Notice of Pre-AIA or AIA Status
Claims 1-3, 5-7 and 9-21 are currently presented for Examination.
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 07/17/2026 has been considered. The submission is in compliance with the provisions of 37 CFR 1.97. Form PTO-1449 is signed and attached hereto.
Response to Amendment
The amendment filed on 07/17/2026 has been entered and considered by the examiner. By the
amendment, claims 1-3, 5-7, 9-10 are amended and claims 11-21 are newly added. Following Applicants arguments and amendments made, Examiner modify the prior art rejections. And the 101 rejection is still maintained. The previous claim interpretation and its corresponding rejection are withdrawn in view of amendment made. See office action.
Applicant 101 arguments
The features of "separate hemoglobin in a blood sample by supplying the blood sample to the analytical column to obtain chromatographic peaks including: a stable hemoglobin A1c peak derived from stable glycohemoglobin, a hemoglobin A2 peak, and hemoglobin A peaks including a hemoglobin Al peak, a hemoglobin #C peak which is an unstable hemoglobin A1c peak, a hemoglobin AO peak and the stable hemoglobin A1c peak," "calculate, based on absorbances detected by the photometer, an area of the stable hemoglobin A1c peak, a total area of the hemoglobin A peaks, and an area of the hemoglobin A2 peak," "find a corrected value of the stable glycohemoglobin by correcting, using the area of the hemoglobin A2 peak, an initial value obtained by dividing the area of the stable hemoglobin A1c peak by the total area of the hemoglobin A peaks so as to lower the initial value," and "output the corrected value of the stable glycohemoglobin for display to a user" reflect technical improvements in the technical field of stable glycohemoglobin measurement method and apparatus. As discussed in paragraphs [0014] and [0054]- [0062] of the published specification, the apparatus and method recited in the claims can correct a value of the stable glycohemoglobin using the area of the hemoglobin A2 peak so as to lower the initial value, and then output the result for display to the user. This allows the system and method to provide a more accurate measurement of the stable glycohemoglobin to the user compared with a method and apparatus that do not consider the hemoglobin A2 peak, thereby avoiding unnecessary treatments and/or misdiagnosis. Such a technical solution to a technical problem was found to be patent eligible. This approach significantly improves the accuracy and consistency of stable glycohemoglobin measurement, which is not conventional in the technical field and amounts to significantly more than the judicial exception. Taking all the additional elements individually, and in combination, claims as a whole amount to significantly more than the abstract idea.
Response to Applicant 101 arguments
Examiner respectfully disagrees. Claim 1 still recites mathematical calculations, data analysis, and mental processes which are abstract ideas. The steps of dividing one peak area by another (calculating an initial ratio) and adjusting that number using a second value (correction using the (HbA1c) peak area) represent mathematical calculation/relationship and data manipulation. The claim recites generic physical components like an analytical column, a photometer, and a display. Using an analytical column to separate samples and a photometer to measure absorbance are standard, well-known laboratory techniques in the prior art (see HASEGAWA (US20190120803A1), DESCHAMPS et al. (US20160077052A1), TAKUJI et al. (JP2014235023A). Simply gathering data through standard equipment and then applying a new mathematical formula or adjustment factor does not transform the abstract calculation into a patent-eligible invention. See also instant published Specification para [0003-0004] states that HPLC apparatuses were already used to separate hemoglobin components and acquired corresponding chromatographic peaks. And para [0033] and [0040] describe the analytical column and its filler are ordinary components of the HPLC apparatus. See Alice Corp. and Mayo, the use of conventional computers or analytical hardware to execute an abstract mathematical formula does not add "significantly more" to the claim. Achieving a "more accurate" mathematical result or a better final number does not make an abstract idea eligible. A better or more precise calculation is still a calculation. Improving the mathematical accuracy of a value through a new mathematical adjustment does not amount to a technical improvement of the physical measuring apparatus itself. Tying an abstract calculation to a generalized medical outcome (like avoiding misdiagnosis) is a field of use limitation. Restricting a mathematical formula to a specific medical field does not save the claim from being an abstract idea. The physical steps recited (supplying a sample, detecting absorbances, displaying an output) are conventional steps used conventionally to gather the raw data needed for the calculation. They do not add an inventive concept to the abstract math. Thus, the 101 rejection is still maintained. See also the office action below.
Response to Applicant 103 arguments
Following Applicants arguments and amendments, the 103 rejections of the claims is Modified. New references are added. See updated 103 below that is necessitated by applicant’s amendment.
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 1-3, 5-7 and 9-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1) Is the claims to a process, machine, manufacture, or composition of matter?
Claims: 1-3, 5-7 and 11-13 are directed to method or process that falls on one of statutory category.
Claims: 9 and 14-17 are directed to apparatus or machine that falls on one of statutory category.
Claims: 10 and 18-21 are directed to a non-transitory recording medium that falls on i.e., manufacture statutory category.
Step 2A) (Prong 1) Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea? (Judicially recognized exceptions)?
Claim 1, 9, 10 recites:
calculate,
find a corrected value of the stable glycohemoglobin Hb A1c by correcting, using the area of the hemoglobin A2 peak, an initial value obtained by dividing the area of the stable hemoglobin A1c peak by the total area of the hemoglobin A peaks so as to lower the initial value; (Claim recites performing a "correction calculation to lower" the value. These are mathematical operations (division, correction calculations) performed on data points. Under the broadest reasonable interpretation, this limitation falls under “Mathematical concepts” of abstract ideas. See MPEP 2106.04(a)(2)(I). See claim 2-Mathematical relationship)
Step 2A, Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application?
