The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Two pages of replacement drawings were received on November 26, 2024. These drawings are acceptable.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 105, 107, 110-112, 114-119 are rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. Claim 105 includes language requiring the capillary-driven flow through the microfluidic network to be between 4-10 mm/s and the capillary fluid flow across the test strip to be between 0.2 to 6 mm/s. Examiner was not able to find basis for this added language in the instant disclosure. Additionally, applicant did not point to where support may be found in the instant disclosure. Thus, claim 105 and the claims dependent therefrom contain new matter. Since this language is not supported by the instant disclosure, claim 105 will be treated for examination purposes as it the language were not present in the claim.
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 105, 107, 110-112, 114-120, 122, 124, 126-128 and 130-134 are rejected under 35 U.S.C. 103 as being unpatentable over Henry (WO 2022/027060) in view of Ahn (US 2019/0072547). With respect to the claims, paragraph [0005] of Henry teaches that immunoassays are a widely used technology for applications ranging from clinical diagnostics to environmental monitoring. The basis of the immunoassay is the binding reaction between antigen and antibody, typically performed on a surface. Either the antigen or the antibody can be the target analyte. After this reaction, the presence of the analyte is detected by one of several methods, including colorimetry, electrochemistry, fluorescence, and chemiluminescence. Additionally, paragraph [0111] teaches that various modifications and additions can be made to the exemplary implementations discussed without departing from the scope of the present invention. For example, while the implementations described above refer to specific features, the scope of this invention also includes implementations having different combinations of features and implementations that do not include all the described features. With specific reference to claim 105, figures 7-8 of Henry and at least their associated description teach a single-use assay device (see at least paragraph [0110), disposable assay, disposable ELISA) comprising: a device body (702) having a continuous capillary-driven flow multi-directional microfluidic network (704) formed by a first path having a front portion and a rear portion in communication with a second path having a front portion and a rear portion (first path is the shorter circuit of network 704 and the second path is the longer circuit of network 704); a sample inlet (single inlet 706) in communication with both the front and rear portions of the first path, and the front and rear portions the second path; a test strip (test strip 710) containing one or more capture probes (see figures 9a-9E, capture probes 752) in communication via a channel with the sample inlet, the front portion of the first path, and the front portion of the second path (the plus shaped set of channels in figure 7 below single inlet 706 constitute this structure); a passive pump in communication with the test strip (waste pad/pump 712 in figure 7) configured to generate continuous capillary-driven flow through the microfluidic network and across the test strip (see paragraphs [0059] and [0066] describing a similar feature of figure 2; the channels of microfluidic network 204 are configured to transport fluids by capillary action . . . Transportation may be further facilitated by a nitrocellulose or similar “wicking” substrate of test strip 210 alone or in combination with a passive pump 212. As shown in figure 2, passive pump 212 may be in the form of a waste pad that also collects excess fluid; at least a portion of sample 230 . . . may be transported to test strip 210 by capillary action and further facilitated by a cellulose or similar passive pumping mechanism. In certain implementations, such pumping functionality may be provided by test strip 210, optional passive pump 212, or a combination therefore); a first dried reagent (dried enzyme pad 714) disposed along the first path, and a second dried reagent (dried substrate pad 716) disposed along the second path, wherein the second dried reagent is positioned further from the test strip than the first dried reagent (see the relative positioning of elements 714 and 716 with element 710), wherein the second dried reagent comprises a substrate that reacts with the first dried reagent; and a first open vent positioned over the first dried reagent (see paragraph [0076]; a first vent 715 corresponding to dried enzyme label pad 714), and a second open vent positioned over the second dried reagent (see paragraph [0076]; a second vent 717 corresponding to dried substrate pad 716); wherein, when a fluid is provided to the microfluidic network via the sample inlet the fluid fills the front and rear portions of the first and second paths such that