The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6 and 9-15 are rejected under 35 U.S.C. 103 as being unpatentable over Harvey (US 2002/0036170) in view of Davis (US 5,416,026) or Subramanian (US 5,223,219) and further in view of Hillman (US 5,135,719).
With respect to claim 1, Harvey teaches a chromatographic assay device (abstract lateral flow chromatographic assay membrane) for detecting the presence of an analyte in a whole blood sample, the device comprising: a chromatographic detection pad (14) which defines a path for capillary fluid flow, the chromatographic detection pad formed of a nitrocellulose membrane and having a pore size in a range of from 8 microns to 40 microns (paragraph [0006], 1 micron to 20 micron porosity; paragraphs [0014] and [0017], nitrocellulose membrane AES-10 or AES-11; figure 1 and paragraphs [0028] and [0033], nitrocellulose membrane AES-110, table 1 and its associated discussion in paragraph [0021], without Con A, there is almost no separation of plasma from red blood cells so that the pore size of the actual nitrocellulose membrane is greater than the size of red blood cells), the chromatographic detection pad comprising: a sample application site on the chromatographic detection pad for application of a portion of the whole blood sample (12, sample application zone), the sample application site being adjacent to a first end of the chromatographic detection pad (see at least paragraph [0014], one end of the strip is a sample application zone (12)), wherein the sample application site is treated with at least one type of red blood cell (RBC) binding or agglutination material such that when the whole blood sample is applied to the chromatographic detection pad, the RBC binding or agglutination material agglutinates with any RBCs in the whole blood sample to produce agglutinated RBCs, and wherein the agglutinated RBCs have a size greater than the pore size of the chromatographic detection pad and thereby are prevented from flowing through the chromatographic detection pad (see at least paragraph [0014], abutting this zone is an area of an erythrocyte binding agent (EBA) within the nitrocellulose matrix; figure 1 and paragraphs [0017], to effect separation of blood components, a lectin, such as concanavalin A (Con A) is placed on the nitrocellulose; table 1 and its associated discussion in paragraph [0021], when Con A is added to the nitrocellulose, substantial separation occurs); a detection site on the chromatographic detection pad, the detection site spaced apart from the sample application site, the detection site being downstream of the sample application site, and wherein free hemoglobin flows through the chromatographic detection pad from the sample application site to the detection site and is detectable via a color change at the detection site (see figure 1 elements 14,16, leaving the liquid portion of blood (plasma) to migrate to the distal end of the strip (16) where it can be assayed). Harvey teaches reagents for non-hemoglobin assays at the detection site but does not teach detection of hemoglobin via a red color change at the detection site or the actual pore size of the nitrocellulose membrane.
In the patent Davis teaches a method of detecting hemolysis in a whole-blood sample, a method of determining an elevation in the potassium ion concentration of a whole-blood sample, an apparatus for detecting hemolysis and/or determining an elevation in the potassium ion concentration in a fluid sample, an apparatus for detecting hemolysis and/or determining an elevation in the potassium ion concentration in a whole-blood sample, and a single-use cartridge containing a plurality of microfabricated biosensors which further contains a hemolysis detection unit. Figures 1-2 show lateral flow embodiments of the apparatus. Figure 3 shows a vertical flow embodiment of the apparatus. Figure 7 shows a single-use cartridge incorporating a modified hemolysis detection device according to figure 2, Columns 5-6 teach that there exists a need in the medical and clinical arts for a method which quickly determines whether a biological fluid sample contains hemolyzed red blood cells, and which does not require use of a centrifuge. The need is particularly strongly felt in methods which determine the presence or concentration of analytes in whole-blood samples. For that purpose, the section teaches a method of detecting hemolysis in a whole-blood sample, comprising the steps of: a) contacting a whole-blood sample comprising intact red blood cells with a dry separation material, the material having physical characteristics effective to separate a fraction, which contains extracellular hemoglobin that may be present in the sample, from the intact red blood cells; b) allowing the sample to remain in contact with the material for a period of time sufficient to effect the separation; and c) detecting the presence of extracellular hemoglobin in the fraction. In the method, the fraction separated from intact red blood cells includes plasma and serum. The sample may be diluted, treated with a solution or reagent, or have an internal standard added thereto, as long as such treatment does not chemically modify the analytes or affect the separation behavior of the separated fraction. The detection step in the method may comprise visually inspecting the fraction for the presence of a color hue. The color hue corresponds to an estimated concentration of extracellular hemoglobin of about 20 mg/dL, which is equivalent to lysis of about 100 red blood cells per µL of whole-blood (blood plasma shows visual evidence of hemolysis when the hemoglobin concentration exceeds 20 mg/dL), resulting in a color change from a yellow hue