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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 24, 2025 has been entered.
Claim Status
Claim listing filed on September 24, 2025 is pending. Claims 9-12 and 15-21 are cancelled. Claim 1 is amended. Claims 1-8, 13-14, and 22 are examined upon their merits.
Withdrawn Claim Rejections
The following rejections under 35 USC 103 are withdrawn in view of Applicant’s amendments to the claims and Applicant’s remarks filed September 24, 2025:
Claims 1, 3, 5, and 7-8 as unpatentable over CHA, KATZ, EMTAGE, DUAN, YAZAKI, BROWN, BARISH, SADELAIN, and KUJAWSKI.
Claims 2 and 4 as unpatentable over CHA, KATZ, EMTAGE, DUAN, YAZAKI, BROWN, BARISH, SADELAIN, and KUJAWSKI as applied to claims 1, 3, 5, and 7-8, and further in view of THISTLETHWAITE.
Claim 6 as unpatentable over CHA, KATZ, EMTAGE, DUAN, YAZAKI, BROWN, BARISH, SADELAIN, and KUJAWSKI as applied to claims 1, 3, 5, and 7-8, and further in view of ZHANG.
Claim 13 as unpatentable over CHA, KATZ, EMTAGE, DUAN, YAZAKI, BROWN, BARISH, SADELAIN, and KUJAWSKI as applied to claims 1, 3, 5, and 7-8, and further in view of WILLIAMS and HUMPHREYS.
Claim 14 as unpatentable over CHA, KATZ, EMTAGE, DUAN, YAZAKI, BROWN, BARISH, SADELAIN, and KUJAWSKI as applied to claims 1, 3, 5, and 7-8, and further in view of WILLIAMS, HUMPHREYS, and BRUENKER.
Claim 22 as unpatentable over CHA, KATZ, EMTAGE, DUAN, YAZAKI, BROWN, BARISH, SADELAIN, and KUJAWSKI as applied to claims 1, 3, 5, and 7-8, and further in view of WILLIAMS, HUMPHREYS, BRUENKER, and KATO.
Rejections I-VI above under 35 USC 103 are withdrawn in view of Applicant’s amendments to Claim 1, and Applicant’s remarks filed September 24, 2025. Specifically, Claim 1 requires the CAR to comprise a Fab that comprises a VH, a CH, a VL, and a CL domain. Applicant’s remarks recite that the receptor taught by DUAN differs from the CAR of CHA, KATZ, and EMTAGE and the other cited CAR references which are single chain CARs having a targeting domain, a co-stimulatory domain, and a CD3zeta signaling domain. The teachings of DUAN are not of a single chain CAR but of a heterodimer TCR. As such, the rejections are withdrawn.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over CHA 2020 (of record) in view of KUJAWSKI (of record) and Williams et al. US 9,574,014 (published 2017 and referred to herein as “WILLIAMS 2017”) as evidenced by YAZAKI 2005 (of record).
In regard to Claim 1, CHA 2020 teaches treating CEA-positive tumors in mice by administering anti-CEA CAR T-cells and an immunocytokine (ICK) comprising IL2 conjugated to a humanized anti-CEA antibody (abstract paragraph 2). The anti-CEA CAR construct was derived from murine anti-CEA antibody T84.66 (abstract paragraph 2).
In regard to Claims 2-8, CHA 2020 teaches that lymphodepletion via cyclophosphamide injection before anti-CEA T-cell therapy further delayed tumor growth (abstract paragraph 2). The ICK was injected after the anti-CEA CAR T-cells into lymphodepleted mice, and four injections of ICK after anti-CEA CAR T-cells eradicated tumors (abstract paragraph 2). Note, administering cyclophosphamide reads on Claim 8 as cyclophosphamide is an anti-cancer therapy. CHA 2020 teaches the administration order of cyclophosphamide followed by the anti-CEA CAR T-cells followed by four doses of ICK. CHA 2020 does not explicitly teach wherein the administrations are separated by 1 to 3 days or 1 to 5 days, but dosages and administration periods are results-effective variables which can be optimized. One of skill in the art would clearly recognize that doses must be timed sufficiently to maintain the efficacy of the drug in vivo and that the timing of dosages can be variable and could easily be optimized by a treating physician based on the needs and physiology of an individual patient. As such, the administration periods would amount to nothing more than routine experimentation that can be optimized on an individual patient basis (see In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977); and In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)). " Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As administration period optimization is routine in the art of medicine and pharmacology, the claims are considered to be prima facie obvious.
