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 .
Claim Objections
Claim 6 is objected to because of the following informalities: “shifty” should be corrected to say –shift--.
Claim 7 is objected to because of the following informalities: “area under a curve of and/or full width half maximum of” should be corrected to say --area under a curve and/or full width half maximum of--.
Claim 18 is objected to because of the following informalities: “control” should be corrected to say –the control--.
Claim 19 is objected to because of the following informalities: “a subject” should be corrected to say –the subject--.
Appropriate correction is required.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Independent Claim 1:
Preamble: “A method of determining at least one of hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or the presence of hemoglobin variants in blood of a subject”
L1: “determining differences of absorption spectra of oxygenated and deoxygenated hemoglobin, red blood, and/or blood obtained from the subject”
L2: “comparing the determined absorption spectra differences to a control value”
Wherein clause: “wherein the absorption spectra differences are indicative of hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or the presence of hemoglobin variants in the blood of the subject”
Independent Claim 15:
Preamble: “A method of detecting hemoglobin variants in blood of a subject”
L1: “determining an optical signature of hemoglobin, red blood cells, and/or blood obtained from the subject that has been chemically deoxygenated and that has a pH from about 6.5 to about 9.0”
L2: “comparing the determined optical signature to a control optical signature”
Wherein clause: “wherein differences between the determined optical signature and the control optical signature is indicative of hemoglobin variants”
Step 1: Statutory category determination.
Claims 1–20 are “processes” (methods) and thus fall within a statutory category under § 101.
Step 2A Prong 1: Identify judicial exception(s) with citations to PEG groupings; quote offending clauses.
Claims 1 and 15 each recite abstract ideas in the mental-process and mathematical-concept groupings (2019 PEG; MPEP 2106.04(a)(2); Oct. 2019 Update):
Mental processes: steps of analyzing, evaluating, determining, comparing, and characterizing information are activities that can be performed in the human mind or with pen and paper (see Electric Power Group v. Alstom; SAP v. InvestPic).
Clauses that recite judicial exceptions:
Claim 1:
“determining at least one of hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or the presence of hemoglobin variants in blood of a subject”
“determining differences of absorption spectra of oxygenated and deoxygenated hemoglobin, red blood, and/or blood obtained from the subject”
“comparing the determined absorption spectra differences to a control value”
Claim 15:
“detecting hemoglobin variants in blood of a subject”
“determining an optical signature …”
“comparing the determined optical signature to a control optical signature”
Mathematical concepts: “determining at least one of hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or the presence of hemoglobin variants in blood of a subject”, “determining differences of absorption spectra of oxygenated and deoxygenated hemoglobin, red blood, and/or blood obtained from the subject”, and “determining an optical signature …” steps reasonably encompass calculations over numeric fields (e.g., histograms, peak detection, statistics), which fall within “mathematical relationships/formulas” per the PEG, even though not explicitly formulaic in the claims.
The “comparing the determined absorption spectra differences to a control value”, “detecting hemoglobin variants in blood of a subject”, and “comparing the determined optical signature to a control optical signature” steps appear as mental process steps surrounding the core analysis, and do not by themselves remove the recited abstract ideas.
Step 2A Prong 2: Analyze integration into a practical application.
Claim 1:
Particular machine or transformation: The claim invokes “A method of determining…” but does not recite a particular machine configuration or an improvement for optical detection of hemoglobin variants, oxygen affinity, and deoxygenation (no specific geometry, calibration, or signal-processing innovation is claimed). The focus is on analyzing a determined absorption spectra in comparison with a control value. No transformation of an article results from the analysis (contrast Diamond v. Diehr).
Meaningful limitations vs. extra-solution activity: The optical detection of hemoglobin variants, oxygen affinity, and deoxygenation is, at most, pre-solution data gathering in a particular field; “determining differences of absorption spectra” and “comparing the determined absorption spectra differences to a control value” are the core abstract steps. Field-of-use (blood of a subject, hemoglobin variants) and data gathering limitations are insufficient to integrate the exception. Thus, claim 1 does not integrate the abstract idea into a practical application.
