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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or
under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims the benefit of U.S. Provisional Application 63/224,061 filed on July 21, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 11, 2024 was filed, and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Application, Amendments and/or Claims
Claim listing filed on July 11, 2024 is pending. Claims 9-12 and 15-21 are cancelled. Claims 1, 7, 13, and 22 are amended. Following the amendment, Claims 1-8, 13-14, and 22 are examined in the instant office action.
Response to Amendments
Any rejection of record pertaining to newly canceled claims 9-12 and 15-21 have been rendered moot by applicant’s amendment.
Applicant’s amendment to the spelling of “cyclophosphamide” in Claim 7 has overcome the claim objection, therefore the claim objection is withdrawn.
The rejections of claims 13-14 under 35 USC 112(b) indefiniteness for lack of antecedent basis for “the Fab” are withdrawn in view of applicant’s amendments to the claims. In particular, the addition of “an antigen-binding fragment (Fab)” to Claim 1 provides antecedent basis.
The rejections of claims 1-22 under 35 USC 112(a) enablement are withdrawn in view of applicant’s arguments on pages 1-2 of Remarks filed 07/11/2024. Examiner agrees that murine studies are sufficient to establish therapeutic utility as stated in MPEP § 2107.03. Further, Yang 2016 teaches clinical trial NCT02349724 that administers CEA-targeting CAR T cells to treat CEA-positive tumors spanning pancreatic, lung, gastric, breast, and colorectal cancers (ClinicalTrials.gov attached in instant 892). Therefore, the state of the prior art supports enablement for the treatment of “cancer characterized by growth of tumor cells expressing CEA” (Claim 1) even though the instant specification only provides working examples in colon and breast cancers. Note, “treating” is not defined in the specification and is interpreted as alleviating the symptoms or complications of an established disease, delay the progression of an established disease, and/or cure or eliminate an established disease.
The rejection of claim 22 under 35 USC 112(d), is withdrawn in view of applicant’s amendments to the claim. In particular, adding “SEQ ID NO: 54” includes the ICK light chain variable domain limitation that was previously missing.
The following rejections under 35 USC 103 are withdrawn in view of applicant’s amendments to the claims:
Claims 1, 3, 5, and 7-8 as unpatentable over CHA 2020"), KATZ 2015, EMTAGE 2008, and YAZAKI 2005.
Claims 2 and 4 as unpatentable over CHA 2020, KATZ 2015, EMTAGE 2008, and YAZAKI 2005 as applied to claims 1, 3, 5, and 7-8, and further in view of THISTLETHWAITE.
Claim 6 as unpatentable over CHA 2020, KATZ 2015, EMTAGE 2008, and YAZAKI 2005 as applied to claims 1, 3, 5, and 7-8, and further in view of ZHANG.
Claim 13 as unpatentable over CHA 2020, KATZ 2015, EMTAGE 2008, and YAZAKI 2005 as applied to claims 1, 3, 5, and 7-8, and further in view of WILLIAMS and HUMPHREYS.
Claim 14 as unpatentable over CHA 2020, KATZ 2015, EMTAGE 2008, and YAZAKI 2005 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 2020, KATZ 2015, EMTAGE 2008, and YAZAKI 2005 as applied to claims 1, 3, 5, and 7-8, and further in view of WILLIAMS, HUMPHREYS, BRUENKER, BROWN, SADELAIN, BARISH, and KATO.
Rejections I-VI above under 35 USC 103 are withdrawn in view of applicant’s amendments to Claim 1. Specifically, changing the CAR that binds CEA from a scFV to a Fab and adding “treating the subject with SRT” overcome the previous rejections. The rejection of previous Claim 9 reads on treatment with SRT and a scFV CAR. The rejection of Claims 13-14 read on treatment with Fab CAR, but do not comprise SRT treatment. Because amended Claim 1 now comprises SRT treatment and a Fab CAR, the amendments overcome the previous rejections.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
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.
Claims 1, 3, 5, and 7-8 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over CHA 2020 (of record), KATZ 2015 (of record), EMTAGE 2008 (of record), DUAN (Duan et al. 2019 - instant 892), YAZAKI 2005 (of record), BROWN (of record), BARISH (of record), SADELAIN (of record), and KUJAWSKI (of record).
The claims are drawn to a method comprising administering:
1. Stereotactic radiation therapy (SRT)
2. T cells expressing a chimeric antigen receptor (CAR) that binds CEA wherein the CAR comprises a Fab, and
3. Anti-CEA-IL-2 immunocytokine (ICK).
The CAR that binds CEA comprises an antigen-binding fragment (Fab) that binds CEA (light chain [LC] and heavy chain [HC] complementary determining regions [CDR] comprising LC CDR1, LC CDR2, LC CDR3, HC CDR1, HC CDR2, and HC CDR3), a spacer (hinge) domain, a CD28 transmembrane domain, a CD28 co-stimulatory domain, and CD3ζ cytoplasmic signaling domain.
The anti-CEA-IL-2 ICK comprises a heavy chain variable domain (VH; HC CDR1, HC CDR2 and HC CDR3), a light chain variable domain (VL; LC CDR1, LC CDR2 and LC CDR3), and IL-2.
Regarding claim 1, CHA 2020 teaches a method comprising the administration of a population of T cells expressing a CAR that binds CEA and the administration of anti-CEA-IL-2 ICK. CHA 2020 discloses: [Abstract] “anti-CEA CAR construct derived from murine anti-CEA antibody (T84.66) expressed on human T-cells targeted CEA+ colon carcinoma cells.” Since the cell has the anti-CEA CAR construct that binds CEA, CHA 2020 teaches a CAR T-cell that binds CEA. CHA 2020 discloses: [Abstract] “To improve the therapeutic potential of anti-CEA CAR T-cells, IL2 was conjugated to a humanized anti-CEA antibody to form an immunocytokine (ICK). The ICK was injected interperitoneally after anti-CEA CAR T-cells…” Since the IL2 was conjugated to an anti-CEA antibody, CHA 2020 teaches an anti-CEA-IL-2 ICK.