In accordance with Step 2A, Prong 2, the judicial exception is not integrated into a practical application. The claim 1, 9 and 10 include the additional elements of “separate hemoglobin in a blood sample by supplying the blood sample to the analytical column to obtain chromatographic peaks including: a stable hemoglobin A1c peak derived from stable glycohemoglobin, a hemoglobin A2 peak, and hemoglobin A peaks including a hemoglobin Al peak, a hemoglobin #C peak which is an unstable hemoglobin A1c peak, a hemoglobin AO peak, and the stable hemoglobin A1c peak” is merely obtaining data and falls under the mere data gathering step as discussed in MPEP 2106.05(g) as insignificant pre-solution activity. The additional elements of analytical column and photometer are used to generate chromatographic peak and absorbance data that serve as inputs to the recited abstract mathematical calculations. Thus, an analytical column configured to separate hemoglobin in a blood sample and a photometer configured to detect absorbances of hemoglobin components eluted from the analytical column are just performing data gathering functions preliminary to the mathematical calculation. The additional elements of output the corrected value of the stable glycohemoglobin for display to a user are insignificant post-solution activity as discussed in MPEP § 2106.05(g). The additional elements of processor to execute a process in claim 1 is merely reciting the words "apply it" (or an equivalent) with the judicial exception or merely including instructions to implement an abstract idea on a computer or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). The additional elements of a stable glycohemoglobin measurement method for use with a liquid chromatography apparatus are more than generally linking the use of a judicial exception to a particular technological environment or field of use, as discussed in MPEP § 2106.05(h).The additional elements of a stable glycohemoglobin measurement apparatus comprising: a processor configured to execute instructions stored in a memory in claim 9 is merely reciting the words "apply it" (or an equivalent) with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). The additional elements of a non-transitory recording medium storing a program that is executable by a computer to perform a process in claim 10 is merely reciting the words "apply it" (or an equivalent) with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). The claim is directed to an abstract idea.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
In view of Step 2B, the claim as a whole does not amount to significantly more than the recited exception,
i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. The claim 1, 9 and 10 include the additional elements of “separate hemoglobin in a blood sample by supplying the blood sample to the analytical column to obtain chromatographic peaks including: a stable hemoglobin A1c peak derived from stable glycohemoglobin, a hemoglobin A2 peak, and hemoglobin A peaks including a hemoglobin Al peak, a hemoglobin #C peak which is an unstable hemoglobin A1c peak, a hemoglobin AO peak, and the stable hemoglobin A1c peak” is merely obtaining data and falls under the mere data gathering step as discussed in MPEP 2106.05(g) as insignificant pre-solution activity and are well‐understood, routine, and conventional (See MPEP 2106.05(d)(II) i. Receiving or transmitting data over a network, e.g., using the Internet to gather data, Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information); TLI Communications LLC v. AV Auto. LLC, 823 F.3d 607, 610, 118 USPQ2d 1744, 1745 (Fed. Cir. 2016) (using a telephone for image transmission); OIP Techs., Inc., v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1093 (Fed. Cir. 2015) (sending messages over a network); buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network); but see DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1258, 113 USPQ2d 1097, 1106 (Fed. Cir. 2014). The additional elements of analytical column and photometer are used to generate chromatographic peak and absorbance data that serve as inputs to the recited abstract mathematical calculations. Thus, an analytical column configured to separate hemoglobin in a blood sample and a photometer configured to detect absorbances of hemoglobin components eluted from the analytical column are just performing data gathering functions preliminary to the mathematical calculation. Specification para [0003-0004] states that HPLC apparatuses were already used to separate hemoglobin components and acquired corresponding chromatographic peaks. And para [0033] and [0040] describe the analytical column and its filler are ordinary components of the HPLC apparatus. The additional elements of output the corrected value of the stable glycohemoglobin for display to a user are insignificant post-solution activity as discussed in MPEP § 2106.05(g) and are well‐understood, routine, and conventional (See MPEP 2106.05(d)(II) iv. Presenting offers and gathering statistics, OIP Techs., 788 F.3d at 1362-63, 115 USPQ2d at 1092-93; The additional elements of processor to execute a process in claim 1 is merely reciting the words "apply it" (or an equivalent) with the judicial exception or merely including instructions to implement an abstract idea on a computer or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). The additional elements of a stable glycohemoglobin measurement method for use with a liquid chromatography apparatus are more than generally linking the use of a judicial exception to a particular technological environment or field of use, as discussed in MPEP § 2106.05(h).The additional elements of a stable glycohemoglobin measurement apparatus comprising: a processor configured to execute instructions stored in a memory in claim 9 is merely reciting the words "apply it" (or an equivalent) with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). The additional elements of a non-transitory recording medium storing a program that is executable by a computer to perform a process in claim 10 is merely reciting the words "apply it" (or an equivalent) with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). Thus, claims 1, 9 and 10 not patent eligible.
Claim 2 recites
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Claim recites dividing the area of a peak (HbA1c) by adding together the areas of the hemoglobin A peaks and the area of the peak selected from among the hemoglobin A2 peaks These are mathematical equations or relationships performed on data points. Under the broadest reasonable interpretation, this limitation falls under “Mathematical concepts” of abstract ideas. See MPEP 2106.04(a)(2)(I). Claim therefore, when taken as a whole, still does not integrate the judicial exception into a practical application nor amount to significantly more than the judicial exception. Claim recites unpatentable ineligible subject matter for the same reasoning and analysis as mentioned for claim 1.
Claims 14 and 18 are like claim 2 and are rejected for the same reason as claim 2.
Claim 3 recites
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“Calculate” limitation are mathematical calculations integrating absorbance over a retention-time region (see spec [0050] and [0053]). Under the broadest reasonable interpretation, this limitation falls under “Mathematical concepts” of abstract ideas. See MPEP 2106.04(a)(2)(I). And “find” limitation recites mathematical operations (division, correction calculations) performed on data points. Under the broadest reasonable interpretation, this limitation falls under “Mathematical concepts” of abstract ideas. See MPEP 2106.04(a)(2)(I).
The additional element of chromatographic peaks further include other hemoglobin- derived peaks that include: a hemoglobin F peak, and variant hemoglobin peaks other than the hemoglobin A peaks, the stable hemoglobin A1c, and the hemoglobin A2 are merely obtaining data and falls under the mere data gathering step as discussed in MPEP 2106.05(g) as insignificant pre-solution activity and are well‐understood, routine, and conventional (See MPEP 2106.05(d)(II) i. Receiving or transmitting data over a network, e.g., using the Internet to gather data, Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information); TLI Communications LLC v. AV Auto. LLC, 823 F.3d 607, 610, 118 USPQ2d 1744, 1745 (Fed. Cir. 2016) (using a telephone for image transmission); OIP Techs., Inc., v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1093 (Fed. Cir. 2015) (sending messages over a network); buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network); but see DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1258, 113 USPQ2d 1097, 1106 (Fed. Cir. 2014). The additional element of processor is merely reciting the words "apply it" (or an equivalent) with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). Claim therefore, when taken as a whole, still does not integrate the judicial exception into a practical application nor amount to significantly more than the judicial exception. Claim recites unpatentable ineligible subject matter for the same reasoning and analysis as mentioned for claim 1.
