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
The instant application 18/259,277 filed on 06/26/2023 is a 371 of PCT/US22/15720 filed on 02/09/2022 of US Provisional applications 63/147,441 and 63/147,237 filed on 02/09/2021. The instant application will be examined with an effective filing date of 02/09/2021.
Status of the Application/Claims
Claims 4, 9-12 and 15 are canceled. Claims 1, 5-8, 13-14 and 16-24 are currently amended. Claims 1-3, 5-8, 14 and 16-24 are currently pending and are herein under examination on the merits.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 06/26/2023 and 08/08/2023 are acknowledged and are in compliance with the provisions of CFR 1.97. They have been considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: The claims recites “anyone”. Anyone refers to a person. The word needs to be amended to “any one”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
Claims 1-3, 6-8 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over US20190359726A1 as, and further in view of WO2015157629A2 and Rossig et al. Carbohydrate Targets for CAR T Cells in Solid Childhood Cancers. Front Oncol. 2018 Nov 12;8:513, herein further referred to as Wang, Lai and Rossig respectively.
Regarding claims 1 and 13, Wang teaches a chimeric antigen receptor 7A12-28BBZ (SEQ ID NO: 80) that consist CD8α signal peptide, 7A12 scFv, CD8 hinge, CD28 transmembrane region, intracellular segment, CD137 intracellular signaling domain and CD3ζ (Wang para. 0226).
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Fig. 1 NCBI showing 82% Sequence alignment of Wang’s SEQ ID NO: 80 with instant SEQ ID NO:16.
Wang does not specifically teach that the 7A12-scFv recognizes Globo series antigens.
Lai teaches antibodies or antigen binding-fragment 2C2 that binds to Globo series antigens such as Globo H, SSEA-3 or SSEA-4 (Lai para. 0053). Lai’s 2C2 (variable heavy chain SEQ ID NO: 3 and variable light chain SEQ ID NO: 2) (Lai pg. 17-18 para. 0071, Tab. 1) has an 87% amino acid sequence alignment with SEQ ID NO: 3 of the instant claim as shown below. Lai further teaches that the functional fragment capable of binding Globo H can be in the form of a Fab, Fab’ and scFv.
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Fig. 2, 2C2 (heavy and light chain) alignment to instant claim SEQ ID NO: 3
Rossig teaches that gangliosides such as Globo series antigens (Globo H and SSEA-4) and GD3 are suitable carbohydrate targets for CAR T cells engineering due to their roles in malignant behaviors (Abstract).
Therefore, it would have been obvious before the effective filling date for a skilled artisan to modify the teachings of Wang in view of Lai and Rossig with a reasonable high degree of predictable success to design a CAR wherein the 7A12-scFv (amino acid numbers 1-242) of Wang is replaced with an scFv or an antigen-binding fragment such as the 2C2 (comprising heavy chain having SEQ ID NO: 3 and light chain having SEQ ID NO: 4) of Lai that is capable of binding to a Globo series antigen such as SSEA-4 that plays a prevalent role in malignancy as indicated by Rossig. As indicated above, Wang’s SEQ ID NO: 80 has an 82% amino acid sequence alignment to SEQ ID NO: 16 of the instant claim. A skilled artisan would have been able to construct a CAR wherein the 7A12-scFv of Wang’s construct is replaced with the 2C2-scFv of Lai to obtain a CAR construct that is able to recognize a Globo series antigen and has an 83% identity to instant SEQ ID NO: 16 as shown in figure 3 below.
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Fig. 3 Instant SEQ ID NO:16 with 83% alignment to Wang’s CAR in view of Lai’s 2C2 scFv
Therefore, a skilled artisan would have been able to modify the CAR of Wang in view of Lai and Rossig to use the 2C2 scFv in place of the 7A12-scFv of Wang with a reasonable expectation of success that the 2C2 scFv would recognize a Globo series antigen.
Regarding claim 2, and incorporating the analysis of claim 1, Wang further teaches that the CAR comprises a second endodomain, theCD137 intracellular signaling domain (Wang para. 0226).
Regarding claim 3, and incorporating the analysis of claim 1 above, Wang does not teach an scFv with 80% to 100% amino acid sequence identity to SEQ ID NO: 3 or 6.
Lai teaches an antibody or antigen-binding fragment, 2C2 (variable heavy chain SEQ ID NO: 3 and variable light chain SEQ ID NO: 2) (Lai pg. 17-18 para. 0071, Tab. 1) with an 87% amino acid sequence alignment with SEQ ID NO: 3 of the instant claim as shown in Fig. 2 above. Lai further teaches that the functional fragment capable of binding Globo H can be in the form of a Fab, Fab’ and scFv.
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Wang in view of Lai and Rossig with a reasonable high degree of predictable success to design a CAR construct where in the amino acids numbers 1-242 of Wang’s SEQ ID NO: 80 is replaced by Lai’s 2C2 scFv (SEQ ID NO: 3 for the heavy chain and SEQ ID NO: 4 for the light chain) to construct the CAR that is 82% identical to SEQ ID NO 16 of the instant claim and having an scFv that is 87% identical to SEQ ID NO: 3 of the instant claim and is capable of binding to a Globo series antigen. As indicated in the figure below amino acids number 243 – 510 of Wang’s SEQ ID NO: 80 is 99% identical to amino acids number 267-534 of instant SEQ ID NO: 16 as shown in Fig.4 below, wherein amino acids 1-266 of instant SEQ ID NO: 16, R783-scFv CAR) is instant SEQ ID NO: 6 (R783 scFv). Therefore, a skilled artisan would have been able to replace the scFv portion of Wang’s CAR with an scFv with Lai’s 2C2 that is 87% identical to instant SEQ ID NO: 3 and can bind to a Globo series antigen.