the fluid contacts and rehydrates the first and second dried reagents from both the front and rear directions (see at least paragraph [0079; the fluid is distributed from inlet 706 to different channels of microfluidic network 704 by capillary action. Such distribution of the test fluid may result in the test fluid contacting dried enzyme label pad 714 and initiating rehydration of the dried enzyme label stored on dried enzyme label pad 714); wherein a portion of the fluid in the microfluidic network positioned between the test strip and the front portion of the second dried reagent forms a fluid wash that does not contain any of the second dried reagent, and wherein the fluid wash arrives at the test strip via the channel after the fluid containing the first rehydrated reagent, and before the fluid containing the second rehydrated reagent arrives at the test strip (see at least paragraph [0081]; figure 9D illustrates assay device 700 during a wash after delivery of rehydrated enzyme label 754. More specifically, microfluidic network 704 is generally shaped and configured such that at least a portion of the test fluid is delivered to test strip 710 after rehydrated enzyme label 754 but before rehydrated substrate 756. By doing so, excess of the enzyme label can be removed from test strip 710 before arrival of rehydrated substrate 756, generally improving the response of test strip 710). Paragraph [0086] teaches that following delivery of the first reagent, the second reagent (e.g., rehydrated substrate) may be delivered to the detection zone. The rehydrated substrate may be preceded at the detection zone by additional buffer fluid, which washes away excess of the first reagent. When the rehydrated second reagent reaches the detection zone, the rehydrated second reagent may react with the first reagent, producing a visible color change or similar effect. Relevant to the reagent combination used by Henry is paragraph [0089] teaching that for the serology assay, a nitrocellulose membrane was striped with SARs-CoV-2 nucleocapsid protein (NP). A first reagent pad (generally corresponding to dried enzyme label pad 614 of assay device 600) was prepared with dried anti-mouse-Horse radish peroxidase (HRP) while a second reagent pad (generally corresponding to dried substrate pad 616 of assay device 600) contained dried p-dimethylaminoazobenzene (DAB), a colorimetric substrate for HRP. The nitrocellulose membrane was blocked with StabilGuard and the buffer used in the buffer inlet contained 0.01% hydrogen peroxide to activate the HRP. Paragraph [0090] teaches that the antigen assay was completed with a single-inlet device, such as assay device 700. The only changes that needed to be made to transition to the antigen assay were switches in the capture and detection antibodies so that SARs-CoV-2 N protein was the target. HRP was still used as the label, but tetramethylbenzidine (TMB) was used as the colorimetric substrate instead of DAB, providing more sensitive results. Henry does not teach that the substrate on the substrate pad ( the second reagent) is a chemiluminescent substrate that reacts with the first dried reagent and emits a chemiluminescent signal.
In the patent publication, Ahn teaches a chemiluminescent assay device (see at least the title). Paragraphs [0005]-[0006] of Ahn teach that standard commercially available assays mostly use optical detection methods like luminescence, fluorescence or absorbance (colorimetric). Therefore, to develop lab-on-a-chip (LOC) based POCT platforms with performance comparable to commercially available gold standard assay procedures optical detection methods are preferable. Several highly sensitive completely integrated “sample-to-answer” LOC based POCT platforms have been developed which employ either absorbance (colorimetric) or fluorescence-based detection methods. However, most colorimetric and fluorescence detection systems lack either the desired sensitivity or are complicated to develop as they require some excitation mechanisms. Another highly sensitive detection method used for conventional ELISA is the chemiluminescence method. Chemiluminescent signal is generated as light by the release of energy (photon) due to a chemical reaction. Unlike absorbance, colorimetric or fluorescent measurements, ELISA reagents typically contribute little or no native background chemiluminescent signal. Detection of chemiluminescent optical signal is relatively simple as it requires only a photomultiplier or photodiode and the associated electronics. The lack of inherent background and the ability to easily measure very low and very high light intensities with simple instrumentation provide a large potential dynamic range of measurement in case of chemiluminescence based assays. The chemiluminescent assay device comprises: a chemiluminescent testing assembly (see for example figures 2 or 7A) comprising: a sample inlet (sample reservoir 210) in communication with a microfluidic network formed by a first path (see elements 214, 222, 