Claims 15 and 19 are like claim 3 and are rejected for the same reason as claim 3.
Claim 5 recites
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Under the broadest reasonable interpretation, this limitation falls under “Mathematical concepts” of abstract ideas See MPEP 2106.04(a)(2)(I) because of mathematical operation dividing, arithmetic operation and subtracting. Claim therefore, when taken as a whole, still does not integrate the judicial exception into a practical application nor amount to significantly more than the judicial exception. Claim recites unpatentable ineligible subject matter for the same reasoning and analysis as mentioned for claim 1.
Claims 16 and 20 are like claim 5 and are rejected for the same reason as claim 4.
Claim 6 recites present the reference value. This limitation is merely presenting the output value of the abstract calculation and falls under the mere data gathering step as discussed in MPEP 2106.05(g) as insignificant post-solution activity and are well‐understood, routine, and conventional (See MPEP 2106.05(d)(II) iv. iv. Presenting offers and gathering statistics, OIP Techs., 788 F.3d at 1362-63, 115 USPQ2d at 1092-93; The additional elements of processor is merely reciting the words "apply it" (or an equivalent) with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). Claim therefore, when taken as a whole, still does not integrate the judicial exception into a practical application nor amount to significantly more than the judicial exception. Claim recites unpatentable ineligible subject matter for the same reasoning and analysis as mentioned for claim 1.
Claims 17 and 21 are like claim 6 and are rejected for the same reason as claim 6.
Claim 7 recites quantify the value of the hemoglobin corresponding to the hemoglobin A2 and, in a case where the quantified value of the hemoglobin is equal to or higher than a predetermined threshold, present information based on the difference between the corrected value of the stable glycohemoglobin and reference value of the stable glycohemoglobin. Under the broadest reasonable interpretation, this limitation falls under “Mathematical concepts” of abstract ideas See MPEP 2106.04(a)(2)(I) because of mathematical operation “difference” and “mathematical arithmetic equation”. Also, this limitation covers mental process including an observation and evaluation that could be performed in the human mind or with the aid of pencil and paper therefore it falls within the “Mental Process” grouping of abstract ideas. (See MPEP 2106.04(a)(2)(III)) Also, “present information” of the abstract calculation and falls under the mere data gathering step as discussed in MPEP 2106.05(g) as insignificant post-solution activity and are well‐understood, routine, and conventional (See MPEP 2106.05(d)(II) iv. iv. Presenting offers and gathering statistics, OIP Techs., 788 F.3d at 1362-63, 115 USPQ2d at 1092-93; The additional elements of processor is merely reciting the words "apply it" (or an equivalent) with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). Claim therefore, when taken as a whole, still does not integrate the judicial exception into a practical application nor amount to significantly more than the judicial exception. Claim recites unpatentable ineligible subject matter for the same reasoning and analysis as mentioned for claim 1.
Claim 11 further recites determine whether the corrected value of the stable glycohemoglobin exceeds a predetermined threshold; and in a case where the corrected value exceeds the predetermined threshold, output an indication that a patient is hyperglycemic or suspected of being hyperglycemic. A doctor or technician can visually review a value and compare it to a baseline number entirely in their head. Merely "identifying" or "flagging" a condition based on a threshold calculation is a mental exercise. This limitation covers mental process including an observation and evaluation that could be performed in the human mind or with the aid of pencil and paper therefore it falls within the “Mental Process” grouping of abstract ideas. (See MPEP 2106.04(a)(2)(III)) Claim therefore, when taken as a whole, still does not integrate the judicial exception into a practical application nor amount to significantly more than the judicial exception. Claim recites unpatentable ineligible subject matter for the same reasoning and analysis as mentioned for claim 1.
Claim 12 further recites to calculate a value of hemoglobin A2 based on the area of the hemoglobin A2 peak; and in a case where the value of hemoglobin A2 is equal to or higher than a predetermined threshold, output a warning that a patient is suspected of having thalassemia. Calculating the value of hemoglobin A2 based on the peak area is a mathematical algorithm or formula. Comparing a number to a predetermined threshold and "suspecting" a diagnosis is a step that can be performed entirely in the human mind (or with a pencil and paper). So, it falls under the combination of “Mental process” and “Mathematical Concepts” of abstract idea. Claim recites unpatentable ineligible subject matter for the same reasoning and analysis as mentioned for claim 1.
Claim 13 further recites wherein the predetermined threshold for the value of hemoglobin A2 is 4%. Comparing value to a 4% threshold to output a warning. Step-by-step thinking, analyzing data, and identifying a medical condition are considered mental processes that can be performed in the human mind (or with a pen and paper).Claim therefore, when taken as a whole, still does not integrate the judicial exception into a practical application nor amount to significantly more than the judicial exception. Claim recites unpatentable ineligible subject matter for the same reasoning and analysis as mentioned for claim 1.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
5. Claim(s) 1-2, 9-10, 11, 14 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over HASEGAWA et al. (PUB NO: US20190120803A1) in view of DESCHAMPS et al. (PUB NO: US20160077052A1)
Regarding claim 1
HASEGAWA teaches a stable glycohemoglobin measurement method for use with a liquid chromatography apparatus comprising an analytical column and a photometer, wherein a processor executes a process to:(see para 0001- The present invention relates to a method and a device for measuring glycated hemoglobin in a blood sample by liquid chromatography. See para 0004- Measurement of glycated hemoglobin has been conducted by means of liquid chromatography. Measurement of glycated hemoglobin by liquid chromatography is roughly classified into measurement by cation exchange chromatography by which hemoglobin is separated into various hemoglobin components. see [0053]- The present invention also relates to a program for measuring stable glycated hemoglobin sA1c which makes each module in the means of analysis executed by a computer. see para 42-46 and fig 11-12 - The means of separation (2) comprising a resin having cation exchange capacity, may, for example, be a column packed with a resin having modification groups bonded thereto for so-called cation exchange chromatography, for example, a sulfonic type. The means of detection (4) for detecting hemoglobin eluted from the means of separation and obtaining a chromatogram is not particularly limited so long as it can detect hemoglobin, and may, for example, be an absorption detector capable of detecting elution of hemoglobin as a protein based on an absorbance at 415 nm or an electric conductivity detector.)
