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
This application claims priority to U.S. provisional application 63/348,998 filed on 03 June 2022. The effective priority date for claims 1, 2, 3, 5, 14, 18, and 19 is 03 June 2022. The effective priority date for claims 4, 6-13, 15-17, and 20 is 02 June 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 31 May 2024 is being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-20 are the original claims filed on 02 June 2023. Claims 1-20 are pending and the subject of this office action.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 6, 14, and 18 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US2016/0339090 A1 (herein Hacohen).
In regard to claims 1, 2, 6, 14, and 18, Hacohen teaches a method for treating neoplasia comprising the administration of neoplasia vaccine, comprising neoantigen peptides, and at least one immune checkpoint inhibitor (i.e. PD-1/PD-L1 inhibitors) ([0011-0013], [0024], claims 1, 2, and 9), which has relevance to instant claims 1 and 2. This method makes use of a pharmaceutical composition comprising the vaccine and checkpoint inhibitor as well as an immunomodulator or adjuvant ([0013-0018]), which is relevant to instant claims 16 and 18. The vaccine, taught by Hacohen, comprises a multitude of a cancer-associated neoantigens, identified through nucleic acid sequencing (e.g. RNA, exome, or genome) of biopsied tumor tissue ([0040-0043], [0100-0105]), which has relevance to instant claim 6. It is also taught that this method is applicable to subjects suffering neoplasia of the pancreas ([0026] and claim 14).
Claim Rejections - 35 USC § 103
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 3-5, 11-13, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over US2016/0339090 A1 (herein Hacohen) in view of Freed-Pastor WA, et al. (2021) The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer. Cancer Cell. 2021 Oct 11;39(10):1342-1360.e14 (herein Freed-Pastor) with Banta KL, et al. (2022) Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity. 2022 Mar 8;55(3):512-526.e9 (herein Banta) providing additional evidentiary value.
In regard to claims 3-5, and 19, Hacohen teaches a method for treating cancer, including pancreatic cancer, comprised of the administration of a neoantigen vaccine and at least one immunosuppression inhibitor (i.e. PD-1/PD-L1 inhibitors) ([0011-0013], [0024], claims 1, 2, and 9).
Hacohen does not teach a method for treating pancreatic cancer comprising a neoantigen vaccine with inhibitors that target both the PD-1/PD-L1 and TIGIT/CD155 axes. Banta and Freed-Pastor teach these deficiencies.
Freed-Pastor teaches that a subset of patients suffering from metastatic pancreatic adenocarcinoma (PDAC) possess dysfunctional/exhausted CD8+ T cells, as indicated by elevated levels of the co-inhibitory cell surface receptor TIGIT (Introduction). Additionally, Freed-Pastor teaches that tumors possessing high overall neoepitope burden have significantly higher CD155 levels compared to tumors with lower burden (Results: Elevated expression of CD155 in murine and human PDAC-paragraph 5). Furthermore, the authors noted an inverse correlation between neoepitope-MHC class I affinity and CD155 level, suggesting a potential role in the CD155/TIGIT axis in mediating immune evasion. The authors then investigated the relevance of this finding in a therapeutic context by assaying the effect of CD155/TIGIT immune checkpoint blockade, either as a single blockade or a dual checkpoint blockade in combination with a PD-1/PD-L1 blockade, in the presence of a CD40 agonist (Results: Preclinical activity of TIGIT/PD-1/CD40a combination immunotherapy in neoantigen-expressing PDAC). In a mouse model using pancreatic tumor-derived orthotopic organoid transplantation, it was found that only mice treated with the combination therapy, PD-1/PD-L1 and CD155/TIGIT blockades, showed significant tumor responses, whereas mice treated with a single blockade therapy showed only disease stabilization (figure 6).
The teachings of Freed-Pastor are in agreement with another relevant study performed by Banta et al. Banta teaches a mechanistic convergence of the TIGIT and PD-1 inhibitory pathway through the overlapping effect of the two pathways (i.e. inhibition of CD226 co-stimulation) (summary). Banta also teaches that combination blockade of PD-1 and TIGIT results in near complete elimination of tumors in various mouse models (discussion-paragraph).
It would have been obvious to one skilled in the art to combine the teachings of Hacohen (combination therapy comprising a neoantigen vaccine with immune checkpoint blockade) and Freed-Pastor (combination immune checkpoint blockade therapy comprising TIGIT and PD-1 inhibitors) for the treatment of pancreatic cancer. One of ordinary skill in the art at the time of filing would have been motivated to use a pancreatic cancer-associated neoantigen vaccine with the pairing of PD-1/PD-L1 and TIGIT/CD155 blockades to treat pancreatic cancer due to the unique tumor microenvironment of pancreatic cancer, high CD155 levels, which results in an exhausted T cell phenotype, as taught by Freed-Pastor. By combining these two blockades, as taught by Freed-Pastor, one is able to boost and reinvigorate an anti-tumor response in order to overcome the immunosuppressive environment presented by pancreatic cancer. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
In regard to claim 11-13, the claims establish efficacy limitations of the invention described in claim 1. MPEP 2121 states: “When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability.” Since each element of claim 1 is taught by the prior art, efficacy similar to that illustrated in the instant application and set-out in claim 11-13 is presumed (see In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980)).
Claims 7-9, 15, 16, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over US2016/0339090 A1 (herein Hacohen) in view of Freed-Pastor WA, et al. (2021) The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer. Cancer Cell. 2021 Oct 11;39(10):1342-1360.e14 (herein Freed-Pastor) and Narayanan JSS, et al. (2019) Irreversible Electroporation Combined with Checkpoint Blockade and TLR7 Stimulation Induces Antitumor Immunity in a Murine Pancreatic Cancer Model. Cancer Immunol Res. 2019 Oct;7(10):1714-1726 (herein Narayanan) with Banta KL, et al. (2022) Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity. 2022 Mar 8;55(3):512-526.e9 (herein Banta) providing additional evidentiary value.