to a red or pink hue. An alternative method estimates the concentration of Hb in a whole-blood sample, and correspondingly, the number of hemolyzed red blood cells per unit volume or concentration of hemolyzed red blood cells in a whole-blood sample, by comparing the color hue of the separated fraction with a number of different color hues on a chart. The chart displays a number of characteristic color hues corresponding to the colors associated with a range of predetermined Hb concentrations in plasma. Column 8, lines 10-36 teach that the detection step may alternatively be performed with the aid of a reflectance meter (medical diagnostic device), the meter providing a reading that is a function of the concentration of extracellular hemoglobin present in the fraction. Thus, the method may further comprise the steps of irradiating the separated fraction with light, and determining the reflectance of the light due to hemoglobin in the separated fraction. When measuring the reflectance due to hemoglobin in the separated fraction directly (where no chromogenic reagent is present), the light may be a wavelength for which hemoglobin exhibits a maximum absorbance. Typically, however, broad-band visible light is used to measure the reflectance. The reflectance is calibrated against a white surface (for example, the unused dry separation material). Reflectance of the dry separation material containing a separated serum or plasma fraction is then based on a scale of grayness (for example, the less white color, the lower the reflectance). Further measurements performed on samples having a known concentration of Hb provide data points on which quantitative reflective measurements can be based. A graph of reflectance versus Hb concentration is plotted. The graph can then be used to determine the Hb concentration of the separated fraction of a whole-blood sample based on the reflectance of the separated fraction. Column 10, lines 19-68 teach that the dry separation material is a dry material which separates biological fluids from intact red blood cells rapidly by wicking action (also known in the art as "capillary forces"), and does not cause visible hemolysis. The phrase "wicking action" refers to the ability of the dry separation material to transport fluid from the site where it is introduced to the dry separation material to the remainder of the dry separation material in a radial fashion. By contrast, red blood cells are not transported readily along the material, and are thus retarded by the dry separation material, relative to the separated fraction. The composite fibrous sheet suitable for use in the apparatus as a dry separation material comprises a blend of glass microfibers, cellulose fibers, and synthetic sample fibers, intermixed in a randomly dispersed fibrous matrix. The dry separation material may be in strip form, having dimensions that include a length of from 5 to 50 mm, a width of from 1 to 10 mm, and a thickness of from 0.1 to 3.0 mm. Preferable dimensions are from 10 to 40 mm length, from 3 to 7.5 mm in width, and from 0.2 to 1.0 mm in thickness. A length about two centimeters and a thickness of about 0.3 mm of the dry separation material gives adequate separation in about one minute. Figure 1 shows a stiff substrate (1) supporting the dry separation material (2). Preferably, however, the dry separation material is sufficiently strong or stiff as to not require a supporting substrate. Accordingly, the apparatus may consist of the dry separation material and the detection means. When separating the fraction lengthwise (in the direction of the arrow in figure 1), the whole-blood sample is applied at a site toward one end (3) of the dry separation material. The fraction to be separated is transported radially by the wicking action of the dry separation material away from the application site. When the separated fraction reaches a site near or at the end (4) opposite the end containing the application site, the detection means is then used to determine the presence of hemoglobin or to estimate the level of hemolysis. In an alternative shown in figure 3, the dry separation material may separate the fraction from intact red blood cells along the axis of thickness of the material. As shown in figure 2, the apparatus may be provided with a viewing region (6), next to which the detection means (a colored chart, 7) is located. The viewing window may be designed to substantially exclude from view that portion of the separated sample which contains the intact red blood cells. Preferably, the viewing region is located a sufficient distance along the separation material and away from the site where the sample is applied so that red blood cells do not reach the viewing region. Column 13, lines 17-39 teach that in a preferred embodiment, the colored chart of the apparatus of figure 2 comprises at least two color hues, each of which is indicative of an estimated concentration of extra cellular hemoglobin present in a given plasma fraction. For example, a yellow hue, correlating to a concentration of less than 20 mg/dL of Hb, may indicate an acceptable sample, whereas a pink hue, correlating to a concentration of greater than 20 mg/dL of Hb, may indicate an unreliable sample. For semi-quantitative estimations, however, the colored chart may contain from three to twelve color hues. In a further embodiment, the detection means may comprise a reflectance meter including a light source and a light detector, the light source being positioned to permit an incident light beam from the light source to strike the separated fraction to provide a reflected light beam and the light detector being positioned to permit detection of the reflected light beam.