separate hemoglobin in a blood sample by supplying the blood sample to the analytical column to obtain chromatographic peaks including: a stable hemoglobin A1c peak derived from stable glycohemoglobin, (see [0003] and fig 4- Hemoglobin A1 is further separated into A1a, A1b and A1c. The proportion of so-called stable hemoglobin A1c (hereinafter sometimes abbreviated as “sA1c”). See [0013]- A method for measuring stable glycated hemoglobin sA1c, which comprises (1) a step of subjecting a blood sample after hemolysis to cation exchange chromatography to elute sA1c as separated from other hemoglobin components thereby to obtain a chromatogram showing elution of hemoglobin fractions, (2) a step of identifying a sA1c peak in the obtained chromatogram and calculating its peak area, (3) a step of identifying peaks of hemoglobin components other than sA1c in the obtained chromatogram and calculating their peak areas, (4) a step of calculating the proportion (%) of the sA1c peak area to the total hemoglobin peak area, (5) a step of identifying a non-glycated peak of abnormal hemoglobin D, abnormal hemoglobin S or abnormal hemoglobin C from peaks which appear after a non-glycated peak of hemoglobin A. 6) a step of estimating the area of a glycated peak of abnormal hemoglobin D, abnormal hemoglobin S or abnormal hemoglobin C based on a non-glycated peak area and the like of the abnormal hemoglobin identified, wherein the proportion (%) of the sA1c peak area in the above step 4 is corrected based on the estimated calculation results. See also [0033-0037] and see fig 5-7- remarkable peaks (H-V0, H-V1 and H-V2) corresponding to the respective abnormal hemoglobin components appear after the peak (A0) of non-glycated hemoglobin A. Further, in the present invention, H-V0, H-V1 and H-V2 indicate remarkable peaks other than hemoglobin)) and
calculate, based on absorbances detected by the photometer, an area of the stable hemoglobin A1c peak, a total area of the hemoglobin A peaks, and an initial value obtained by dividing the area of the stable hemoglobin A1c peak by the total area of the hemoglobin A peaks;(see para 14-16 the proportion (%) of the sA1c peak area to the total peak area of hemoglobin A. see para 46-47- The means of detection (4) for detecting hemoglobin eluted from the means of separation and obtaining a chromatogram is not particularly limited so long as it can detect hemoglobin, and may, for example, be an absorption detector capable of detecting elution of hemoglobin as a protein based on an absorbance at 415 nm or an electric conductivity detector. The means of analysis (5) is a means for analyzing the chromatogram detected by the means of detection, and the measurement device of the present invention is characterized by this means of analysis. The means of analysis first sets a baseline to calculate peak areas which appear in the chromatogram.)
output the corrected value of the stable glycohemoglobin for display to a user. (see para 53-55- The above-calculated A1c % is further calibrated and corrected by means of calibration using a reference material specified by each academic society such as National Glycohemoglobin Standardization Program (NGSP), International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) or The Japan Diabetes Society (JDS) to calculate A1c % as an index to carry out e.g. diagnosis in accordance with the standard specified by the academic society, and further, good correlation with measurement results by affinity chromatography can be achieved by excluding the influence by abnormal hemoglobin D, S and C. The results analyzed by the means of analysis 15 may be displayed or printed by a means of output 20. )
HASEGAWA does not teach separate hemoglobin in a blood sample by supplying the blood sample to the analytical column to obtain chromatographic peaks including: a hemoglobin A2 peak, and an area of the hemoglobin A2 peak and find a corrected value of the stable glycohemoglobin Hb A1c by correcting, using the area of the hemoglobin A2 peak, an initial value obtained by dividing the area of the stable hemoglobin A1c peak by the total area of the hemoglobin A peaks so as to lower the initial value.
In the related field of invention, DESCHAMPS teaches separate hemoglobin in a blood sample by supplying the blood sample to the analytical column to obtain chromatographic peaks including; a hemoglobin A2 peak, and an area of the hemoglobin A2 peak;(see para 64- area of peak corresponding to HbA2. See para 151-155- The step for separating the constituents of the biological sample by capillary electrophoresis in particular consists of applying to the capillary(ies) an electric field with a sufficient voltage to allow the separation of one or several glycated hemoglobin(s) of interest from other proteins and in particular from other hemoglobin’s which may be present in the biological sample. The step for separating the constituents of the biological sample is generally followed by a step for detection of one or several protein(s). This detection step may in particular be carried out by measuring the absorbance, for example at a wavelength of approximately 415 nm, which is specific to hemoglobin; the hemoglobin’s may be analyzed at a wavelength of approximately 200 nm, but in order to avoid interference with plasma proteins in particular, they are preferably analyzed at a wavelength of 415 nm. See fig 11 and fig 13(Hemoglobin-A2))
find a corrected value of the stable glycohemoglobin Hb A1c by correcting, using the area of the hemoglobin A2 peak, an initial value obtained by dividing the area of the stable hemoglobin A1c peak by the total area of the hemoglobin A peaks so as to lower the initial value; (see para 004- n an adult human, three types of haemoglobin are normally present: haemoglobin A (HbA), which is the vast majority (it generally represents approximately 97% of the haemoglobin in an adult), constituted by 2 alpha chains and two beta chains (haemoglobin α2β2), haemoglobin A2 (HbA2, which generally represents approximately 1-3% of the haemoglobin in an adult) constituted by two alpha chains and two delta chains (haemoglobin α2β2),see para 64 and fig - The assay carried out in the context of the invention may be semi-quantitative; thus, the percentage of a given hemoglobin is measured with respect to the quantity of another hemoglobin or the other hemoglobin(s) present in said sample. Thus, in the case of HbA1c, in general the percentage of HbA1c is measured with respect to the quantity of one or several other A hemoglobin(s); in general, the area of the electrophoretic peak corresponding to HbA1c is divided by the area of the peak corresponding to HbA0 or by the sum (area of peak corresponding to HbA1c+area of peak corresponding to HbA0), by the sum (area of all of the HbA peaks) or by the sum (area of peak corresponding to HbA1+area of peak corresponding to HbA0+area of peak corresponding to HbA2), or even by the total surface area of the electrophoretic profile. see fig17 (table -corrected values))
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA to include separate hemoglobin in a blood sample by supplying the blood sample to the analytical column to obtain chromatographic peaks including: a hemoglobin A2 peak, and an area of the hemoglobin A2 peak and find a corrected value of the stable glycohemoglobin Hb A1c by correcting, using the area of the hemoglobin A2 peak, an initial value obtained by dividing the area of the stable hemoglobin A1c peak by the total area of the hemoglobin A peaks so as to lower the initial value as taught by DESCHAMPS in the system of HASEGAWA in order separate and assay haemoglobin HbA1c present in a biological sample optionally comprising other haemoglobins. The detection of glycated haemoglobins, particularly the detection of an increase in the HbA1c level, is thus of manifest interest for the diagnosis of diabetes (type 1 or type 2) or monitoring diabetic patients, in particular to evaluate the efficacy of a treatment against diabetes (type 1 or type 2). (See Abstract and [0014], DESCHAMPS)
Regarding claim 9
HASEGAWA teaches a stable glycohemoglobin measurement apparatus comprising: an analytical column configured to separate hemoglobin in a blood sample; a photometer configured to detect absorbances of hemoglobin components eluted from the analytical column; and a processor configured to execute instructions stored in a memory to:(see para 0001- The present invention relates to a method and a device for measuring glycated hemoglobin in a blood sample by liquid chromatography. See para 0004- Measurement of glycated hemoglobin has been conducted by means of liquid chromatography. Measurement of glycated hemoglobin by liquid chromatography is roughly classified into measurement by cation exchange chromatography by which hemoglobin is separated into various hemoglobin components. see [0053]- The present invention also relates to a program for measuring stable glycated hemoglobin sA1c which makes each module in the means of analysis executed by a computer. see para 42-46 and fig 11-12 - The means of separation (2) comprising a resin having cation exchange capacity, may, for example, be a column packed with a resin having modification groups bonded thereto for so-called cation exchange chromatography, for example, a sulfonic type. The means of detection (4) for detecting hemoglobin eluted from the means of separation and obtaining a chromatogram is not particularly limited so long as it can detect hemoglobin, and may, for example, be an absorption detector capable of detecting elution of hemoglobin as a protein based on an absorbance at 415 nm or an electric conductivity detector.)
The rest of claim 9 is rejected for the same reasons as Claim 1, as they share the same elements.
Regarding claim 10
HASEGAWA teaches a non-transitory recording medium storing a program that is executable by a computer operatively connected to a liquid chromatography apparatus comprising an analytical column and a photometer to perform a process, the process comprising: (see para 0001- The present invention relates to a method and a device for measuring glycated hemoglobin in a blood sample by liquid chromatography. See para 0004- Measurement of glycated hemoglobin has been conducted by means of liquid chromatography. Measurement of glycated hemoglobin by liquid chromatography is roughly classified into measurement by cation exchange chromatography by which hemoglobin is separated into various hemoglobin components. see [0053]- The present invention also relates to a program for measuring stable glycated hemoglobin sA1c which makes each module in the means of analysis executed by a computer. see para 42-46 and fig 11-12 - The means of separation (2) comprising a resin having cation exchange capacity, may, for example, be a column packed with a resin having modification groups bonded thereto for so-called cation exchange chromatography, for example, a sulfonic type. The means of detection (4) for detecting hemoglobin eluted from the means of separation and obtaining a chromatogram is not particularly limited so long as it can detect hemoglobin, and may, for example, be an absorption detector capable of detecting elution of hemoglobin as a protein based on an absorbance at 415 nm or an electric conductivity detector.)
The rest of claim 10 is rejected for the same reasons as Claim 1, as they share the same elements.
Regarding claim 2
The combination of HASEGAWA and DESCHAMPS teaches the stable glycohemoglobin measurement method of claim 1. HASEGAWA does not teach the elements of claim 2, however, DESCHAMPS further teaches the elements of claim 2.
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(see DESCHAMPS para 004- n an adult human, three types of haemoglobin are normally present: haemoglobin A (HbA), which is the vast majority (it generally represents approximately 97% of the haemoglobin in an adult), constituted by 2 alpha chains and two beta chains (haemoglobin α2β2), haemoglobin A2 (HbA2, which generally represents approximately 1-3% of the haemoglobin in an adult) constituted by two alpha chains and two delta chains (haemoglobin α2β2),see para 64 and fig - The assay carried out in the context of the invention may be semi-quantitative; thus, the percentage of a given hemoglobin is measured with respect to the quantity of another hemoglobin or the other hemoglobin(s) present in said sample. Thus, in the case of HbA1c, in general the percentage of HbA1c is measured with respect to the quantity of one or several other A hemoglobin(s); in general, the area of the electrophoretic peak corresponding to HbA1c is divided by the area of the peak corresponding to HbA0 or by the sum (area of peak corresponding to HbA1c+area of peak corresponding to HbA0), by the sum (area of all of the HbA peaks) or by the sum (area of peak corresponding to HbA1+area of peak corresponding to HbA0+area of peak corresponding to HbA2), or even by the total surface area of the electrophoretic profile. see fig17 (table -corrected values))
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA to include elements of claim 2 as taught by DESCHAMPS in the system of HASEGAWA in order separate and assay haemoglobin HbA1c present in a biological sample optionally comprising other haemoglobins. The detection of glycated haemoglobins, particularly the detection of an increase in the HbA1c level, is thus of manifest interest for the diagnosis of diabetes (type 1 or type 2) or monitoring diabetic patients, to evaluate the efficacy of a treatment against diabetes (type 1 or type 2). (See Abstract and [0014], DESCHAMPS)
Claims 14 and 18 are like claim 2 and are rejected for the same reason as claim 2.
Claims 17 and 21 are like claim 3 and are rejected for the same reason as claim 3.
Regarding claim 11
The combination of HASEGAWA and DESCHAMPS teaches the stable glycohemoglobin measurement method of claim 1. HASEGAWA does not teach to calculate a value of hemoglobin A2 based on the area of the hemoglobin A2 peak; and in a case where the value of hemoglobin A2 is equal to or higher than a predetermined threshold, output a warning that a patient is suspected of having thalassemia.