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Fig. 4
Regarding claims 7 and 8, and incorporating the analysis of claims 1, 2 and 6 above, Wang further teaches a CD8 hinge region having an amino acid sequence SEQ ID NO: 25 (amino acid numbers 243-287 of Wang’s SEQ ID NO: 80, as indicated in Fig. 1 above and Fig 5 below) that is 100% identical to SEQ ID NO: 7 of the instant claims.
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Fig. 5 Wang’s CD8 hinge SEQ ID NO: 25 alignment with instant SEQ ID NO: 7
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Wang, Lai and Rossig as applied to claim 1 above, and further in view of US20200407456A1, herein further referred to as You.
Regarding claim 5, and incorporating the analysis of claim 1 above, Wang, Lai and Rossig do not teach CAR where in the antigen-binding fragment (Fab) comprises a heavy chain variable region Vh or a light chain variable region Vl with amino acid sequence identity as claimed.
You teaches anti-CD137 antibodies that possess cross-linking dependent agonist activity that may circumvent liver toxicity. You also teach that the Fab of the antibody may have a heavy chain sequence of SEQ ID NO: 40 (anti-glycan-CD137) and a light chain variable sequence of SEQ ID NO: 39 (anti-glycan) as indicated below (You para. 0018). You further teaches that the antibodies can be modified to bind to CD137 and a tumor specific glycan and can be in the form of an scFv or Fab (You para. 21-22). You further teaches that exemplary glycans expressed in cancer cells are Globo H to which the antibodies can recognize (You para 0084).
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Fig. 6 SEQ ID NO: 40 (91.6% Identity to SEQ ID NO: 5)
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Fig. 7 SEQ ID NO: 39 (91.2% Identity to SEQ ID NO: 4)
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Wang, Lai and Rossig in view of You with a reasonable high degree of predictable success to use a Fab for the CAR design wherein the Fab comprise the heavy and light chain variable sequences (SEQ ID NO: 39 and 40) where the Fab recognizes a glycan is a Globo series antigen such as Globo H that is expressed in cancer cells wherein the and Fab comprises an anti-CD137 recognition fragment that possess crosslinking dependent activity that may circumvent liver toxicity of the caused by the CAR. As indicated in the sequence alignment above, SEQ ID NO: 39 and 40 have amino acid sequence identity of 91.2% and 91.6% to SEQ ID NO: 4 and 5 respectively. Therefore a skilled artisan would have been able to use SEQ ID NO: 39 and 40 to design the Fab used in the design of the CAR as claimed wherein the Fab recognizes a Globo series antigen and possesses crosslinking dependent activity that may circumvent liver toxicity.
Claim 14, 16-24 is rejected under 35 U.S.C. 103 as being unpatentable over Wang and further in view of Lai, Rossig and Levine et al. Global Manufacturing of CAR T Cell Therapy. Mol Ther Methods Clin Dev. 2016 Dec 31;4:92-101, herein further referred to as Levine.
Regarding claim 14, 17-24, Wang teaches a method for treating a subject with tumor comprising, generating CAR T cells by transducing T cells with a vector (lentivirus) comprising a nucleic acid sequence encoding a CAR (Wang para. 0288-0299) and injecting the prepared CAR T cells in B-NDG mice with peripheral blood B lymphocytes RPMI-8226 of multiple myeloma (Wang para. 0306-0309) which elicited an immune response (Wang para. 0143). Wang also teaches an example chimeric antigen receptor 7A12-28BBZ (SEQ ID NO: 80) that consist CD8α signal peptide, 7A12 scFv, CD8 hinge, CD28 transmembrane region, intracellular segment, CD137 intracellular signaling domain and CD3ζ (Wang para. 0226).
Wang does not specifically teach that the 7A12-scFv recognizes Globo series antigens. Wang does not teach that T cells where obtained from the subject or that the CAR T cells where expanded.
Lai teaches antibodies or antigen binding-fragment 2C2 that binds to Globo series antigens such as Globo H, SSEA-3 or SSEA-4 (Lai para. 0053) that are expressed on breast cancers (Lai para. 0003).
Rossig teaches that gangliosides such as Globo series antigens (Globo H and SSEA-4) and GD3 are suitable carbohydrate targets for CAR T cells engineering due to their roles in malignant behaviors (Abstract).
Levine teaches that immunotherapy using CAR codified T cells has demonstrated high response rates in patients with B cell malignancies and that CAR T cell therapy is being investigated in other hematologic and solid tumor types. Levine further teaches that the CAR T cells are generated by removing T cells from the patient’s blood and engineering the T cells to express a CAR which is further expanded which programs the T cells to target a tumor (Levine Abstract, Fig. 1 -2).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the method of Wang in view of Lai, Rossig and Levine with a reasonable high degree of predictable success to design a CAR comprising the an scFv or Fab such as the 2C2 of Lai that recognizes a Globo series antigen and wherein the CAR comprises an amino acid sequence such as SEQ ID NO: 80 of Wang with 82% identity to SEQ ID NO: 16 of the instant claim, where in the CAR is prepared by obtaining T cells from a subject as indicated by Levine and transducing the T cells with the CAR, expanding the T cells as indicated by Levine and inducing the expanded CAR T cells into the subject whereby the CAR T cells will elicit an immune response to the target tumor that expresses a Globo series antigen that are expressed on breast cancer.
Regarding claim 16, and incorporating the analysis of claim 14 above, Levine further teaches that the subject can be a human (Levine Abstract).
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMMANUEL LED YOUTCHOM PENDIE whose telephone number is (571)272-6313. The examiner can normally be reached Mon - Fri: 8AM - 5PM CST.
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/EMMANUEL LED YOUTCHOM PENDIE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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