Claim 15:
Particular machine or transformation: The claim invokes “A method of detecting…” but does not recite a particular machine configuration or an improvement for optical detection of hemoglobin variants, oxygen affinity, and deoxygenation (no specific geometry, calibration, or signal-processing innovation is claimed). The focus is on analyzing a determined an optical signature in comparison with a control optical signature. No transformation of an article results from the analysis (contrast Diamond v. Diehr).
Meaningful limitations vs. extra-solution activity: The detection of hemoglobin variants is, at most, pre-solution data gathering in a particular field; “determining an optical signature” and “comparing the determined optical signature to a control optical signature” are the core abstract steps. Field-of-use (blood of a subject, hemoglobin variants) and data gathering limitations are insufficient to integrate the exception. Thus, claim 15 does not integrate the abstract idea into a practical application.
Step 2B: Assess whether additional elements are significantly more; discuss WURC with evidentiary considerations.
The non-abstract elements across the claims are:
Using a “method of determining at least one of hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or the presence of hemoglobin variants in blood of a subject” (claims 1-14 via claim 1).
In claim 2, “oxygenated and chemically deoxygenated hemoglobin are measured at the same pH”.
In claim 3, “generating a first optical absorption spectrum” and “generating a second optical absorption spectrum”.
In claim 4, “a bathochromic shift and/or hypochromic shift” in peak wavelength.
In claim 5, “hemoglobin variants in the hemoglobin, reb blood cells, or blood of the subject”.
In claim 6, “hemoglobin oxygen affinity”, “hemoglobin deoxidation”, and “the subject having sickle cell disease”.
In claim 7, “area under a curve of and/or full width half maximum of peak wavelengths” and “anemia of the subject and homogeneity of hemoglobin in the subject”.
In claim 8, “the hemoglobin, red blood cells, and/or blood” and “an amount of chemical deoxygenant effective to deplete oxygen from the hemoglobin”.
In claim 9, “the chemical deoxygenant comprises sodium metabisulfite”.
In claim 10, “the hemoglobin variant is selected from HbSA, HbSS, HbSC, and HbA2”.
In claim 11, “diagnoses the subject as having a sickle cell trait”.
In claim 12, “diagnoses the subject as having a sickle cell disease”.
In claim 13, “diagnoses the subject as having a hemoglobin SC disease”.
In claim 14, “diagnoses the subject as having thalassemia”.
Using “a method of detecting hemoglobin variants in blood of a subject” (claims 16-20 via claim 15).
In claim 16, “UV-VIS light spectroscopy”.
In claim 17, “an absorption spectra of the deoxygenated hemoglobin, red blood cells, and/or blood”.
In claim 18, “an absorption spectra of chemically deoxygenated normal hemoglobin, red blood cells, and/or blood obtained at substantially the same pH as the optical signature of the hemoglobin, red blood cells, and/or blood obtained from the subject”.
In claim 19, “adding hemoglobin, red blood cells, and/or blood obtained from a subject to a pH buffer solution”.
In claim 20, “the buffer solution has a weak acidic or weak basic pH”.
On the present record, these are well-understood, routine, conventional (WURC) in optical detection of hemoglobin variants, oxygen affinity, and deoxygenation:
The specification itself acknowledges that spectroscopic devices are existing, known measurement techniques used to determine an optical signature of hemoglobin, red blood cells, and/or blood obtained from the subject. Such admissions support a Berkheimer-compliant factual finding that the use of optical detection of hemoglobin variants, oxygen affinity, and deoxygenation, as broadly claimed, is conventional.
Measuring pH, optical absorption spectra, peak wavelength shifts and area under a curve and/or full width half maximum are standard metrology practices in spectroscopy; the claims do not recite any non-conventional arrangement or processing.
Specifying the sample/subject under test, the chemical deoxygenant, the hemoglobin variant, the diagnoses, and the pH are routine parameter choices absent evidence of a non-conventional implementation that improves the machine or yields unexpected performance.