In the related field of invention, DESCHAMPS further to calculate a value of hemoglobin A2 based on the area of the hemoglobin A2 peak. see DESCHAMPS para 187-189- The HbA1c level is generally in the range 4% to 6% (i.e. 20 to 42 mmoles of HbA1c per mole of haemoglobin in the blood) in a human non-diabetic, and more than 7% in a diabetic patient (in the absence of treatment). In the case of HbA1c levels in the range 6% to 7% (i.e. a concentration of 42 to 53 mmoles of HbA1c per mole of haemoglobin in the blood), it is recommended that an anti-diabetic treatment be commenced. Beyond a threshold of 8%, which is equivalent to a concentration of 64 mmoles of HbA1c per mole of haemoglobin in the blood, the patient runs an increased risk of developing one of the complications of diabetes (microangiopathy, macroangiopathy, etc). It is then recommended that the patient's anti-diabetic treatment be modified.)
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA to include to determine whether the corrected value of the stable glycohemoglobin exceeds a predetermined threshold; and in a case where the corrected value exceeds the predetermined threshold, output an indication that a patient is hyperglycemic or suspected of being hyperglycemic as taught by DESCHAMPS in the system of HASEGAWA in order separate and assay haemoglobin HbA1c present in a biological sample optionally comprising other haemoglobins. The detection of glycated haemoglobins, particularly the detection of an increase in the HbA1c level, is thus of manifest interest for the diagnosis of diabetes (type 1 or type 2) or monitoring diabetic patients, to evaluate the efficacy of a treatment against diabetes (type 1 or type 2). (See Abstract and [0014], DESCHAMPS)
Claim(s) 3, 15 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over HASEGAWA et al. (PUB NO: US20190120803A1) in view of DESCHAMPS et al. (PUB NO: US20160077052A1) and further in view of HPA, Protection Assay. "510 (k) substantial equivalence determination decision summary assay only template." (2017), hereinafter NPL (510(k)).
Regarding claim 3
The combination of HASEGAWA and DESCHAMPS teaches the stable glycohemoglobin measurement method of claim 2. HASEGAWA further teaches chromatographic peaks furth include other hemoglobin derived peak that include: hemoglobin F peak and variant hemoglobin peaks other than hemoglobin A peaks, the stable hemoglobin A1C and See [0047-0048] and fi 4-7--the respective peak areas of A1a, A1b, HbF, LA1c, sA1c, A′ and H-V0 or H-V1 are calculated. in a case where a peak corresponding to abnormal hemoglobin D or abnormal hemoglobin S, that is, H-V0 or H-V1 is identified at the time of the peak identification. Further, in a case where a peak corresponding to abnormal hemoglobin C, that is, H-V2 is identified at the time of the peak identification, the respective peak areas of A1a, A1b, HbF, LA1c, sA1c, A′ and H-V2 are calculated. See also example 1-2) and
calculate, based on absorbances detected by the photometer, a total area of the other hemoglobin-derived peaks;( see para 46-47- The means of detection (4) for detecting hemoglobin eluted from the means of separation and obtaining a chromatogram is not particularly limited so long as it can detect hemoglobin, and may, for example, be an absorption detector capable of detecting elution of hemoglobin as a protein based on an absorbance at 415 nm or an electric conductivity detector. The means of analysis (5) is a means for analyzing the chromatogram detected by the means of detection, and the measurement device of the present invention is characterized by this means of analysis. The means of analysis first sets a baseline to calculate peak areas which appear in the chromatogram. the total peak area (Total area) in the chromatogram and the respective peak areas of A1a, A1b, HbF, LA1c, sA1c, A′ and H-V0 or H-V1 are calculated See para 24- Further, in the present invention, H-V0, H-V1 and H-V2 indicate remarkable peaks other than hemoglobin A of which the identification and elution times are set by the compositions of the elution buffers and their flow rates in the chromatogram. See para 52- Specifically, when the peak identification module 17 judges that H-V0 or H-V1 is present, the total peak area (Total area))
DESCHAMPS teaches hemoglobin A2 peak;( see DESCHAMPS para 64- area of peak corresponding to HbA2. See para 151-155- The step for separating the constituents of the biological sample by capillary electrophoresis in particular consists of applying to the capillary(ies) an electric field with a sufficient voltage to allow the separation of one or several glycated hemoglobin(s) of interest from other proteins and in particular from other hemoglobin’s which may be present in the biological sample. The step for separating the constituents of the biological sample is generally followed by a step for detection of one or several protein(s). This detection step may in particular be carried out by measuring the absorbance, for example at a wavelength of approximately 415 nm, which is specific to hemoglobin; the hemoglobin’s may be analyzed at a wavelength of approximately 200 nm, but in order to avoid interference with plasma proteins in particular, they are preferably analyzed at a wavelength of 415 nm. See fig 11 and fig 13(Hemoglobin-A2))
The combination of HASEGAWA and DESCHAMPS does not teach find the corrected value of the stable glycohemoglobin using an arithmetic equation expressed as: Equation (2), where HbA corresponds to All Hb - (F + Other Hb + A2), and (HbA + A2) corresponds to All Hb - (F + Other Hb), A1c represents the area of the stable hemoglobin A1c peak, All Hb represents the total area of the hemoglobin in the blood sample, and (F + Other Hb) represents the total area of the other hemoglobin-derived peaks.
In the related field of invention, NPL (510(k) teaches find the corrected value of the stable glycohemoglobin using an arithmetic equation expressed as:
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where HbA corresponds to All Hb - (F + Other Hb + A2), and (HbA + A2) corresponds to All Hb - (F + Other Hb), A1c represents the area of the stable hemoglobin A1c peak, All Hb represents the total area of the hemoglobin in the blood sample, and (F + Other Hb) represents the total area of the other hemoglobin-derived peaks. (see NPL (510(k) page 5- The Total Area of the sA1c is divided by the sum of the total areas of all peaks, excluding the HbF peak and any variant peak(s) to obtain a raw sA1c percentage.)
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA and DESCHAMPS to include the corrected value of the stable glycohemoglobin using an arithmetic equation expressed as: Equation (2), where HbA corresponds to All Hb - (F + Other Hb + A2), and (HbA + A2) corresponds to All Hb - (F + Other Hb), A1c represents the area of the stable hemoglobin A1c peak, All Hb represents the total area of the hemoglobin in the blood sample, and (F + Other Hb) represents the total area of the other hemoglobin-derived peaks as taught by NPL (510(k)) in the system of HASEGAWA and DESCHAMPS in order to use as an aid in diagnosis of diabetes and identifying patients who may be at risk for developing diabetes. (See page 2, NPL (510(k)))
Claim(s) 12 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over HASEGAWA et al. (PUB NO: US20190120803A1) in view of DESCHAMPS et al. (PUB NO: US20160077052A1) and further in view of TAKUJI et al. (PUB NO: JP2014235023A).