In the patent, Subramanian teaches a diagnosis system, which comprises a monitor, comprising a detector providing multiple reflectance readings in an array of individual locations, registering an analytical cartridge in the monitor at a fixed location and orientation relative to the array, and determines and displays analytical results from reflectance readings; and an analytical cartridge, comprising a liquid impervious housing, a sample application site in the housing located outside the monitor when the cartridge is registered in the monitor by the means for registering, one or more reflectance reading sites in the housing that register with one or more of the locations in the array, a capillary pathway in the housing leading from the sample application site to each of the reflectance reading sites, and a reflectance matrix located in at least one of the reflectance reading sites. In some embodiments, control features that optimize accuracy of measurement by controlling when and if sample reaches reflectance reading sites and by drawing excess sample away from undesirable locations in the cartridge are present. One control element balances the liquid-holding capacities of the application site, the sample-transporting capillary passageway that leads to the reflectance reading site, and the porous matrices from which the reflectance reading will be made, so that excess sample is excluded from entry into the cartridge while sample volumes that are below the minimum necessary for accurate operation do not reach the matrix, thereby avoiding false readings.
Relevant to the instant claims, Subramanian teaches that the monitor is equipped with light sources, usually one or more light-emitting-diodes (LEDs) with emissions that cover the visible and near infrared (IR) part of the electromagnetic spectrum. The visible and IR LEDs cover a broad wavelength range, which allows for measurement of a large variety of color-forming chemistries, especially those that generate a colored product by oxidation of a leucodye by hydrogen peroxide catalyzed by peroxidase. In one preferred version of the monitor, light from the LEDs is mixed and routed from the sources to the stacks using a fiber optic. In this way all of the stacks can be illuminated by all the light sources. By operating the sources in a timed sequence and multiplexing the response from the reflectance detectors, it is possible to measure reflectance at all illuminating wavelengths at all the stacks over the assay time courses. The monitor displays a set of instructions for the user prompting them to apply a sample to an application port which is located on the upper side of a part of a cartridge that projects from the monitor. The monitor records the reflectance of the carrier layer during the assay reaction, typically at three wavelengths. By comparing the change in reflectance with those for known calibration materials, the monitor can compute the analyte concentration. The second and third wavelengths can be used for quality control operations and for other purposes. The monitor can also determine if operation of the device has been compromised or if the sample has been damaged (for example hemolyzed), since these conditions produce characteristic reflectance values.
