeled. Such variants will have at least about 80% sequence identity to the amino acid sequence of the domain from which they are derived” [0214]. Additionally, SAHIN teaches “CARs of the 3rd generation encompass additional domains of co-stimulatory molecules such as OX40 and 4-1BB to enhance the proliferative capacity and persistence of modified T-cells (Fig. 2)” [0024].
Therefore, SAHIN 2017 teaches a preferred Gen 2 CAR comprising an identical anti-CLDN6 binding domain and further suggests substituting or adding 4-1BB and CD28 co-stimulatory domains.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the anti-CLDN6 antigen-binding domain in the CAR of SAHIN 2017 in the CAR backbone of ESCARPE in order to benefit from the anti-CLDN6 antigen binding domain useful for immunotherapy with high affinity anti-CLDN6 binding as taught by SAHIN 2017 and the increased persistence of the hinge/transmembrane/4-1BB/CD3Z intracellular domain of ESCARPE. Replacing the antigen binding domain of ESCARPE SEQ ID NO: 9 (residues 1-270) with the one taught by SAHIN 2017 comprised by SEQ ID NO: 46 (residues 1-263) results in a new CAR comprising a sequence that is 100% identical to SEQ ID NO: 36 as shown below. This would have a predictable effect because both ESCARPE and SAHIN 2017 teach anti-CLDN6 antigen binding domains for use in immunotherapy; further, SAHIN suggests that the CARs of the invention would be useful with additional co-stimulatory domains such as 4-1BB and ESCARPE teaches that the 4-1BB CAR backbone is useful to increase persistence and overcome limitations in treating solid tumors.
GenCore version 6.5.2
Copyright (c) 1993 - 2025 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: January 31, 2025, 14:42:51 ; Search time 1 Seconds
(without alignments)
0.236 Million cell updates/sec
Title: US-17-310-463-36
Perfect score: 2590
Sequence: 1 MDWIWRILFLVGAATGAHSE..........LSTATKDTYDALHMQALPPR 486
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 486 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 1 summaries
Database : AASEQ2_01312025_114248.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 2590 100.0 486 1 AASEQ2_01312025_114248
ALIGNMENTS
RESULT 1
AASEQ2_01312025_114248
Query Match 100.0%; Score 2590; DB 1; Length 486;
Best Local Similarity 100.0%;
Matches 486; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MDWIWRILFLVGAATGAHSEVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSH 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MDWIWRILFLVGAATGAHSEVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSH 60
Qy 61 GKNLEWIGLINPYNGGTIYNQKFKGKATLTVDKSSSTAYMELLSLTSEDSAVYYCARDYG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GKNLEWIGLINPYNGGTIYNQKFKGKATLTVDKSSSTAYMELLSLTSEDSAVYYCARDYG 120
Qy 121 FVLDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVLTQSPSIMSVSPGEKVTITCSASSSV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 FVLDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVLTQSPSIMSVSPGEKVTITCSASSSV 180
Qy 181 SYMHWFQQKPGTSPKLSIYSTSNLASGVPARFSGRGSGTSYSLTISRVAAEDAATYYCQQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SYMHWFQQKPGTSPKLSIYSTSNLASGVPARFSGRGSGTSYSLTISRVAAEDAATYYCQQ 240
Qy 241 RSNYPPWTFGGGTKLEIKRSDPATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 RSNYPPWTFGGGTKLEIKRSDPATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHT 300
Qy 301 RGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 RGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC 360
Qy 361 SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG 420
Qy 421 GKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHM 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHM 480
Qy 481 QALPPR 486
||||||
Db 481 QALPPR 486
ESCARPE in view of SAHIN 2017 does not explicitly teach the methods of providing an effective amount of a population of immune effector cells of claim 28 as recited in claims 31-32, 35, 39, and 41. This deficiency is resolved by the teachings of ESCARPE.
Regarding claims 31-32 and 35, ESCARPE discloses administering an effective amount of the CLDN sensitized lymphocytes (see p. 66 last paragraph: “the subject may be administered pharmaceutically effective amounts of the disclosed CLDN CAR treatments”), as well as general dosing strategies effective for the invention (see p. 62 par. 3 to p. 64 par. 1).
ESCARPE further discloses:
Regarding claim 31, ESCARPE discloses the CLDN sensitized lymphocytes activate certain lymphocytes and generates an immune response directed to CLDN6+ tumor cells (see p. 2 lines 17-23: "the CLDN CAR are expressed on cytotoxic lymphocytes (preferably autologous) to provide CLDN sensitive lymphocytes that are used to target and kill CLDN positive tumor cells... that activates certain lymphocytes and generates an immune response directed to CLDN positive tumor cells (i.e., those that are CLDN6+)"; reads on “stimulating a cell-mediated immune response to a CLDN6 expressing target cell population” in instant claim 31).
Regarding claim 32, ESCARPE discloses a method of treating a patient suffering from cancer comprising the step of administering the CLDN sensitized lymphocytes (see claims 22-23) wherein the cancer is CLDN6+ (see p. 2 lines 17-23: "… directed to CLDN positive tumor cells (i.e., those that are CLDN6+)"; reads on “a disease associated with expression of CLDN6” in instant claim 32).
Regarding claim 35, ESCARPE discloses a method of inducing anti-tumor immunity with the CLDN sensitized lymphocytes (see bottom of p. 60 to the top of p. 61: "Such vectors allow for the in vivo generation of CLDN sensitized lymphocytes which can then induce the desired antitumor immune response"; reads on “method of providing anti-tumor immunity in a subject” in instant claim 35).
Regarding claim 74, ESCARPE discloses that the anti-CLDN CARs of the invention are directed towards treatment of CLDN-6 positive solid tumors (p. 23 lines 3-9; p. 65 lines 1-p. 66 line 9) and that CLDN6 is elevated in particular types of solid tumors (Example 1 p. 87-88; Example 10 p. 105; Example 13 p. 108). ESCARPE teaches T cell activation and tumor cell killing of the anti-CLDN6 CARs against and CLDN6-expressing patient-derived ovarian cancer cell line OV78 PDX target cells (Example 14 p. 109).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have developed the methods of instant claims 31-32, 35, and 74 comprising administering an effective amount of CLDN6 CAR cells to the subject, as the prior art of ESCARPE discloses general dosing strategies effective for the invention and suggests that administering the CLDN6 CAR cells: generates an immune response directed to CLDN6+ tumor cells; targets disease associated with CLDN6+ cells, including cancer; and provides anti-tumor immunity in a subject.
Regarding claim 39, ESCARPE discloses administering an additional agent, including a cytokine or an anti-Treg agent, that increases the efficacy of the CLDN sensitized lymphocytes (see p. 67 line 23 to p. 68 line 9: "the CLDN CAR treatments described herein may be used in combination… with a therapeutic moiety… including… cytokines... wherein the combination preferably has therapeutic synergy or improves the measurable therapeutic effects in the treatment of cancer over (i) the CLDN CAR treatment used alone, or (ii) the therapeutic moiety used alone, or (iii) the use of the therapeutic moiety in combination with another therapeutic moiety without the addition of CLDN CAR treatment"; see also p. 64 lines 23-30: “in selected preferred embodiments the CLDN sensitized lymphocytes will be administered in conjunction with lymphotoxic therapies to increase the availability of homeostatic cytokines (e.g., IL-7, IL-15, etc.) to support T cell expansion… More specifically it is believed that a lymphodepleting preparative regimen may enhance the efficacy of adoptive cell therapy by reducing endogenous lymphocytes thereby leading to the accumulation of homeostatic cytokines that support expansion and persistence of the administered sensitized lymphocytes. Further, such preparative treatments may lead to a transient reduction in the number and frequency of Tregs”).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have co-administered the CLDN6 CAR cells with a therapeutic agent, such as a cytokine or an anti-Treg agent, as the addition of certain cytokines and depletion of Tregs are known to support the expansion and persistence of adoptive cell therapy, per the teachings of ESCARPE.
Regarding claim 41, and as discussed above, ESCARPE discloses administering the CLDN sensitized lymphocytes (see claims 22-23) to a subject having CLDN6+ cells (see p. 2 lines 17-23), and in doing so, contacting the CLDN6 CAR with the cognate antigen, CLDN6 (reads on “the step of contacting the population of immune effector cells with a cognate antigen molecule” in instant claim 41).
Claims 44, 47-49, 55-56, 58-59, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over ESCARPE in view of SAHIN 2017 (supra) and in further view of SAHIN 2016 (WO2016180778; cited on the IDS filed on 03/19/2024).
