The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-2, 4, 7-11, 13-20 and 22-25 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. With respect to claim 1, it is not clear if additional steps are required such as placing a cap on a single sample tube without a cap prior to mixing the whole blood sample or centrifuging the sample and/or removing a cap prior to analyzing a portion of the mixed whole blood or the plasma. In addition, it would appear that the capper and/or the decapper would be required elements of the pretreatment module if any of the above steps were a required step in the method. If either of the capper or decapper are required for performing a required step, then there structural relationship with the other elements of the pretreatment module are also needed. With respect to claims 8 and 11, are the limitations of the pipetting steps further definition of the delivering a portion of the plasma step of claim 1 and/or in addition to that step of claim 1? Additionally it appears that the transporter structure needs to have some sort of pipetting structure to be able to perform the pipetting steps. With respect to claim 13, it is not clear which details of analyzing the portion of the plasma are automatically determined based on the results of the mixed whole blood analysis. This is in part due to a lack of definition of what the analyte of the mixed whole blood is and how it relates to any analytes that might be measured in the plasma. For example, is there a threshold for the analyte of the mixed whole blood sample that if the result is above or below the threshold defines whether a plasma analyte needs to be measured and/or which plasma analyte needs to be measured? Is the amount of plasma needed determined based upon the results of the mixed whole blood analysis result? Is the analyte to be measured in the plasma sample based on the analyte of the mixed whole blood sample? Does the result of the mixed whole blood sample provide a correction to the result of the plasma sample? Or is there some other relationship between the analyte/result of the mixed whole blood and the analyte or its measurement details? With respect to claims 14-15, is there a structural relationship between the capper and the other elements of the pretreatment module and/or are there additional steps required to present the single sample tube prior to mixing the whole blood sample or centrifuging the sample (i.e. moving a single sample tube without a cap to the capper)? Is there a single capper that is used for capping all single sample tubes or at least two different cappers dedicated to capping tube prior to sample mixing and centrifuging respectively? With respect to claims 16-17, is there a structural relationship between the decapper and the other elements of the pretreatment module and/or are there additional steps required to present the single sample tube after mixing the whole blood sample or centrifuging the sample (i.e. moving a single sample tube to the decapper)? Is there a single decapper that is used for decapping all single sample tubes or at least two different decappers dedicated to decapping tubes after to sample mixing and centrifuging respectively? With respect to claim 24, “the storage location” does not have antecedent basis in claim 1. All other claims not specifically addressed above depend from at least one of the claims addressed above and fail to correct the problem(s) of the claim(s) from which they depend.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 4, 9, 13, 18-20 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Miller (US 2007/0020764) in view of Ciotti (US 2009/0311736) and Veiner (US 2005/0196320) or Le Comte (US 20070189926). With respect to claim 1 Miller teaches a method of automatically processing a whole blood sample with an integrated automated analyzer (see figure 1 and paragraph [0010], overall analytical throughput of a laboratory may be increased by linking together analyzers of different types, each adapted to perform a certain menu of assays within a single workcell . . . overall analytical throughput of a laboratory may be increased by linking together analyzers of different types, each adapted to perform a certain menu of assays within a single workcell), the whole blood sample presented to a pretreatment module (centrifuge 24) of the integrated automated analyzer in a single sample tube (sample tubes 20 in sample container carriers 22) with or without a cap (paragraph [0015] teaches that capped sample tubes 20) , the method comprising: suppling the integrated automated analyzer, the integrated automated analyzer comprising: a detector arrangement (at least elements 32,36 and 42) including at least one detector (each of the elements have their own