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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/26/22 is being considered by the examiner.
Claim Status
Claims 1-24 are pending and are examined.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to “a method of determining whether a host has an infection by measuring a threshold value of leukocytes” without significantly more steps or structures. The independent claims recite two steps of “obtaining” and/or “comparing” and/or “modifying”. Additionally, claims 5, 7, 10, 12, 13, 17, 19 and 21 recite mathematical concepts, which are also considered abstract ideas.
These judicial exceptions are not integrated into a practical application because no particular treatment/prophylaxis has been recited for the natural correlation.. No additional element or combination of elements have been recited in the claims to apply, rely on, or use the mathematical concepts in a manner that imposes a meaningful limit on the abstract idea. Further, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims are natural correlation without significantly more and therefore there is no practical application.
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, 2, 3, 4, 5, 6, 8, 14, 15, 16, 17, 18, 19, 20, 22, and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang (“The diagnostic and predictive role of NLR, d-NLR, and PLR in COVID-19 patients. 2020.” 84. 1-7.).
Regarding Claim 1, Yang teaches a method of determining whether a host has an infection, the method comprising: obtaining measured values comprising a number of leukocytes and a number of a first type of leukocytes in a blood sample from the host, and comparing the measured values with one or more stored threshold value(s) to determine whether the host has said infection (3.2. Use of the optimum cut-off values of laboratory results to discern severe from non-severe COVID-19 infection. Given that NLR, LMR, PLR, d-NLR, WBC count, and CRP were used to identify patients with severe or non-severe cases of COVID-19, patients with pneumonia were limited. No unified laboratory reference value was found. Therefore, we analyzed the optimal cut-off values calculated by the ROC analysis, and the ROC curves were presented in Fig. 1. In Fig. 1, areas under the curve (AUC) of age, NLR, d-NLR, CRP, LMR and PLR were 0.743, 0.841, 0.815, 0.714, 0.265, and 0.784.).
Regarding Claim 2, Yang teaches a method according to claim 1, wherein the infection is infection by the virus SARS-CoV2 (2. Materials and methods, 2.1 Patients. (4) Positive result of RT-PCR for SARS-CoV-2 RNA.).
Regarding Claim 3, Yang teaches a method according to claim 1, wherein comparing the measured values with one or more stored threshold value(s) to determine whether the host has the infection comprises performing at least one calculation on the measured values and comparing the result of the calculation(s) with a respective one of the threshold value(s) (Therefore, we analyzed the optimal cut-off values calculated by the ROC analysis, and the ROC curves were presented in Fig. 1. In Fig. 1, areas under the curve (AUC) of age, NLR, d-NLR, CRP, LMR and PLR were 0.743, 0.841, 0.815, 0.714, 0.265, and 0.784. See Section 3.2 Use of the Optimum Cutoff Values).
Regarding Claim 4, Yang teaches a method according to claim 1, wherein the first type of leukocytes is neutrophils (See Table 1, Neutrophils (NEU)).
Regarding Claim 5, Yang teaches a method according to claim 3 , wherein one of the at least one calculation(s) is A , A being the number of leukocytes, L, minus the number of neutrophils, N (White blood count cell (WBC), neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR) (neutrophil count divided by the result of white cell count minus neutrophil count), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), C-reactive protein (CRP), lymphocyte (LYM), Neutrophils (NEU). See Section 3.2).
Regarding Claim 6, Yang teaches a method according to claim wherein the measured values further comprise a number of eosinophils (Section 2.2, Laboratory assessments consisted of complete blood count, blood chemistry. The complete blood count would include a number of eosinophils.).
Regarding Claim 8, Yang teaches a method according to claim wherein the measured values further comprise a number of lymphocytes (Table 1. White blood count cell (WBC), neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR) (neutrophil count divided by the result of white cell count minus neutrophil count), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), C-reactive protein (CRP), lymphocyte (LYM), Neutrophils (NEU)).