Also relevant to the instant claims is column 5, line 12 to column 6, line 57 of Subramanian teaching, in part, that sample moves through a capillary in the cartridge until it reaches one or more junctions to other branching channels that lead to a set of assay stacks, each of which is a porous matrix or a series of porous matrices in close contact with each other. Different layers of the assay stack can provide for different functions, such as filtering of red cells from blood, separating reagents from each other, or acting as a reflective matrix of which an optical reading is taken. Such assay stacks are conventional, as discussed below. The stack itself is composed of a series of (generally) disc-shaped, porous components disposed co-axially with the cavity axis and captured in the cavity in preferred embodiments by a ledge in the outer surface of the cartridge projecting from the cavity wall towards the center. In tests where plasma is the desired sample and whole blood is the sample, the stack acts as a red cell filter. Filter stacks comprise a fibrous layer (typically polypropylene) containing a red cell agglutinating agent dried onto the fibrous material. As the sample moves through the filter, the agent dissolves in the plasma and causes red cells to agglutinate and thus to become trapped within the fibrous filter. Plasma, now largely free of red cells, proceeds through the stack. Plasma then moves into a layer impregnated with assay chemistry which dissolves in the plasma and reacts with the analyte to form a colored product. Assay chemistry will typically include salts, buffers, detergents, enzymes, chromogens, stabilizing agents, and bactericides or bacteriostats. Usually the layer that carries the assay chemistry is the outermost layer of the stack. The outer layer, which functions as a reflective matrix, and the chromogen are carefully selected such that in the range of clinical interest the layer is optically thick and the reflectivity of the layer after the assay reaction corresponds to K/S values in the range 0.2-2. Column 8, lines 51-60 teach that in assays for plasma analytes, fail-safe operation of the invention can be monitored with respect to leakage of red cells and hemolysis of sample by provision of a fail-safe stack which has no chemistry or by spectral analysis of the color of the assay stacks. The monitor can measure any red pigment (hemoglobin) which reaches the reflective membrane. The fail-safe stack is physically equivalent to the assay stacks in dimensions and in the construction of the red cell filter. Example 4 (columns 21-22) demonstrated the red cell filtration effectiveness of the filter, prototype 4-window cartridges and monitors were used. Cartridges contained stacks comprised of antibody impregnated-polypropylene filters, Gelman TR-3000 membrane and two layers of ST-69 (Schleicher and Schuell). No assay chemistry was present in the stacks. Blood (45% hematocrit), the corresponding plasma, and serum samples with known levels of hemolysis were applied to the cartridges in the usual way and K/S values recorded after 3 minutes at 585 nm. To evaluate the effects red cells that were not removed by the filter blood containing known, samples with low hematocrits were applied directly to the optical surface of the stack. The results given in Table 4 show that >99% of the red cells were removed and that <1% hemolysis occurred. Example 5, column 22, lines 29-46 teaches the use of an antibody to red cells as the impregnated red cell filtration agent. The paragraph bridging columns 23-24 in the results section teaches that the efficiency of the red cell filter was evaluated in glucose assay stacks omitting assay reagent and measuring the color of the optical membrane at 585 nm corresponding to a major absorbance of hemoglobin. Any leaked red cells or hemolysis would be detected in this way. Less than 1% leakage or hemolysis would be detected in this way. Less than 1% leakage or hemolysis was found. The filter works by agglutination of the red cells and depth filtration of the agglutinated cells in the fibrous mesh of the filter. The filter is effective for blood up to 60% hematocrit. Column 25, lines 12-24 teach that hemolysis can occur due to inappropriate handling of the specimen. A simple algorithm constructed from the known spectral properties of the reaction product and of hemoglobin permits the calculation of both chromogen and hemoglobin concentrations from data collected at 585 nm (where the reaction product and hemoglobin both absorb strongly and 637 nm (where the reaction product absorbs and hemoglobin has little absorption). Hemoglobin concentrations less than those at which there is interference in the glucose and cholesterol assays are easily measured. Hemolyzed samples that would give incorrect assay results can be identified in this way.
In the patent Hillman teaches a method for separating plasma from red blood cells and a device utilizing the method in which a low-pressure filter is interposed in a pathway between an inlet port and a reaction area. The sole driving force for the movement of plasma from the filter to the reaction area is capillary force provided by a tubular capillary. The filter is selected from glass microfiber filters of specified characteristics, which can operate in the absence of agglutinins, and filters capable of separating agglutinated red cells from plasma, which require the use of an agglutinin.