The courts have decided: Phenomena of nature, though just discovered, mental processes, abstract intellectual concepts, are not patentable, as they are the basic tools of scientific and technological work (Gottschalk v Benson, 409 U.S.63, 175 USPQ 673 (1972)). It is well established that the mere physical or tangible nature of additional elements, such as a data input or detection step, does not automatically confer eligibility on a claim directed to an abstract idea (see Alice Corp. Pty. Ltd. V CLS Bank, 573 US, 134 S. Ct. 2347, 110 USPQ.2d 1976 (2014)). Subject matter eligibility examples with regard to Abstract Ideas are found at: https://www.uspto.gov/sites/default/files/documents/abstract_idea_examples.pdf.
Therefore, the claimed subject matter does not recite patent eligible subject matter under 35 U.S.C. § 101.
Conclusion: Eligible/ineligible under § 101.
Claims 1 and 15: Ineligible under § 101. The claim recites mental-process/mathematical-concept abstract ideas and does not integrate them into a practical application; remaining elements are WURC data gathering.
Claims 2-14: Ineligible under § 101 for the same reasons as claim 1; the added limitations do not integrate the exception or add significantly more.
Claims 16-20: Ineligible under § 101 for the same reasons as claim 15; the added limitations do not integrate the exception or add significantly more.
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, 10-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Burshteyn et al. (US20040214243A1), hereinafter Burshteyn.
As to claim 1, Burshteyn teaches a method of determining at least one of hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or the presence of hemoglobin variants in blood of a subject (Burshteyn claim 1; method of analyzing a hemoglobin type or variant in a test sample), the method comprising:
determining differences of absorption spectra of oxygenated and deoxygenated hemoglobin, red blood, and/or blood obtained from the subject (Burshteyn [0012]; “a method of analyzing one or more hemoglobin types and/or variants in a sample comprising mixing a test sample from a patient…; measuring the test sample to determine a signal generated from the first label on the pan-hemoglobin antibody and a signal generated from the second label on the hemoglobin type or variant-specific affinity reagent; comparing the signal from said pan-hemoglobin antibody and said hemoglobin type or variant specific affinity reagent; and reporting the result of the comparison”)
and comparing the determined absorption spectra differences to a control value (Burshteyn [0013]; “The control product can contain a known quantity of one or more hemoglobin types and/or variants”. [0091]; Combined tubes 2 and 3… were used as a color compensation control. Tube 4 was prepared using RBC prepared… and stained with an antibody conjugate according to the general procedure... Tube 4 was used as a dual color sample to determine percent positive of RBC with Hb of interest”. Thus, the signals from the first and second label are compared to the control),
wherein the absorption spectra differences are indicative of hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or the presence of hemoglobin variants in the blood of the subject (Burshteyn claim 3; “said comparing of the signal from said pan-hemoglobin antibody and from said hemoglobin type or variant specific affinity reagent comprises a determination of the percent concentration of the hemoglobin type or variant”).
As to claim 10, Burshteyn teaches the method of claim 1, wherein the hemoglobin variant is selected from HbSA, HbSS, HbSC, and HbA2 (Burshteyn [0032]; “The detection includes analyzing the amount of type and/or variant present in the sample. Hemoglobin types include, but are not limited to, HbA 1C, HbA, HbA2, embryonic Hb, HbS, HbF, HbC, HbD, HbE and glycosylated Hb. In addition, hemoglobin variants include many hemoglobin derivatives of the hemoglobin types”).
As to claim 11, Burshteyn teaches the method of claim 10, wherein detection of HbSA hemoglobin variant diagnoses the subject as having a sickle cell trait (Burshteyn [0038]; “Hb S has been associated with sickle cell disease”, therefore, HbSA, which has the sickle hemoglobin HbS, indicates having a sickle cell trait).