Regarding Claim 14, Yang teaches a method of calculating a threshold value for use in determining whether a host has an infection, the method comprising: obtaining measured values comprising a number of leukocytes and a number of a first type of leukocytes in a blood sample from each of a plurality of subjects, obtaining an infection status for each of the subjects, analyzing the measured values and infection statuses to determine the threshold value (Table 1, the examiner notes the numbers can be compared manually. Non-severe and severe are shown in Table 1).
Regarding Claim 15, Yang teaches a method according to claim 14 wherein analyzing the measured values and infection statuses to determine a threshold value comprises separating the measured values into an infected set and an uninfected set, wherein the infected set contains measured values for subjects with an infection status of infected and the uninfected set contains values measured values for subjects with an infection status of uninfected (Table 1, the examiner notes the numbers can be compared manually. Non-severe and severe are shown in Table 1).
Regarding Claim 16, Yang teaches a method according to claim 15 wherein the analysis further comprises performing a calculation on the measured values of each subject and comparing results of the calculation for measured values in the infected set with results of the calculation for measured values in the uninfected set (Table 1, the examiner notes the numbers can be compared manually. Non-severe and severe are shown in Table 1).
Regarding Claim 17, Yang teaches a method according to claim 16, wherein comparing results in the infected set with results in the uninfected set comprises calculating a mean of the results for each set and determining a threshold value comprises selecting a value between the mean of the results for the infected set and the mean of the results in the uninfected set (In our study, the applicable thresholds for NLR, d-NLR, PLR, and LMR were observed using the ROC curve. The optimal threshold at 3.3 for NLR showed a superior prognostic possibility of clinical symptoms to change from mild to severe, which had the highest of sensitivity and specificity and the largest of AUC. When age ≥ 49.5 years old and NLR ≥ 3.3, 46.1% of the COVID-19 patients with mild disease will become severe, and the mean time is 6.3 days. So, these patients must be closely attended by clinicians. By contrast, when age < 49.5 years old and NLR < 3.3, COVID-19 patients with mild disease can be cured and discharged at approximately 13.5 days. The difference included numerous COVID-19 patients from a different geographic region and race may be an important factor that contribute to this phenomenon. See page 6, second paragraph. The examiner notes also that using the values in Table 1, these calculations can be done manually.)
Regarding Claim 18, Yang teaches a method according to claim 14, wherein the first type of leukocytes is neutrophils (Table 1. White blood count cell (WBC), neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR) (neutrophil count divided by the result of white cell count minus neutrophil count), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), C-reactive protein (CRP), lymphocyte (LYM), Neutrophils (NEU).).
Regarding Claim 19, Yang teaches a method according to claim 18 when dependent on claim 16 wherein the calculation is the number of leukocytes minus the number of neutrophils L-N = A (Table 1. Baseline characteristics and results of NLR, PLR, d-NLR, WBC, CRP above 93 2019-nCoV pneumonia patients. Calculation can be done using the values of leukocytes (WBC) and neutrophils).
Regarding Claim 20, Yang teaches a method according to claim 14, wherein the first type of leukocytes is eosinophils (Section 2.2, Laboratory assessments consisted of complete blood count, blood chemistry. The complete blood count would include a number of eosinophils.).
Regarding Claim 22, Yang teaches a method of adjusting the threshold value determined using a method of claim 14, the method comprising: obtaining the threshold value and an allowed range for the threshold value and modifying the threshold value in response to a received sensitivity parameter, within the allowed range (In our study, the applicable thresholds for NLR, d-NLR, PLR, and LMR were observed using the ROC curve. The optimal threshold at 3.3 for NLR showed a superior prognostic possibility of clinical symptoms to change from mild to severe, which had the highest of sensitivity and specificity and the largest of AUC. When age ≥ 49.5 years old and NLR ≥ 3.3, 46.1% of the COVID-19 patients with mild disease will become severe, and the mean time is 6.3 days. So, these patients must be closely attended by clinicians. By contrast, when age < 49.5 years old and NLR < 3.3, COVID-19 patients with mild disease can be cured and discharged at approximately 13.5 days. The difference included numerous COVID-19 patients from a different geographic region and race may be an important factor that contribute to this phenomenon. See page 6, second paragraph).