However, specific to the anti-CEA CAR, CHA 2020 does not disclose the design of the CAR construct. KATZ 2015 discloses the clinical trial NCT01373047 (CEA-Expressing Liver Metastases Safety Study of Intrahepatic Infusions of Anti-CEA Designer T-Cells [HITM]; RWH 11-335-99) and teaches the techniques for the design of a CAR construct (CAR MN14 scFv-CD8hinge-CD28–CD3ζ; humanized scFv; pg. 3) and administration of the second-generation CEA specific CAR T-cells and combination therapy. KATZ 2015 discloses: (pg. 2) “We utilized a second generation anti-CEA CAR, containing the CD28 co-stimulatory and CD3ζ signaling domains. We treated an initial cohort with CAR-T HAI (hepatic artery infusions) intra-patient dose escalations without IL2 support and a second cohort that received fixed CAR-T doses with continuous IL2 infusions…” (pg. 3) “Human CAR-T cell production The 2nd generation anti-CEA scfv-CD28/CD3ζ (Tandem) chimeric antigen receptor was cloned into the MFG retroviral backbone as previously described (FDA BB IND 10791) (Emtage 2008)… Briefly, the tandem molecule was generated by fusing the hMN14 sFv-CD8 hinge segment of the IgTCR (IgCEA) in the MFG retroviral backbone with a hybrid CD28/CD3ζ molecule.” More specifically, EMTAGE 2008 discloses the molecular construction and expression of the tandem construct: (pg. 8115) “Fig. 1 Anti-CEA IgCD28TCR molecular construction and expression. A… The IgCD28TCR construct was created from IgTCR by molecular insertion of the complete CD28 transmembrane (TM) and cytoplasmic domains and a portion of the CD28 extracellular domain (ED). A, schematic representation of surface expressed molecules. B, molecular design of colinear constructs… sFv-CD8α hinge and TCRζ cytoplasmic domains.” KATZ 2015 teaches the design of a CAR construct (CAR MN14 scFv-CD8hinge-CD28–CD3ζ; humanized scFv; pg. 3), which meets the limitations of the anti-CEA CAR comprising a spacer domain (CD8 hinge), a transmembrane domain (CD28), a co-stimulatory domain (CD28) and CD3ζ cytoplasmic, intracellular signaling domain.
Given CHA 2020 teaches a method comprising administering T cells expressing a CAR that binds CEA and anti-CEA-IL-2 ICK, and KATZ 2015 and EMTAGE 2008 teach a second-generation anti-CEA CAR construct comprising a spacer domain, a transmembrane domain, a co-stimulatory domain and a CD3ζ cytoplasmic signaling domain and the administration of the CEA specific CAR T-cells and combination IL2 therapy, it would have been obvious to combine the teachings of CHA 2020 and KATZ 2015 and EMTAGE 2008, to develop and administer second-generation T cells expressing CAR that binds CEA and anti-CEA-IL-2 ICK for combination cancer immunotherapy for treatment of CEA-positive solid tumors. It would have been obvious to combine the teachings of CHA 2020 and KATZ 2015 and EMTAGE 2008 because CHA 2020 teaches a method comprising administering anti-CEA CAR T-cells and anti-CEA-IL-2 ICK to treat cancer, motivating a person of ordinary skill to use the known anti-CEA CAR design (anti-CEA CAR comprising a spacer domain, a CD28 transmembrane domain, a CD28 co-stimulatory domain and CD3ζ cytoplasmic, intracellular signaling domain) such as that taught by KATZ 2015 and EMTAGE 2008.
However, CHA 2020, KATZ 2015, and EMTAGE 2008 do not disclose the anti-CEA comprising a Fab. The construct taught by KATZ 2015 specifically comprises a scFv. DUAN teaches that scFv CAR constructs can have low target affinity, but the development of a Fab CAR construct recognizes the tumor antigens independent of MHC/peptide complex and extend the life span of CAR-engineered T cells to generate durable clinical effects (abstract). “The 2nd generation CARs include CD28 co-stimulatory signaling domains to enhance T-cell activation, persistence, and antitumor efficacy…One of the reasons for unsatisfying clinical results might be the relative lower affinity of scFv…For overcoming this drawback, we designed a novel chimeric antigen receptor that incorporated the antibody Fab fragment in tandem with natural TCR intracellular signaling domain…The stability and affinity of Fab fragment are superior to scFv fragment, using the Fab instead of scFv could completely avoid the issue of aggregation of scFv and retains the high affinity of antibody to its antigen” (Discussion).
It would have been obvious to one of ordinary skill in the art at the time of filing to modify the CAR construct as taught in KATZ 2015 to comprise a Fab fragment instead of an scFv as taught in DUAN. The Fab CAR construct as taught in DUAN is compatible with 2nd and 3rd generation CAR co-stimulatory signaling domains, and has superior function over scFv. Therefore, it would have been obvious to modify the known CAR construct of KATZ 2015 to comprise a Fab instead of scFv with a reasonable expectation of success in improving the function of the CAR construct as taught in DUAN. It is obvious to use the improved Fab construct in the anti-CEA CAR cancer treatment as taught by CHA 2020.