As to claim 12, Burshteyn teaches the method of claim 10, wherein detection of HbSS hemoglobin variant diagnoses the subject as having a sickle cell disease (Burshteyn [0038]; “Hb S has been associated with sickle cell disease”, therefore, HbSS, which has two copies of the sickle cell gene, also indicates having sickle cell disease).
As to claim 13, Burshteyn teaches the method of claim 10, wherein detection of HbSC hemoglobin variant diagnoses the subject as having a hemoglobin SC disease (Burshteyn [0038]; “Hb S has been associated with sickle cell disease. Hb C and Hb D have been associated with Hb C and Hb D diseases, respectively”. Thus, Hb SC would indicate hemoglobin SC disease).
As to claim 14, Burshteyn teaches the method of claim 10, wherein detection of HbA2 hemoglobin variant diagnoses the subject as having thalassemia (Burshteyn [0038]; “Hb A2 has been associated with some forms of β-thalassemias”).
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 of this title, 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 2-7 are rejected under 35 U.S.C. 103 as being unpatentable over Burshteyn in view of "Single-cell measurement of red blood cell oxygen affinity" to Di Caprio, G et al., hereinafter Dicaprio (from the IDS).
As to claim 2, Burshteyn teaches the method of claim 1.
However, Burshteyn does not explicitly disclose wherein the absorption spectra of the oxygenated and chemically deoxygenated hemoglobin are measured.
Dicaprio, in the same field of endeavor as the claimed invention, teaches wherein the absorption spectra of the oxygenated and chemically deoxygenated hemoglobin are measured (Dicaprio Fig. 6A; page 5 col. 2 fig. 6 description; Comparing the absorption spectra of HbO2 and Hb in two-wavelength spectroscopy to differentiate between HbO2 (oxygenated) and Hb (deoxygenated)).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of Dicaprio to include wherein the absorption spectra of the oxygenated and chemically deoxygenated hemoglobin are measured; for the advantage of enhanced analysis, including comparing the difference between first and second optical absorption values with the hemoglobin structure stability and its capacity to bind oxygen (Dicaprio page 3 col. 2 para. 1).
As to claim 3, Burshteyn teaches the method of claim 1, wherein the differences of absorption spectra are determined by: generating a first optical absorption spectrum of oxygenated hemoglobin, red blood, and/or blood obtained from the subject; generating a second optical absorption spectrum of deoxygenated hemoglobin, red blood, and/or blood obtained from the subject; comparing the first optical absorption spectrum with second optical absorption to determine differences of the absorption spectra ([0149]; The difference in the intensity of the band (i.e. the absorption spectra) is calculated by evaluating the difference in color between Hb (i.e. the first absorption) and the standard calibrator mixed with the blood sample (i.e. the second absorption). Thus, the first and second absorptions are measured from a blood sample of a subject and compared).
However, Burshteyn does not explicitly disclose comparing the first optical absorption spectrum with second optical absorption to determine differences of the absorption spectra.
Dicaprio, in the same field of endeavor as the claimed invention, teaches comparing the first optical absorption spectrum with second optical absorption to determine differences of the absorption spectra (Dicaprio Fig. 6A; page 5 col. 2 fig. 6 description; Comparing the absorption spectra of HbO2 and Hb in two-wavelength spectroscopy to differentiate between HbO2 and Hb. The samples were illuminated with two blue LEDs at 410nm (i.e. the first optical absorption) and 430 nm (i.e. the second optical absorption).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of Dicaprio to include comparing the first optical absorption spectrum with second optical absorption to determine differences of the absorption spectra; for the advantage of enhanced analysis, including comparing the difference between first and second optical absorption values with the hemoglobin structure stability and its capacity to bind oxygen (Dicaprio page 3 col. 2 para. 1).
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Dicaprio Fig. 6A
As to claim 4, Burshteyn teaches the method of claim 3.
However, Burshteyn does not explicitly disclose wherein the differences of the absorption spectra include at least one of a bathochromic shift and/or hypochromic shift in peak wavelength from the first absorption spectrum to the second absorption spectrum.