The disclosures/teachings of ESCARPE in view of SAHIN 2017 are discussed above and are incorporated herein.
Regarding claim 44, ESCARPE discloses the administering the CLDN6 CAR cell in combination with a cancer vaccine (see p. 67 lines 23-30). However, ESCARPE fails to expressly disclose the step of administering the cognate antigen molecule/encoding nucleic acid. SAHIN 2016 discloses the method comprising administering to CAR-T cells targeted to an antigen in combination with administering a nucleic acid encoding the antigen or a variant thereof (see claim 4; where “the antigen” reads on “cognate antigen” in instant claim 44). SAHIN 2016 further discloses (see p. 4 par. 2: “It is generally thought that the number of transferred T cells is correlated with therapeutic responses. However, the number of cells which can be administered to a patient for adoptive T cell transfer is limited and the generation of a large amount of T cells for adoptive T cell transfer still remains a challenge… The present inventors found that it is possible to expand adoptively transferred CAR- T cells using nucleic vaccination, in particular RNA-vaccination to provide antigen for CAR-T cell stimulation. Following adoptive transfer of CAR-T cells, the T cells are subjected to an antigen-specific expansion by exposing the T cells to cells, preferably antigen presenting cells, expressing the antigen on the cell surface. Thus, it is possible to only transfer small amounts of CAR-engineered T cells into the patient and then expand the T cells in vivo by administering a nucleic acid vaccine providing an antigen.”).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have co-administered the CLDN6 CAR cells with the cognate antigen (CLDN6 or variant) molecule/encoding nucleic acid, as doing so promotes antigen-specific expansion of the adoptively transferred CAR- T cells, and thus, reduces the need for high amounts of initial T cells transferred for treatment, per the teachings of SAHIN 2016.
Regarding claim 47, SAHIN 2016 discloses the method, wherein the nucleic acid encoding the antigen or variant thereof is transiently expressed in cells of the mammal (see claim 11; reads on instant claim 47).
Regarding claim 48, SAHIN 2016 discloses the method, wherein the nucleic acid encoding the antigen or variant thereof is RNA (see claim 12; reads on instant claim 48).
Regarding claim 49, SAHIN 2016 discloses the method, wherein the nucleic acid encoding the antigen or variant thereof is administered systemically (see claim 13; reads on instant claim 49).
Regarding claims 55-56, SAHIN 2016 discloses the method, wherein the nucleic acid encoding the antigen or variant thereof is formulated in a delivery vehicle such as in particles (see claim 20; reads on instant claims 55-56).
Regarding claim 58, SAHIN 2016 discloses the method, wherein the delivery vehicle comprises at least one lipid, and wherein the at least one lipid comprises at least one cationic lipid (see claims 21-22; reads on instant claim 58).
Regarding claim 59, SAHIN 2016 discloses the method, wherein the lipid forms a complex with and/or encapsulates the nucleic acid encoding the antigen or variant thereof (see claim 23; reads on instant claim 59).
Regarding claim 61, SAHIN 2016 discloses the method, wherein the nucleic acid encoding the antigen or variant thereof is formulated in liposomes (see claim 25; reads on instant claim 61).
Claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over ESCARPE (WO2016073649; cited on the IDS filed on 03/19/2024) in view of SAHIN 2017 (US 20170015720 published 19 January 2017; PTO-892 2/11/2025) and in further view of SAHIN 2016 (WO2016180778; cited on the IDS filed on 03/19/2024).
The disclosures/teachings of ESCARPE in view of SAHIN 2017 are discussed above and are incorporated herein, especially in regards to claims 1, 28, 31, 41, and 44.
Regarding claim 70, ESCARPE discloses the administering the CLDN6 CAR cell in combination with a cancer vaccine (see p. 67 lines 23-30). However, ESCARPE fails to expressly disclose the step of administering the cognate antigen molecule/encoding nucleic acid. SAHIN 2016 discloses the method comprising administering to CAR-T cells targeted to an antigen in combination with administering a nucleic acid encoding the antigen or a variant thereof (see claim 4; where “the antigen” reads on “cognate antigen” in instant claim 44). SAHIN 2016 further discloses (see p. 4 par. 2: “It is generally thought that the number of transferred T cells is correlated with therapeutic responses. However, the number of cells which can be administered to a patient for adoptive T cell transfer is limited and the generation of a large amount of T cells for adoptive T cell transfer still remains a challenge… The present inventors found that it is possible to expand adoptively transferred CAR-T cells using nucleic vaccination, in particular RNA-vaccination to provide antigen for CAR-T cell stimulation. Following adoptive transfer of CAR-T cells, the T cells are subjected to an antigen-specific expansion by exposing the T cells to cells, preferably antigen presenting cells, expressing the antigen on the cell surface. Thus, it is possible to only transfer small amounts of CAR-engineered T cells into the patient and then expand the T cells in vivo by administering a nucleic acid vaccine providing an antigen.”).
Claims 71-72 are rejected under 35 U.S.C. 103 as being unpatentable over ESCARPE (WO2016073649; cited on the IDS filed on 03/19/2024) in view of SAHIN 2017 (US 20170015720 published 19 January 2017; PTO-892 2/11/2025) and of SAHIN 2016 (WO2016180778; cited on the IDS filed on 03/19/2024) and in further view of IRVINE (WO2019060425, effectively filed 19 September 2017; PTO-892 dated 5/29/2025)
The disclosures/teachings of ESCARPE in view of SAHIN 2017 are discussed above and are incorporated herein, especially in regards to claims 1, 28, 31, 41, and 44.
The disclosures/teachings of ESCARPE in view of SAHIN 2017 and SAHIN 2016 in regards to claim 70 are discussed above and are incorporated herein.
Regarding claims 71 and 72, ESCARPE discloses the administering the CLDN6 CAR cell in combination with a cancer vaccine. ESCARPE also separately discloses repeated administration of the compositions of the invention: “” (p. 63 line 30- p. 64 line 2). SAHIN 2017 discloses “An "effective amount" refers to the amount which achieves a desired reaction or a desired effect alone or together with further doses” ([0378]).
ESCARPE in view of SAHIN 2017 AND SAHIN 2016 dose not explicitly disclose repeated administration of the cognate antigen molecule or the nucleic acid coding therefor. This deficiency is resolved by IRVINE.
Regarding claims 71 and 72, IRVINE discloses administering a combination of a CAR ligand (e.g. EGFRvIII) conjugated to DSPE-PEG (called “VAX”) and T cells expressing a CAR specific for the peptide (e.g. EGFRvIII CAR-T), wherein the peptide is administered repeatedly (e.g. day 9, 16, and 23, See Fig. 18A). IRVINE teaches that in a mouse model of EGFRvIII-positive cancer, the mice experienced increased tumor control and survival in groups that received repeated vaccines in additional to CAR-T cells compared to groups that received only CAR-T cells, even at low doses (See Fig. 18A-B, Example 6 p. 98-100).
In light of these teachings, it would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to practice the method of repeated vaccination with CAR ligand as taught by IRVINE with the CLDN-6 peptide or nucleic acid vaccine as taught by ESCARPE in view of SAHIN 2017 and SAHIN 2016 to benefit from the increased tumor control with a smaller dose of CAR-T cells as taught by IRVINE. This would have a predictable effect because both modified ESCARPE and IRVINE are in the field of boosting CAR-T cells in vivo using cognate antigen, and therefore an artisan would expect to benefit from a similar increased tumor control by the CAR-T cells with the target antigen vaccine.
Response to Arguments
Applicant’s arguments filed 12/23/2025 have been considered but are not persuasive. First, Applicants argue that the Office has not established a prima facie case of obviousness because it would have not have been predictable because domains of CARs have been shown to not be substitutable for each other and “submit the is ample evidence of record that the art is unpredictable” (Remarks 12/23/2025 p. 7-8).