CHA 2020 fails to teach treating with stereotactic radiation therapy (SRT) (Claim 1) or wherein the ICK comprises CDR SEQ ID NOs: 7-9 and 11-13 (Claim 1).
KUJAWSKI teaches treating CEA-positive tumor models with an anti-CEA-IL-2 ICK in combination with stereotactic tumor irradiation (SRT) (abstract). SRT is commonly used in cancer therapy and has immunomodulatory effects, and SRT in combination with ICK resulted in greater tumor inhibition (abstract). The ICK was generated by fusion of human IL-2 to the antibody M5A (results paragraph 1) wherein M5A is a humanized version of the anti-CEA antibody T84.66 (introduction paragraph 1). KUJAWSKI teaches that the protein sequences of M5A heavy and light chain have been previously published. As evidenced by YAZAKI 2005, the heavy and light CDR sequences of M5A are 100% identical to instant SEQ ID NOs: 11-13 and 7-9, respectively (Figure 3).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute equivalents, each of which is taught by the prior art to be useful for the same purpose (MPEP 2144.06-II). Specifically, it would have been obvious to substitute the generic anti-CEA-IL-2 ICK taught by CHA 2020 with the specific anti-CEA-IL-2 ICK comprising the M5A antibody as taught by KUJAWSKI because both ICKs comprise the same domains and are both used to treat CEA-expressing tumors. It would have been obvious to combine SRT in combination with anti-CEA-IL-2 ICK treatment, because KUJAWSKI teaches that the combination resulted in greater tumor inhibition. The motivation to increase tumor inhibition is to more effectively treat the cancer, and combination therapy is standard of care in oncology.
CHA 2020 fails to teach wherein the anti-CEA CAR comprises an antigen-binding domain Fab comprising a VH, a CH, a VL, and a CL; CDR SEQ ID NOs: 7-9 and 11-13; a spacer domain comprising SEQ ID NO: 35; a CD28 transmembrane domain comprising SEQ ID NO: 21; a CD28 co-stimulatory domain comprising SEQ ID NO: 48; and a CD3zeta cytoplasmic signaling domain comprising SEQ ID NO: 39 (Claim 1).
WILLIAMS 2017 teaches CAR formats wherein the antigen-binding fragment is a Fab comprising a VH, a CH, a VL, and a CL (Figure 1A, Figure 1A caption, Claims 1-2, col. 31 lines 38-59, col. 61 lines 64-67). CARs specific for CEA can comprise murine T84.66 or humanized M5A antibody fragments (Figures 7 and 8 captions). Note, as evidenced by YAZAKI 2005 above, the heavy and light CDR sequences of M5A are 100% identical to instant SEQ ID NOs: 11-13 and 7-9, respectively (YAZAKI 2005 Figure 3). WILLIAMS 2017 teaches a CAR comprising an anti-Her2 Fab – spacer – CD28 transmembrane – CD28 costimulatory domain – CD3zeta cytoplasmic signaling domain comprising SEQ ID NO: 17 (col. 71-74). SEQ ID NO: 17 comprises instant SEQ ID NOs: 35, 21, 48, and 39 (col. 71-74). The domains are individually defined wherein SEQ ID NOs: 20-21 are 100% identical to instant SEQ ID NO: 35; SEQ ID NO: 22 is 100% identical to instant SEQ ID NO: 21; SEQ ID NO: 23 is 100% identical to instant SEQ ID NO: 48; and SEQ ID NO: 25 is 100% identical to instant SEQ ID NO: 39 (col. 73-74). It is understood from WILLIAMS 2017 that the antigen-binding fragments of the CAR can be exchanged depending on the desired antigen target (col. 47 line 30 to col. 48 line 36). Therefore, it would be obvious to substitute the anti-HER2 Fab on SEQ ID NO: 17 for an anti-CEA Fab as CEA is taught as an alternate CAR target. It would be obvious to make the scFv anti-CEA (Figures 7 and 8 captions) a Fab anti-CEA, because WILLIAMS 2017 teaches that both scFv and Fab antigen-binding fragments can be used on the CARs (Figure 1A, Figure 1A caption, col. 31 lines 38-59). Further, one of ordinary skill would understand that scFv and Fabs both comprise the same VH and VL domains that are responsible for antigen-binding, and only differ in that the Fab further comprises a CH and CL domain. The CARs can be administered to treat cancer (col. 2 lines 48-67).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute the generic anti-CEA CARs taught CHA 2020 with the specific anti-CEA-CARs comprising SEQ ID NOs: 7-9, 11-13, 21, 35, 39, and 48 as taught by WILLIAMS 2017 because both anti-CEA-CARs are used to target T-cells to CEA-expressing tumor cells. WILLIAMS 2017 teaches that it was understood in the art that a Fab antibody fragment could be used instead of a scFv antibody fragment on the extracellular antigen-binding region of the CAR. Further, WILLIAMS 2017 teaches that the anti-CEA antigen-binding fragment can comprise the CDR sequences of antibody M5A and teaches the sequences for the standard CAR components (spacer, transmembrane domain, co-stimulatory domain, cytoplasmic signaling domain). One of ordinary skill could have combined the elements by known methods, and in combination, each element merely performs the same function as it does separately with predictable results. CHA 2020 teaches the method of treatment using anti-CEA-CAR T-cells but does not elaborate on the specific sequences for the anti-CEA-CAR. One of ordinary skill wanting to apply the method of CHA 2020 would rely on the state of the art to teach the specific format and amino acid sequence of an anti-CEA-CAR (as provided in WILLIAMS 2017) to make and use the method of treatment.
Claims 1-8 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over CHA 2020 (of record) in view of KUJAWSKI (of record) and WILLIAMS 2017 as evidenced by YAZAKI 2005 (of record) as applied to Claims 1-8 above, and further in view of WILLIAMS 2012 (of record), HUMPHREYS (of record), and BRUENKER (of record).
The teachings of CHA, KUJAWSKI, and WILLIAMS 2017 are summarized above and teach a method for treating cancer comprising administering SRT, anti-CEA-CAR T-cells, and anti-CEA-IL-2 ICK. While the teachings of CHA, KUJAWSKI, and WILLIAMS 2017 teach the CDR sequences of anti-CEA, they do not disclose the Fab amino acid sequences as recited in claim 13, specifically a Fab comprising VL (SEQ ID NO: 61), CL (SEQ ID NO: 62), VH (SEQ ID NO: 63), and CH1 (SEQ ID NO: 64). Note, the VL, CL, VH, and CH1 domains defined in Claim 13 are interpreted as the same VL, CL, VH, and CH domains, respectively, defined in lines 7-9 of Claim 1. The teachings of CHA, KUJAWSKI, and WILLIAMS 2017 do not disclose wherein the Fab comprises SEQ ID NO: 65 (Claim 14).
WILLIAMS 2012 discloses an anti-CEA VL, CL, and VH comprising SEQ ID NOs: 69, 68, and 70 that are 100% identical to the amino acid SEQ ID NOs: 61, 62 and 63, respectively (paragraph [0020], Fig. 56, and Fig. 56 caption). HUMPHREYS discloses a wild type human Fab CH1 domain comprising SEQ ID NO: 9 which is 100% identical to instant SEQ ID NO: 64 (paragraphs [0069]-[0070]).