detector) and the pretreatment module, the pretreatment module comprising: a centrifuge (24); and a transporter arrangement (see elements 14,26,28,30,34,36,40 and 44); presenting the whole blood sample to the pretreatment module in the single sample tube; delivering the single sample tube to the centrifuge with the transporter arrangement; centrifuging the whole blood sample in the single sample tube with the centrifuge and thereby separating plasma (60)-from the whole blood sample in the single sample tube; delivering a portion of the plasma from the single sample tube to the detector arrangement; and analyzing the portion of the plasma with the detector arrangement (see at least paragraph [0019]. Paragraph [0015] teaches that there may be more than three analyzers. Paragraph [0017] teaches that at each operating station 24, 30, 32, 38, 42 and 16, various types of assay processing occurs. Paragraph [0019] teaches that analyzer 32 is, for example, a clinical chemistry analyzer 32 and analyzer 38 is a coagulation analyzer. Paragraph [0009] describes coagulation tests, of which popular diagnostic tests are activated partial thromboplastin time (aPTT), prothrombin time (PT), and activated clotting time (ACT). Popular laboratory coagulation tests typically employ turbidimetric or other measuring techniques (photometric or other sensing devices). For most coagulation tests, whole-blood samples are collected into a citrate vacutainer and then centrifuged to obtain a plasma sample. The assay is performed with plasma to which a sufficient excess of calcium has been added to neutralize the effect of citrate. The PT reported as time in seconds, represents how long a plasma sample takes to clot after a mixture of thromboplastin and calcium are added. The aPTT measures the clotting time of plasma, from the activation of factor XII by a reagent (a negatively charged activator such as silica and a phospholipid) through the formation of a fibrin clot. Activated clotting time (ACT) is test that is used to monitor the effectiveness of high dose heparin therapy. ACT tests however use undiluted blood from sites which have not been contaminated by heparin infusion. The whole blood sample is transferred to appropriate test vial, mixed with the activator and a timer activated on an ACT analyzer. Paragraph [0008] teaches that clinical chemistry diagnostic analyzers associated with such sample preparation systems are adapted to automatically perform chemical assays and immunoassays on biological samples such as urine, blood serum, plasma, cerebrospinal liquids and the like, these samples generally being contained in capped sample tubes. While capped, the samples may be subjected to a centrifuging operation to separate the sample's constituents prior to testing. Chemical reactions between an analyte in a patient's biological sample and reagents used to conduct the assay generate various signals that can be measured by the analyzer. From these signals the concentration of the analyte in the sample may be calculated. Paragraph [0011] teaches that the invention provides for detecting and classifying patient samples at the input station of an automated clinical sample handling workcell with two or more independent coagulation and clinical chemistry analyzers prior to analysis enabling samples to receive pre-analysis centrifuging meeting the requirement needed to be subsequently processed by an analyzer associated with said workcell. Miller does not teach that the pretreatment module includes a whole blood mixer; and that the process includes delivering the single sample tube to the whole blood mixer with the transporter arrangement; mixing the whole blood sample in the single sample tube with the whole blood mixer; delivering a portion of the mixed whole blood sample from the single sample tube to the at least one detector with the transporter arrangement; and analyzing the portion of the mixed whole blood sample with the at least one detector.
In the patent publication Ciotti teaches an integrated apparatus and method for hematological analyses, wherein the apparatus, comprises, arranged substantially in line and integrated substantially in a single machine, a device (14) of the optical type to detect substantially instantaneously the speed of blood sedimentation (ESR) by measuring the optical density, or absorbance, of the blood sample, and a measuring assembly (18) with a cell-counter function or suchlike. Paragraph [0001] teaches that the disclosure concerns an integrated apparatus for detecting inflammatory states present in a sample of whole blood, and the relative method. In particular, the integrated apparatus is able to perform a plurality of analyses of the physical type, such as measuring the erythrocyte sedimentation rate