In regard to claims 7-9, 15, 16, and 20, Hacohen and Freed-Pastor teach a method for treating pancreatic cancer comprising of the administration of a neoantigen vaccine and immune checkpoint blockades of the PD-1/PD-L1 and CD155/TIGIT pathways, as discussed for the 103 rejections of claims 3-5, and 19.
Hacohen and Freed-Pastor do not teach the use of neoantigens comprising sequences (SEQ ID Nos: 1-5) or neoantigens derived from CAR12, CDK12, FOXP3, FAM129C, or ANK2. These deficiencies are taught by Narayanan.
Narayanan teaches that a subset of immunocompetent mice implanted with KPC4580P-initiated tumors showed complete tumor regression after undergoing irreversible electroporation (IRE) treatment (abstract, results-paragraphs 1-3, and figure 1). Whole exome and RNA sequencing was used to identify tumor-specific expressed non-synonymous variants (results-paragraph XX, supplementary figure S4). Two of the identified neoantigen peptides were from CAR12 and CDK12, which is relevant to instant claims 7 and 15. Additionally, neoantigen peptide sequences from this study, listed in supplemental table 2, share 100% sequence identity with SEQ ID NO: 1 -5, as shown below:
SEQ ID 1 ERLVYISFRQGLLTDTGLSL 20
3960.0013 ERLVYISFRQGLLTDTGLSL 20
********************
SEQ ID 2 SSPFLSKRSLSRSPIPSRKS 20
3960.0016 SSPFLSKRSLSRSPIPSRKS 20
********************
SEQ ID 3 LSRSPIPSRKSMKSRSRSPA 20
33960.0018 LSRSPIPSRKSMKSRSRSPA 20
********************
SEQ ID 4 LMTKDAPDSLSPENYGNFDT 20
3960.0054 LMTKDAPDSLSPENYGNFDT 20
********************
SEQ ID 5 RTTGQMVAPSLSPNKKMSSE 20
3960.0055 RTTGQMVAPSLSPNKKMSSE 20
********************
It would have been prima facie obvious to use neoantigen peptides identified from this study in a pancreatic cancer neoantigen vaccine, as the peptides were identified in KPC4580P cells, a well-established pancreatic cancer model known in the art. Additionally, when considering the teachings of Narayanan, a person skilled in would have recognized the high likelihood of success when applying these peptides to a pancreatic cancer neoantigen vaccine, and would have provided ample motivation for their use.
Claims 10 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US2016/0339090 A1 (herein Hacohen) in view of Freed-Pastor WA, et al. (2021) The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer. Cancer Cell. 2021 Oct 11;39(10):1342-1360.e14 (herein Freed-Pastor) and King DA, et al. (2021) Complete remission in a patient with widely metastatic HER2-amplified pancreatic adenocarcinoma following multimodal therapy informed by tumor sequencing and organoid profiling. medRxiv. https://doi.org/10.1101/2021.12.16.21267326 (herein King) with Banta KL, et al. (2022) Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity. 2022 Mar 8;55(3):512-526.e9 (herein Banta) providing additional evidentiary value.
In regard to claims 10 and 17, Hacohen and Freed-Pastor teach a method for treating pancreatic cancer comprising of the administration of a neoantigen vaccine and immune checkpoint blockades of the PD-1/PD-L1 and CD155/TIGIT pathways, as discussed for the 103 rejections of claims 3-5, and 19.
Hacohen and Freed-Pastor do not teach the use of neoantigens comprising sequences (SEQ ID Nos: 7-12). These deficiencies are taught by King.
King et al relates to a study performed on a patient with HER2+ metastatic pancreatic ductal adenocarcinoma in which the patient underwent multimodal therapy. The patient demonstrated complete clinical response after multiple rounds of treatment, which culminated with a coordinated barrage of anti-HER2, personalized vaccine and checkpoint inhibition immunotherapy, radiation, and chemotherapy (abstract). The neoantigen vaccine administered to the patient included antigen peptides comprising sequences sharing 100% identity to SEQ ID NOs: 7-9 of the instant application, as shown below (supplementary table 2):
SEQ ID 10 -----HPATWKNTI----------- 9
SEQ ID AFFRNHPATWKNTIRHNLSLHKCFV 25
FOXP3 AFFRNHPATWKNTIRHNLSLHKCFV 25
*********
SEQ ID 11 -----------SRLAQRRFI----- 9
SEQ ID 8 RGRVLKKFKSDSRLAQRRFIRGWGL 25
FAM129C RGRVLKKFKSDSRLAQRRFIRGWGL 25
*********
SEQ ID 12 -------HLAEDHHAV------------ 9
SEQ ID 9 EEKDSESHLAEDHHAVSTEAEDRSY--- 25
ANK2 EEKDSESHLAEDHHAVSTEAEDRSYSEQ 28
*********
It is also taught that the vaccine induced a robust T cell response to these antigens, whereas other antigens included in the vaccine did not induce consistent responses over time (results: Molecular analyses and organoid profiling, figure 4).
It would have been prima facie obvious to use neoantigen peptides identified from this study in a pancreatic cancer neoantigen vaccine, as the peptides were shown to be effective at producing a robust T cell response, as taught by King. Additionally, when considering the teachings of King, a person skilled in would have recognized the high likelihood of success when applying these peptides to a pancreatic cancer neoantigen vaccine, and would have provided ample motivation for their use.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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/MATTHEW CURRAN METCALF/ Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647