MPEP 2144.06 states “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. MPEP 2144.06.II also states that when substituting equivalents known for the same purpose, “an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”. As described in the 103 rejection above, both Escarpe and Sahin 2017 teach scFvs that binds to CLDN6 for use in the context of chimeric immunoreceptors including chimeric antigen receptors to target immune cells expressing the chimeric immunoreceptors to CLDN6-expressing cancers for anti-CLDN6 immunotherapy. Thus, it would have been obvious to substitute the one scFv, which is effective for the purpose of binding CLDN6 in a chimeric receptor immunotherapy, for another scFv that binds CLDN6 and is effective in a chimeric receptor immunotherapy. This would have a predictable effect because, as described above, the teachings of Sahin 2017 and Escarpe would lead an artisan to believe that substituting the scFv of Sahin 2017 for the antigen binding domain of Escarpe would lead to a functional chimeric antigen receptor that effectively bound CLDN6 and lead to immune cell binding and killing of CLDN6+ cells in the context of a chimeric immune receptor therapy for cancer and would lead an artisan to make the substitution in order to make a third equivalent chimeric immune receptor for the treatment of CLDN6-positive cancer. “[A]n express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)” (MPEP 2144.06.II). However, Escarpe and Sahin 2017 also both implicitly carry the suggestion that substitution of the scFv in order to make a new immunotherapy is obvious by teaching more than one anti-CLDN6 CAR. Escarpe teaches both SCT1-h27.108 and SCT1-h27.204v2 (Figs. 6B, 6D), which have different anti-CLDN6 scFvs but the same CAR backbone as shown below:
RESULT 1
AASEQ2_10212025_123751
Query Match 79.9%; Score 2089.5; DB 1; Length 480;
Best Local Similarity 79.0%;
Matches 391; Conservative 41; Mismatches 46; Indels 17; Gaps 3;
Qy 1 MALPVTALLLPLALLLHAARPEIVLTQSPATLSLSPGERATLSCSVSSSISSSNLHWYQQ 60
|||||||||||||||||||||:| :||||::|| | |:| |::| :: :| : |:||
Db 1 MALPVTALLLPLALLLHAARPDIQMTQSPSSLSASVGDRVTITCKAGQNVGTS-VAWFQQ 59
Qy 61 KPGQAPRLLIYGTSNLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSSYPHTF 120
|||:||: ||| | ||:|:||||||||||||||||||:||||| |||||: :||:||
Db 60 KPGKAPKSLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYITYPYTF 119
Qy 121 GGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYLIEW 180
||||||||||||||||||||||||:|||::|| : :|| |:::|| |||:||: | : |
Db 120 GGGTKVEIKGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFSRYWMSW 179
Qy 181 VRQAPGQGLEWMGLINPGSGGTNYNEKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYC 240
||||||:||||: ||| | | | | |:: | | :| |::: |||::|||||||
Db 180 VRQAPGKGLEWVSEINPDSSTIQYTPSLKARFTISRDNSKNTLYLQMNSLRAEDTAVYYC 239
Qy 241 ARRSPLGSWIYYAYDGVAYWGQGTLVTV--SSTTTPAPRPPTPAPTIASQPLSLRPEACR 298
| ||||||||||| ||||||||||||||||||||||||||||||
Db 240 T--------------GPAYWGQGTLVTVSSSSTTTPAPRPPTPAPTIASQPLSLRPEACR 285
Qy 299 PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV 358
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 286 PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV 345
Qy 359 QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDK 418
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 346 QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDK 405
Qy 419 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT 478
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 406 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT 465
Qy 479 KDTYDALHMQALPPR 493
|||||||||||||||
Db 466 KDTYDALHMQALPPR 480
Escarpe teaches that both of these CARs are sufficient to induce IL-2 expression in Jurkat cells upon exposure to CLDN6 (Fig. 9A-B) and that primary T cells expressing both CARs produced cytokines indicating T-cell activation (Fig. 12, 13) and resulted target cell killing (Fig. 14A-B). The SCT1-h27.204v2 CAR appeared to have a stronger effect than the 108 CAR for cytokine expression, but both CARs resulted in similar levels of target cell killing (Fig 14A-B). This would indicate to an artisan that substitution of art-known anti-CLDN6 scFvs that are expressed in the context of a chimeric immune receptor and are art-known as effective in that context would predictably result in a functional anti-CLDN6 chimeric immune receptor on the backbone as taught by ESCARPE.
Applicant states “CAR activity is architecture-dependent and cannot be assumed for all antigen-CAR combinations as discussed by Jayaraman” (Remarks 12/23/2025 p. 7-8). The Examiner agrees that in general CAR activity is unpredictable for combinations of untested domains, as taught by Jayaraman (Of record, PTO-892 dated 10/31/2025), and for optimization of design parameters; there is little in Jayaraman to suggest that simple substitution of art-known scFvs, previously described in the context of a CAR, would be so unpredictable as to make a CAR that is not functional for its purpose of activating immune cells for anti-tumor activity. MPEP 2143.02 states “Obviousness does not require absolute predictability, but at least some degree of predictability is required”. As described in the 103 rejection above, this is the case for the instant combination: the anti-CLND6 scFv is shown to properly target CLDN6 and activate on multiple, distinct CAR backbones with different architecture by SAHIN 2017, and both SAHIN 2017 and ESCARPE implicitly suggest that it is reasonable to substitute different anti-CLDN6 scFvs onto well-described CAR backbones. In support of the idea that substituting an scFv onto a different CAR backbone or assessing the functionality of different scFvs binding the same antigen on different CAR backbones was well within the skill of a person of ordinary skill in the art, Krug, Christian, et al. "Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone." Cancer Immunology, Immunotherapy 64.12 (2015): 1623-1635 teaches assessment of CARs targeting the melanoma-associated antigen MCSP and teaches that the expression level after mRNA transfection of Gen2 CARs varied based on scFv and that expression levels were higher in the more stable CAR (Fig. 1B) and that the ability of the CAR to lyse target cells was directly related to expression levels of the CAR (Fig. 2). This suggests that a person of ordinary skill in the art would understand that CARs containing an scFv that has already been shown to have both in vitro and in vivo activity are unlikely to be destabilized by the scFv and have a reasonable expectation of being expressed, and thus clearing one of the first bars of the unpredictability of CAR design. This is further supported by Yi, Zhongzhen, et al. "Optimizing EphA2-CAR T cells for the adoptive immunotherapy of glioma." Molecular Therapy Methods & Clinical Development 9 (2018): 70-80, which teaches developing four anti-EphA2 CARs with the same scFv to target glioblastoma. The authors had previously demonstrated CAR T cells targeting EphA2 have anti-glioma activity in vitro and in a preclinical glioma xenograft model using a CAR “consisted of an EphA2-specifc single-chain variable fragment (scFv) derived from the monoclonal antibody (mAb) 4H5, which recognizes a conformational epitope that is exposed only on malignant cells,14 a CH2CH3 spacer, a CD28 transmembrane domain, and a CD28.ζ signaling domain. However, CH2CH3 spacers may limit the antitumor activity of CAR T cells in vivo by rendering T cells sensitive to Fc receptor-expressing immune cells”. When substituting the previously tested scFv onto four CAR backbones, the CARs comprising either CD28 or 4-1BB costimulatory domains were expressed in a similar number of cells (Fig. 1), had similar IFNγ, IL-2 production and target cells lysis in vitro (Fig. 2), and antigen-stimulated proliferation (Fig. 3). Additionally, the CD28z, 41BBz, or CD2841BBz CARs with a shortened hinge showed improved in vivo efficacy against a U373 glioma xenograft mouse model in comparison to the CH2CH3 hinge (Fig. 4). Thus, there is at least some predictability in swapping scFv domains across different backbones, especially once a functioning CAR has been established. Additionally, U.S. 20180371053 to Dotti et al. published 27 December 2018 (hereinafter ‘Dotti 2018’) teaches that CARs with both 28z and 4-1BBz intracellular domains targeting domain and the same scFv and CD8a hinge and transmembrane domains are “previously validated” formats [0207] and that both the B7H3-CAR-28z and B7H3-CAR-BBz “efficiently eliminated” PDAC cells ([0208], Fig. 4, Fig. 5) which was validated in vivo and demonstrated equivalent anti-tumor activity of B7H3-CAR-28z and B7H3-CAR-BBz against Panc-1 tumor cell xenograft models ([0209], Fig. 6B); in another orthotopic BxPc-3 tumor model the B7-H3.CAR-BBz showed improved anti-tumor efficiency ([0209, Fig. 6F). All of the CARs with these backbones showed variations in T cell activation and signaling, but Yi et. al. and Dotti 2018 support that a person of ordinary skill in the art would have a reasonable expectation of success in using a previously characterized scFv and substituting it onto well-characterized and commonly used in the art CAR backbone in order to obtain a CAR capable of antigen-induced activation.