220, 224 and 244) extending to a detection area (reaction chambers 270, 272 and 274) and a second path (see elements 212, 232, 230, 234, 216, 242, 240, 244, 252 and 260) extending to the detection area, wherein said detection area is configured to capture a target analyte (see paragraph [0059] - capture antibody immobilization); a first dried reagent disposed along the first path (see paragraph [0053] - a detection antibody drying or lyophilization chamber 220); and a second dried reagent disposed along the second path (see paragraph [0053] - first and second substrate drying or lyophilization chambers 230 and 240), wherein, when a fluid is provided to the sample inlet the fluid fills the microfluidic network and directs a portion of the fluid through the microfluidic channel to the detection area where a target analyte is captured, and wherein a first portion of the fluid rehydrates the first dried reagent to produce a first rehydrated reagent, a second portion of the fluid rehydrates the second dried reagent to produce a second rehydrated reagent, and the first rehydrated reagent and the second rehydrated reagent are sequentially delivered to the detection area by capillary-driven flow, and wherein the first reagent, and the second reagent react, optionally in the presence of a catalyst, the reaction thereby emitting an chemiluminescent signal (see at least paragraph [0059] - the flow resistance of the first delay channel 260 is so calculated that the sample reconstituting the dried or lyophilized detection antibody in the detection antibody drying or lyophilization chamber 220 will reach the end of the reaction chambers 270, 272, 274 before the sample reconstituting the dried or lyophilized substrates in the substrate drying or lyophilization chambers 230 and 240 enters the reaction chambers 270, 272, 274). Ahn teaches that the first path is shorter than the second path (see the comparative lengths of the first and second paths in at least figure 1). Ahn teaches that the device further includes a catalyst (see at least paragraph [0049] – the chemiluminescence substrate is obtained in 2 parts, the enhancer and the peroxide). Paragraph [0059] of Ahn teaches that the flow resistance of the first delay channel 260 is so calculated that the sample reconstituting the dried or lyophilized detection antibody in the detection antibody drying or lyophilization chamber 220 will reach the end of the reaction chambers 270, 272, 274 before the sample reconstituting the dried or lyophilized substrates in the substrate drying or lyophilization chambers 230 and 240 enters the reaction chambers 270, 272, 274. Paragraph [0055] teaches that the lab-on-a-chip device 200 involves two parallel paths: one path incorporates the HRP labelled detection antibody drying or lyophilization chamber 220 and the other path has the substrate drying or lyophilization chambers 230, 240. The two components of the chemiluminescent substrate, namely the enhancer and the peroxide, need to be dried or lyophilized individually on the lab-on-a-chip device 200. Hence, the first substrate drying or lyophilization chamber 230 and the second substrate drying or lyophilization chamber 240 are envisaged on the lab-on-a-chip device 200. The enhancer may be dried or lyophilized in the first substrate drying or lyophilization chamber 230 and the peroxide may be dried or lyophilized in the second substrate drying or lyophilization chamber 240. The HRP labelled detection antibody may be dried or lyophilized in the detection antibody drying or lyophilization chamber 220.
It would have been obvious to one of ordinary skill in the art at the time the application was filed to use the chemiluminescent substrate of Ahn in the Henry device because of the sensitivity afforded by chemiluminescent assays compared to colorimetric assays as taught by Ahn, the use of the HRP enzyme by both Henry and Ahn and the teaching by Henry that the substrate was switched to provide more sensitive results.
With respect to claim 107, paragraphs [0050] and [0103] of Henry in combination with figure 16 teach that the passive pump generates a capillary-driven flow through microfluidic network such that the fluid containing the first rehydrated reagent arrives at the test strip via the channel before the fluid containing the second rehydrated reagent arrives at the test strip via the channel.
With respect to claim 110, Henry teaches that the first dried reagent comprises a dried enzyme label disposed on an enzyme label pad positioned within the first path (see the description related to dried enzyme pad 714 in at least paragraphs [0074] and [0078]-[0080]). With respect to claim 111, paragraphs [0054] and [0089]-[0090] teach that the dried enzyme label comprises a secondary antibody directed to a target analyte (dried anti-mouse-Horse radish peroxidase (HRP), the only changes needed to transition to the antigen assay were switches in the capture and detection antibodies so that SARs-CoV-2 N protein was the target with HRP as the label).