ESR, of the immunological type and coagulative type, using a single sample of whole blood. Paragraphs [0004]-[0011] describe the ESR test and its ability to indicate a variety if conditions. However, due to the non-specific nature of the ESR test, it necessary to use it in the context of clinical and anamnestic data, which retain a primary role. Therefore, when the ESR value exceeds normal values, it is consolidated practice to carry out other diagnostic tests which are more specific, even if they are more expensive. Paragraphs [0012]-[0029] describe a second group of tests, of the immunological type, that is, based on an antigen-antibody reaction, serves to assess the concentration of C-reactive protein (CRP), streptococcus infections (ASO) and the rheumatic factor RF. Paragraph [0020] teaches that the standard test to determine CRP consists in measuring the level of turbidity caused by the agglutination due to the mixing of a determinate quantity of blood serum or plasma with latexes consisting of balls, mainly polystyrene, with an average diameter of about 0.120 micron, covered with an anti-CRP antibody and dispersed or diluted in particular liquids, called buffers. Paragraph [0023] teaches that together methods use whole blood, instead of blood serum or plasma, and provide an initial lysis of the red corpuscles present and then agglutination due to the antigen present in the volume of the plasma, which meets the CRP-specific antibody present in the sensitized carrier. In this case, the value of the CRP measured is corrected with the hematocrit value of the whole blood sample. Paragraph [0030] teaches a third group of tests that involve coagulation and, in particular, the evaluation of the concentration of fibrinogen present in the blood. Coagulation depends on factors found in the plasma and the platelets, thrombin, prothrombin, thromboplastin. Paragraphs [0061]-[0069] teach a method with variants for detecting inflammatory states present in a single sample of whole blood and derived from metabolic damage, physical damage or behavioral damage. The method includes the steps of: measuring the value of the erythrocyte sedimentation rate ESR of said sample, in order to obtain a preliminary indication of a possible inflammatory state present in said sample; subjecting to a pre-treatment, in a pre-treatment unit, a part of said sample in order to substantially eliminate the influence of red corpuscles, wherein a predetermined amount of said sample is dispensed to the pre-treatment unit by using a first dispensing unit; performing at least an immunological and/or coagulative reaction between a predetermined amount of said part of the sample pre-treated in the pre-treatment unit and a latex, by using a first reactor of a reaction group, said latex being suitably sensitized so as to cause said immunological reaction; wherein the predetermined amount of the pre-treated sample is dispensed to the first reactor by using a second dispensing unit and wherein the latex is dispensed to said first reactor by using a third dispensing unit; and measuring at least the kinetics of said reaction, indicative of said inflammatory states present in said sample. According to a variant, the method also comprises the step of measuring the value of the equivalent hematocrit factor of said sample; in this case the pre-treating step comprises a lysis reaction step of a part of said sample in order to obtain a lysed sample and further comprises the step of correcting the measurement of the kinetics of said reaction performed with the portion of lysed sample, by means of said equivalent hematocrit factor. According to another variant, the pre-treating step comprises a centrifuge step in order to obtain a centrifuged sample wherein the corpuscular part of the blood is separated from the liquid one, in particular the red corpuscles are separated from the whole blood. According to a further embodiment, the method also comprises a step of performing at least a coagulation reaction between a part of said sample or a portion of the sample pre-treated in the pre-treatment unit and a coagulation reagent, by using a coagulation reactor of the reaction group and measuring at least the kinetics of the coagulation reaction; wherein a predetermined amount of the coagulation reagent is dispensed to the coagulation reactor by using the third dispensing unit. The method allows carrying out a plurality of diagnostic tests, which use different reaction techniques and different quotas of whole blood, deriving from a single sample of whole blood which has been subjected to a single pre-analytical treatment. The method is thus economical and reliable, and reduces the possibility of errors due to the different pre-analytical steps of the state of the art.