Relevant to the instant claims are the following sections and teachings. Column 3, lines 4-11 and column 4, lines 44-53 teaching that glass fiber filters are used and that the strict control described does not need to be maintained when utilizing an agglutinin. Column 5, line 16 to column 6, line 39, teaching that it is possible to separate plasma from red blood cells in a single drop of blood in a capillary flow device using antibodies to red blood cells or other agglutinins in combination with a filter. The filter can be either the described glass fiber filters (including the filters that do not work in the absence of agglutinins), paper, or any other type of filter that can filter agglutinated red blood cells. Paper, non-woven fabrics, sheet-like filter material composed of powders or fibers (such as carbon or glass fibers), and membranes having suitable pore sizes can all be utilized with antibodies and other agglutinins. Cellulose fibers, cotton linters, nitrocellulose, wood pulp, a-cellulose, cellulose nitrate, and cellulose acetate are all suitable for manufacturing acceptable filters and/or membranes. Agglutinins can be present in the filter (in soluble form). Any chemical or biochemical agent capable of causing agglutination of red blood cell can be used, including but not limited to antibodies and lectins. Such agglutinins are well known in the field of chemical analysis. Antibodies are preferred agglutinins, particularly for use with undiluted whole blood. However, other soluble agglutinins are also satisfactory, both for direct and indirect agglutination of red blood cells. It is preferred to utilize a source of mixed antibodies that will react with all red blood cells of the species being tested. For example, an antiserum against human red blood cells can be utilized or a mixture of monoclonal antibodies that react with all of the major blood types. Such antibodies are available commercially. For example, an IgG fraction of rabbit anti-human red blood cell antibodies are commercially available. The antibody can be adsorbed onto the surface of the solid used to prepare the filter. In the case of paper filters, antibody can be effectively adsorbed onto paper by merely contacting the paper with an aqueous solution containing the antibody and then removing the water by evaporation. If desired, an antiserum can be applied neat or it may be diluted. Column 8 lines 1-17 teaching that the described filters typically comprise a single layer of material rather than multiple layers for separation of a single drop of blood, which typically has a volume of 30-50 ml or less. Filters used with agglutinins can be more porous, but should retain agglutinated red blood cells, which typically form clumps of cells with apparent diameters from 6-10 mm for a few cells to greater than 0.1 mm (100 mm) for a large number of cells. Column 9, line 59 to column 10, line 2, teaching a hemolysis measurement in which the percentage hemolysis was quantitated by measuring the absorbance of 570 nm light by the plasma. Absorbance was measured on a Hewlett-Packard 8451A spectrophotometer. The readings were taken using cells having path lengths of approximately 0.01 cm. The 0.01 cm path length was in a tape cartridge. The absorbance was converted to percent hemolysis by multiplication of the absorbance by a conversion factor. The peak at 570 nm was used for the 0.01 cm pathlength cell, and the conversion constant was 42.0.
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 measure hemoglobin resulting from hemolysis in the device taught by Harvey by incorporating an additional strip with the structure taught by Harvey having the assay components removed from the detection area as taught for the fail-safe example of Subramanian, the device of Davis or the hemolysis example of Hillman because of the need to know if hemolysis has occurred so that the analysis of other analytes can be corrected as taught by Davis and/or identified as possibly being inaccurate as taught by Subramanian (see column 25, lines 12-24). Also 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 use a nitrocellulose membrane in Harvey having pore sizes capable of retaining the agglutinated red blood cell sizes taught by Hillman (6-10 mm) because as taught by Hillman, the presence of an agglutinin in the filter allows for a larger pore size as long as it is capable of retaining the agglutinated red blood cells.
With respect to claim 2, Harvey teaches that the RBC binding or agglutination material comprises a lectin, concanavalin A (Con A).
With respect to claims 3-4 Harvey teaches that the RBC binding or agglutination material is an anti-erythrocyte antibody or a lectin. Thus it would be obvious to use any known agglutinins such as those described by Subramanian or Hillman because of their known use for that purpose as taught by Subramanian or Hillman.
With respect to claim 5, the agglutinated red blood cell size taught by Hillman (6-10 mm), the combination of Harvey in view of Hillman would have pointed to the pore size of the chromatographic detection pad being in a range of from 8 microns to 13 microns.
With respect to claim 6, Harvey teaches that the chromatographic detection pad is a lateral flow strip (see at least the abstract).
With respect to claim 9, Harvey teaches a sample application pad in fluidic contact with the sample application site of the chromatographic detection pad (see at least figure 1 and paragraph [0032], sample application pad).
With respect to claim 10, Harvey does not teach that the sample application pad contains at least one type of red blood cell (RBC) binding or agglutination material. However, Subramanian teaches an analysis stack which contains a separation membrane in addition to the agglutinin containing membrane for additional separation ability. Thus it would have been obvious to one of ordinary skill in the art at the time the application was filed to also include at least one type of red blood cell (RBC) binding or agglutination material in the sample application pad because the purpose of the agglutinin is to separate red blood cells from plasma and having at least one type of red blood cell (RBC) binding or agglutination material in the sample application pad as taught by Subramanian would have been expected to assist in the separation of red blood cells from plasma.