With respect to claim 112, Henry teaches that the second dried reagent comprises a dried substrate disposed on a dried substrate pad positioned within the second path (see the description related to dried substrate pad 716 in at least paragraphs [0074] and [0078]-[0080]) thus modification of Henry by Ahn would have placed the chemiluminescent substrate on the second reagent pad of Henry for the same reasons given above for claim 105. With respect to claim 114, Ahn clearly teaches that the chemiluminescent substrate includes a catalyst peroxide. Paragraph [0055] teaches that the lab-on-a-chip device 200 involves two parallel paths: one path incorporates the HRP labelled detection antibody drying or lyophilization chamber 220 and the other path has the substrate drying or lyophilization chambers 230, 240. The two components of the chemiluminescent substrate, namely the enhancer and the peroxide, need to be dried or lyophilized individually on the lab-on-a-chip device 200. Hence, the first substrate drying or lyophilization chamber 230 and the second substrate drying or lyophilization chamber 240 are envisaged on the lab-on-a-chip device 200. The enhancer may be dried or lyophilized in the first substrate drying or lyophilization chamber 230 and the peroxide may be dried or lyophilized in the second substrate drying or lyophilization chamber 240. Thus modification of Henry by the teachings of Ahn would have place the catalyst in at least one of the fluid, in a buffer, on the dried substrate pad, or on the test strip for the reasons given above for claim 105.
With respect to claim 115, figure 7 of Henry shows that the first path is shorter than the second path (the loop containing enzyme pad 714 is shorter than the loop containing substrate pad 716), or the cross-sectional area of the second path is greater than the first channel (see paragraph [0073]; similar results may be achieved by altering other geometric characteristics (e.g., surface area, cross-section shape, etc.) of flow paths within the microfluidic network).
With respect to claim 116 Henry teaches that a greater volume of fluid flows through the second path (this would have been an inherent property due to the loop containing enzyme pad 714 is shorter than the loop containing substrate pad 716 while the diameter/width of both loops is shown to be substantially equivalent).
With respect to the delay element of claims 117-118 and 132, it would have been obvious to one of ordinary skill in the art at the time the application was filed to include a delay element as taught by Ahn in the appropriate flow path of Henry because of the ability to cause a delay that allows the enzyme reagent to reach the detection chamber ahead of the substrate reagent in a manner equivalent to that desired by Henry.
With respect to claim 119, figure 7 of Henry shows that the microfluidic network comprises a centering element configured to direct flow through the channel to the center of the test strip (the channel between the inlet and the test strip places fluid on a central part of the test strip).
With respect to claim 120, see the description of claim 105 in combination with the description of claim 116 above.
With respect to claim 122, see the description of claim 107 above.
With respect to claim 124, see the description of claim 105 above relative to the presence of capture probes on the test strip.
With respect to claim 126, see the description of claim 110 above.
With respect to claim 127, see the description of claim 111 above.
With respect to claim 128, see the description of claim 112 above.
With respect to claim 130, see the description of claim 114 above.
With respect to claim 131, see the description of claim 115 above.
With respect to claim 133, see the description of claim 119 above.
With respect to claim 134, see the description of claim 105 above.
The declaration under 37 CFR 1.132 of Dr, Brian Geiss filed June 17, 2025 is insufficient to overcome the rejection of claims 105, 107, 110-112, 114-120, 122, 124, 126-128 and 130-134 based upon Henry in view of Ahn as set forth in the instant Office action because of the following reasons. First, with respect to the sensitivity of the detection, those comments/arguments are not commensurate in scope with the instant claims. The instant claims are general in nature regarding the first and second reagents, capture probes and the specific structure of things such as the test strip and/or dimensions of the multi-directional microfluidic network. At this point the claims do not require any particular detection sensitivity or minimum level of analyte detection capability. Thus the instant claims cover analyte detection at any level to include the referenced PCR-level detection limits (see at least paragraph 4) as well as levels significantly above that level. Relative to actual detection limits possible, the applied Ahn reference in paragraphs [0087]-[0088] teaches a limit of detection (LOD) around 1 pg/mL which is almost 14 times less than the LOD obtained using a conventional 96-well plate assay. Thus there is an indication that the chemiluminescent assay in a flowthrough format would produce a result that should be lower than a conventional assay.
Relative to the argument that the oxidized chemiluminescent HRP substrates would not precipitate and would remain soluble resulting in their quick removal into the waste pad in a flow regime, examiner points to some previously cited references directly dealing with similar situations that point to the result seen by applicant as not unexpected contrary to the urging of Dr. Geiss.