In the patent publication Veiner teaches a specimen-transport module adapted for use with each of a plurality of specimen-processing instruments of a multi-instrument clinical workcell. Such module is adapted to transport individual racks of specimen-containers relative to a specimen-aspiration probe of an associated instrument in a workcell, as well as to transfer selected racks of specimen-containers to an adjacent and identical specimen-transport module associated with another clinical instrument of the workcell. Since the same transport system is used to both present specimens for aspiration and to transfer specimens between instruments, there is no need for two independent conveyances as is characteristic of the prior art. Of particular relevance to claim 1, Paragraph [0014] teaches that it is preferred that the module housing further defines a specimen-processing station at which the racks of specimens can be processed, e.g., repeatedly inverted to homogeneously mix the specimens, prior to specimen-aspiration by an instrument directly associated with the module. Paragraph [0043] teaches that the workcell 10 comprises a plurality of identical specimen-transporting modules (MOD 22, MOD 24, MOD 26 and MOD 28), one being operatively connected to, or otherwise associated with, each of the four clinical instruments 12, 14, 16 and 18. Each of the specimen-transporting modules provides at least two functions: Firstly, it functions to satisfy all specimen-presentation needs of the instrument with which it is directly associated, i.e., it functions to (i) receive multiple racks of specimen containers manually delivered to an input buffer of the module, (ii) selectively transport such racks from the input buffer to a specimen-aspiration station in which all of the specimen containers of given rack are accessible to the aspiration probe of the associated instrument, and (iii) deliver a rack to an output buffer following a desired specimen aspiration from all or selected ones of the containers in the rack. Upon being delivered to the output buffer, a rack, may be advanced to an off-loading position where it can be manually removed from the module or, alternatively, it may be returned to the specimen-aspiration station for reflex or repeat testing, as may be the case if a first test result indicates that a second aspiration of a given sample is required, or if a first test result is clearly erroneous. Secondly, the specimen-transporting module of the invention functions to transfer racks of specimen-containers between adjacent instruments, thereby enabling all instruments of the workcell to process a given specimen without need for any independent specimen-transfer mechanism, e.g., a robotic arm, or a conveyor system. Preferably, each of the specimen-transport modules of the invention provides a third function, namely, that of preparing a specimen for subsequent processing. Such sample-preparation preferably comprises the step of mixing the contents of a specimen-container immediately prior to being aspirated by its associated instrument for processing. Such mixing is achieved by repeatedly inverting a specimen-container rack and the multiple containers it holds.
In the patent publication Le Comte teaches a device for supplying whole blood analyzers with tubes of blood. A stirring device is arranged upstream with respect to at least one analyzer. A first transport device conveys blood tubes one after another in front of the stirring device, and a second transport device conveys the blood tubes stirred by the stirring device one after another to a sampling point of the analyzer. A mechanism picks up separately the blood tubes which are not yet stirred, places the tubes in front of the stirring device to be stirred thereby, and to be separately removed from the stirring device and placed on a transport for conveying the stirred tubes to the sampling point of the analyzer, thereby making it possible to use at least one analyzed devoid of stirring. Paragraph [0003] teaches that in contrast to the analyses carried out on blood plasma or serum the blood which is to be analyzed by a whole blood analyzer has to be carefully mixed a very short time before the analysis. This agitation phase is absolutely necessary in order to homogenize the blood so as to re-suspend the cells which naturally settle out when the tube is motionless, and it has to be carried out in accordance with the recommendations of the standardization committees. Figures 5A to 9B respectively show first, second, third, fourth and fifth embodiments of a conveying and agitating device for tubes. The agitator 5 of figures 5A and 5B includes a plurality of wheels 16 aligned on the same rotation axis inside a housing 17. The wheels 16 are provided with indentations 18 to accommodate the tubes 2 which are to be agitated. The tubes 2 are introduced into the agitator 5 by a manipulating arm 24 resting on a base 25. In the embodiment shown in figures 8A and 8B, a manipulating arm 26 is carried by the agitator 5 and is made to rotate about its longitudinal axis XX' under the control of the analyzer 4 or the control station in order to allow agitation of the tube 2 gripped by the gripper 27 placed at its end. In the embodiment shown in figures 9A and 9B, the agitator 5 comprises a cylinder or barrel 28 which allows a free indentation 18 to be positioned vertically with respect to a tube 2 which is to be agitated, placed on the conveyor 1. A downward vertical movement of the indentation 18 allows the tube 2 and its support 12 to be picked up. Then the indentation 18 moves upwards and positions itself in the barrel 28 which undertakes a series of rotations in order to agitate the tube 2. At the end of the agitation the barrel 28 positions itself so as to be able to set the tube 2 and its support 12 down on the conveyor 1.