SEQ ID NO: 65 [1-131] has an amino acid sequence 100% similarity to VL (SEQ ID NO: 61); SEQ ID NO: 65 [132-238] has an amino acid sequence 100% similarity to CL (SEQ ID NO: 62); SEQ ID NO: 65 [239-270] has an amino acid sequence GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGG; SEQ ID NO: 65 [271-391] has an amino acid specific 100% similarity to VH (SEQ ID NO: 63); SEQ ID NO: 65 [392-499] has an amino acid specific 100% similarity to VH (SEQ ID NO: 64). BRUENKER discloses “Fab fragments are connected via a peptide linker… the Fab fragments are linked by peptide bonds, either directly or via one or more peptide linker” (paragraph [0053]), and that a Fab linker sequence can comprise SEQ ID. NO: 147 (paragraph [0053] and page 98) which is 100% identical to instant SEQ ID NO: 65 [239-270] GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGG.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to combine the teachings of CHA, KUJAWSKI, and WILLIAMS 2017 with WILLIAMS 2012, HUMPHREYS, and BRUENKER to result in the amino acid structures for the anti-CEA Fab as recited in Claims 13-14. CHA, KUJAWSKI, and WILLIAMS 2017 teach the method comprising administering anti-CEA-CAR T-cells wherein the CAR comprises an anti-CEA Fab, motivating a person of ordinary skill to use the known anti-CEA VH and VL domains taught by WILLIAMS 2012 in an anti-CEA Fab with a reasonable expectation of success. Further, HUMPHREYS teaches a wild type human Fab CH1 domain, and BRUENKER teaches a known linker sequence used to connect the Fab domains via a peptide linker. One of ordinary skill would understand that the VH and VL domains of a Fab are the antigen-specific portions, and the CH, CL, and linker regions act as a framework that can be altered without affecting antigen-binding. The teachings of HUMPHREYS and BRUENKER are generic to all Fab fragments and could be applied to the known anti-CEA VH and VL domains with a reasonable expectation of success.
Claims 1-8, 13-14, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over CHA 2020 (of record) in view of KUJAWSKI (of record), WILLIAMS 2017, WILLIAMS 2012 (of record), HUMPHREYS (of record), and BRUENKER (of record) as applied to Claims 1-8 and 13-14 above, and further in view of KATO (of record).
The teachings of CHA 2020, KUJAWSKI, WILLIAMS 2017, WILLIAMS 2012, HUMPHREYS, and BRUENKER as outlined above teach a method for treating cancer comprising administering SRT, anti-CEA-CAR T cells, and anti-CEA-IL-2 ICK wherein the anti-CEA-CAR comprises an anti-CEA Fab comprising SEQ ID NO: 65. In regard to the CAR of Claim 22 comprising SEQ ID NO: 66:
CAR comprises SEQ ID NO: 66 [1-812]
CAR SEQ ID No. 66 [1-499] has an amino acid sequence 100% similarity to Fab (SEQ ID No. 65);
CAR SEQ ID No. 66 [500-628] has an amino acid sequence 100% similarity to spacer domain (SEQ ID No. 35);
CAR SEQ ID No. 66 [629-656] has an amino acid sequence 100% similarity to CD28 transmembrane domain (SEQ ID No. 21);
CAR SEQ ID No. 66 [657-697] has an amino acid sequence 100% similarity to CD28 co-stimulatory domain (SEQ ID No. 48);
CAR SEQ ID No. 66 [698-700] has amino acid sequence GGG is a linker positioned between co-stimulatory domain and the CD3ζ signaling domain;
CAR SEQ ID No. 66 [701-812] has an amino acid sequence 100% similarity to CD3ζ (SEQ ID No. 39).