First, examiner points to the previously cited Roda paper in which analytes were measured using a chemiluminescent reagent in a flow system in which the enzymes used to cause the chemiluminescence were immobilized in a tube placed before the detector of the luminometer (see figure 1). Figure 7 of the paper shows that light emission intensity varies with flow rate. However the change was small over the range shown and relatively small near the maximum intensity point. This points to the ability to detect the chemiluminescent intensity at the point the enzyme causing the chemiluminescent process to begin are immobilized as an expected result. Also, as expected, the flowrate had an effect on the intensity of the emission, but the change in intensity with respect to the flow rate was minimal.
Next, examiner points to the previously cited Davidsson paper looking at the development and optimization of enzymatic chemiluminescent microfluidic biosensing systems based on silicon microchips. The abstract calls the system a microfluidic sequential injection analysis (µSIA) system and the sensing structure a µ-biosensor. Glucose oxidase (GOX) or alcohol oxidase (AOX) was co-immobilized with horseradish peroxidase (HRP) on porous silicon flow through microchips. The hydrogen peroxide produced from oxidation of the corresponding analyte (glucose or ethanol) took part in the chemiluminescent (CL) oxidation of luminol catalyzed by HRP enhanced by addition of p-iodophenol (PIP). The influence of flow rate and luminol- and PIP concentration were investigated using a 23-factor experiment using the GOX-HRP sensor. The optimum was found at 250 µM luminol and 150 µM PIP at a flow rate of 18 µl min-1, the latter as a compromise between signal intensity and analysis time. Two different immobilization chemistries were investigated for both µ-biosensors based on 3-aminopropyltriethoxsilane (APTS)- or polyethylenimine (PEI) functionalization followed by glutaraldehyde (GA) activation. Using the optimized system settings one sample was processed within 5 minutes. Figure 1(b) presents the configuration of the µSIA system. Section 2.3 on pages 482-483 teaches the process used to immobilize the enzymes on the silicon microchips. The first paragraph of section 2.4 on page 483 teaches that the enzyme microchip was incorporated in a specially designed holder made of transparent poly(methyl methacrylate). The PMT was positioned directly on top of the flow cell so that the light emitted in the CL reaction was collected approximately 6 mm above the microchip surface. The paragraph bridging the columns of page 483 teaches that an assay cycle was performed by aspirating 2 µl sample followed by 2 µl CL reagent buffer into the tubing that connected the MPV valve and syringe pump (see Figure 1b). This was repeated three times in total resulting in a sequence of 12 µl, which then was dispensed to the µ-biosensor to register the corresponding CL signal. One assay cycle was processed within 5 minutes. The first full paragraph of the right column on page discussed the flow rate experiments as follows. Looking in Table 2 it is predicted that an increase of the flow rate F will have a large negative effect on the response (F ~ 214241). This was checked experimentally, keeping luminol and PIP concentrations fixed, and showed that going from 5 to 50 µl min-1 the sensor response decreased more than ten times, as predicted by the factor experiment. At high flow rates, the co-immobilized enzymes of the µ-biosensor convert smaller fractions of the analytes and the excited species that give rise to CL are transported faster out of the µ-biosensor so that a lower light yield is detected. From the signal point of view, the flow rate should be chosen as low as possible, however, this will in turn compromise the analysis time. The latter is related to the total volume of the system, which was approximately 18 µl from the MPV to the microchip outlet. Further downscaling would therefore be feasible. But since the detection limit itself was not of primary interest to them, but rather a broad dynamic range to monitor relatively high glucose-respective ethanol concentrations, the flow rate was set to 18 µl min-1 for all further experiments. Here again it is clear that detectable chemiluminescent intensity was obtained directly above the immobilized enzyme even when the sample and chemiluminescent substrate were sequentially passed through the sensor at a rate as high as 50 µl min-1. This is a significant rebuttal of the above argument that the results were unexpected because of an expectation the light producing components would be carried from the detection region.
