DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 2/11/2026 is acknowledged.
Accordingly, Claims 1 and newly added claims 3-15 are pending and will be examined on the merits.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the numbering system used to determine the position of the CDRs within the variable regions, ex. Abm, IGMT, Kabat, Chothia, etc. The metes and bounds of the specific CDR regions claimed is unclear based on the lack of recitation of which numbering system is being utilized. Applicant is invited to amend claim 13 to recite for example “wherein the CDRs are numbered according to Kabat” or recite the residues of the corresponding CDRs.
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.
Claims 1, 3, 4, 7 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Katou et al. (Cancer Res. 2007, 67(23):11195-11201, cited on IDS filed 2/6/2023).
The claims are drawn to an in vitro method for detecting a NKG2A+ and PD-1+ lymphocyte, comprising providing a biological sample comprising tumor infiltrating lymphocytes and determining whether the lymphocytes express NKG2A and PD-1. The claims are further drawn to wherein the biological sample is obtained from an individual having an HLA-E expressing cancer and the sample comprises cancer or cancer adjacent tissue and wherein the antibodies used for detection of NKG2A and PD-1 are neutralizing antibodies.
Katou et al. discloses the detection of cancer cells expressing NKG2A and PD-1 by tumor infiltrating lymphocytes (TIL). Katou et al. teach using frozen sections of human early-stage tongue cancers, the TILs in the cancer nests and those in the cancer stroma were compared for the expression of PD-1, NKG2A, NKG2D, CD69, and Ki-67 and discovered all of the cancer specimens were abundantly infiltrated by CD8+ T cells and CD56+ natural killer (NK) cells in the stroma, as well as in the tumor nest. Commercially available antibodies for the immunoperoxidase staining using fixed frozen sections were used for immunohistochemistry (see supplementary data). Katou et al. further disclose “NK cells are closely regulated by a balance between the signals transmitted by activating receptors (NKG2D) that recognize the ligands on tumors and by inhibitory receptors (NKG2A) that recognize HLA-E to protect HLA class I transfectants from NK cell–mediated lysis.” Katou et al. state “further accumulation of knowledge on the TILs in different stages of various human cancers may help to develop a more effective design for immunostimulatory therapy.” In the absence of evidence to the contrary, the burden is on the applicant to prove that the antibodies used are not neutralizing antibodies, see In re Best 526F.2d 1252, 195 USPQ 430 (CCPA 1977).
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 3-15 are rejected under 35 U.S.C. 103 as being unpatentable over Katou et al. (Cancer Res. 2007, 67(23):11195-11201) in view of Zhang et al. (Cellular and Molecular Immunol. 2010, 7, 389-395), Yu et al. (Asian Pac J Cancer Prev, Vol. 15 (6) 2014, 2685-2688), Spee (WO2008009545) and Wang et al. (Cancer Immunol Res, (9):846-856, epub May 28, 2014).
The claims are drawn to an in vitro method for detecting a NKG2A+ and PD-1+ lymphocyte, comprising providing a biological sample comprising tumor infiltrating lymphocytes and determining whether the lymphocytes express NKG2A and PD-1. The claims are further drawn to wherein the biological sample is obtained from an individual having an HLA-E expressing lung cancer and the sample comprises cancer or cancer adjacent tissue and wherein the antibodies used for detection of NKG2A comprising CDR sequences recited in Claims 13-14 and wherein the PD-1 antibody comprises nivolumab.
The teachings of Katou et al. are presented in the 102(a)(1) rejection above. Katou et al. does not teach wherein the cancer is non-small lung cancer or the specific NKG2A antibody or anti-PD-1 antibody nivolumab. These deficiencies are made up for by Zhang et al., Yu et al., Wang et al. and Spree.
Zhang et al. teach detecting PD-1 expression on CD8+ T cells from healthy control peripheral blood mononuclear cells (PBMCs) and the PBMCs of NSCLC patients as well as NSCLC tissues. Results showed that tumor-infiltrating CD8+ T cells had increased PD-1 expression and impaired immune function, including reducing cytokine production capability and impairing capacity to proliferate. Blockade of the PD-1/PD-L1 pathway by the PD-L1-specific antibody partially restored cytokine production and cell proliferation. These data provide direct evidence that the PD-1/PD-L1 pathway is involved in CD81 T-cell dysfunction in NSCLC patients. Moreover, blocking this pathway provides a potential therapy target in lung cancer.
Yu et al. investigated the expressions and relevant factors of lymphocyte subgroups CD3+ CD4+ and CD3+ CD8+ and their surface receptors NKG2D and NKG2A in patients with NSCLC. The results of Yu et al. indicated that NSCLC patients in advanced group was obviously higher in CD3+ CD8+ NKG2A expression rate but apparently lower in CD3+ CD4+ NKG2A and expression rate than early group, according to different TNM staging, suggesting that because of the different time of TNM staging, the expression of NKG2A ligands on the surface of T lymphocytes might increase or decrease relevantly, bringing about different suppressive severity on cellular immunity, and autologous ability of tumor resistance was in negative relationship with the increase of TNM staging.
Wang et al. teach in vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558. Wang et al. disclose Nivolumab binds to PD-1 with high affinity and specificity.
Spee discloses the recited anti-NKG2A antibody humZ270 having the same CDRs (see SEQ ID NOs 4 and 5 of Spee) as well as their use for diagnostic assays for NKG2A protein by detecting its expression in specific cells, tissues, or serum. Spee further discloses certain lymphomas such as, e.g., NK-lymphomas, are characterized by CD94/NKG2A expression.
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to combine the teachings of Katou et al., Zhang et al., Yu et al. and Spee to detect expression of NKG2A and PD-1 in lymphocyte samples from other solid tumor types, such as lung cancer and hematological cancer. Zhang et al. and Yu et al. both teach methods of detecting NKG2A and PD-1 lymphocyte expression in samples from NSCLC patients. Spee teaches the same anti-NKG2A antibody instantly claimed for use in diagnostic assays. One of ordinary skill in the art would have a reasonable expectation of success, based on the teachings of Zhang et al. and Yu et al. to extend the patient population samples taught by Katou et al. to include lung cancer and hematological cancer as well as use the specific NKG2A antibody taught by Spee and Nivolumab taught by Wang et al. for detection. Combining prior art elements according to known methods to yield predictable results is considered to be prima facie obvious (see MPEP 2143(I)).
Conclusion
Claims 1, 3-15 are rejected.
No Claim is allowed.
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/Meera Natarajan/Examiner, Art Unit 1643
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