CHA 2020, KATZ 2015, EMTAGE 2008, and DUAN teach a method for treating cancer comprising administering T cells expressing a CAR that binds CEA and anti-CEA-IL-2 ICK wherein the CAR comprises a Fab. However, specific to the anti-CEA CAR Fab and anti-CEA-IL-2 ICK VH and VL constructs, CHA 2020, KATZ 2015, EMTAGE 2008, and DUAN do not disclose the sequences specific to the light chain [LC] and heavy chain [HC] complementary determining regions [CDR] comprising LC CDR1 (SEQ ID No. 7), LC CDR2 (SEQ ID No. 8), LC CDR3 (SEQ ID No. 9), HC CDR1 (SEQ ID No. 11), HC CDR2 (SEQ ID No. 12), and HC CDR3 (SEQ ID No. 13). As to claim 1, the VH and VL of the anti-CEA CAR are identical to the VH and VL of the anti-CEA-IL2 ICK. YAZAKI 2005 discloses [0019] “FIG. 3: Structure-based sequence alignment of T84.66 variable light (VL) and variable heavy (VH) domains with Herceptin, M5A, and M5B” and teaches VL (LC CDR1, LC CDR2 and LC CDR3) and VH (HC CDR1, HC CDR2 and HC CDR3) amino acid sequences 100% identical to SEQ ID Nos. 7, 8, 9, 11, 12, and 13.
VL:
LC CDR1 SEQ ID No. 7: RAGESVDIFGVGFLH
LC CDR2 SEQ ID No. 8: RASNLES
LC CDR3 SEQ ID No. 9: QQTNEDPYT
PNG
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200
400
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Greyscale
VH:
HC CDR1 SEQ ID No. 11: DTYMH
HC CDR2 SEQ ID No. 15: RIDPANGNSKYVPKFQ (Note: HC CDR2 SEQ ID NO: 15 is pictured here, but SEQ ID NO: 12 is an alternate HC CDR2 taught by YAZAKI below in the red box.)
HC CDR3 SEQ ID No. 13: FGYYVSDYAMAY
PNG
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200
400
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HC CDR2 SEQ ID No. 12: RIDPANGNSKYADSVKG:
PNG
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637
410
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Greyscale
It would have been obvious to combine the teachings of CHA 2020 and YAZAKI 2005 because CHA 2020 teaches a method comprising administering anti-CEA CAR T-cells and anti-CEA-IL-2 ICK to treat cancer, motivating a person of ordinary skill to use the known anti-CEA CDRs as taught by YAZAKI 2005 for both the anti-CEA CAR and anti-CEA-IL-2 ICK constructs.
In regard to the specific sequence of the spacer domain (SEQ ID NO: 35), CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, and YAZAKI 2005 teach a method for treating cancer comprising administering T cells expressing a CAR that binds CEA and anti-CEA-IL-2 ICK. CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, and YAZAKI 2005 do not disclose the spacer domain amino acid sequences. BROWN (of record) discloses an amino acid sequence 100% similarity to amino acid SEQ ID NO: 35.
Spacer domain Seq ID 35.
SEQ ID NO: 35
ESKYGPPCPP CPGGGSSGGG SGGQPREPQV YTLPPSQEEM TKNQVSLTCL VKGFYPSDIA 60
VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ 120
KSLSLSLGK 129
RESULT
US-15-167-869-20
Sequence 20, US/15167869
Patent No. 9914909
GENERAL INFORMATION
APPLICANT: CITY OF HOPE
TITLE OF INVENTION: COSTIMULATORY CHIMERIC ANTIGEN RECEPTOR T CELLS TARGETING
TITLE OF INVENTION: IL13R-ALPHA-2
FILE REFERENCE: 40056-0002WO1
CURRENT APPLICATION NUMBER: US/15/167,869
CURRENT FILING DATE: 2016-05-27
PRIOR APPLICATION NUMBER: PCT/US2015/051089
PRIOR FILING DATE: 2015-09-18
PRIOR APPLICATION NUMBER: 62/053,068
PRIOR FILING DATE: 2014-09-19
NUMBER OF SEQ ID NOS: 54
SEQ ID NO 20
LENGTH: 129
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
NAME/KEY: source
OTHER INFORMATION: /note="Description of Artificial Sequence: Synthetic
polypeptide"
Query Match 100.0%; Score 710; Length 129;
Best Local Similarity 100.0%;
Matches 129; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA 60
Qy 61 VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ 120
Qy 121 KSLSLSLGK 129
|||||||||
Db 121 KSLSLSLGK 129
It would have been obvious to combine the teachings of CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, and YAZAKI 2005 with BROWN (the method comprising administering anti-CEA CAR T-cells and anti-CEA-IL-2 ICK) with the spacer domain taught by BROWN. A skilled artisan would have expected success in substituting the spacer domain, as the CAR construct includes a spacer (hinge) domain in the design (KATZ 2015). The person of ordinary skill in the art would have found it obvious to make the substitution of a spacer domain for another known spacer domain to provide flexibility, length and positioning of the CAR to the target antigen.
In regard to the specific sequences of the CD28 transmembrane domain (SEQ ID NO: 21), the CD28 co-stimulatory domain (SEQ ID NO: 48), and the CD3ζ cytoplasmic signaling domain (SEQ ID NO: 39), CHA 2020, KATZ 2015, EMTAGE 2008, DUAN YAZAKI 2005, and BROWN do not disclose CD28 transmembrane domain, CD28 co-stimulatory domain, and CD3ζ cytoplasmic signaling domain amino acid sequences.
In regard to the specific sequences of the CD28 transmembrane domain and the CD28 co-stimulatory domain, BARISH discloses amino acid sequences with 100% similarity to amino acid SEQ ID No. 21 and SEQ ID No. 48.