With respect to claim 1, it would have been obvious to one of ordinary skill in the art at the time the application was filed to provide the pretreatment module of Miller with a whole blood mixer as taught by Veiner or Le Comte prior to an analyzer using whole blood because Miller clearly teaches that the analysis samples can include whole blood and the agitation of a whole blood sample a very short time before the analysis is absolutely necessary in order to homogenize the blood so as to re-suspend the cells which naturally settle out when the tube is motionless as taught by at least Le Comte. It further would have been obvious to incorporate a mixing step and analysis of the whole blood into the Miller method because Miller is clearly concerned with providing the appropriate pretreatment for each sample prior to analysis and the pretreatment of a sample for a whole blood analyzer is recognized as clearly different from a plasma sample as taught by at least Ciotti and Le Comte and the processing of a single sample for different analytes related by there ability to diagnose a condition is capable with a single workcell as taught by Ciotti.
With respect to claims 2 and 4, the whole blood and plasma coagulation tests described by Miller employ turbidimetric or other techniques so that the at least one detector of the detector arrangement includes a photometer for performing absorption photometry and wherein the portion of the mixed whole blood sample and/or the plasma is analyzed with the photometer. With respect to claim 9, paragraph [0004] of Miller teaches that to prevent clotting, an anticoagulant such as citrate or heparin is added to the blood specimen immediately after it is obtained or the anticoagulant is present in the evacuated blood collection tube when the patient sample is originally obtained. Thus Miller teaches that the single sample tube comprises a lithium heparin or EDTA additive. With respect to claim 13, it would have been obvious to one of ordinary skill in the art at the time the application was filed to use the result obtained from analysis of a whole blood portion of a single sample to determine the details/correct the details/result of a plasma sample from the same sample tube as taught by Ciotti because as taught by Ciotti, the ESR assay on the whole blood sample was preliminary leading to the need of performing secondary analyses when a threshold was exceeded or can be used to correct a subsequent analysis as taught by Ciotti when performing analysis on related analytes from a single sample. With respect to claims 16-17, Miller teaches a de-capper 30 or automatically removing caps from capped sample containers 20 prior to analysis of the fluid contained therein at the one or more analyzers (see paragraph [0015]). Thus the modified Miller method would cover removing the cap from the single sample tube prior to delivering a portion of the mixed whole blood sample and/or a portion of the plasma from the single sample tube to the at least one detector with the transporter arrangement. With respect to claim 18, paragraphs [0014]-[0015] of Miller teach that each of the sample containers 20 is provided with identification indicia, such as a bar code, machine readable by a sensor 19 and indicating a patient's identification as well as the assay procedures to be accomplished upon the sample therein. The sample handling workcell 10 has a number of sensors 19 for detecting the location of a sample tube container 20 by means of identifying indicia placed on or within each sample tube carrier 22. Conventional bar-code readers may be employed in such tracking operations. Thus Miller teaches a reader configured to identify the single sample tube, the method further comprising: reading an identity of the single sample tube after presenting the whole blood sample to the pretreatment module in the single sample tube. With respect to claim 19, Miller teaches at least one rack (18) and wherein the whole blood sample is presented to the pretreatment module of the integrated automated analyzer with the single sample tube in the rack (see at least paragraph [0014]). With respect to claims 2 and 22-34, paragraph [0015] of Miller teaches that the workcell has a sample container loading/unloading station 16 to which each sample container 20 is retuned after various processing steps. Paragraph [0021] of Miller teaches that if a sample in a container 20 does not have centrifuging requirements which match the currently established centrifuge operating protocols, container 20 is replaced back into an available input rack 18 at station 16 and retained there until the centrifuge operating protocols are changed appropriately. Thus, sample container loading/unloading station 16 constitutes at least one storage location configured to store the single sample tube after presenting the whole blood sample to the pretreatment module in the single sample tube, after delivering the portion of the mixed whole blood sample from the single sample tube to the at least one detector with the transporter arrangement, after delivering the portion of the plasma from the single sample tube to the detector arrangement or storing the single sample tube in the rack.