Regarding claim 12
The combination of HASEGAWA and DESCHAMPS teaches the stable glycohemoglobin measurement method of claim 1. HASEGAWA does not teach to calculate a value of hemoglobin A2 based on the area of the hemoglobin A2 peak; and in a case where the value of hemoglobin A2 is equal to or higher than a predetermined threshold, output a warning that a patient is suspected of having thalassemia.
In the related field of invention, DESCHAMPS further teaches to calculate a value of hemoglobin A2 based on the area of the hemoglobin A2 peak;( see DESCHAMPS para 0004- haemoglobin A2 (HbA2, which generally represents approximately 1-3% of the haemoglobin in an adult) constituted by two alpha chains and two delta chains (haemoglobin α2β2 see DESCHAMPS. para 64- area of peak corresponding to HbA2. See fig 11 and fig 13(Hemoglobin-A2))
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA to include to calculate a value of hemoglobin A2 based on the area of the hemoglobin A2 peak as taught by DESCHAMPS in the system of HASEGAWA in order separate and assay haemoglobin HbA1c present in a biological sample optionally comprising other haemoglobins. The detection of glycated haemoglobins, particularly the detection of an increase in the HbA1c level, is thus of manifest interest for the diagnosis of diabetes (type 1 or type 2) or monitoring diabetic patients, to evaluate the efficacy of a treatment against diabetes (type 1 or type 2). (See Abstract and [0014], DESCHAMPS)
The combination of HASEGAWA and DESCHAMPS does not teach in a case where the value of hemoglobin A2 is equal to or higher than a predetermined threshold, output a warning that a patient is suspected of having thalassemia.
In the related field of invention, TAKUJI teaches in a case where the value of hemoglobin A2 is equal to or higher than a predetermined threshold, output a warning that a patient is suspected of having thalassemia.(SEE para 003- hemoglobin A2 is as small as 2% to 3.5% in healthy people and 4% to 7% in patients with thalassemia, and quantification in a low concentration range of 2% to 7% is required.)
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA and DESCHAMPS to include in a case where the value of hemoglobin A2 is equal to or higher than a predetermined threshold, output a warning that a patient is suspected of having thalassemia as taught by TAKUJI in the system of HASEGAWA and DESCHAMPS in order to diagnose thalassemiasemia and aberrant hemoglobinopathy by quantifying the concentration. It important to quantify hemoglobin A2 simultaneously with hemoglobin F for the diagnosis of hemoglobinopathies. (See para 0002, TAKUJI)
Regarding claim 13
The combination of HASEGAWA, DESCHAMPS and TAKUJI teaches the stable glycohemoglobin measurement method of claim 12. The combination of HASEGAWA and DESCHAMPS does not teach wherein the predetermined threshold for the value of hemoglobin A2 is 4%.
In the related field of invention, TAKUJI teaches wherein the predetermined threshold for the value of hemoglobin A2 is 4%. (SEE para 003- hemoglobin A2 is as small as 2% to 3.5% in healthy people and 4% to 7% in patients with thalassemia, and quantification in a low concentration range of 2% to 7% is required.)
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA and DESCHAMPS to include wherein the predetermined threshold for the value of hemoglobin A2 is 4% as taught by TAKUJI in the system of HASEGAWA and DESCHAMPS in order to diagnose thalassemiasemia and aberrant hemoglobinopathy by quantifying the concentration. It important to quantify hemoglobin A2 simultaneously with hemoglobin F for the diagnosis of hemoglobinopathies. (See para 0002, TAKUJI)
Claim(s) 5-6, 16-17 and 20-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over HASEGAWA et al. (PUB NO: US20190120803A1) in view of DESCHAMPS et al. (PUB NO: US20160077052A1) and further in view of HPA, Protection Assay. "510 (k) substantial equivalence determination decision summary assay only template." (2017), hereinafter NPL (510(k)) and further in view of Oishi et al. (PUB NO: JP2009109231A)
Regarding claim 5
The combination of HASEGAWA and DESCHAMPS teaches the stable glycohemoglobin measurement method of claim 1.
NPL (510(k) teaches find the corrected value of the stable glycohemoglobin using an arithmetic equation expressed as:
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where HbA corresponds to All Hb - (F + Other Hb + A2), and (HbA + A2) corresponds to All Hb - (F + Other Hb), A1c represents the area of the stable hemoglobin A1c peak, All Hb represents the total area of the hemoglobin in the blood sample, and (F + Other Hb) represents the total area of the other hemoglobin-derived peaks. (see NPL (510(k) page 5- The Total Area of the sA1c is divided by the sum of the total areas of all peaks, excluding the HbF peak and any variant peak(s) to obtain a raw sA1c percentage.)
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA and DESCHAMPS to include the corrected value of the stable glycohemoglobin using an arithmetic equation expressed as: Equation (2), where HbA corresponds to All Hb - (F + Other Hb + A2), and (HbA + A2) corresponds to All Hb - (F + Other Hb), A1c represents the area of the stable hemoglobin A1c peak, All Hb represents the total area of the hemoglobin in the blood sample, and (F + Other Hb) represents the total area of the other hemoglobin-derived peaks as taught by NPL (510(k)) in the system of HASEGAWA and DESCHAMPS in order to use as an aid in diagnosis of diabetes and identifying patients who may be at risk for developing diabetes. (See page 2, NPL (510(k)))
The combination does not teach wherein the processor further executes a process to find a reference value of the stable glycohemoglobin using a reference arithmetic equation expressed as:
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where A1c represents the area of the stable hemoglobin A1c peak, All Hb represents the total area of the hemoglobin in the blood sample, and (F + A2 + Other Hb) represents a total area of the other hemoglobin-derived peaks and the area of the hemoglobin A2.
In the related field of invention, Oishi teaches wherein the processor further executes a process to find a reference value of the stable glycohemoglobin using a reference arithmetic equation expressed as:
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where A1c represents the area of the stable hemoglobin A1c peak, All Hb represents the total area of the hemoglobin in the blood sample, and (F + A2 + Other Hb) represents a total area of the other hemoglobin-derived peaks and the area of the hemoglobin A2. (see page 7 example 2-Furthermore, the peak area value of each Hb component is divided by the peak area value b excluding the peak area value of HbA2 and the peak area value of HbF from the peak area value of all Hb components, and the percentage (%) of each Hb component is calculated.)