Finally examiner points to the previously cited Varsamis paper teaching the development of a photosystem II-based optical microfluidic sensor for herbicide detection. From the abstract, herbicides, under illumination, can inhibit photosystem II electron transfer. Photosynthetic membranes isolated from higher plants and photosynthetic micro-organisms, immobilized and stabilized, can serve as a biorecognition element for a biosensor. The inhibition of photosystem II causes a reduced photoinduced production of hydrogen peroxide, which can be measured by a chemiluminescence reaction with luminol and the enzyme horseradish peroxidase. In the paper, a compact and portable sensing device that combines the production and detection of hydrogen peroxide in a single flow assay was proposed for herbicide detection. The first paragraph of section 2.1 on page 43 teaches that the detection principle used in this system is chemiluminescence-based monitoring of the concentration of photosynthetically produced H2O2, which can be disrupted by herbicides. The sensor unit is able to perform the assays and optically stimulate photosystem II within the unit and detect the enzyme-mediated chemiluminescence of luminol/hydrogen peroxide. The sensor comprises of a short fluidic channel with two “active” regions including: i) immobilized PSII and ii) immobilized HRP to catalyze luminol/hydrogen peroxide chemiluminescence. Initial design consists of a flow channel constructed of machined Perspex sandwiching a laser-cut elastomer spacer/flow channel in which regions of appropriate reagents will be magnetically entrapped (see Figure 1). Section 2.6 describes the flow assay for hydrogen peroxide with HRP immobilized on magnetic beads. The flow system (Figure 1) consisted of one peristaltic pump, delivering a 10 mM luminol and a H2O2 sample pre-mixed at a continuous flow rate of 2.5 ml min-1. Luminol and H2O2 were freshly prepared in a Tris–HCl buffer, 10 mM, pH 8.5. PTFE tubing (0.8 mm i.d.) was used to connect the flow system components. First, the HRP-immobilized beads (1 mg) were pumped into the flow system by a peristaltic pump. A permanent magnet was used to attract the beads as they were flowing, thus immobilizing them in a specific area of the channel, underneath the area “viewed” by the optical fiber (50 µm in diameter, for detection in wavelength: 200–800 nm). The magnet was not moved during the experiment, in order to ensure that the beads were not carried away by the continuous flow. The reaction was initiated once the pre-mixed luminol– H2O2 reached the area of the flow channel that was covered with the beads. The chemiluminescence was transduced to an electric signal by a SD2000 portable CCD luminometer. The chemiluminescence intensity profiles (see figure 4) were recorded and the maximum intensity was used to plot the graphs. The paragraph bridging the columns of page 45 teaches that for detecting H2O2, four concentrations of luminol (10 mM, 1 mM, 100 µM and 50 µM) and four concentrations of HRP (50 U ml-1, 10 U ml-1, 5 U ml-1 and 1 U ml-1) were tested in all possible combinations. At higher concentrations of H2O2 (mM region), the reaction acts like a typical “glow-type” chemiluminescence reaction expanding over minutes. At concentrations lower than micromolar, the result is typically a flash for less than 1 second. Having identified the peak light production of luminol at 431 nm, measurements of light intensity over time were performed, at a wavelength of 431±20 nm. Such a large “window” was chosen in order to allow the maximum detectable light and, as the reaction was performed in the dark, any light detected would only be from the chemiluminescence reaction. Section 3.5 on page 46 looked at a flow assay for hydrogen peroxide with HRP immobilized on magnetic beads in two different flow channels shown in figure 6 in which the beads confined to different areas/shapes. The circular area of channel B is the area covered by the beads, and attracted by the magnet (area = 200 mm2). For flow channel A, the rectangular area, 16 mm2 covered by beads was smaller. In both cases 1 mg of beads was used, so the only difference was in the spreading of the beads and not the actual amount of HRP. The light produced by the reaction was measured and the results are shown in Figure 7. Channel B, allowing the beads to spread over a larger surface area, allowing for more HRP to be employed in the reaction, gave an increased response, as well as a lower LOD of 100 µM, compared to channel A, that had the beads stacked on a smaller area, as the HRP on the beads was not fully used, as a lot of the beads were covered by others, not allowing the luminol-H2O2 to reach them. Therefore, the key to the maximization of the possible chemical interaction between the H2O2, luminol and HRP was in the ability to spread out the HRP bound on the beads in a two-dimensional plane. Here again is evidence that one of ordinary skill in the art would expect a chemiluminescent reaction initiated underneath the area “viewed” by the detector (optical fiber) to produce significant amounts of measurable chemiluminescent light at a continuous flow rate of 2.5 ml min-1 contrary to the expectation of Dr. Geiss. Additionally, it is clear that the type of chemiluminescent emission can also vary based on the concentration of the different components/reactants from a glow that lasts minutes to a flash that of light that last less than a second. This would point to the capability of the chemiluminescent emission being localized to a relatively small area of the channel in a continuously flowing system. This also provides a significant rebuttal of the above argument that the results were unexpected because of an expectation the light producing components would be carried from the detection region. This reference also shows that those of skill in the art would have understood how to increase the amount of chemiluminescence measured and subsequently lower the limit of detection through increasing the area of immobilized enzyme that is viewed by the detector.