Claims 7-8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Miller in view of Ciotti and Veiner or Le Comte as applied to claim 1 above, and further in view of Hardy (Journal of Clinical Laboratory Analysis 2000), Petersen (Journal of Pharmaceutical and Biomedical Analysis 2010) or Poulsen (Journal of Biomolecular Screening 2007). Miller does not teach a luminometer or measuring C-peptide or insulin with a luminometer using a luminescent reagent.
In the paper Hardy teaches an automated chemiluminescent assay for C-peptide. C-peptide is secreted in equimolar concentrations with insulin, and is often measured to assess pancreatic b-cell function. C-peptide analysis is most often performed by radioimmunoassay (RIA) which has several disadvantages. They evaluated an automated, chemiluminescent immunoassay for C-peptide in terms of precision, linearity, interference, and correlation with a RIA method. The chemiluminescent assay demonstrated acceptable correlation with the RIA method (slope = 0.82, y-intercept = 0.88 ng/ml, r-value = 0.97). Between-run CVs ranged from 8 to 9%, which compared well with the RIA method. Linearity extended beyond the manufacturer’s recommendations and recovery ranged from 87 to 112% across the concentrations tested, with a slope of 1.007. No significant interference was noted with hemoglobin, bilirubin, or triglyceride. Overall this method compared favorably with the RIA method and offers an alternative to RIA for the analysis of C-peptide. The paragraph bridging the columns of page 17 teach that the DPC assay consists of a solid-phase enzyme immunoassay that can measure C-peptide concentrations in serum or heparinized plasma. The assay was developed for an automated, continuous, random-access system (DPC, Immulite®). It consists of enzyme-labeled C-peptide molecules that compete with C-peptide molecules from the sample for purified polyclonal antibodies immobilized on polystyrene beads. A chemiluminescent substrate is added, and the emission of light is measured by a luminometer. The emission of light is inversely proportional to the concentration of C-peptide in the sample.
In the paper Petersen compared a Luminescent Oxygen Channeling Immunoassay (LOCITM) and an enzyme-linked immunosorbent assay (ELISA) for quantification of Insulin Aspart (IAsp) in human serum. The advantage of LOCITM compared to ELISA is reduced workload and higher throughput. The ELISA assay was performed as published (Andersen et al., 2000 [5]). The LOCITM followed a 2-step reaction. First, the sample was incubated for 1 h with a mixture of biotinylated antibody specific for IAsp and beads coated with insulin-detecting antibody. This step was followed by a 30-min incubation with beads covalently coated with streptavidin. When the beads were brought in proximity through binding of IAsp, light was generated from a chemiluminescent reaction in the beads. This light was measured and quantified. Spiked samples with different concentrations of IAsp were prepared in human serum to compare ELISA and LOCITM. Human serum samples (n = 510) from a pilot study with healthy subjects receiving IAsp were also analyzed and compared in the two assays. Higher precision, improved accuracy and a wider analytical range were found using LOCITM compared to ELISA. However, sample hemolysis interfered more when using LOCITM than ELISA. The IAsp concentrations determined in the human serum samples from the pilot study gave a good correlation between the two assays. In conclusion, LOCITM can determine IAsp in human serum just as well as ELISA. Using LOCITM reduces the workload, which is particularly useful when handling large sample sizes. The first paragraph of section 2-2-5 on page 218 teaches that in the LOCITM assay, a bead-aggregate-immunecomplex was formed, which combines the three reactants with analyte. The SAD beads captured the biotinylated X14-6F34 antibody and together with the HUI-018 antibody coupled A beads they were brought in proximity through the binding of IAsp. Illumination of the complex released singlet oxygen from the SA-D beads, which travelled to the nearby A beads and triggered chemiluminescence that was read on an EnVision plate reader. The amount of light generated was proportional to the concentration of IAsp.