Specific to the CAR construct (SEQ ID NO: 66), WILLIAMS 2012, HUMPHREYS, AND BRUENKER disclose amino acid sequences with 100% similarity to SEQ ID No. 65 (see above Claim 14 rejection for detailed explanation as to why it is obvious to combine these references with the teachings of CHA 2020, KUJAWSKI, and WILLIAMS 2017). As outlined in the rejection above pertaining to Claim 1, WILLIAMS 2017 teaches a CAR comprising an anti-Her2 Fab – spacer – CD28 transmembrane – CD28 costimulatory domain – CD3zeta cytoplasmic signaling domain comprising SEQ ID NO: 17 (col. 71-74). SEQ ID NO: 17 comprises instant SEQ ID NOs: 35, 21, 48, and 39 with a GGG linker between the CD28 co-stimulatory domain and the CD3zeta cytoplasmic signaling domain (col. 71-74). Therefore, residues 246-558 of WILLIAMS 2017 SEQ ID NO: 17 are 100% identical to residues 500-812 of instant SEQ ID NO: 66. It is outlined in the rejections above why it is obvious to substitute the anti-HER2 Fab of SEQ ID NO: 17 with an anti-CEA Fab. Therefore, the previously cited prior art comprises all components of a CAR comprising SEQ ID NO: 66.
The teachings of CHA 2020, KUJAWSKI, WILLIAMS 2017, WILLIAMS 2012, HUMPHREYS, and BRUENKER do not disclose wherein the ICK comprises SEQ ID NOs: 60 and 54 (Claim 22).
ICK comprises SEQ ID NO: 60 [1-583]
ICK SEQ ID No. 60 [1-450] has an amino acid sequence 100% similarity to HC (SEQ ID No. 53).
ICK SEQ ID No. 60 [451-583] has amino acid sequence 100% similarity to IL2 (SEQ ID. No. 56).
Specific to the ICK construct, SEQ ID NO: 53 describes the anti-CEA heavy chain and SEQ ID NO: 54 describes the anti-CEA light chain. WILLIAMS 2012 discloses anti-CEA M5A antibody heavy chain comprising SEQ ID NO: 70 (paragraph [0020], Fig. 56, and Fig. 56 caption) which is 99.1% identical to instant SEQ ID NO: 53. The two sequences only differ by 4 amino acid substitutions in the constant domain of the antibody framework. One of ordinary skill would understand that amino acid substitutions in the constant region can be made without affecting antigen-binding function, as long as the variable domains remain the same (which is the case in the instant scenario). WILLIAMS 2017 also teaches the anti-CEA M5A antibody light chain protein comprising SEQ ID NO: 69 (paragraph [0020], Fig. 56, and Fig. 56 caption) which is 100% identical to instant SEQ ID No. 54. Therefore, the only aspect of ICK SEQ ID NOs: 54 and 60 not taught by the previously cited art is residues 451-583 of SEQ ID NO: 60 which encodes IL-2.
KATO discloses the amino acid sequence of IL-2 comprising SEQ ID NO: 1 (Fig. 1 and Fig. 1 caption) which is 100% identical to instant SEQ ID NO: 56.
It would have been obvious to combine the teachings of CHA 2020, KUJAWSKI, WILLIAMS 2017, WILLIAMS 2012, HUMPHREYS, and BRUENKER that teach a method comprising administering SRT, anti-CEA-CAR T-cells, and anti-CEA-IL-2 ICK wherein the CAR comprises SEQ ID NO: 66 with the known sequence of IL-2 taught by KATO. Specifically, CHA 2020 and KUJAWSKI are directed to administering an anti-CEA-IL-2 ICK to treat cancer, WILLIAMS 2012 teaches the sequences for the anti-CEA portion of the ICK, and KATO teaches the sequence for the IL-2 portion of the ICK. One of ordinary skill would be motivated to use an anti-CEA-IL-2 ICK to treat cancer from the teachings of CHA 2020 and KUJAWSKI, and it would be obvious to use known anti-CEA and IL-2 sequences to make the ICK with a reasonable expectation of success. The person of ordinary skill in the art would have found it obvious to make the substitutions for such elements for functional anti-CEA-IL-2 ICK to use in the method of treating cancer.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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