The declaration under 37 CFR 1.132 of Dr. Charles Henry filed June 17, 2025 is insufficient to overcome the rejection of claims 105, 107, 110-112, 114-120, 122, 124, 126-128 and 130-134 based upon Henry in view of Ahn as set forth in the instant Office action because of the following reasons. First, with respect to the sensitivity of the detection, those comments/arguments are not commensurate in scope with the instant claims. As noted above, the instant claims are general in nature regarding the first and second reagents, capture probes and the specific structure of things such as the test strip and/or dimensions of the multi-directional microfluidic network. At this point the claims do not require any particular detection sensitivity, limit of detection for a specific analyte or analytes in general or that the device/system is able to detect an analyte or analytes in general below some threshold with a particular detector/sensor or detecting/sensing technique. Thus the instant claims cover analyte detection by the device/system at any level to include the referenced PCR-level detection limits (see at least paragraph 4) as well as levels significantly above that level. Relative to actual detection limits possible, the applied Ahn reference in paragraphs [0087]-[0088] teaches a limit of detection (LOD) around 1 pg/mL which is almost 14 times less than the LOD obtained using a conventional 96-well plate assay. Thus there is an indication that the chemiluminescent assay in a flowthrough format would produce a result that should be lower than a conventional assay.
With respect to the long felt need, examiner looked at the instant disclosure to see if applicant disclosed any of the particular analytes described in the declaration. Examiner was not able to find any disclosure directed toward the analytes described/listed in paragraph 4 of the declaration. In contrast, the previously cited McDade (US 2013/0224771), Kohlmann (US 2020/0371031), Divaranyia (UA 2021/0264604) and Goux (Practical Laboratory Medicine 2023) references show the development of lateral flow devices for the anti-Mullerian hormone prior to and/or within days of the filing date of the instant application. Additionally the previously cited Cao (Lancet 2022) paper shows the development of a lateral flow device for two biomarkers to infer bacterial infections, particularly in the context of sepsis (abstract) also available prior to the instant application’s filing date. If applicant is trying to argue that the long-felt need was for a device that is capable of detecting these compounds at a certain level, the argument is not commensurate in scope with the claims as noted above. If the argument is that devices capable of measuring these analytes using the LFA format have not been developed, the above noted references rebut that argument.
Additionally, with respect to a multiplexed assay and/or an assay that has test and control lines, the instant claims require a test strip containing one or more capture probes. Thus, the claim scope covers a single capture probe as well as multiple capture probes without limitation of how they are placed on the test strip. Here again the argument is not commensurate in scope with the claim.
With respect to the unexpected results argument, applicant is referred to the discussion of the Roda, Davidsson and Varsamis papers above showing that chemiluminescent detection of analytes using a flow through system having an immobilized enzyme capable of causing the luminescence was known. These references also show that the capability of the chemiluminescent emission being localized to a relatively small area of the channel in a continuously flowing system was known and/or would have been expected by those of skill in the art. This also provides a significant rebuttal of the above argument that the results were unexpected because of an expectation the light producing components would be carried from the detection region. At least one of these references, Varsamis, also shows that those of skill in the art would have understood how to increase the amount of chemiluminescence measured and subsequently lower the limit of detection through increasing the area of immobilized enzyme that is viewed by the detector.