In the paper Poulsen describes homogeneous, sensitive, and rapid bead-based sandwich immunoassay with a broad analytical range for quantifying insulin in human plasma. The assay was performed as a 2-step reaction by incubating the sample with a mixture of biotinylated anti-insulin antibody and beads covalently coated with anti-insulin antibody for 1 h. This was followed by incubation with beads covalently coated with streptavidin for 30 min. After the incubation steps, light generated from a chemiluminescent reaction within the beads was quantitated. The assay was run in 384-well plates with a sample volume of 5 μL. The analytical range extended from 1 to 10,000 pM. Intra-assay precision (% coefficient of variation) ranged from 1.9% to 3.8% for various insulin concentrations. Interassay precision ranged from 4.6% to 7.3%. Assay detection limit was 0.3 pM. There was no interference from moderate hemolysis (with hemoglobin up to 375 mg/dL), bilirubin (up to at least 50 mg/dL), triglyceride (up to at least 1000 mg/dL), biotin (up to at least 7.7 ng/mL), or ascorbic acid (up to 100 mg/dL). However, gross hemolysis did affect the assay. Comparable results were obtained for plasma (ethylenediamine tetra-acetic acid, citrate, and heparin treated) and serum. The correlation with enzyme-linked immunosorbent assay (ELISA) was good (y = 1.25x + 1.19, R2 = 0.98). This method is convenient and represents an alternative to ELISA. The first full paragraph on page 242 teaches that the results were measured on an Envision Turbo Alpha with 1 detector, 70 ms excitation and 140 ms detection. The total processing time per 384-well plate was about 2.75 min, and the time for measuring from the 1st to the last well was about 2.33 min.
It would have been obvious to one of ordinary skill in the art at the time the application was filed to use a detector such as taught by Hardy, Petersen or Poulsen that is capable of measuring luminescence produced from a luminescent reagent and modify the Miller method to measure either S-peptide as taught by Hardy or insulin as taught by Petersen or Poulsen because of the variability in the number and/or type of detectors taught by Miller and the value of performing the C-peptide and/or insulin assays as taught by Hardy, Petersen or Poulsen.
Claims 10 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Miller in view of Ciotti and Veiner or Le Comte as applied to claims 9 and 1 above respectively, and further in view of Jeng (US 6,087,182). With respect to claim 10 and 25, Miller does not teach the detector including an ion selective electrode (ISE) for performing electrolyte analysis.
In the patent Jeng teaches apparatus and method for determining at least one parameter, e. g., concentration, of at least one analyte, e.g., urea, of a biological sample, e.g., urine. A biological sample particularly suitable for the apparatus and method of this invention is urine. In general, spectroscopic measurements can be used to quantify the concentrations of one or more analytes in a biological sample. In order to obtain concentration values of certain analytes, such as hemoglobin and bilirubin, visible light absorption spectroscopy can be used. In order to obtain concentration values of other analytes, such as urea, creatinine, glucose, ketones, and protein, infrared light absorption spectroscopy can be used. The apparatus and method of this invention utilize one or more mathematical techniques to improve the accuracy of measurement of parameters of analytes in a biological sample. The invention also provides an apparatus and method for measuring the refractive index of a sample of biological fluid while making spectroscopic measurements substantially simultaneously. Figure 1 illustrates a system showing various types of measurements that can be carried out with the method and apparatus. The reagentless system 10 comprises a sample handling subsystem 12, the purpose of which is to introduce samples of biological fluid, e. g., urine, to the optical measurement subsystems. The reagentless system 10 further comprises a refractive index determination subsystem 14, a visible light spectroscopic subsystem 16, and an infrared light spectroscopic subsystem 18. In the case of urinalysis, the refractive index determination subsystem 14 can be used to determine the specific gravity of urine, the visible light spectroscopic subsystem 16 can be used to determine color, turbidity, bilirubin, hemoglobin, urobilinogen, and protein, or other analytes with a usable visible spectral signature, and the infrared light spectroscopic subsystem 18 can be used to determine urea, creatinine, glucose, protein, and ketones, or other analytes that have a usable near-infrared or mid-infrared spectral signature. The reagentless system 10 may further comprise a subsystem 20 for determining pH and nitrites. Column 13, lines 16-24 teach that nitrites (NO2) can be measured by means of spectroscopy, by means of ion selective electrodes, or by adding a reagent and making a colorimetric measurement. The purpose of a NO2 measurement, with respect to a sample of urine, is to determine if NO2 has been added to the sample of urine for the purpose of producing a false negative test result for a drug of abuse in a drug of abuse adulteration test. Determination of NO2 can also be used as an indicator for an infection in a urinalysis test. Column 5, lines 23-28 teach that an ion selective electrode can be used to provide nitrite values of a sample of biological fluid when nitrites are present at low concentration, while infrared spectroscopy can be used to provide nitrite values of a sample of biological fluid when nitrites are present at higher concentration. The paragraph bridging columns 13-14 teaches that A system that combines cell counting technology with one or more of spectroscopic measurements, refractive index measurements, pH measurements, and ion selective electrodes could bring about complete automation of urinalysis, thereby saving time for a trained technician and saving cost for the testing institution.