Applicant argues that “the PTAB has recently adopted the opinion that “from 2014 to at least 2019, CAR engineering was highly unpredictable, dependent on a multitude of variables, and a domain that worked in one construct could not be expected to work in all constructs””. The Examiner notes that the PTAB case in Emtage (Applicant Exhibit A) was not precedential and that each case is decided on its own fact pattern and merits. Further, the entire PTAB quote from the Emtage decision reads “Appellant cites two references, Guedan and Dotti, which we agree support Appellant’s contention “that from 2014 to at least 2019, CAR engineering was highly unpredictable, dependent on a multitude of variables, and domains that worked in one construct could not be expected to work in all constructs.” Appeal Br. 6”; therefore, the Examiner notes that rather than being representing an opinion of the PTAB, this quote indicates the PTAB agrees that the Appellant in Emtage has support for an opinion of the Appellant under the particular fact pattern of Emtage.
Regarding each case being decided on its own facts, the Examiner notes that the Emtage decision is directed to a different type of domain substitution within a CAR: “The Examiner finds that ‘Smith teaches several exemplary features of CARs, including a single-chain antibody fragment (scFv) which binds CD19 (para. 0076 and 0078), a co-stimulatory signal molecule comprising CD28 (para. 0086-0087), and a signal transducing domain comprising CD3-zeta which contains immunoreceptor tyrosine-based activation motifs (ITAMs) (para. 0085).’ Ans. 3. The Examiner finds that Smith does not teach inclusion of a DAP12 domain. Id. at 4.” See ex parte Emtage, Appeal 202025-000779 p. 3. This is combined with a generic teaching of Cooper that Engels teaches that the DAP12 domain enhances the anti-tumor efficiency of CAR-bearing T cells (See ex parte Emtage, Appeal 202025-000779 p. 3-4). This is very different than the instant fact pattern, which, as described in the 103 rejection above, describes the substitution of one anti-CLDN6 binding domain for another anti-CLDN6 binding domain, where both anti-CLDN6 binding domains have demonstrated function in multiple contexts of CAR backbones (See above; e.g. the anti-CLDN6 domain of SAHIN 2017 is demonstrated to have functional CAR activity across multiple backbones). Here, both SAHIN 2017 and ESCARPE support that, although there is not complete predictability across substituting the scFv domains because each CAR has some differences in function, as shown by the different cytokine profiles of the two anti-CLDN6 scFvs of ESCARPE, the examiner contends that both ESCARPE and SAHIN 2017 implicitly teach a reasonable expectation of success by performing variations of the suggested substitution and arriving at multiple CARs that activate T cells.
Further, the Emtage decision states that “As Appellant aptly established, ‘the engineered CAR of Engels is based on NK cell components and not T cells, and based on a construct in which the signaling domain is a separate polypeptide being co-expressed with the CAR.’ […] Given the differences between Engels’ NK constructs and the claimed CAR T cells, we agree with Appellant that “[t]he Examiner’s selective reliance on the teachings of DAP12 to support the combination for alleged obviousness appears to rely on the instant claims as a road map’”. As described in the 103 rejection above, this is not the case for the instant art and fact pattern. Both SAHIN 2017 and ESCARPE are particularly directed at CARs, expressed in T cells, and the functionality of anti-CLDN6 scFvs in a CAR backbone of CAR-T cells for immunotherapy targeting solid tumors expressing CLDN6. The differences between the two references are extremely limited: SAHIN 2017 recites 4-1BB co-stimulatory domains but only explicitly recites an anti-CLDN6-IgG1-28z CAR, and does not explicitly recite the CD8 hinge/spacer and transmembrane domain; ESCARPE teaches an anti-CLDN6-CD8-41BBz CAR but does not teach the anti-CLDN6 binding domain of SEQ ID NO: 35. Both references cited in the 103 rejection above suggest that 1) persistence is a desirable quality for CAR-T cells to have in order to be able to treat a CLDN6+ solid tumor and 2) that co-stimulatory domains, in particular CD28 and 4-1BB, affect the persistence of CAR-T cells.
Applicant then quotes Dotti (Applicant Exhibit B, Remarks 12/23/2025) describing the difficulty “to develop [CAR-T cells] to a stage at which they can be predictably successful and widely implemented as a standard of care” and further points to statements from Dotti regarding optimization of CARs for ‘one size fits all’ that testing is required in a range of pre-clinical models and that limited clinical experience is available for 2nd or 3rd generation CARs in solid tumors (Remarks 12/23/2025 p. 8). Examiner would like to note that reasonable expectation of success is also based on the scope of the instant claims. Dotti discusses the predictability of creating a clinically successful CAR in a T-cell as of the publishing date in 2014; however, the instant claims are never narrowed to expression in the T cell which is required for any of the functional attributes of the instant CAR. The narrowest instant claims are directed towards a method comprising administering immune effector cells comprising multiple T cells (claim 35) and a CAR comprising SEQ ID NO: 35 and wherein the CAR comprises SEQ ID NO: 36 (claim 69). Additionally, as described above, even where there is not a lot of predictability in the art, the explicit teachings and implicit suggestion of the art about the express, particular sequences and domains and highly identical domains cannot be ignored in favor of general statements about the unpredictability of CARs. Both SAHIN 2017 and ESCARPE demonstrate experimental evidence in T cells and suggest a reasonable expectation of success of substituting anti-CLDN6 scFv as described in the 103 rejection above. This application was filed in the context of a time where it was commonplace in the art to substitute different scFvs onto a second or third generation CAR backbones for optimization of CAR-T signaling. To further confirm how commonly used these particular sequences and domains were, a search of the PATGENE database in STN for CARs comprising the exact instant hinge, transmembrane, and co-stimulatory domain/CD3z endodomain yields 216 distinct patent documents with effective filing dates prior to the instant date of 02/08/2019, of which 198 appear to teach the exact Gen 2 CAR hinge/transmembrane/endodomain combination. For comparison, there are 13 distinct patent documents in PATGENE comprising the same sequence CD8hinge/transmembrane with the CD28 costimulatory substituted for 4-1BB and 28 that have any hinge/transmembrane combination with CD28 costimulatory domain/CD3z explicitly recited. This is an underrepresentation of the number of CARs tested using these particular backbones because it does not account for how many CARs are taught per patent, sequence variants, and non-patent literature and patents that frequently identify the CAR domains solely by name (e.g. “4-1BB costimulatory domain”) rather than by exact sequence. As evidenced by the art at the state of filing, the state of the art in general as the context in which a person of ordinary skill in the art would read SAHIN 2017 and ESCARPE would give an artisan significantly more than a hope at making a cytotoxic CAR-T cell by combining the two CARs. This is further evidenced by the instant specification, which shows that cytotoxic CARs with effective anti-CLDN6 target cell killing were achieved in 3 out of 3 alternate CAR backbones tested, where effective indicates the appearance of better target cell killing than UTD T cells (Fig. 1B).
Applicant argues that Guedan, published March 2019 (Applicant Exhibit C, Remarks 12/23/2025) similarly explains that domains having the same function may not simply be swapped out with each other with the expectation that they would maintain the same function or effect and that CD28 and 4-1BB showed differences with regard to T cell persistence. First, the examiner would like to note that Applicant is arguing limitations which are not required by the claims because the claims are directed towards the CAR peptide in general or, at the narrowest, any effector immune cell population comprising multiple T-cells comprising the peptide, whereas Guedan is referring to T cell persistence, which suggests at least a population of T cells. By saying that CARs are so unpredictable that an artisan would not be able to substitute two different anti-CLDN6 scFvs, the Applicant also appears to assert that the full scope of the claims is not enabled. If this was the case, an artisan would not be able to make and use third-generation CARs comprising additional costimulatory domain except for the CLDN6-CAR-IgG-28-BBZ, which has been reduced to practice in the specification. The scope of the instant claims, however, by “comprising” language, includes CLDN6-CAR-CD8-(costim)-BBZ, wherein the additional costimulatory domain (costim) can be anything. The reason the Applicants are enabled for the entire scope of the independent claim is because it was within the understanding and abilities of an artisan at the time of filing to modify CARs by substituting or adding described domains with a reasonable expectation of success, wherein the reasonable expectation was that the CAR would still function as a CAR by inducing T-cell activation upon target antigen binding.