SEQ ID No: 21
US-15-767-960A-45
Sequence 45, US/15767960A
Patent No. 11230577
GENERAL INFORMATION
APPLICANT: CITY OF HOPE
TITLE OF INVENTION: CHIMERIC ANTIGEN RECEPTORS CONTAINING A CHLOROTOXIN DOMAIN
FILE REFERENCE: 40056-0024US1
CURRENT APPLICATION NUMBER: US/15/767,960A
CURRENT FILING DATE: 2018-04-12
PRIOR APPLICATION NUMBER: PCT/US2016/056901
PRIOR FILING DATE: 2016-10-13
PRIOR APPLICATION NUMBER: US 62/241,021
PRIOR FILING DATE: 2015-10-13
NUMBER OF SEQ ID NOS: 77
SEQ ID NO 45
LENGTH: 230
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: chimeric CLTX-L-CD28tm-CD28-zeta excluding signal
Query Match 100.0%; Score 146; Length 230;
Best Local Similarity 100.0%;
Matches 28; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MFWVLVVVGGVLACYSLLVTVAFIIFWV 28
||||||||||||||||||||||||||||
Db 47 MFWVLVVVGGVLACYSLLVTVAFIIFWV 74
SEQ ID No: 48
US-15-767-960A-45
Sequence 45, US/15767960A
Patent No. 11230577
GENERAL INFORMATION
APPLICANT: CITY OF HOPE
TITLE OF INVENTION: CHIMERIC ANTIGEN RECEPTORS CONTAINING A CHLOROTOXIN DOMAIN
FILE REFERENCE: 40056-0024US1
CURRENT APPLICATION NUMBER: US/15/767,960A
CURRENT FILING DATE: 2018-04-12
PRIOR APPLICATION NUMBER: PCT/US2016/056901
PRIOR FILING DATE: 2016-10-13
PRIOR APPLICATION NUMBER: US 62/241,021
PRIOR FILING DATE: 2015-10-13
NUMBER OF SEQ ID NOS: 77
SEQ ID NO 45
LENGTH: 230
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: chimeric CLTX-L-CD28tm-CD28-zeta excluding signal
Query Match 100.0%; Score 231; Length 230;
Best Local Similarity 100.0%;
Matches 41; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 41
|||||||||||||||||||||||||||||||||||||||||
Db 75 RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 115
As to the CD3ζ cytoplasmic signaling domain comprising SEQ ID No. 39, SADELAIN discloses an amino acid sequence 100% similarity to amino acid SEQ ID No. 39.
SEQ ID No: 39
RESULT
US-10-448-256C-14
Sequence 14, US/10448256C
Patent No. 7446190
GENERAL INFORMATION
APPLICANT: Sadelain, Michel
APPLICANT: Brentjens, Renier
APPLICANT: Maher, John
TITLE OF INVENTION: Chimeric T Cell Receptors
FILE REFERENCE: MSK.P-058
CURRENT APPLICATION NUMBER: US/10/448,256C
CURRENT FILING DATE: 2003-05-28
PRIOR APPLICATION NUMBER: 60/383,872
PRIOR FILING DATE: 2002-05-28
NUMBER OF SEQ ID NOS: 23
SEQ ID NO 14
LENGTH: 112
TYPE: PRT
ORGANISM: homo sapiens
Query Match 100.0%; Score 593; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 60
Qy 61 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 112
SADELAIN discloses: [0018] The zeta chain portion sequence employed in the present application includes the intracellular domain. This domain, which spans amino acid residues 52-163 (Seq. ID No: 14 (nucleotides 154-489, Seq. ID No. 3) of the human CD3 zeta chain… [0019] “CD28 sequences can be found in the present application on either side of the zeta chain portion sequence. In either case, the CD28 sequences include the signaling elements from CD28. In one embodiment, where CD28 is between the zeta chain portion and the scFv, the CD28 portion suitably includes the transmembrane and signaling domains of CD28.”
It would have been obvious to combine the teachings of CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, and BROWN with BARISH and SADELAIN because CHA 2020, KATZ 2015, EMTAGE 2008 DUAN, YAZAKI 2005, and BROWN teach the method comprising administering anti-CEA CAR T-cells wherein the CAR construct comprises a CD28 transmembrane, a CD28 co-stimulatory domain, and a CD3ζ cytoplasmic signaling domain. It would be obvious to use the exact structures of these domains as taught by BARISH (CD28 transmembrane domain and CD28 co-stimulatory domain) and SADELAIN (CD3ζ cytoplasmic signaling domain). A skilled artisan would have expected success in substituting the known elements of the CD28 transmembrane, CD28 co-stimulatory, and CD3ζ cytoplasmic signaling domains, because the CAR construct as taught by KATZ 2015 includes the known elements in the design. The person of ordinary skill in the art would have found it obvious to make the substitutions.
In regard to treating the subject with SRT, CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, and SADELAIN teach a method for treating cancer comprising administering T cells expressing a CAR that binds CEA and anti-CEA-IL-2 ICK. CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, and SADELAIN do not disclose treating the subject with stereotactic radiation therapy (SRT). KUJAWSKI discloses the method for Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of SRT. KUJAWSKI discloses the composition of anti-CEA-IL-2 ICK (“fusion protein of humanized anti-CEA with human IL-2 [M5A-IL-2]”), the method comprising treating the subject with anti-CEA-IL-2 ICK, and the method of treatment further comprising treatment with an additional anti-cancer therapy such as SRT (“commonly used in cancer therapy”) (Abstract pg. 1). It would have been obvious to combine the teachings of CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, and SADELAIN (a method for treating cancer comprising administering T cells expressing a CAR that binds CEA and anti-CEA-IL-2 ICK) with the teachings of KUJAWSKI (a method for treating cancer comprising administering anti-CEA-IL-2 ICK and SRT) to obtain predictable results. Both methods of treating cancer target tumor cells expressing CEA, and combination therapy is an established cancer treatment strategy.
