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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Feb. 07, 2024. Claims 1-6 are pending and are examined.
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.
Claims 1-6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The base claim 1 and claims 3 and 5 recite a phrase “…the presence or quantity of the T cell receptor α motif…” that render the claims indefinite. It is unclear what the “quantity” is, for example, zero can be considered a “quantity” as well. Thus, it is not clear if “the presence or quantity” is “yes” or “no” for the T cell receptor alpha motif.
Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claim.
Claims 5 and 6 recite a phrase “wherein the presence or quantity of the T cell receptor α motif is indicative of a personalized SARS-CoV-2 treatment plan for the subject” that renders the claims indefinite. It is unclear what the “a personalized SARS-CoV-2 treatment plan” is, and how the “the presence or quantity of the T cell receptor α motif” is related to “a personalized SARS-CoV-2 treatment plan”.
Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claim.
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, 3 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bacher et al. ( Immunity. 2020 Dec 15;53(6):1258-1271.e5., hereinafter, “Bacher”, submitted in IDS filed on 03/04/2024).
The base claim 1 is directed to a method for determining whether a subject~ exhibits a CD4+ memory T cell response to SARS-CoV-2 infection or vaccination comprising detecting, in a population of immune cells from the subject, the presence or quantity of a T cell receptor alpha motif having the amino acid sequence SEQ ID NO: 2 (CAX1X2NYGGSQGNLIF), wherein X1 is G, A or V and X2 is any amino acid residue, wherein the presence or quantity of the T cell receptor α (alpha) motif indicates that the subject exhibits a CD4+ memory T cell response to SARS-CoV-2 infection or vaccination.
Bacher studies the low-avidity CD4+ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19 and teaches that their findings identifying low-avidity CD4+ T cell responses as a hall-mark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection (See Abstract).
Bacher also discloses that the differences between patients and unexposed individuals were mainly quantitative rather than qualitative (See page 1261, left column, paragraph 2). and the picture emerges that, with regard to the CD4+ T cell response, COVID-19 is associated with quantitative differences rather than unique differentiation profiles (See page 1268, right column, paragraph 3), which teaches that the CD4+ memory T cell response in SARS-COV-2 infected patient is quantitative difference as “Increased Frequencies of Human SARS-CoV-2-Reactive CD4+ T Cells against the Spike, Membrane, and Nucleocapsid Proteins in COVID-19 Patients” (See page 1259, right column).
Bacher also teaches that the clonotypes were stringently filtered for possible doublets by removing clonotypes (i) found in 1 cell only and containing more than 1 TCR alpha and 1 TCR beta (ii) containing more than 1 TCR alpha and no TCR beta sequence (iii) containing more than 1 TCR beta and no TCR alpha sequence (iv) containing more than 2 TCR alpha or more than 2 TCR beta sequences. Alpha diversity measures were calculated for each patient either for the whole repertoire or divided based on Seurat clusters. R packages “vegan” and “tcR” were used to calculate the Inverse Simpson diversity index and the Gini inequality index, respectively. For these analyses samples were normalized by selection of the most abundant 50 clonotypes in order to remove the impact of different sample sizes (number of cells per sample) and to analyze only the distribution of the most expanded clonotypes (See page e5, paragraphs 2-4).
Based on the description above, it teaches that the quantity CD4+ memory T cell is important and the TCR alpha is measured.
Bacher also teaches a TCR sequence as shown in the Table S3 that is identical to the claimed SEQ ID NO: 2. Table S3 shows a TCR sequences as CAVGNYGGSQGNLIF in Column A-25502 (See Table 3 and below with highlighted line).
Although Bacher does not specifically use the term “ motif”, they teach an identical TCR peptide of SEQ ID NO: 2 as claimed. Accordingly, the TCR peptide of Column A-25502 “CAVGNYGGSQGNLIF” teaches the TCR alpha motif seqeunce.
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Regar claim 3, Bacher teaches that the size of the naive T cell pool corresponds to vaccination success, and the potential effect of pre-existing memory on COVID-19 disease course as well as efficacy of SARS-CoV-2 vaccination has to be carefully evaluated in future studies (See page 1268, right column, paragraph 2), and it will be important to independently test the effect of pre-existing memory, infection history, CD4+ memory size and age by using paired samples from larger patient cohorts upon natural infection and before and after vaccination, and to identify potential predictive parameters for the quality of the SARS-CoV-2-specific T cell response (See page 1269, left column, paragraph 3). At the same time, Bacher discloses a method for single cell T cell receptor (TCR) sequence analysis including TCR alpha analysis (See page e5) and a method for comparing the T Cell Cross-Reactivity between CCCoVs and SARS-CoV-2 (See Figure 5, page 1266).