Dicaprio, in the same field of endeavor as the claimed invention, teaches wherein the differences of the absorption spectra include at least one of a bathochromic shift and/or hypochromic shift in peak wavelength from the first absorption spectrum to the second absorption spectrum (Dicaprio Fig. 6A; page 5 col. 2 fig. 6 description; Comparing the absorption spectra of HbO2 and Hb in two-wavelength spectroscopy, the differences of the two spectra results in a bathochromic shift in peak wavelength from 410 nm to 430 nm, wherein the absorption maximum is shifted towards longer wavelengths).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of Dicaprio to include wherein the differences of the absorption spectra include at least one of a bathochromic shift and/or hypochromic shift in peak wavelength from the first absorption spectrum to the second absorption spectrum; for the advantage of achieving valuable insights into the distribution of Hb variants and therefore increasing the ability of detecting diseases/disorders such as anemia (Dicaprio page 5 col. 1 para. 4).
As to claim 5, Burshteyn teaches the method of claim 4.
However, Burshteyn does not explicitly disclose wherein the magnitude of barochromic shift in peak wavelength is indicative of at least one hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or presence and/or percentage of hemoglobin variants in the hemoglobin, red blood cells, or blood of the subject.
Dicaprio, in the same field of endeavor as the claimed invention, teaches wherein the magnitude of barochromic shift in peak wavelength is indicative of at least one hemoglobin oxygen affinity (Dicaprio abstract; oxygen affinity), rate of hemoglobin deoxygenation, or presence and/or percentage of hemoglobin variants in the hemoglobin, red blood cells, or blood of the subject (Dicaprio Fig. 6A; page 1 col. 2 “Funtional RBC Analyzer”; page 5 col. 2 fig. 6 description and “Sample Preparation”; The differences of the absorption spectra of HbO2 and Hb in the two-wavelength spectroscopy results in a bathochromic shift in peak wavelength from 410 nm to 430 nm, wherein the absorption maximum is shifted towards longer wavelengths. The blood samples were measured as a function of ppO2 (i.e. magnitude of barochromic shift wherein the absorption maximum is shifted towards longer wavelengths)).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Gurkan to incorporate the teachings of Burshteyn to include wherein the magnitude of barochromic shift in peak wavelength is indicative of at least one hemoglobin oxygen affinity, rate of hemoglobin deoxygenation, or presence and/or percentage of hemoglobin variants in the hemoglobin, red blood cells, or blood of the subject; for the advantage of increased understanding of variability and determinants of oxygen affinity on a cellular level (Dicaprio abstract).
As to claim 6, Burshteyn teaches the method of claim 5.
However, Burshteyn does not explicitly disclose wherein an increase in magnitude of biochromatic shift and/or hypochromic shift in peak wavelength is indicative of decreased hemoglobin oxygen affinity, increased hemoglobin deoxidation, or the subject having sickle cell disease.
Dicaprio, in the same field of endeavor as the claimed invention, teaches wherein an increase in magnitude of biochromatic shift and/or hypochromic shift in peak wavelength is indicative of decreased hemoglobin oxygen affinity, increased hemoglobin deoxidation, or the subject having sickle cell disease (Dicaprio Fig. 6A; page 5 col. 2 fig. 6 description; The two-wavelength spectroscopy indicates decreased hemoglobin oxygen affinity Hb curve and increased Hb oxygen affinity Hb curve, corresponding to an increase in biochromatic shift in peak wavelength: The higher shift indicating decreased hemoglobin oxygen affinity Hb curve).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Gurkan to incorporate the teachings of Burshteyn to include wherein an increase in magnitude of biochromatic shift and/or hypochromic shift in peak wavelength is indicative of decreased hemoglobin oxygen affinity, increased hemoglobin deoxidation, or the subject having sickle cell disease; for the advantage of achieving valuable insights into the distribution of Hb variants and therefore increasing the ability of detecting diseases/disorders such as anemia (Dicaprio page 5 col. 1 para. 4).
As to claim 7, Burshteyn teaches the method of claim 4.