Regarding Claim 23, Yang teaches a method of determining whether a host has an infection according to claim 1, wherein the one or more stored threshold value(s) are calculated using a method of calculating a threshold value for use in determining whether a host has an infection.
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 7, 9, 10, 11, 12, 13, 21 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Yang (“The diagnostic and predictive role of NLR, d-NLR, and PLR in COVID-19 patients. 2020.”), in view of Sun (“Abnormalities of peripheral blood system in patients with COVID-19. Clinica Chimica Acta. 507. 2020. 174-180.).
Regarding Claim 7, Yang teaches a method according to claim 3.
Yang is silent to one of the at least one calculation(s) is κ, κ being the number of leukocytes, L, minus the number of eosinophils, E.
Sun teaches in the related art of measuring cell counts in blood. See Tables 1 and 2 for leucocytes and eosinophils and the measurement can be made to calculate leucocytes minus eosinophils.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added the step of at least one calculation(s) is κ, κ being the number of leukocytes, L, minus the number of eosinophils, E, as taught by Sun, to the method of Yang, to allow for prediction of severe COVID-19 cases, as taught by Sun in the Conclusions section of the Abstract.
Regarding Claim 9, Yang teaches a method according to claim 1.
Yang is silent to comparing measured values with one or more stored threshold values(s) comprises comparing each of λ, κ, the number of leukocytes, the number of neutrophils, the number of eosinophils and the number of lymphocytes with a respective threshold.
Sun teaches in the related art of measuring cell counts in blood. See Tables 1 and 2 for leucocytes and eosinophils and neutrophils and lymphocytes. This table can be used to compare the number of each of these cell types. The examiner notes that the step of comparing can be done manually by visually comparing the numbers in the table.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added the step of comparing measured values with one or more stored threshold values(s) comprises comparing each of λ, κ, the number of leukocytes, the number of neutrophils, the number of eosinophils and the number of lymphocytes with a respective threshold, as taught by Sun, to the method of Yang, to allow for prediction of severe COVID-19 cases, as taught by Sun in the Conclusions section of the Abstract.
Regarding Claim 10, modified Yang teaches a method according to claim 9,
wherein the respective threshold for the calculation λ is v (nu) = 2.02 10^9/L,
wherein when the result of λ is less than v (nu) then a result of a comparison for λ is positive, and/or (the examiner notes that with the recitation of “and/or”, the limitation following is optional. At minimum, only one of the options of “when the results” has to be met.)
wherein the respective threshold for the calculation κ is (mu) = 7.00 10^9/L, wherein when the result of κ is greater than (mu) then a result of a comparison for K is positive, and/or (the examiner notes that with the recitation of “and/or”, the limitation following is optional.)
wherein the respective threshold for the number of eosinophils is ξ (xi) = 0.09 10^9/L, wherein when the number of eosinophils is less than ξ (xi) then a result of a comparison for the number of eosinophils is positive See Table 2, eosinophils see “common” column 0.03 x 109), and/or
wherein the respective threshold for the number of lymphocytes is ο (omicron) = 1.64 10^9/L, wherein when the number of lymphocytes is less than ο (omicron) then a result of a comparison for the number of lymphocytes is positive, and/or (the examiner notes that with the recitation “and/or”, the limitation following is optional.),
wherein the respective threshold for the number of neutrophils is ρ (ro) = 5.07 10^9/L, wherein when the number of neutrophils is greater than ρ (ro) then a result of a comparison for the number of neutrophils is positive, and/or(the examiner notes that with the recitation of “and/or”, the limitation following is optional)
wherein the respective threshold for the number of leukocytes is a (sigma) = 8.00 10^9/L, wherein when the number of neutrophils is greater than a (sigma) then a result of a comparison for the number of leukocytes is positive (the examiner notes that with the recitation of “and/or”, the limitation following is optional).