Regarding scFvs, Guedan et. al. teaches “These results suggest that the scFv, a critical component of a CAR molecule, can be carefully designed and manipulated to influence specificity and differential targeting of tumors versus normal tissues. Given that these differences may only be measurable with CAR T cells (as opposed to soluble antibodies), pre-clinical testing of normal tissues for expression of the target, and susceptibility to on-target toxicities requires live-cell assays rather than immunohistochemistry on fixed tissues” (p. 146 right column ¶2). This suggests that Guedan et. al. also believes that scFvs that have been developed and pre-clinically tested in the context of a CAR molecule would increase the expectation of success. Guedan et. al. further teaches that “CD28 and 4-1BB are the most widely used costimulatory endodomains in CARs. Clinical trials with CARs incorporating CD28 or 4-1BB intracellular domains showed similar response rates in patients with hematologic malignancies. However, the persistence of T cells engineered with these two CAR designs is strikingly different. Pre-clinical studies identified these T cell persistence difference in head-to-head comparisons of CD28 and 4-1BB-based CAR T cells in animal models48,60. Clinical trials for B cell malignancies have shown that CD28-based CAR T cells are typically undetectable beyond 3 months6, 61, whereas 4-1BB based CAR T cells can persist in patients for several years after treatment62” (p. 147 right column-p. 148 left column). Although Applicant uses this reference to show that these co-stimulatory domains are not considered equivalent, Guedan et. al. supports that up to the context of the clinical trials, an artisan would consider exchanging these domains in order to optimize a T cell for the ideal co-stimulatory function for the indication and further suggests particular characteristics of each domain (persistence, cytokine production) without suggesting that these signaling functions are not possible to predict across different scFvs. As of the effective filing date, all of the references cited by Guedan et. al. in that section were published and would have been the context in which an artisan would have read SAHIN 2017 and ESCARPE. Guedan et. al. states that “Exhaustive studies indicate that signaling through CD28-based CARs results in more rapid T cell activation, proliferation, cytolysis, and increased glycolysis, but shorter T cell persistence” (p. 148 left column). These statement summaries suggest that while choosing the optimal CAR for every scFv was unpredictable, an artisan would expect some properties to stay consistent to particular domains across multiple CARs with a reasonable expectation of success.
Second, Applicants argue that secondary considerations of nonobviousness have been improperly and unjustifiably disregarded by the Office. Applicant has amended to remove references to amino acid sequences having at least 95% identity to SEQ ID NOs: 35 and 36 and has replaced it with reciting a CAR molecule that comprises identity to each particular domain (Remarks p. 12/23/2025 p. 10). The Examiner notes that, while this narrows the scope of the CAR, the independent claim is still drawn towards a genus of CARs that would include, for example, any third-generation CAR further comprising any additional co-stimulatory domain. The claims also cover the CAR peptide in general (comprised by any cell) and the surprising results in Mackensen et. al. (Of record, PTO-892 dated 5/29/2025) do not support this scope. First, Mackensen et. al. teaches a clinical trial for dose-escalation to characterize safety and tolerability of CLDN6 CAR-T cells with or without “CARVac”, a CLDN6 mRNA vaccine (Results, Study design and execution, patient selection and treatment, ¶2). The Mackensen et. al. trial included 22 enrolled patients, all of whom underwent leukapheresis and manufacturing of autologous T cells which were enriched, activated, transduced using gamma-retroviral self-inactivating pES.12-6 retroviral vector at an MOI of one followed by cryopreservation (“CAR-T cell manufacturing” section). The patients were treated at two dose-levels and with or without CARVac, and Mackensen et. al. further teaches that “Five of the seven patients with PD had either received CLDN6 CAR-T cells at DL1 or had not received LD before DL2” (“Efficacy” section, ¶1). Additionally, Mackensen et. al. teaches “All objective responses occurred in patients with either EOC (two of four patients with PR) or GCT (four PRs plus one CR in 13 patients; Fig. 3a,c). The five patients with other tumor entities all had SD as BOR (including the patient treated <DL1)” (“Efficacy” section, ¶2); “Tumor responses were primarily observed at DL2. However, the late timing of CARVac dosing at this DL, combined with the diverse, small cohorts, prevented analysis of how CARVac influences the antitumor activity of CLDN6 CAR-T cells” (“Efficacy” section, ¶5). The unpredictable results, therefore, appear to be limited to, at the very broadest, a CAR comprising 100% identity to the instant CAR expressed in a T-cell, and at narrowest they require the particular patient population with the particular expression of CLDN6 and T-cells manufactured using the particular vector and process and administered at dose-level 2. There are no claims that recite all of these limitations. The Examiner suggests that an amended combination of claims 28 and 69 requiring the CAR comprise the entire CAR comprising SEQ ID NO: 36, and that the population of immune effector cells require a population of T cells is in line with the unexpected results at the broadest suggested by Mackensen et. al.
The Applicant further argues that the instant specification provides evidence that the instant CAR comprising a 4-1BB costimulatory domain and CD8 hinge is unexpectedly better than the closest prior art because the specification states that “an accelerated lysis of CLDN6-expressing tumor spheroids by 4-1BB containing CARs compared to a CAR carrying the CD28 domain could be detected” [404] (See Remarks 12/23/2025 p. 10) and that “The Office's conclusory dismissal of the express statements in the specification as "opinion" is unsupported and has no basis in the record. The Office has provided no reason that a POSA would doubt the inventors' interpretation of the data nor their express statement that "an accelerated lysis of CLDN6-expressing tumor spheroids by 4-1BB containing CARs compared to a CAR carrying the CD28 domain could be detected." [0404]. Thus, contrary to the Office's assertion, Example 2 provides a direct, controlled comparison between Sahin 2017's CAR and the claimed CAR under identical conditions. As such, Example 2 is further probative evidence of unexpected results, which has not been rebutted by the Office” (Remarks 12/23/2025 p. 11). This is not persuasive because the Examiner has explained on the record why Example 2 and Fig. 1B are insufficient for a person of ordinary skill in the art to reach the same conclusions as described in the specification, and therefore the statements such as accelerated lysis cannot be substantiated as evidence rather than opinion. As described in the Final Office Action dated 10/31/2025, “The data in Fig. 1B is a single image of a single experiment showing that spheroids were specifically killed more than untransduced cells with a various CLDN-6 CARs with different backbones. It is not discernable from a single image to what degree there is a difference between the tested CARs or whether this is a biologically meaningful or statistically significant result. This data demonstrates that the scFv of Sahin 2017 substituted onto three art-known CAR backbones successfully killed CLND6+ spheroids in a single replicate of an experiment with one human T-cell donor” (p. 19-20). In regards to secondary considerations of non-obviousness, MPEP §716.02(c) teaches “Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness” and MPEP §2145 states “A showing of unexpected results must be based on evidence, not argument or speculation”. Here, the Applicant has not provided sufficient evidence to show nonobviousness because ESCARPE teaches a specific reason (better persistence) to use a 4-1BB co-stimulatory domain and SAHIN 2017 teaches a specific reason to use the particular CLDN6-scFv (high lysis even in response to low expression of CLDN6) as described in the 103 rejection above. As described in Dotti 2018 and Yi et. al. above, it was commonplace at the time of filing to substitute the 4-1BB and CD28 co-stimulatory domains for optimization and observe some variation in the various measures of T cells function such as cytotoxicity and cytokine production: although it was not fully predictable, variation in cytotoxicity, especially in one well of one assay with one T cell donor, would have been well within the expectation of a person of ordinary skill in the art.
Applicant further Argues that “to the extent the Office is relying on a theory of inherency, its analysis is legally insufficient” (Remarks p. 11 12/23/2025). The Examiner has reconsidered and would like to clarify that what was meant is that there is a reasonable expectation of success that the instant claimed CAR domains would achieve the described results or perform as described in the art when combined. For example, as described in the 103 above, both SAHIN 2017 and ESCARPE suggest optimization of the CARs and that a person of ordinary skill may see different results such as higher cytokine production or increased persistence for CD28 and 4-1BB, respectively. Additionally, as discussed above, it is implicit in the disclosures of SAHIN 2017 and ESCARPE that across CAR backbones the scFv is expected to retain its property of binding to CLDN6. The instant rebuttal evidence is insufficient to establish that the results shown in Example 2 are outside the range of what could be expected from simple substitution of an scFv based on the prior art of SAHIN 2017 and ESCARPE because there is no quantification or replicates and, as previously described, the scope of the claims is not narrowed to the results that could be considered unexpected from Mackensen et. al.
MPEP §2145 states “However, where the claims are not limited to a particular use, and where the prior art provides other motivation to select a particular species or subgenus, a showing of a new use alone may not be sufficient to confer patentability. See Dillon, 919 F.2d at 692, 16 USPQ2d at 1900-01. Accordingly, each case should be evaluated individually based on the totality of the circumstances.” Presented below is a side-by-side comparison of Fig. 21B of Sahin 2017 and instant Fig. 5C:
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Sahin 2017 teaches that 10 NSG mice/group were engrafted on day -4 with 1x107 OV90-SC12 target cells. On Day 0, 1x107 CAR-transduced human CD3 T cells were administered i.v. In comparison, the instant specification engrafted 5x106 OV90-SC12 target cells in 10 NSG mice/group (half the amount of tumor target cells) and administered i.v. with 1x107 CLDN6-CAR cells. The examiner has added arrows to both figures to show that at day 30, both the instant CAR and the CAR of Sahin 2017 appear to show tumor control in vivo. This again supports that there was a reasonable expectation of success to make and use a CAR commensurate in scope to the instant claims because an artisan would not require 100% predictability to determine from Sahin 2017 and Escarpe that a combination of the two CARs could be made in order to create a functional anti-CLDN6 CAR with cytotoxic properties in vitro and in preclinical test in vivo that are within the scope of what would be expected from the prior art of Sahin 2017.