However, Burshteyn does not explicitly disclose wherein the differences of area under a curve of and/or full width half maximum of peak wavelengths of the first absorption spectrum and the second absorption spectrum are indicative of anemia of the subject and homogeneity of hemoglobin in the subject.
Dicaprio, in the same field of endeavor as the claimed invention, teaches wherein the differences of area under a curve of and/or full width half maximum of peak wavelengths of the first absorption spectrum and the second absorption spectrum are indicative of anemia of the subject and homogeneity of hemoglobin in the subject (Dicaprio page 5 col. 1 para. 2-4; fig. 6A; page 5 col. 2 fig. 6 description; The difference of area under the HbO2 curve and the Hb curve (i.e. the first and second absorption spectra) are capable of indicating “anemia” of the subject. Since the spectroscopy measures oxygen saturation for “individual RBCs” (red blood cells), the homogeneity of hemoglobin in the subject can be estimated).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of Dicaprio to include wherein the differences of area under a curve of and/or full width half maximum of peak wavelengths of the first absorption spectrum and the second absorption spectrum are indicative of anemia of the subject and homogeneity of hemoglobin in the subject; for the advantage of achieving valuable insights into the distribution of Hb variants and therefore increasing the ability of detecting diseases/disorders such as anemia (Dicaprio page 5 col. 1 para. 4).
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Burshteyn in view of Srinivasan et al. (US 20220283188 A1), hereinafter Srinivasan.
As to claim 8, Burshteyn teaches the method of claim 1.
However, Burshteyn does not explicitly disclose wherein the hemoglobin, red blood cells, and/or blood is chemically deoxygenated by mixing the hemoglobin, red blood cells, and/or blood with an amount of chemical deoxygenant effective to deplete oxygen from the hemoglobin.
Srinivasan, in the same field of endeavor as the claimed invention, teaches wherein the hemoglobin, red blood cells, and/or blood is chemically deoxygenated by mixing the hemoglobin, red blood cells, and/or blood with an amount of chemical deoxygenant effective to deplete oxygen from the hemoglobin (Srinivasan claim 15; the deoxygenated condition comprises mixing the blood sample with phosphate buffer comprising sodium metabisulfite to obtain a sample/buffer mixture).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of Srinivasan to include wherein the hemoglobin, red blood cells, and/or blood is chemically deoxygenated by mixing the hemoglobin, red blood cells, and/or blood with an amount of chemical deoxygenant effective to deplete oxygen from the hemoglobin; for the advantage of rapid identification in a blood sample in a point-of-care setting (Srinivasan abstract).
As to claim 9, Burshteyn teaches the method of claim 8.
However, Burshteyn does not explicitly disclose wherein the chemical deoxygenant comprises sodium metabisulfite.
Srinivasan, in the same field of endeavor as the claimed invention, teaches wherein the chemical deoxygenant comprises sodium metabisulfite (Srinivasan claim 15; the deoxygenated condition comprises mixing the blood sample with phosphate buffer comprising sodium metabisulfite to obtain a sample/buffer mixture).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of Srinivasan to include wherein the chemical deoxygenant comprises sodium metabisulfite; for the advantage of rapid identification in a blood sample in a point-of-care setting (Srinivasan abstract).
Claims 15 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Burshteyn in view of van Agthoven et al. (US20070020612A1), hereinafter van Agthoven.