As for the claimed SEQ ID NO: 2, Bacher teaches the claimed motif of SEQ ID NO: 2 in Table S3 (See description above and Table S3 above). and teaches that the differences between patients and unexposed individuals were mainly quantitative rather than qualitative (See page 1261, left column, paragraph 2).
Accordingly, Bacher teaches a method for determining efficacy of a SARS-CoV-2 vaccine through detecting the presence or quantity of a T cell receptor alpha motif with the amino acid sequence of SEQ ID NO: 2 as claimed.
Regarding claim 5, Bacher teaches it will be important to independently test the effect of pre-existing memory, infection history, HLA composition, CD4+ memory size and age by using paired samples from larger patient cohorts upon natural infection and before and after vaccination, and to identify potential predictive parameters for the quality of the SARS-CoV-2-specific T cell response, and this will be necessary to identify parameters of pre-existing T cell memory that might predict the quality of the SARS-CoV-2-specific T cell response and potentially disease severity in individual patients. (See page 1269, left column, paragraph 3; page 1269, bridging columns left and right). Bacher also teaches that defining the parameters that contribute to the high clinical variability of COVID-19 is critical in predicting disease outcome and for the development of effective therapeutic and vaccination strategies (See page 1265, right column, paragraph 2). Bacher also teaches a method for quantification and statistical analysis of alpha T cell receptor motif (See page e5) and states that that the differences between patients and unexposed individuals were mainly quantitative rather than qualitative (See page 1261, left column, paragraph 2).
Accordingly, Bacher teaches developing a individuals or personalized treatment by detecting the presence or quantity of a T cell receptor responses that include TCR alpha measurement (See page e5, paragraphs 2-3).
For the SEQ ID NO:2, Table S3 of Bacher (See Table S3 above) discloses that one of the TCR alpha motifs of Column A-25502 (“CAVGNYGGSQGNLIF) is identical to the claimed SEQ ID NO: 2.
Accordingly, Bacher teaches each and every aspect of the claims 1, 3 and 5.
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.
Claims 2, 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Bacher as applied to claims 1, 3 and 5 above, and in view of Vishnubhotla et al. (Immun Inflamm Dis. 2021 Dec;9(4):1781-1785. Epub 2021 Jul 21).
The claims 2, 4 and 6 require the subject has at least a DPB1*04:01 or DPB1*04:02 HLA allele.
Bacher teaches a method for determining whether a subject exhibits a CD4+ memory T cell response to SARS CoV-2 infection or vaccination, for determining the efficacy of a SARS-CoV-2 vaccine, and for developing an individual SARS-CoV-2 treatment plan, respectively, based on detecting the presence or quantity of a T cell receptor alpha motif with SEQ ID NO: 2. However, it is silent on the subject has at least a DPB1*04:01 or DPB1*04:02 HLA allele.
Vishnubhotla uses high‐resolution HLA genotyping to identify alleles associated with severe COVID‐19, and teaches that human leukocyte antigen (HLA) variability has been demonstrated to be associated with susceptibility/severity of COVID‐19, and genotyping for these alleles will enable identification of individuals at risk of severe disease and stratification for preferential vaccination (See Abstract). Vishnubhotla discloses that the clinical characteristics of the asymptomatic and symptomatic (mild to moderate/severe) COVID‐19 patients are presented in Table 1. Association analysis between the two groups identified a total of five alleles to be significantly different between the groups. HLAC* 04:01:01:01, HLA‐DRB5*01:01:01:02, HLA‐DQA1*03: 01:01:01, HLA‐DQA1*01:03:01:02, and HLA‐DPB1*04: 01:01:41 conferred an enhanced risk of mild to moderate/ severe disease (Table 2) (See page 1783, right column, paragraph 2; Bridging pages 1783-1784). Here the description teaches that the DPB1*04:01 HLA allele is present in a subject as claimed.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the teaching of Vishnubhotla into Bacher’s study to arrive at an invention as claimed. Because Vishnubhotla teaches the HLA‐DPB1*04 is associated with severe COVID‐19, one of skill in the art would have been motivated to identify DPB1*04:01 HLA allele in the subject with SARS-CoV-2 infection or vaccination. There would be a reasonable expectation of success to develop a method wherein the subject has at least a DPB1*04:01 or DPB1*04:02 HLA allele.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am to 4:30 pm, EST.
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/RUIXUE WANG/ Examiner, Art Unit 1672
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