It would have bee obvious to one of ordinary skill in the art at the time the application was filed to include an ion selective electrode into the Miller detector arrangement because of the measurement of urine samples by Miller and the possibility of complete automation of urinalysis when including an ion selective electrode in the detector arrangement as taught by Jeng.
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Miller in view of Ciotti and Veiner or Le Comte as applied to claim 1 above, and further in view of Thomas (US 2014/0113278). Miller does not teach a capper configured to apply a cap on the single sample tube.
In the patent publication Thomas teaches and automated process for converting samples includes: receiving tube strips having a number of sample tubes and samples therein, transferring multiple tube strips to a tube strip holder, dispensing sample conversion buffer into each tube, shaking the tube strip holder a first time, centrifuging the tube strip holder, removing a liquid supernatant from each tube, simultaneously inspecting the contents of each tube, dispensing a specimen transport medium and a denaturation reagent into each tube, shaking the tube strip holder a second time, heating the tube strip holder for a first length of time, shaking the tube strip holder a third time, heating the tube strip holder for a second length of time, shaking the tube strip holder a fourth time, and transferring at least a portion of each sample to a respective well on an output plate. Paragraph [0010] teaches that a pelleting/decanting step involves a number of substeps. First, a predetermined amount of sample conversion buffer is added to the processing tube, and then the tube is capped and thoroughly mixed using a vortex mixer with a cup attachment. Next, the tube is centrifuged in a swinging bucket rotor at 2,900 (±150)Xg for 15 (±2) minutes. Following centrifuging, the operator visually verifies that a pink/orange cell pellet is present in the bottom of the tube. Even if no pellet is detected, the protocol continues, a pellet that is too small to see can still provide a positive test result (however, if there is no visible pellet, a negative test result might be dismissed as a false negative, and such an indeterminate result may require further testing). Next, the supernatant is carefully decanted by inverting the tube and gently blotting (approximately 6 times) on absorbent low-lint paper towels until liquid no longer drips from the tube. Each blot is done on a clean area of the towel. During blotting, the operator observes the tube to ensure that the cell pellet does not slide down the tube. Paragraph [0106] teaches that vial racks 402 may hold the sample vials 404 in any suitable fashion. For example, each vial rack 402 may have a plurality of vial wells in which the sample vials 404 are dropped before sliding the vial rack 402 into the processing module 400. Such wells may be vertical or tilted at an angle to facilitate pipetting of the contents from the sample vials 404. The wells also may be mounted to tilt during the pipetting process. The wells may have openings or slots through which barcodes on the sides of the sample vials 404 can be read before, during, or after insertion of the vial rack 402 into the processing module 400. The sample vials 404 may be provided in the vial racks 402 with their caps removed, or a decapping/recapping unit may be integrated into the processing module 400 to remove and replace the vial caps during processing. If desired, the vial racks 402 may include features, such as shakers or the like, to suspend the samples.
It would have been obvious to one of ordinary skill in the art at the time the application was filed to provide the Miller system with a capper as taught by Thomas because there are clearly times such as during mixing and/or centrifuging that a cap is desirable and/or necessary as taught by Thomas.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The additionally cited art is related to various aspect of automated analyzers and method using them.
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/ARLEN SODERQUIST/ Primary Examiner, Art Unit 1797