As to claim 15, Burshteyn teaches a method of detecting hemoglobin variants in blood of a subject (Burshteyn claim 1; method of analyzing a hemoglobin type or variant in a test sample), the method comprising:
determining an optical signature of hemoglobin, red blood cells, and/or blood obtained from the subject (Burshteyn [0012]; “a method of analyzing one or more hemoglobin types and/or variants in a sample comprising mixing a test sample from a patient…; measuring the test sample to determine a signal generated from the first label on the pan-hemoglobin antibody and a signal generated from the second label on the hemoglobin type or variant-specific affinity reagent; comparing the signal from said pan-hemoglobin antibody and said hemoglobin type or variant specific affinity reagent; and reporting the result of the comparison”)
and comparing the determined optical signature to a control optical signature (Burshteyn [0013]; “The control product can contain a known quantity of one or more hemoglobin types and/or variants”. [0091]; Combined tubes 2 and 3… were used as a color compensation control. Tube 4 was prepared using RBC prepared… and stained with an antibody conjugate according to the general procedure... Tube 4 was used as a dual color sample to determine percent positive of RBC with Hb of interest”. Thus, the signals from the first and second label are compared to the control)
wherein differences between the determined optical signature and the control optical signature is indicative of hemoglobin variants (Burshteyn claim 3; “said comparing of the signal from said pan-hemoglobin antibody and from said hemoglobin type or variant specific affinity reagent comprises a determination of the percent concentration of the hemoglobin type or variant”).
However, Burshteyn does not explicitly disclose hemoglobin, red blood cells, and/or blood obtained from the subject that has been chemically deoxygenated and that has a pH from about 6.5 to about 9.0.
Van Agthoven, in the same field of endeavor as the claimed invention, teaches hemoglobin, red blood cells, and/or blood obtained from the subject that has been chemically deoxygenated and that has a pH from about 6.5 to about 9.0 (van Agthoven [0049]-[0050]; “The neutralization reagent is hypertonic and essentially neutral, with a pH slightly above 7.0. When mixed with the first sample mixture, the neutralization reagent brings pH of the sample mixture to neutral, and increases the ionic strength and osmolality of the sample mixture” (i.e. the blood sample). “The buffer can be an organic or inorganic buffer, which provides a neutral pH. The pH of the neutralization reagent is preferably from about 7.1 to about 7.5, more preferably from about 7.2 to about 7.4”).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of van Agthoven to include hemoglobin, red blood cells, and/or blood obtained from the subject that has been chemically deoxygenated and that has a pH from about 6.5 to about 9.0; for the advantage of increasing the ionic strength and osmolality of the sample (van Agthoven [0049]).
As to claim 18, Burshteyn teaches the method of claim 15.
However, Burshteyn does not explicitly disclose wherein control optical signature includes an absorption spectra of chemically deoxygenated normal hemoglobin, red blood cells, and/or blood obtained at substantially the same pH as the optical signature of the hemoglobin, red blood cells, and/or blood obtained from the subject.
Van Agthoven, in the same field of endeavor as the claimed invention, teaches wherein control optical signature includes an absorption spectra of chemically deoxygenated normal hemoglobin, red blood cells, and/or blood (van Agthoven [0095]; “The reference control is typically made of fluorescent particles with known hemoglobin concentration, or equivalent hemoglobin concentration, known side scatter and fluorescence intensities”. Hemoglobin concentration itself is deoxygenated from the blood sample) obtained at substantially the same pH as the optical signature of the hemoglobin, red blood cells, and/or blood obtained from the subject (van Agthoven [0049]-[0050]; “The neutralization reagent is hypertonic and essentially neutral, with a pH slightly above 7.0. When mixed with the first sample mixture, the neutralization reagent brings pH of the sample mixture to neutral, and increases the ionic strength and osmolality of the sample mixture” (i.e. the blood sample). Thus, the control optical signature and the optical signature must share substantially the same pH).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of van Agthoven to include wherein control optical signature includes an absorption spectra of chemically deoxygenated normal hemoglobin, red blood cells, and/or blood obtained at substantially the same pH as the optical signature of the hemoglobin, red blood cells, and/or blood obtained from the subject; for the advantage of increasing the ionic strength and osmolality of the sample (van Agthoven [0049]).
As to claim 19, Burshteyn teaches the method of claim 15.
However, Burshteyn does not explicitly disclose adding hemoglobin, red blood cells, and/or blood obtained from a subject to a pH buffer solution prior to determining the optical signature, wherein the hemoglobin, red blood cells, and/or blood added to the pH buffer solution undergoes a conformational change.