As to claim 3, specific to administration of at least one additional dose of the anti-CEA-IL-2 ICK, CHA 2020 discloses: [Abstract] “A single injection of the ICK delayed subcutaneous MC38CEA tumor growth even further. Four injections of ICK after anti-CEA CAR T-cells eradicated subcutaneous MC38CEA tumors.” Since four injections of ICK were administered, CHA 2020 teaches the administration of more than one dose of anti-CEA-IL-2 ICK.
As to claim 5, specific to administering a lymphodepleting agent, CHA 2020 discloses: [Abstract] “Lymphodepletion via cyclophosphamide injected before anti-CEA T-cells therapy further delayed subcutaneous MC38CEA tumor growth…” CHA 2020 teaches lymphodepletion with an injection of a lymphodepleting agent, which meets the limitations of claim 5.
As to claim 7, specific to administration of lymphodepleting agent cyclophosphamide, CHA 2020 discloses: [Abstract] “Lymphodepletion via cyclophosphamide injected before anti-CEA T-cells therapy further delayed subcutaneous MC38CEA tumor growth…” CHA 2020 teaches lymphodepletion with an injection of a lymphodepleting agent cyclophosphamide before administration of CAR T-cells, which meets the limitations of claim 7.
As to claim 8, specific to treatment with an additional anti-cancer therapy, CHA 2020 discloses: [Abstract] “Lymphodepletion via cyclophosphamide injected before anti-CEA T-cells injection… to improve the therapeutic potential of anti-CEA CAR T-cells, IL2 conjugated to humanized anti-CEA antibody (M5A-IL2, ICK) was interperitoneally injected after anti-CEA CAR T-cells…” CHA 2020 teaches the administration of additional anti-cancer therapy such as lymphodepleting agent cyclophosphamide and additional doses of anti-CEA-IL-2 ICK. CHA 2020 teaches lymphodepletion with an injection of a lymphodepleting agent cyclophosphamide, which meets the limitations of claim 8 because cyclophosphamide is an established type of anti-cancer chemotherapy used to treat cancer.
Claims 2 and 4 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over CHA 2020 (of record), KATZ 2015 (of record), EMTAGE 2008 (of record), DUAN (Duan et al. 2019 - instant 892), YAZAKI 2005 (of record), BROWN (of record), BARISH (of record), SADELAIN (of record), and KUJAWSKI (of record) as applied to claims 1, 3, 5, and 7-8 listed above, and further in view of THISTLETHWAITE (of record).
As to claim 2, specific to the administration of population of T-cells prior to administration of the anti-CEA-IL-2 ICK, CHA 2020 discloses: [Abstract] “The ICK was injected interperitoneally after anti-CEA CAR T-cells…” CHA 2020 teaches the administration of anti-CEA CAR T-cells prior to administering the anti-CEA-IL-2 ICK. KATZ 2015 discloses: (pg. 2) “We treated an initial cohort with CAR-T HAI (hepatic artery infusions) intra-patient dose escalations without IL2 support and a second cohort that received fixed CAR-T doses with continuous IL2 infusions.” CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI do not disclose the administration of a population of T cells 1-3 days prior to administering the anti-CEA-IL-2 ICK.
THISTLETHWAITE discloses: pg. 1426 “All patients received pre-conditioning chemotherapy, MFEζ T cells then intravenous IL2 therapy… Patients in cohort 4 received maximum MFEζ T cell dose with cyclophosphamide (60 mg/kg/day for 2 days) prior to fludarabine (25 mg/m2/day for 5 days) chemotherapy. All patients received IV IL2 (600,000 IU/Kg 15-min infusion every 8 h maximum 12 doses). IL2 was commenced 90 min after MFEζ T cells. Criteria for IL2 dose delay, reduction or discontinuation defined within the protocol resulted in administration of a variable number of IL2 doses,” with the number of IL2 infusions ranging from 3-12 infusions (THISTLEWAITE, Table 2).
The MPEP states [2144.05 II. ROUTINE OPTIMIZATION A. Optimization Within Prior Art Conditions or Through Routine Experimentation]: "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions." It would have been obvious to combine the teachings of CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI with THISTLEWAITE because a person of ordinary skill in the art would have recognized the known technique of administering a population of T cells expressing anti-CEA CAR prior to anti-CEA-IL-2 ICK as taught by CHA 2020 combined with known technique of administration of MFEζ T cells prior to intravenous IL2 therapy as taught by THISTLEWAITE. The person of ordinary skill in the art would further have predicted the combination and recognized that the order of administration was known and that the spacing was variable, leading to routine optimization of that variance, with the administration of a population of T-cells administered 1-3 days prior to the administration of anti-CEA-IL-2 ICK or IL2 for combination therapy, with routine optimization based on the criteria for anti-CEA-IL-2 ICK dose delay.
As to claim 4, specific to administration of 3-6 doses of the anti-CEA-IL-2 ICK, each administered 1-5 days after the prior dose, CHA 2020 discloses: [Abstract] “A single injection of the ICK delayed subcutaneous MC38CEA tumor growth even further. Four injections of ICK after anti-CEA CAR T-cells eradicated subcutaneous MC38CEA tumors.” CHA 2020 teaches the administration of 4 doses of anti-CEA-IL-2 ICK, which meets the limitations of claim 4 of administration of 3-6 doses. KATZ 2015 teaches administering a fixed CAR-T doses with continuous IL2 infusions. CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI do not disclose the administration of the anti-CEA-IL-2 ICK 1-5 days after the prior dose. THISTLETHWAITE teaches the administration of a variable number of IL2 doses ranging from 3-12 infusions, with the infusion every 8 hours and a maximum of 12 doses. It would have been obvious to combine the teachings of CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI with THISTLEWAITE because a person of ordinary skill in the art would have recognized applying the known technique of administering anti-CEA-IL-2 ICK or IL2 for combination therapy, including 3-6 doses, each administered 1-5 days after the prior dose, with routine optimization based on the criteria for anti-CEA-IL-2 ICK dose delay.