With respect to claim 11, Harvey does not teach any specific device used to analyze the device. However, it would have been obvious to one of ordinary skill in the art at the time the application was filed to place the Harvey device in a cartridge such as taught by Davis or Subramanian for measurement by a medical diagnostic device because such monitoring devices are known to be used for the purpose of analyte measurement as taught by Davis or Subramanian.
With respect to claim 12, Harvey does not teach any method of testing for liquid sample hemolysis or use of a specific device to make that analysis. However, it would have been obvious to one of ordinary skill in the art at the time the application was filed to place the Harvey device in a cartridge such as taught by Davis or Subramanian and incorporate steps to place a sample on the assay device, take readings of reflected light and determine the amount of hemoglobin present with a monitor as taught by Davis or Subramanian because such monitoring methods and devices are known to be used for the purpose of analyte measurement as taught by Subramanian and Davis and Subramanian teach the need to know whether hemolysis has occurred so that the analysis of other analytes can be corrected as taught by Davis and/or identified as possibly being inaccurate as taught by Subramanian (see column 25, lines 12-24).
With respect to claims 13-15, Davis and Subramanian teach determination of hemolysis and the notification of an operator when hemolysis is at a certain point so that the limitations of claims 13-15 would have at least been obvious due to the combined teachings of Harvey in view of Davis or Subramanian for the reasons given for claim 1.
Applicant's arguments filed February 26, 2026 have been fully considered but they are not persuasive. In response to the claim changes, the rejection under 35 U.S.C. 112(b) and the obviousness rejection of claims 16-21 over Ray or Schrier in view of Chandler or Stankov and further in view of Davis or Subramanian have been withdrawn. The previous obviousness rejection of claims 1-21 over Harvey in view of Davis or Subramanian and further in view of Hillman has been modified to account for the claim changes. The arguments are moot with respect to the withdrawn rejections. Examiner recognizes applicant’s right to change claims and/or bring back the subject matter of cancelled claims as they see fit and reserves the right to apply withdrawn rejections and/or reference combinations to claims for which they appropriate.
With respect to the remaining obviousness rejection, applicant has started the discussion by described the independent claims. Examiner notes that applicant’s description of independent claim 1 has characterized the sample application site as having been treated with at least one type of “soluble” red blood cell (RBC) binding or agglutination material. Examiner notes that claim 1 does not have the word “soluble” preceding the respective language. Examiner further notes that while the specific RBC binding or agglutination material of claims 2-4 might be soluble, there is no basis in the instant disclosure to limit the RBC binding or agglutination material to a soluble one. This issue was raised in the parent application of the instant application. Thus applicant’s characterization of instant claim 1 is not commensurate in scope with the actual claim language. Examiner further notes that the RBC binding or agglutination material taught by Harvey is at least one of the specifically claimed materials so that any argument directed toward the RBC binging or agglutination material not being soluble in not persuasive.
Applicant has argued that a major object of the Harvey device is the removal of hemoglobin from plasma. Examiner agrees with that statement. In particular, applicant has argued that “plasma is separated from a whole blood sample in the separation zone so that proteins present in the serum migrate to and are analyzed in the hemoglobin-free analysis zone.” Applicant further argued that “an erythrocyte binding agent is added to the separation zone of the membrane in an amount sufficient to bind any erythrocytes present in the sample, to ensure that the analytes can be assayed in the absence of hemoglobin in the analysis zone”. Paragraphs [0006]-[0007] of Harvey were cited for the basis of those characterizations of what Harvey teaches. A proper analysis of what Harvey teaches in those paragraphs, they have been reproduced below with added emphasis.