Regarding Claim 11, Yang teaches a method according to claim 1.
Yang is silent the measured values further comprise a number of lymphocytes, wherein comparing measured values with one or more stored threshold values(s) comprises comparing each of λ, the number of eosinophils and the number of lymphocytes with a respective threshold.
Sun teaches in the related art of measuring cell counts in blood. See Tables 1 and 2 for leucocytes and eosinophils and neutrophils and lymphocytes. This table can be used to compare the number of each of these cell types.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added the step of the measured values further comprise a number of lymphocytes, wherein comparing measured values with one or more stored threshold values(s) comprises comparing each of λ, the number of eosinophils and the number of lymphocytes with a respective threshold, as taught by Sun, to the method of Yang, to allow for prediction of severe COVID-19 cases, as taught by Sun in the Conclusions section of the Abstract.
Regarding Claim 12, modified Yang teaches a method according to claim 11, wherein the respective threshold for the calculation λ is (upsilon) = 1.50 10^9/L, wherein when the result of A is less than u (upsilon) then a result of a comparison for λ is positive, and/or (the examiner notes that with and/or the limitation following is optional) wherein the respective threshold for the number of eosinophils is (phi) = 0.03 10^9/L and when the number of eosinophils is less than (phi) then a result of a comparison for number of eosinophils is positive, and/or (the examiner notes that with and/or the limitation following is optional; See Table 2, eosinophils see “common” column 0.03 x 109) wherein the respective threshold for the number of lymphocytes is χ (chi) = 1.10 10^9/L and when the number of lymphocytes is less than χ (chi) then a result of a comparison for the number of lymphocytes is positive.
Regarding Claim 13, Yang teaches a method according to claim 10.
Yang is silent to when the result of at least one of the comparisons is positive, comparing the measured values with one or more stored threshold value(s) determines that the host has said infection.
Sun teaches in the related art of measuring cell counts in blood. See Tables 1 and 2 for leucocytes and eosinophils and neutrophils and lymphocytes. This table can be used to compare the number of each of these cell types.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added the step of when the result of at least one of the comparisons is positive, comparing the measured values with one or more stored threshold value(s) determines that the host has said infection, as taught by Sun, to the method of Yang, to allow for prediction of severe COVID-19 cases, as taught by Sun in the Conclusions section of the Abstract.
Regarding Claim 21, Yang teaches a method according to claim 20.
Yang is silent to the calculation is the number of leukocytes minus the number of eosinophils L-E = K.
Sun teaches in the related art of measuring cell counts in blood. See Tables 1 and 2 for leucocytes and eosinophils and the measurement can be made to calculate leucocytes minus eosinophils.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added the step of at least one calculation(s) is κ, κ being the number of leukocytes, L, minus the number of eosinophils, E, as taught by Sun, to the method of Yang, to allow for prediction of severe COVID-19 cases, as taught by Sun in the Conclusions section of the Abstract.
Regarding Claim 24, Yang teaches a system configured to carry out a method according to of claim 1.
Yang is silent to the system comprises: a user device and a server, wherein the user device is configured to obtain the measured values and compare the measured values with a respective one of the stored threshold value(s)to determine whether the host has said infection, wherein the server is configured to store the stored threshold value(s) and wherein the user device is configured to obtain the stored threshold value(s) from the server.
Sun teaches in Section 2.2 statistical analysis- PSS19.01 statistical software was used for processing data. The hematological cell count data are expressed as 109/L. The examiner notes that software would be on a computer which would be connected to a server.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a user device and a server, as taught by Sun, to perform the method steps, as taught by Yang, such as to obtain the measured values and compare the measured values with a respective one of the stored threshold value(s)to determine whether the host has said infection, and to obtain the stored threshold value(s) from the server, to allow for quick calculations to determine whether a clinical blood sample is infected or not.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACQUELINE BRAZIN whose telephone number is (571)270-1457. The examiner can normally be reached M-F 8-6.
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/JB/
/JILL A WARDEN/Supervisory Patent Examiner, Art Unit 1798