Weighing the totality of the evidence of the instant specification and the prior art, such as the similarities between the in vivo results of SAHIN 2017 and the instant specification, the Examiner concludes that the results presented in Example 2 are not outside of the scope of what a person of ordinary skill would expect when making the combination of ESCARPE and SAHIN 2017 as described in the 103 rejection above; and further, that the unexpected results of Mackensen et. al. are not commensurate with the scope of the instant claims.
Double Patenting- Maintained/Modified
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.
U.S. Patent No. 12186275 (Previously Copending Application No. 16/988,117)
Claims 1, 17, 19, 28, 31-32, 35, 39, 41, 44, 47-49, 55-56, 58-59, 61, 65, 69, 73, and 74 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 over U.S. Patent No. 12186275 in view of ESCARPE and SAHIN 2017 (supra).
The disclosures/teachings of ESCARPE are discussed above and are incorporated herein.
Regarding claims 1, 17, 28, 31, 41, 44, 48, 61, 65, 69, and 73 ‘275 claims: A method for stimulating an immune response to a target cell population or target tissue expressing an antigen in a mammal, the method comprising: (a) transfecting a T cell of the mammal with a first nucleic acid encoding a CAR targeted to the antigen; and (b) administering a second nucleic acid encoding the antigen or a variant thereof, wherein the second nucleic acid is in vitro transcribed RNA disposed in liposomes (see claim 1), wherein the antigen is CLDN18.2 or CLDN6 (see claims 4-6; reads on instant claims 1, 17, 28, 31, 41, 44, 48, 61 and 65). ‘275 does not claim the particular structure of the CAR, as required by claims 1, 68, and 69. However, this is remedied by the teachings of ESCARPE in view of SAHIN 2017, as set forth above in the rejections under 35 USC 103. Further, ESCARPE discloses that CLDN6 expression is associated with various tumorigenic cell populations (see p. 18 par. 2). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have developed the CLDN6 CAR of the present invention, as CLDN6 expression is known to be associated with tumors. It would have been prima facie obvious to have developed the CAR specifically with the CAR design outlined in claim 1, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. See MPEP § 2143 and the 103 rejection, above.
Regarding claim 19, ‘275 does not expressly claim the vector. However, this is remedied by the teachings of ESCARPE, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to have developed the vector as required by instant claim 19, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. See MPEP § 2143.
Regarding claim 32, ‘275 claims: A method of treating a mammal having a disease, disorder, or condition associated with expression or elevated expression of an antigen (see claim 28; reads on instant claim 32).
Regarding claim 35, ‘275 claims the method of stimulating an immune response, wherein the immune response is an anti- tumor immune response (see claim 3; reads on instant claim 35).
Regarding claim 39, ‘275 does not claim administering an additional agent. However, this is remedied by the teachings of ESCARPE, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to have administered an additional agent, such as a cytokine or an anti-Treg agent, as the addition of certain cytokines and depletion of Tregs are known to support the expansion and persistence of adoptive cell therapy, per the teachings of ESCARPE.
Regarding claims 47, 49, 55-56 and 58-59, ‘275 claims the method, wherein: the nucleic acid encoding the antigen or variant thereof is transiently expressed in cells of the mammal (see claim 8; reads on instant claim 47); the nucleic acid is administered systemically (see claim 12; reads on instant claim 49); the nucleic acid formulated in a delivery vehicle (see claim 19; reads on instant claim 55); wherein the delivery vehicle comprises particles (see claim 20; reads on instant claim 56) or at least one cationic lipid (see claim 22; reads on instant claim 58); the at least one lipid forms a complex with and/or encapsulates the first nucleic acid (see claim 23; reads on instant claim 59).
Regarding claim 74, ‘275 claims do not explicitly disclose that the CLDN6 positive tumor is a solid tumor. This is remedied by the teachings of SAHIN 2017 and ESCARPE, which both disclose solid tumors expressing CLDN6 as described in the 103 rejection above.
Claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 over U.S. Patent No. 12186275 in view of ESCARPE and SAHIN 2017 (supra).
The disclosures/teachings of the ‘275 patent, ESCARPE, and SAHIN 2017 are discussed above and are incorporated herein, especially in regards to claims 1, 28, 31, 41, and 44.
Regarding claim 70, ‘275 claims: A method for stimulating an immune response to a target cell population or target tissue expressing an antigen in a mammal, the method comprising: (a) transfecting a T cell of the mammal with a first nucleic acid encoding a CAR targeted to the antigen; and (b) administering a second nucleic acid encoding the antigen or a variant thereof, wherein the second nucleic acid is in vitro transcribed RNA disposed in liposomes (see claim 1), wherein the antigen is CLDN18.2 or CLDN6 (see claims 4-6; reads on instant claims 1, 17, 28, 31, 41, 44, 48, 61, 65, and 70). ‘275 does not claim the particular structure of the CAR, as required by claims 1, 68, and 69. However, this is remedied by the teachings of ESCARPE in view of SAHIN 2017, as set forth above in the rejections under 35 USC 103. Further, ESCARPE discloses that CLDN6 expression is associated with various tumorigenic cell populations (see p. 18 par. 2). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have developed the CLDN6 CAR of the present invention, as CLDN6 expression is known to be associated with tumors. It would have been prima facie obvious to have developed the CAR specifically with the CAR design outlined in claim 1, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. See MPEP § 2143.
Claims 71-72 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 over U.S. Patent No. 12186275 in view of ESCARPE and SAHIN 2017 (supra) as applied to claims above and in further view of IRVINE (supra).
The disclosures/teachings of the ‘275 patent, ESCARPE, and SAHIN 2017 are discussed above and are incorporated herein, especially in regards to claims 1, 28, 31, 41, 44, and 70.
‘275 in view of ESCARPE and SAHIN 2017 does not teach the methods of claims 70 or claim 44 wherein the cognate antigen molecule or the nucleic acid coding therefor are administered repeatedly. This deficiency is resolved by IRVINE.
Regarding claims 71 and 72, IRVINE discloses administering a combination of a CAR ligand (e.g. EGFRvIII) conjugated to DSPE-PEG (called “VAX”) and T cells expressing a CAR specific for the peptide (e.g. EGFRvIII CAR-T), wherein the peptide is administered repeatedly (e.g. day 9, 16, and 23, See Fig. 18A). IRVINE teaches that in a mouse model of EGFRvIII-positive cancer, the mice experienced increased tumor control and survival in groups that received repeated vaccines in additional to CAR-T cells compared to groups that received only CAR-T cells, even at low doses (See Fig. 18A-B, Example 6 p. 98-100).
In light of these teachings, it would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to practice the method of repeated vaccination with CAR ligand as taught by IRVINE with the CLDN-6 peptide or nucleic acid vaccine as taught by ‘275 in view of ESCARPE and SAHIN 2017 to benefit from the increased tumor control with a smaller dose of CAR-T cells as taught by IRVINE. This would have a predictable effect because both modified ESCARPE and IRVINE are in the field of boosting CAR-T cells in vivo using cognate antigen, and therefore an artisan would expect to benefit from a similar increased tumor control by the CAR-T cells with the target antigen vaccine.
U.S. Patent No. 12559531 (Previously copending Application No. 17/712,562)
Claims 1, 17, 19, 28, 31-32, 35, 39, 41, 65, 69, 73 and 74 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12559531 in view of ESCARPE and SAHIN 2017.