“[0006] The present invention encompasses a novel device for separating plasma from a whole blood sample on a treated membrane, whereby the sample can be assayed thereon after separation has occurred. No sample transfer is necessary. A 1 micron to 20 micron porosity lateral flow chromatographic assay membrane can be used, eliminating extensive reformulation of chemistries for existing plasma based chromatographic assays. Suitable membrane materials having the requisite porosity, chromatographic properties, and binding characteristics include cellulose acetate, nitrocellulose, nylon, and polyethersulfones, polyvinylidene fluoride, as well as combinations or composites of these materials. These membranes can be either unsupported or supported with conventional materials, such as non-woven or woven polymers. An erythrocyte binding agent (EBA) is added to the membrane, associating therewith. (For the purposes of the present invention an EBA refers to any material that attaches to, binds to, or otherwise associates with the surface of red blood cells so as to retard lateral migration through the interstial spaces of the membrane). Preferably, the membrane is treated with the EBA in either a gradient concentration fashion or in a series of transverse, i. e, perpendicular to the flow direction, rows of increasing concentration. Suitable EBAs include either an anti-erythrocyte antibody or a lectin, preferably concananvalin A (Con A), which binds to sugar residues on the membranes of the red blood cells and white blood cells. In order to decrease the separation time and increase the sample capacity, a wick, is placed at the membrane distal to a sample application zone.”
“[0007] The plasma created by the present device is quite good for analysis on the distal end of the membrane, even if treated with an anti-coagulant. Red blood cells and nucleated cells are removed from whole blood without hemolysis and the concomitant presence of hemoglobin in the analysis zone. Recoverable levels of human serum proteins migrate to the analysis zone. Even glucose levels are unaffected by the presence of the EBA. The present invention is suitable for binding assays, such as immunoassays or nucleic acid assays, as well as any other binding assay format requiring a plasma sample as opposed to a whole blood sample.”
From paragraph [0006] it is clear that the erythrocyte binding agent of Harvey attaches to, binds to, or otherwise associates with the surface of red blood cells. Even the preferred concananvalin A (Con A) binds to sugar residues on the membranes of the red blood cells and white blood cells. There is nothing in paragraph [0006] that teaches or even hints that the EBA is required to bind with or capable of binding to free hemoglobin. Thus the only way that the EBA of Harvey can separate hemoglobin from plasma is by separating erythrocytes from plasma. From paragraph [0007] it is clear that removing red blood cells and nucleated cells without hemolysis is what Harvey is trying to accomplish. One of ordinary skill in the art certainly knows/understands that red blood cells contain hemoglobin. If hemolysis occurs during the separation of red blood cells from plasma, hemoglobin is released from red blood cells producing a concomitant presence of hemoglobin that would travel with the plasma to the analysis zone. In other words, removing/separating red blood cells and nucleated cells without hemolysis prevents the accompanying (concomitant) release of hemoglobin that would end up in the analysis. This teaching of Harvey says nothing would indicate that the device of Harvey is capable of removing/separating free hemoglobin that was present in the whole blood sample prior to its application on the Harvey device.
Part of that argument is that while Harvey teaches a device that separates plasma from the whole blood sample, Harvey explicitly teaches that the separated plasma CANNOT have free hemoglobin therein. In support of this applicant cited and reproduce paragraphs [0007], [0015]-[0016] and [0023] of Harvey. Paragraph [0007] has been discussed above in conjunction with paragraph [0006]. Paragraph [0015] discusses the detection of human chorionic gonadotropin (hCG) by visualizing a red color of a colloidal gold complex. While the color of free hemoglobin and/or erythrocytes would certainly interfere with this detection, the paragraph fails to teach that the device of Harvey is capable of removing/separating or required to remove/separate free hemoglobin that was present in the whole blood sample prior to its application on the Harvey device. Paragraph [0016] discusses the detection of troponins by lateral flow immunoassay and characterize it as relatively easy as long as clear plasma is generated so that red blood cells do not interfere with antibody/antigen binding or interpretation of the colorimetric result. This paragraph is concerned about red blood cells interfering with the antibody/antigen binding or interpretation of the colorimetric result. It also does not teach that the device of Harvey is capable of removing/separating or required to remove/separate free hemoglobin that was present in the whole blood sample prior to its application on the Harvey device. In paragraph [0023], it is clear that removal of hemoglobin from plasma is one of the major objects for the Harvey device. However, probably the most important statement in the paragraph is that “not only were the red blood cells contained in the separation zone, but detectable hemolysis which would allow free hemoglobin to migrate up the strip did not occur.” In other words, the erythrocyte binding agent is not capable of stopping free hemoglobin released by hemolysis from migrating up the strip into the analysis/read zone. This is one of the clearest teachings that the device of Harvey is not capable of removing/separating or required to remove/separate free hemoglobin that was present in the whole blood sample prior to its application on the Harvey device.