Claim 6 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over CHA 2020 (of record), KATZ 2015 (of record), EMTAGE 2008 (of record), DUAN (Duan et al. 2019 - instant 892), YAZAKI 2005 (of record), BROWN (of record), BARISH (of record), SADELAIN (of record), and KUJAWSKI (of record) as applied to claims 1, 3, 5, and 7-8 listed above, and further in view of ZHANG 2017 (of record).
As to claim 6, specific to administration of a lymphodepleting agent prior to administration of the population of T cells, CHA 2020 discloses: [Abstract] “Lymphodepletion via cyclophosphamide injected before anti-CEA T-cells therapy further delayed subcutaneous MC38CEA tumor growth…” CHA 2020 teaches lymphodepletion with an injection of a lymphodepleting agent before administration of CAR T-cells. CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI do not disclose the administration of lymphodepleting agent 1-3 days prior to administering the population of T cells.
ZHANG 2017 teaches (pg. 1248-1249) “To improve the efficacy of CAR-T therapy, we used lymphodepletion before CAR-T cell infusion.” ZHANG 2017 discloses the trial schedule specific to the administration of the lymphodepleting agent cyclophosphamide 2 days prior to administering the population of T cells (Figure 1 Procedure of Clinical Trial and Characteristics of CAR-T Cells (A) Trial schedule; pg. 1249). It would have been obvious to combine the teachings of CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI (a known method for treating cancer comprising administering a lymphodepleting agent prior to administering a population of T cells expressing anti-CEA CAR) with the teachings of ZHANG 2017 (specifically administering the lymphodepleting agent 1 to 3 days prior to the population of T cells) to obtain predictable results.
Claim 13 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over CHA 2020 (of record), KATZ 2015 (of record), EMTAGE 2008 (of record), DUAN (Duan et al. 2019 - instant 892), YAZAKI 2005 (of record), BROWN (of record), BARISH (of record), SADELAIN (of record), and KUJAWSKI (of record) as applied to claims 1, 3, 5, and 7-8 listed above, and further in view of WILLIAMS (of record) and HUMPHREYS (of record).
CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI teach a method for treating cancer comprising administering T cells expressing a CAR that binds CEA and anti-CEA-IL-2 ICK. CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI do not disclose the Fab amino acid sequence as to claim 13, specific to the Fab comprising VL (SEQ ID No. 61), CL (SEQ ID No. 62), VH (SEQ ID No. 63), and CH1 (SEQ ID No. 64). WILLIAMS discloses that VL, CL, and VH that have amino acid sequences at 100% similarity to amino acid SEQ ID No. 61, SEQ ID No. 62 and SEQ ID No. 63; and HUMPHREYS discloses that the CH1 has an amino acid sequence 100% similarity to amino acid SEQ ID No. 64.
SEQ ID No: 61
RESULT 1
US-13-443-804A-69
Sequence 69, US/13443804A
Patent No. 8962804
GENERAL INFORMATION
APPLICANT: WILLIAMS, John C.
APPLICANT: HORNE, David A.
APPLICANT: MA, Yuelong
APPLICANT: CHANG, Heng Wei
APPLICANT: DONALDSON, Joshua Michael
APPLICANT: ZER, Cindy
APPLICANT: BZYMEK, Krzysztof
APPLICANT: AVERY, Kendra Nicole
APPLICANT: XIE, Jun
TITLE OF INVENTION: MEDITOPES AND MEDITOPE-BINDING ANTIBODIES
TITLE OF INVENTION: AND USES THEREOF
FILE REFERENCE: 706122000120
CURRENT APPLICATION NUMBER: US/13/443,804A
CURRENT FILING DATE: 2012-04-10
PRIOR APPLICATION NUMBER: US 61/391,558
PRIOR FILING DATE: 2010-10-08
PRIOR APPLICATION NUMBER: US 13/270,207
PRIOR FILING DATE: 2011-10-10
PRIOR APPLICATION NUMBER: PCT/US11/55656
PRIOR FILING DATE: 2011-10-10
PRIOR APPLICATION NUMBER: US 61/597,708
PRIOR FILING DATE: 2012-02-10
NUMBER OF SEQ ID NOS: 189
SEQ ID NO 69
LENGTH: 238
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: synthetic light chain
Query Match 100.0%; Score 687; Length 238;
Best Local Similarity 100.0%;
Matches 131; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 METDTLLLWVLLLWVPGSTGDIQLTQSPSSLSASVGDRVTITCRAGESVDIFGVGFLHWY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 METDTLLLWVLLLWVPGSTGDIQLTQSPSSLSASVGDRVTITCRAGESVDIFGVGFLHWY 60
Qy 61 QQKPGKAPKLLIYRASNLESGVPSRFSGSGSRTDFTLTISSLQPEDFATYYCQQTNEDPY 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QQKPGKAPKLLIYRASNLESGVPSRFSGSGSRTDFTLTISSLQPEDFATYYCQQTNEDPY 120
Qy 121 TFGQGTKVEIK 131
|||||||||||
Db 121 TFGQGTKVEIK 131
SEQ ID No: 62
RESULT
US-13-443-804A-68
Sequence 68, US/13443804A
Patent No. 8962804
GENERAL INFORMATION
APPLICANT: WILLIAMS, John C.
APPLICANT: HORNE, David A.