Although the claims at issue are not identical, they are not patentably distinct from each other because Application ‘562 anticipates the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1, 69, and 73 ‘531 claims an artificial T cell receptor comprising a binding domain for claudin-6 (CLDN6) comprising the amino acid sequence of SEQ ID NO: 40 which comprises 100% identity to all but the 5 terminal residues of SEQ ID NO: 35, a costimulatory domain, and a T cell signaling domain that activates cytotoxic lymphocytes upon binding to CLDN6 (see claim 1, where “artificial T cell receptor” reads on “CAR”), wherein the costimulatory domain is CD137 (4-1BB) (see claim 2), wherein the artificial TCR further comprises a transmembrane domain (see claim 3), and wherein the T cell signaling domain comprises the endodomain of CD3-zeta (see claim 5). ‘531 does not claim the structure of SEQ ID NO: 36, as required by claims 1 and 69. However, this is remedied by the teachings of SAHIN 2017 and ESCARPE, as set forth above in the rejections under 35 USC 103. This would result in CAR comprising the antigen binding domain of SEQ ID NO: 40 plus the 5 terminal residues of SEQ ID NO: 46 as taught by SAHIN 2017 and the transmembrane and intracellular 4-1BB and CD3-zeta domains of application ‘562. Further, ESCARPE discloses that CLDN6 expression is associated with various tumorigenic cell populations (see p. 18 par. 2). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have developed the CLDN6 CAR of the present invention.
Regarding claims 17, 19, 28, 31-32, 35, 39, 41, 65, and 74 Application ‘562 does not claim the elements required by these claims. However, these deficiencies are remedied by the teachings of ESCARPE and SAHIN 2017, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to have modified Application ‘562 to incorporate the teachings of ESCARPE, by developing: a nucleic acid encoding the CAR; a vector; a population of immune cells; methods for stimulating an immune response, treating disease, and providing anti-tumor immunity; administering an additional agent; contacting the CAR+ immune cells to a cognate antigen; a kit comprising the immune cells, to arrive at the instant invention. One would have been motivated to do so, as it amounts to no more than combining prior art elements according to known methods to yield predictable results. See MPEP § 2143.
Claims 44, 47, 49, 55-56, 58-59, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 44-55 of U.S. Patent No. 12559531 in view of ESCARPE and SAHIN 2017 as applied to claims 1, 17, 19, 28, 31-32, 35, 39, 41, 65, and 69 above and in further view of SAHIN 2016 (supra).
This is a provisional nonstatutory double patenting rejection.
The disclosures/teachings of SAHIN 2016 are discussed above and are incorporated herein.
Regarding claim 44, Application ‘562 in view of ESCARPE does not administering the cognate antigen. However, this deficiency is remedied by the teachings of SAHIN 2016, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have co-administered the CLDN6 CAR cells with the cognate antigen (CLDN6 or variant) molecule/encoding nucleic acid, as doing so promotes antigen-specific expansion of the adoptively transferred CAR- T cells, and thus, reduces the need for high amounts of initial T cells transferred for treatment, per the teachings of SAHIN 2016.
Regarding claims 47, 49, 55-56, 58-59, and 61, Application ‘562 in view of ESCARPE does not claim the elements required by these claims. However, these deficiencies are remedied by the teachings of SAHIN 2016, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to have modified Application ‘562 to incorporate the teachings of SAHIN 2016, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. See MPEP § 2143.
Claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 44-55 of copending U.S. Patent No. 12559531 in view of ESCARPE (supra); SAHIN 2017 (supra); and SAHIN 2016 (supra).
The disclosures/teachings of the ‘562 application and ESCARPE are discussed above and are incorporated herein, especially in regards to claims 1, 28, 31, 41, and 44.
Regarding claim 70, Application ‘562 in view of ESCARPE does not administering the cognate antigen or a nucleic acid encoding therefor. However, this deficiency is remedied by the teachings of SAHIN 2016, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have co-administered the CLDN6 CAR cells with the cognate antigen (CLDN6 or variant) molecule/encoding nucleic acid, as doing so promotes antigen-specific expansion of the adoptively transferred CAR- T cells, and thus, reduces the need for high amounts of initial T cells transferred for treatment, per the teachings of SAHIN 2016.
Claims 71-72 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 44-55 of U.S. Patent No. 12559531 in view of ESCARPE (supra); SAHIN 2017 (supra); and SAHIN 2016 as applied to claims above and in further view of IRVINE (supra).
The disclosures/teachings of the ‘562 application and ESCARPE are discussed above and are incorporated herein, especially in regards to claims 1, 28, 31, 41, 44, and 70.
‘275 in view of ESCARPE and SAHIN 2016 does not teach the methods of claims 70 or claim 44 wherein the cognate antigen molecule or the nucleic acid coding therefor are administered repeatedly. This deficiency is resolved by IRVINE.
Regarding claims 71 and 72, IRVINE discloses administering a combination of a CAR ligand (e.g. EGFRvIII) conjugated to DSPE-PEG (called “VAX”) and T cells expressing a CAR specific for the peptide (e.g. EGFRvIII CAR-T), wherein the peptide is administered repeatedly (e.g. day 9, 16, and 23, See Fig. 18A). IRVINE teaches that in a mouse model of EGFRvIII-positive cancer, the mice experienced increased tumor control and survival in groups that received repeated vaccines in additional to CAR-T cells compared to groups that received only CAR-T cells, even at low doses (See Fig. 18A-B, Example 6 p. 98-100).
In light of these teachings, it would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to practice the method of repeated vaccination with CAR ligand as taught by IRVINE with the CLDN-6 peptide or nucleic acid vaccine as taught by ‘275 in view of ESCARPE and SAHIN 2017 to benefit from the increased tumor control with a smaller dose of CAR-T cells as taught by IRVINE. This would have a predictable effect because both modified ESCARPE and IRVINE are in the field of boosting CAR-T cells in vivo using cognate antigen, and therefore an artisan would expect to benefit from a similar increased tumor control by the CAR-T cells with the target antigen vaccine.
U.S. Patent No. 11,858,988
Claims 1, 17, 19, 28, 31-32, 35, 39, 41, 65, 69, and 73-74 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of Patent No. 11,858,988 in view of ESCARPE (supra).
The disclosures/teachings of ESCARPE are discussed above and are incorporated herein.
Regarding claim 1, 69, and 73 Patent ‘988 claims: a method of producing an anti-CLDN6 single-chain antibody that binds to CLDN6 (see claim 1). Patent ‘988 claims the method wherein the antibody comprises the VH/VL SEQ ID NO: 36 and 37, which share 100% identity to the VH/VL of instant SEQ ID NO: 35 (see claim 1; reads on instant claim 4). Products are obvious over methods comprising the product, and therefore patent ‘988 makes obvious the instant antigen-biding domain. However, Patent ‘988 does not claim the CAR (SEQ ID NO: 36), as required by claim 1. However, this is remedied by the teachings of ESCARPE, as set forth above in the rejections under 35 USC 103. Further, ESCARPE discloses: conventional therapeutic treatments, including immunotherapy (i.e., antibody therapy), are limited and often ineffective; their invention, a CLDN6 CAR therapy, addresses the need for more targeted and potent therapies for proliferative disorders (see p. 1 line 28 to p. 2 par. 1). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have produced the anti-CLDN6 antibody, using the method claimed by Patent ‘988, and using the antibody to develop the CLDN6 CAR of the present invention, as CAR therapy is known to be more potent and targeted in comparison to conventional therapeutics like antibody therapies, for proliferative disorders, per the teachings of ESCARPE.
Regarding claims 17 and 19, Patent ‘988 claims the nucleic acid and vector (see claims 1-24; reads on instant claims 17 and 19).
Regarding claims 28, 31-32, 35, 39, 41, 65, and 74 Patent ‘988 does not claim the elements required by these claims. However, these deficiencies are remedied by the teachings of ESCARPE, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to have modified Patent ‘988 to incorporate the teachings of ESCARPE, by developing: a population of immune cells; methods for stimulating an immune response, treating disease, and providing anti-tumor immunity; administering an additional agent; contacting the CAR+ immune cells to a cognate antigen; a kit comprising the immune cells, to arrive at the instant invention. One would have been motivated to do so, as it amounts to no more than combining prior art elements according to known methods to yield predictable results. See MPEP § 2143.
Claims 44, 47, 49, 55-56, 58-59, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of Patent No. 11,858,988 in view of ESCARPE and further in view of SAHIN 2016 (supra).
The disclosures/teachings of SAHIN 2016 are discussed above and are incorporated herein.
Regarding claim 44, Patent ‘988 does not administering the cognate antigen. However, this deficiency is remedied by the teachings of SAHIN 2016, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have co-administered the CLDN6 CAR cells with the cognate antigen (CLDN6 or variant) molecule/encoding nucleic acid, as doing so promotes antigen-specific expansion of the adoptively transferred CAR- T cells, and thus, reduces the need for high amounts of initial T cells transferred for treatment, per the teachings of SAHIN 2016.