Examiner note: NPL 510(k) teaches the total Area of the sA1c is divided by the sum of the total areas of all peaks, excluding the HbF peak and any variant peak(s) to obtain a raw sA1c percentage. Oishi teaches the total Area of the sA1c is divided by the sum of the total areas of all peaks, excluding the HbF peak and the area of the hemoglobin A2 to obtain a raw sA1c percentage. Thus, the combination of NPL (510(k) and Oishi meets this limitation.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA and DESCHAMPS to include wherein the processor further executes a process to find a reference value of the stable glycohemoglobin using a reference arithmetic equation expressed as: equation 3 where A1c represents the area of the stable hemoglobin A1c peak, All Hb represents the total area of the hemoglobin in the blood sample, and (F + A2 + Other Hb) represents a total area of the other hemoglobin-derived peaks and the area of the hemoglobin A2 taught by Oishi in the system of HASEGAWA, DESCHAMPS and NPL (510(k)) in order to provides a stable hemoglobin A1c value that enables highly accurate measurement even when a measurement sample contains abnormal hemoglobin or the like (See page 1, Oishi)
Claims 16 and 20 are like claim 5 and are rejected for the same reason as claim 5.
Regarding claim 6
The combination of HASEGAWA, DESCHAMPS, NPL (510(k) and Oishi teaches the stable glycohemoglobin measurement method of claim 5. HASEGAWA teaches wherein the processor further executes a process to further present the reference value. (See para 53- The results analyzed by the means of analysis 15 may be displayed or printed by a means of output 20. The present invention also relates to a program for measuring stable glycated hemoglobin sA1c which makes each module in the means of analysis executed by a computer. See para 55- Further, the measurement device of the present invention may further be such constituted that the means of display indicates the measurement results (A1c %) relating to the blood sample in which H-V0, H-V1 or H-V2 is identified and that the present invention is applied.)
Claims 17 and 21 are like claim 6 and are rejected for the same reason as claim 6.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over HASEGAWA et al. (PUB NO: US20190120803A1) in view of DESCHAMPS et al. (PUB NO: US20160077052A1) and further in view of HPA, Protection Assay. "510 (k) substantial equivalence determination decision summary assay only template." (2017), hereinafter NPL (510(k)) and further in view of Oishi et al. (PUB NO: JP2009109231A) and still further in view of TAKUJI et al. (PUB NO: JP2014235023A).
Regarding claim 7
The combination of HASEGAWA, DESCHAMPS, NPL (510(k)) and Oishi teaches stable glycohemoglobin measurement method of claim 5. HASEGAWA further teaches wherein the processor executes a process to present information based on the difference between the corrected value of the stable glycohemoglobin and the reference value of the stable glycohemoglobin. (see para 52-55-A1c % is calculated from the formula (1). and A1c % is calculated from the formula (4). The results analyzed by the means of analysis 15 may be displayed or printed by a means of output 20. The present invention also relates to a program for measuring stable glycated hemoglobin sA1c which makes each module in the means of analysis executed by a computer. Further, the measurement device of the present invention may further be such constituted that the means of display indicates the measurement results (A1c %) relating to the blood sample in which H-V0, H-V1 or H-V2 is identified and that the present invention is applied. See para 102- The present invention shown in Examples 1, 2 and 3 were applied to the chromatograms obtained by subjecting the blood samples containing abnormal hemoglobin D, S and C shown in FIGS. 5, 6 and 7 to cation exchange chromatography, and the results are shown in FIGS. 8, 9 and 10, respectively. As shown in these Figs., as a result of application of the present invention, the differences with measurement results by affinity chromatography are improved, and the slopes in the correlation coefficients were improved from 0.8841 to 0.9731, from 0.8767 to 0.9732, and from 0.8919 to 1.018, respectively as compared with FIGS. 1, 2, and 3)
The combination does not teach to quantify the value of the hemoglobin corresponding to the selected hemoglobin A2 peak and, in a case where the quantified value of the hemoglobin A2is equal to or higher than a predetermined threshold.
In the related field of invention, TAKUJI teaches to quantify the value of the hemoglobin corresponding to the selected hemoglobin A2 peak and, in a case where the quantified value of the hemoglobin A2is equal to or higher than a predetermined threshold. (SEE para 0002-0003- It is also important to quantify hemoglobin A2 simultaneously with hemoglobin F for the diagnosis of hemoglobinopathies. hemoglobin A2 is as small as 2% to 3.5% in healthy people and 4% to 7% in patients with thalassemia, and quantification in a low concentration range of 2% to 7% is required.)
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method measuring glycated hemoglobin as disclosed by HASEGAWA and DESCHAMPS to include to quantify the value of the hemoglobin corresponding to the selected hemoglobin A2 peak and, in a case where the quantified value of the hemoglobin A2is equal to or higher than a predetermined threshold as taught by TAKUJI in the system of HASEGAWA, DESCHAMPS, NPL (510(k)) and Oishi in order to diagnose thalassemiasemia and aberrant hemoglobinopathy by quantifying the concentration. It important to quantify hemoglobin A2 simultaneously with hemoglobin F for the diagnosis of hemoglobinopathies. (See para 0002, TAKUJI)
Conclusion
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Shigemitsu et al. US20200400690A1
i. Discussing the method measuring stable A1c in a blood sample based on a time distribution of an optical measured value of hemoglobin at a flow path which separates hemoglobin in the blood sample on a basis of amounts of the charges of hemoglobin.
SEZAKI et al. US 20170307571 A1
i. Discussing the liquid chromatography measurement method, a liquid chromatography measurement instrument, a liquid chromatography measurement program, and a storage medium that are used to analyze biological samples such as blood.
10. All claims 1-3, 4-7 and 9-21 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PURSOTTAM GIRI whose telephone number is (469)295-9101. The examiner can normally be reached 7:30-5:30 PM, Monday to Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, RENEE CHAVEZ can be reached at 5712701104. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PURSOTTAM GIRI/
Examiner, Art Unit 2186
/RENEE D CHAVEZ/Supervisory Patent Examiner, Art Unit 2186
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