APPLICANT: MA, Yuelong
APPLICANT: CHANG, Heng Wei
APPLICANT: DONALDSON, Joshua Michael
APPLICANT: ZER, Cindy
APPLICANT: BZYMEK, Krzysztof
APPLICANT: AVERY, Kendra Nicole
APPLICANT: XIE, Jun
TITLE OF INVENTION: MEDITOPES AND MEDITOPE-BINDING ANTIBODIES
TITLE OF INVENTION: AND USES THEREOF
FILE REFERENCE: 706122000120
CURRENT APPLICATION NUMBER: US/13/443,804A
CURRENT FILING DATE: 2012-04-10
PRIOR APPLICATION NUMBER: US 61/391,558
PRIOR FILING DATE: 2010-10-08
PRIOR APPLICATION NUMBER: US 13/270,207
PRIOR FILING DATE: 2011-10-10
PRIOR APPLICATION NUMBER: PCT/US11/55656
PRIOR FILING DATE: 2011-10-10
PRIOR APPLICATION NUMBER: US 61/597,708
PRIOR FILING DATE: 2012-02-10
NUMBER OF SEQ ID NOS: 189
SEQ ID NO 68
LENGTH: 238
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: synthetic light chain
Query Match 100.0%; Score 552; Length 238;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RTVAAPSVFIFPPSDEQLKSGAASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 132 RTVAAPSVFIFPPSDEQLKSGAASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD 191
Qy 61 SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 192 SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 238
SEQ ID No: 63
RESULT
US-13-443-804A-70
Sequence 70, US/13443804A
Patent No. 8962804
GENERAL INFORMATION
APPLICANT: WILLIAMS, John C.
APPLICANT: HORNE, David A.
APPLICANT: MA, Yuelong
APPLICANT: CHANG, Heng Wei
APPLICANT: DONALDSON, Joshua Michael
APPLICANT: ZER, Cindy
APPLICANT: BZYMEK, Krzysztof
APPLICANT: AVERY, Kendra Nicole
APPLICANT: XIE, Jun
TITLE OF INVENTION: MEDITOPES AND MEDITOPE-BINDING ANTIBODIES
TITLE OF INVENTION: AND USES THEREOF
FILE REFERENCE: 706122000120
CURRENT APPLICATION NUMBER: US/13/443,804A
CURRENT FILING DATE: 2012-04-10
PRIOR APPLICATION NUMBER: US 61/391,558
PRIOR FILING DATE: 2010-10-08
PRIOR APPLICATION NUMBER: US 13/270,207
PRIOR FILING DATE: 2011-10-10
PRIOR APPLICATION NUMBER: PCT/US11/55656
PRIOR FILING DATE: 2011-10-10
PRIOR APPLICATION NUMBER: US 61/597,708
PRIOR FILING DATE: 2012-02-10
NUMBER OF SEQ ID NOS: 189
SEQ ID NO 70
LENGTH: 451
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: synthetic heavy chain
Query Match 100.0%; Score 641; Length 451;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYMHWVRQAPGKGLEWVARIDPANGNSKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYMHWVRQAPGKGLEWVARIDPANGNSKY 60
Qy 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCAPFGYYVSDYAMAYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCAPFGYYVSDYAMAYWGQGTLVTVS 120
Qy 121 S 121
|
Db 121 S 121
SEQ ID No: 64
US-10-562-746-9
Sequence 9, US/10562746
Patent No. 7989594
GENERAL INFORMATION
APPLICANT: Humphreys, David P
APPLICANT: Heywood, Sam P
TITLE OF INVENTION: Modified antibody fab fragments
FILE REFERENCE: 07-1049-WO-US
CURRENT APPLICATION NUMBER: US/10/562,746
CURRENT FILING DATE: 2009-11-19
PRIOR APPLICATION NUMBER: PCT/GB04/002810
PRIOR FILING DATE: 2004-07-01
PRIOR APPLICATION NUMBER: GB 0319588.0
PRIOR FILING DATE: 2003-08-20
PRIOR APPLICATION NUMBER: GB 0315457.2
PRIOR FILING DATE: 2003-07-01
NUMBER OF SEQ ID NOS: 9
SEQ ID NO 9
LENGTH: 111
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Synthetic
Query Match 100.0%; Score 563; Length 111;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
Qy 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT 108
It would have been obvious to combine the teachings of CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI with WILLIAMS and HUMPHREYS because CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI 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 Fab such as that taught by WILLIAMS and HUMPHREYS with a reasonable expectation of success. Specifically, WILLIAMS teaches the heavy and light chain sequences of M5A (an anti-CEA antibody), and HUMPHREYS teaches Fab antibody fragments capable of selectively binding CEA. Together, WILLIAMS and HUMPHREYS obviate the amino acid structures for the anti-CEA Fab as recited in Claim 13.
Claim 14 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over CHA 2020 (of record), KATZ 2015 (of record), EMTAGE 2008 (of record), DUAN (Duan et al. 2019 - instant 892), YAZAKI 2005 (of record), BROWN (of record), BARISH (of record), SADELAIN (of record), and KUJAWSKI (of record) as applied to claims 1, 3, 5, and 7-8 listed above, and further in view of WILLIAMS (of record), HUMPHREYS (of record), and BRUENKER (of record).
CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI teach a method for treating cancer comprising administering T cells expressing a CAR that binds CEA wherein the CAR comprises a Fab and administering anti-CEA-IL-2 ICK. CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI do not disclose the Fab amino acid sequence SEQ ID NO: 65 (Claim 14).
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).
As to claim 14, specific to the Fab comprising VL (SEQ ID No. 61), CL (SEQ ID No. 62), VH (SEQ ID No. 63), and CH1 (SEQ ID No. 64), WILLIAMS discloses that the VL, CL, and VH has an amino acid sequence 100% similarity to amino acid SEQ ID No. 61, SEQ ID No. 62 and SEQ ID No. 63 (see above rejection for Claim 13); HUMPHREYS discloses that the CH1 has an amino acid sequence 100% similarity to amino acid SEQ ID No. 64 (see above rejection for Claim 13); and BRUENKER discloses [0053] “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,” and [0322] that the linker sequence (Linker 4; SEQ ID. No. 147) has an amino acid sequence 100% similarity to amino acid SEQ ID No. 65 [239-270] GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGG.