From paragraph [0007] it is clear that the teaching is the removal of red blood cells and nucleated cells from whole blood without hemolysis and the concomitant presence of hemoglobin that would result if hemolysis were to occur. In other words, Harvey is concerned about hemolysis occurring as a result of and/or during the removal of red blood cells and nucleated cells from the whole blood. Harvey is not concerned with removal of free hemoglobin already present in blood prior to its application to the device. This can also be seen from paragraph [0023] in the “detectable hemolysis which would allow free hemoglobin to migrate up the strip” language of that paragraph. In other words the Con A lectin would not separate free hemoglobin in the whole blood sample. Rather if free hemoglobin were present in the blood sample, it would be expected to migrate up the strip to the analysis zone. Based on this, if free hemoglobin due to hemolysis was present in the sample, Harvey teaches that it would be expected to end up migrating to the analysis zone. Thus the argument is not persuasive.
Examiner agrees that any one of ordinary skill in the art would clearly and unambiguously recognize that the presence of ANY hemoglobin in the analysis zone would potentially interfere with the detection process, thereby rendering the device of Harvey defective for its intended purpose by placing the validity of the interpretation of the colorimetric result in doubt. However, as shown above, the separation of erythrocytes by the erythrocyte binding agent of Harvey only removes hemoglobin contained by intact erythrocytes. It does not remove/separate hemoglobin released by hemolysis of erythrocytes or free hemoglobin that was present in the whole blood sample prior to its application on the Harvey device. However, in the absence of free hemoglobin in the whole blood sample prior to its application to the Harvey device, the Harvey device is completely operable.
It appears that applicant has not understood the modification to Harvey that examiner is asserting as being obvious. Both Davis and Subramanian teach a structure for detecting the presence of hemoglobin that is in addition to the structure for detecting the various analytes. The Davis structure for detecting hemoglobin is a lateral flow type of structure devoid of and/or without the reagent to measure another analyte and the Subramanian fail-safe structure for detecting hemoglobin is in addition to and physically equivalent to the assay stacks in dimensions and in the construction of the red cell filter except the assay reagent was omitted. Based on those teachings, examiner is saying that adding a second lateral flow strip having the structure of the Harvey lateral flow strip except that it is devoid of any reagent to measure an analyte to the lateral flow strip of Harvey would have been an obvious modification of Harvey because of the ability to measure free hemoglobin, the recognized need to determine if hemolysis has occurred so that the analysis of other analytes can be corrected as taught by Davis and/or identified as possibly being inaccurate as taught by Subramanian (see column 25, lines 12-24). Or as Subramanian teaches the obvious modification provides multiple results obtained from a single unmeasured sample drop (see column 7, lines 29-36). It is the additional strip devoid of reagent in the detection site that meets the instant claim limitations. The modification that examiner is putting forth as an obvious modification is not unreasonable based on the teachings of Davis or Subramanian and it does not make the Harvey device unsuitable for its intended purpose since the modification would still have a lateral flow device capable of measuring the intended analyte.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Examiner notes that the above explanation is based on the findings of fact in the above description of the applied Hillman and Davis or Subramanian references and the need and/or desire (motivation) taught by the secondary references to detect and/or measure hemolysis when conducting analysis on whole blood. Thus contrary to the urging of applicant, the rejection is clearly based on findings of fact and clear reasons/rationale that would have been within the level of ordinary skill at the time the claimed invention was made to make the changes required to meet the instant claim language. Thus the previous rejection does not contain impermissible hindsight as applicant has urged. While the argument is made, applicant has not pointed to any specific portion of the claim that was gleaned only from the applicant's disclosure. Therefore, the argument is not supported and thereby not persuasive.
For the above reasons the arguments of applicant are not persuasive.
THIS ACTION IS MADE FINAL. 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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The additionally cited art is related to detection of hemolysis and other analytes. Of note, the Sterling paper is an alternate description of the above applied Subramanian device/reference.
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/ARLEN SODERQUIST/ Primary Examiner, Art Unit 1797
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