Van Agthoven, in the same field of endeavor as the claimed invention, teaches adding hemoglobin, red blood cells, and/or blood obtained from a subject to a pH buffer solution prior to determining the optical signature (van Agthoven [0054]; When a specific hemoglobin variant is to be measured… an antibody specific to the hemoglobin variant of interest can be added into the neutralization reagent. As the cell membrane is permeated by the permeation reagent, these large antibody molecules can penetrate through cellular membrane and bind to the antigen sites of the intracellular proteins”. Thus, adding hemoglobin, red blood cells, and/or blood obtained from a subject to a pH buffer solution occurs before determining the optical signature),
wherein the hemoglobin, red blood cells, and/or blood added to the pH buffer solution undergoes a conformational change (van Agthoven [0049]-[0050]; “The neutralization reagent is hypertonic and essentially neutral, with a pH slightly above 7.0. When mixed with the first sample mixture, the neutralization reagent brings pH of the sample mixture to neutral, and increases the ionic strength and osmolality of the sample mixture” (i.e. the blood sample). Thus, causing a conformational change, conforming to the buffer solution pH).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn to incorporate the teachings of van Agthoven to include adding hemoglobin, red blood cells, and/or blood obtained from a subject to a pH buffer solution prior to determining the optical signature, wherein the hemoglobin, red blood cells, and/or blood added to the pH buffer solution undergoes a conformational change; for the advantage of increasing the ionic strength and osmolality of the sample (van Agthoven [0049]).
As to claim 20, Burshteyn teaches the method of claim 19, wherein the buffer solution has a weak acidic or weak basic pH (van Agthoven [0049]-[0050]; “The pH of the neutralization reagent is preferably from about 7.1 to about 7.5, more preferably from about 7.2 to about 7.4”, which is a weak basic pH).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Burshteyn in view of van Agthoven, further in view of Chalmers et al. (US 20240168005 A1), hereinafter Chalmers.
As to claim 16, Burshteyn teaches the method of claim 15.
However, Burshteyn in view of van Agthoven does not explicitly disclose wherein the optical signature is determined using UV-VIS light spectroscopy.
Chalmers, in the same field of endeavor as the claimed invention, teaches wherein the optical signature is determined using UV-VIS light spectroscopy (Chalmers [0042]; A comparison is made of the quantity of Hb per RBC between CTM measurements and UV-visible spectrophotometry. Thus, optical signatures are determined using UV-visible spectrophotometry).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn in view of van Agthoven to incorporate the teachings of Chalmers to include wherein the optical signature is determined using UV-VIS light spectroscopy, for the advantage of simple, point of care test to relieve patients’ burden (Chalmers [0010]).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Burshteyn in view of van Agthoven, further in view of Dicaprio (from the IDS).
As to claim 17, Burshteyn teaches the method of claim 15.
However, Burshteyn in view of van Agthoven does not explicitly disclose wherein the determined optical signature includes an absorption spectra of the deoxygenated hemoglobin, red blood cells, and/or blood.
Dicaprio, in the same field of endeavor as the claimed invention, teaches wherein the determined optical signature includes an absorption spectra of the deoxygenated hemoglobin, red blood cells, and/or blood (Dicaprio Fig. 6A; page 5 col. 2 fig. 6 description; Comparing the absorption spectra of HbO2 and Hb in two-wavelength spectroscopy to differentiate between HbO2 (oxygenated) and Hb (deoxygenated) in the blood sample).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Burshteyn in view of van Agthoven to incorporate the teachings of Dicaprio to include wherein the determined optical signature includes an absorption spectra of the deoxygenated hemoglobin, red blood cells, and/or blood; for the advantage of enhanced analysis, including comparing the difference between first and second optical absorption values with the hemoglobin structure stability and its capacity to bind oxygen (Dicaprio page 3 col. 2 para. 1).
Conclusion
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/KEMAYA NGUYEN/Examiner, Art Unit 2877
/TARIFUR R CHOWDHURY/Supervisory Patent Examiner, Art Unit 2877