It would have been obvious to combine the teachings of CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI with WILLIAMS, HUMPHREYS and BRUENKER because CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI teach the method comprising administering anti-CEA CAR T-cells to treat cancer wherein the CAR comprises an anti-CEA Fab, motivating a person of ordinary skill to use the known anti-CEA Fab sequences such as those taught by WILLIAMS and HUMPHREYS and the known linker sequence such as that taught by BRUENKER to connect the Fab via a peptide linker as taught by the prior art with a reasonable expectation of success.
Claim 22 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over CHA 2020 (of record), KATZ 2015 (of record), EMTAGE 2008 (of record), DUAN (Duan et al. 2019 - instant 892), YAZAKI 2005 (of record), BROWN (of record), BARISH (of record), SADELAIN (of record), and KUJAWSKI (of record) as applied to claims 1, 3, 5, and 7-8 listed above, and further in view of WILLIAMS (of record), HUMPHREYS (of record), BRUENKER (of record), and KATO (of record).
CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI teach a method for treating cancer comprising administering T cells expressing a CAR that binds CEA and anti-CEA-IL-2 ICK and teach the amino acid sequences for the CAR (SEQ ID NOs: 7-9, 11-13, 35, 21, 48, and 39) and for the anti-CEA-IL-2 ICK (SEQ ID NOs: 7-9 and 11-13). CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI do not disclose wherein the CAR comprises SEQ ID NO: 66 and the ICK comprises SEQ ID NOs: 60 and 54 (Claim 22).
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).
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 CAR construct (SEQ ID NO: 66), WILLIAMS, 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 SEQ ID NOs: 35, 21, 48, and 39 as taught by CHA 2020, KATZ 2015, EMTAGE 2008, DUAN, YAZAKI 2005, BROWN, BARISH, SADELAIN, and KUJAWSKI). Therefore, prior art comprises all components of SEQ ID NO: 66 except for residues [698-700] that comprise amino acid sequence GGG as a linker positioned between co-stimulatory domain and the CD3ζ signaling domain. BRUENKER discloses [0053] “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,” which obviates the addition of the GGG linker at residues [698-700] in the anti-CEA CAR construct.
Specific to the ICK construct, WILLIAMS discloses anti-CEA M5A antibody heavy chain protein with an amino acid sequence at 99.1% similarity to amino acid SEQ ID No. 53 and anti-CEA M5A antibody light chain protein with an amino acid sequence at 100% similarity to amino acid SEQ ID No. 54. KATO discloses IL2 amino acid sequence 100% similarity to amino acid SEQ ID No. 56.
SEQ ID. No 53:
RESULT
BAN38386
ID BAN38386 standard; protein; 451 AA.
XX
AC BAN38386;
XX
DT 06-JUN-2013 (first entry)
XX
DE Anti-CEA M5A antibody heavy chain protein SEQ: 70.
XX
KW CD66e; CEA protein; antiallergic; antiarthritic; antiasthmatic; antibody;
KW antibody production; antibody therapy; antiinflammatory; antipsoriatic;
KW appendicitis; asthma; autoimmune disease; cancer; cardiovascular disease;
KW cardiovascular-gen.; crohns disease; cytostatic; diagnostic test;
KW gastrointestinal-gen.; hematological-gen.; hemoglobinuria;
KW immunosuppressive; light chain; macular degeneration; metabolic-gen.;
KW multiple sclerosis; nephrotropic; neuroprotective; ophthalmological;
KW psoriasis; recombinant protein; respiratory syncytial virus infection;
KW respiratory-gen.; rheumatoid arthritis; screening; transplant rejection;
KW virucide.
XX
OS Unidentified.
XX
CC PN WO2013055404-A1.
XX
CC PD 18-APR-2013.
XX
CC PF 10-APR-2012; 2012WO-US032938.
XX
PR 10-OCT-2011; 2011US-00270207.
PR 10-OCT-2011; 2011WO-US055656.
PR 10-FEB-2012; 2012US-0597708P.
XX
CC PA (CITY ) CITY OF HOPE.
XX
CC PI Williams JC, Horne DA, Ma Y, Chang HW, Donaldson JM, Zer C;
CC PI Bzymek K, Avery KN, Xie J;
XX
DR WPI; 2013-F73224/30.
XX
CC PT New antibody for treating e.g. cancer comprises heavy and light chain
CC PT variable regions, having amino acid sequences of framework regions from
CC PT specific sequences, and complementarity determining region(s) distinct
CC PT from specific sequences.
XX
CC PS Disclosure; SEQ ID NO 70; 259pp; English.
XX
CC The present invention relates to a novel antibody useful for treating
CC cancer. The antibody comprises heavy and light chain variable regions
CC comprising framework regions and complementarity determining regions. The
CC invention further provides: (1) an isolated meditope-enabled antibody-
CC meditope complex; (2) a new isolated meditope comprising: a peptide that
CC binds to a meditope binding site of a meditope-enabled antibody; (3)
CC diagnostic methods; (4) a method for screening antibodies or their
CC fragments; (5) a method for selecting a meditope analog or meditope
CC variant; (6) a method for modifying a meditope; and (7) a method for
CC modifying a meditope-enabled antibody. The present sequence is a anti-CEA
CC M5A antibody heavy chain which is useful in generating a meditope-enabled
CC antibody.
XX
SQ Sequence 451 AA;
Query Match 99.3%; Score 2387; Length 451;
Best Local Similarity 99.1%;
Matches 446; Conservative 2; Mismatches 2; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYMHWVRQAPGKGLEWVARIDPANGNSKY 60
|||||||