Regarding claims 47, 49, 55-56, 58-59, and 61, Patent ‘988 does not claim the elements required by these claims. However, these deficiencies are remedied by the teachings of SAHIN 2016, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to have modified Patent ‘988 to incorporate the teachings of SAHIN 2016, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. See MPEP § 2143.
Claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of Patent No. 11,858,988 in view of ESCARPE (supra) and SAHIN 2016 (supra).
The disclosures/teachings of the ‘988 patent and ESCARPE are discussed above and are incorporated herein, especially in regards to claims 1, 28, 31, 41, and 44.
Regarding claim 70, Patent ‘988 does not administering the cognate antigen. However, this deficiency is remedied by the teachings of SAHIN 2016, as set forth above in the rejections under 35 USC 103. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have co-administered the CLDN6 CAR cells with the cognate antigen (CLDN6 or variant) molecule/encoding nucleic acid, as doing so promotes antigen-specific expansion of the adoptively transferred CAR- T cells, and thus, reduces the need for high amounts of initial T cells transferred for treatment, per the teachings of SAHIN 2016.
Claims 71-72 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of Patent No. 11,858,988 in view of ESCARPE (supra) and SAHIN 2016 (supra) as applied to claims above and in further view of IRVINE (supra).
‘988 in view of ESCARPE and SAHIN 2016 does not teach the methods of claims 70 or claim 44 wherein the cognate antigen molecule or the nucleic acid coding therefor are administered repeatedly. This deficiency is resolved by IRVINE.
Regarding claims 71 and 72, IRVINE discloses administering a combination of a CAR ligand (e.g. EGFRvIII) conjugated to DSPE-PEG (called “VAX”) and T cells expressing a CAR specific for the peptide (e.g. EGFRvIII CAR-T), wherein the peptide is administered repeatedly (e.g. day 9, 16, and 23, See Fig. 18A). IRVINE teaches that in a mouse model of EGFRvIII-positive cancer, the mice experienced increased tumor control and survival in groups that received repeated vaccines in additional to CAR-T cells compared to groups that received only CAR-T cells, even at low doses (See Fig. 18A-B, Example 6 p. 98-100).
In light of these teachings, it would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to practice the method of repeated vaccination with CAR ligand as taught by IRVINE with the CLDN-6 peptide or nucleic acid vaccine as taught by ‘275 in view of ESCARPE and SAHIN 2017 to benefit from the increased tumor control with a smaller dose of CAR-T cells as taught by IRVINE. This would have a predictable effect because both modified ESCARPE and IRVINE are in the field of boosting CAR-T cells in vivo using cognate antigen, and therefore an artisan would expect to benefit from a similar increased tumor control by the CAR-T cells with the target antigen vaccine.
Additional Provisional Nonstatutory Double Patenting (NSDP) Rejections:
Claims 1, 4, 17, 19, 28, 31-32, 35, 39, 41, 44, 47-49, 55-56, 58-59, 61, 65, 69, 73, and 74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following copending applications, in view of ESCARPE (supra); SAHIN 2017 (supra); and/or SAHIN 2016 (supra), for similar reasons as discussed in the (provisional) nonstatutory double patenting rejections above:
Copending Application No.:
Rejected over Application Claims:
SEQ ID NOs teaching an antigen-binding domain identical to instant SEQ ID NO: 35:
Application/Patent with similar (prov.) NSDP rejections:
18/051,850
1, 30-32, 34-36, 38-37
22
Patent ‘988
18/520,242
36-55
36 and 37
Patent ‘988
18/578,844
1-126
6
Patent ‘988
18/717,782
1-87
35
Patent ‘275 and ‘531
Additional NSDP Rejections:
Claims 1, 4, 17, 19, 28, 31-32, 35, 39, 41, 44, 47-49, 55-56, 58-59, 61, 65, 69, and 73-74 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following patents, in view of ESCARPE (supra); SAHIN 2017 (supra); and/or SAHIN 2016 (supra), for similar reasons as discussed in the (provisional) nonstatutory double patenting rejections above:
Patent No.:
Rejected over Patent Claims:
SEQ ID NOs identical to instant SEQ ID NO: 35
Application/Patent with similar (prov.) NSDP rejections:
9,487,584
1-20
36 and 37
Patent ‘988
9,932,401
1-19
36 and 37
Patent ‘988
10,370,423
1-8
46
Patent ‘275 and ‘531
11,345,731
1-12
46
Patent ‘275 and ‘531
Additional Provisional Nonstatutory Double Patenting (NSDP) Rejections:
Claims 70-72 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following copending applications, in view of ESCARPE (supra); SAHIN 2017 (supra); and/or SAHIN 2016 (supra); and IRVINE (supra), for similar reasons as discussed in the (provisional) nonstatutory double patenting rejections above:
Copending Application No.:
Rejected over Application Claims:
SEQ ID NOs teaching an antigen-binding domain identical to instant SEQ ID NO: 35:
Application/Patent with similar (prov.) NSDP rejections:
18/051,850
1, 30-32, 34-36, 38-37
22
Patent ‘988
18/520,242
36-55
36 and 37
Patent ‘988
18/578,844
1-126
6
Patent ‘988
18/717,782
1-87
35
Patent ‘275 and ‘531
Additional NSDP Rejections:
Claims 70-72 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following patents, in view of ESCARPE (supra); SAHIN 2017 (supra); and/or SAHIN 2016 (supra); and IRVINE (supra), for similar reasons as discussed in the (provisional) nonstatutory double patenting rejections above:
Patent No.:
Rejected over Patent Claims:
SEQ ID NOs identical to instant SEQ ID NO: 35
Application/Patent with similar (prov.) NSDP rejections:
9,487,584
1-20
36 and 37
Patent ‘988
9,932,401
1-19
36 and 37
Patent ‘988
10,370,423
1-8
46
Patent ‘275 and ‘531
11,345,731
1-12
46
Patent ‘275 and ‘531
Response to Arguments
Applicant argues that to the extent the office relies on the same references put forth in the 103 rejection, the arguments presented above also overcome the NSDP rejections because none of the reference patent claims would have provided a POSA with a reasonable expectation of success in achieving the presently claimed CAR molecule having the properties disclosed in the specification and the references are also overcome by the secondary considerations of unexpected results (Remarks 12/23/2025 p. 12-13). These arguments are not persuasive for the reasons outlined in the response to arguments for the 103 rejections above. To summarize, 1) the Examiner has made a prima facie case of obviousness for simple substitution of prior-art known elements as described in MPEP 2143; 2) the scope of the claims is not commensurate with the scope of the unexpected results; and 3) there is insufficient evidence of record that the unexpected results are truly unpredictable compared to the closest prior art. The examiner respectfully submits that an artisan would have a reasonable expectation that a prior art antigen-binding domain in single chain format in a synthetic immune receptor (as in SAHIN 2017) against a known target substituted for another prior-art antigen binding domain in a known exemplary CAR backbone (as in ESCARPE) would predictably function as a CLDN6-specific CAR.
The examiner would also like to draw particular attention to two of the NSDP rejections that are more similar to the instant claims than the others:
Issued U.S. Patent No. 12559531 (effective filing date 4/1/2014), which as described above teaches an artificial T cell receptor comprising a binding domain for claudin-6 (CLDN6), a costimulatory domain, and a T cell signaling domain that activates cytotoxic lymphocytes upon binding to CLDN6 (see claim 44, where “artificial T cell receptor” reads on “CAR”), wherein the costimulatory domain is CD137 (4-1BB) (see claim 45), wherein the artificial TCR further comprises a transmembrane domain (see claim 46), and wherein the T cell signaling domain comprises the endodomain of CD3-zeta (see claim 48). Application ‘562 also teaches a CAR comprising the antigen binding domain of SEQ ID NO: 40, which comprises 100% identity to all but the 5 terminal residues of SEQ ID NO: 35, which are deleted. The examiner suggests that although the rejection of the claims is reliant on ESCARPE, the scope of the current claims of the ‘562 claims a genus which encompasses the instant CAR and specifically suggests elements (such as the CD137 costimulatory domain) which would more strongly motivate arrival at SEQ ID NO: 36.
Copending application 18/71772 (effective filing date 12/9/2021) which teaches a method of treating cancer comprising a CAR of SEQ ID NO: 36 (100% identical to instant SEQ ID NO: 36, claim 20) and comprising contacting with a cognate antigen CLDN6 or a fragment thereof (claim 30), which appears to anticipate the instant CAR species and make obvious elements of the instant methods of treating. The examiner suggests that although the rejection of the claims is in part reliant on SAHIN 2016, the scope of the current claims of the ‘772 application claims the instant CAR molecule and significant portions of the instant methods.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678