The declaration under 37 CFR 1.132 of Dr David Gandy filed June 17, 2025 is insufficient to overcome the rejection of claims 105, 107, 110-112, 114-120, 122, 124, 126-128 and 130-134 based upon Henry in view of Ahn as set forth in the instant Office action because of the following reasons. With respect to the unexpected results argument, applicant is referred to the discussion of the Roda, Davidsson and Varsamis papers above showing that chemiluminescent detection of analytes using a flow through system having an immobilized enzyme capable of causing the luminescence was known. These references also show that the capability of the chemiluminescent emission being localized to a relatively small area of the channel in a continuously flowing system was known and/or would have been expected by those of skill in the art. This also provides a significant rebuttal of the above argument that the results were unexpected because of an expectation the light producing components would be carried from the detection region. At least one of these references, Varsamis, also shows that those of skill in the art would have understood how to increase the amount of chemiluminescence measured and subsequently lower the limit of detection through increasing the area of immobilized enzyme that is viewed by the detector.
The declarations under 37 CFR 1.132 of Dr. Zachary Call and Allison Dolence filed June 17, 2025 is insufficient to overcome the rejection of claims 105, 107, 110-112, 114-120, 122, 124, 126-128 and 130-134 based upon Henry in view of Ahn as set forth in the instant Office action because of the following reasons. With respect to the unexpected results argument, applicant is referred to the discussion of the Roda, Davidsson and Varsamis papers above showing that chemiluminescent detection of analytes using a flow through system having an immobilized enzyme capable of causing the luminescence was known. These references also show that the capability of the chemiluminescent emission being localized to a relatively small area of the channel in a continuously flowing system was known and/or would have been expected by those of skill in the art. This also provides a significant rebuttal of the above argument that the results were unexpected because of an expectation the light producing components would be carried from the detection region. At least one of these references, Varsamis, also shows that those of skill in the art would have understood how to increase the amount of chemiluminescence measured and subsequently lower the limit of detection through increasing the area of immobilized enzyme that is viewed by the detector.
Examiner notes that whether or not the chemiluminescent emission will be seen, is as much a function of the rate of the emitted light formation as it is of the flow rate of fluid in the test strip. The fact that the detectors of Roda, Davidsson and Varsamis were placed at a point that was directly adjacent to or so that it could “view” the location the immobilized enzyme clearly shows that there was an expectation by those of ordinary skill in the art that the rate of light formation was fast enough that the flow rate of liquid past the immobilized enzyme would not have been a critical factor related to the detection of the emitted light.
With respect to the wash discussion, Henry clearly teaches that the wash step was part of what the Henry CaID device structure could do along with its benefits (see at least paragraphs [0022]-[0023], [0052], [0061], [0081], [0106] and [0109]). Provision of a wash fluid/step was also part of the Ahn device structure and process (see paragraphs [0060] and [0062]) with a similar purpose as taught by Henry (washing/removing the unbound reagent). This clearly points to the CaID device as a device capable of performing steps needed to reach the limit of detection levels taught by Ahn. Relative to actual detection limits possible, the applied Ahn reference in paragraphs [0087]-[0088] teaches a limit of detection (LOD) around 1 pg/mL which is almost 14 times less than the LOD obtained using a conventional 96-well plate assay. Thus there is an indication that the chemiluminescent assay in a flowthrough format would produce a result that should be lower than a conventional assay. In other words, the Ahn reference teachings rebut the idea that the CaID device would not be suitable to perform a chemiluminescent immunoassay.
The declaration under 37 CFR 1.132 of Dr. Kevin Nicols filed June 17, 2025 is insufficient to overcome the rejection of claims 105, 107, 110-112, 114-120, 122, 124, 126-128 and 130-134 based upon Henry in view of Ahn as set forth in the instant Office action because of the following reasons. First, with respect to the sensitivity of the detection, Those comments/arguments are not commensurate in scope with the instant claims. As noted above, the instant claims are general in nature regarding the first and second reagents, capture probes and the specific structure of things such as the test strip and/or dimensions of the multi-directional microfluidic network. At this point the claims do not require any particular detection sensitivity, limit of detection for a specific analyte or analytes in general or that the device/system is able to detect an analyte or analytes in general below some threshold with a particular detector/sensor or detecting/sensing technique. Thus the instant claims cover analyte detection by the device/system at any level to include the referenced PCR-level detection limits (see at least paragraph 4) as well as levels significantly above that level. Relative to actual detection limits possible, the applied Ahn reference in paragraphs [0087]-[0088] teaches a limit of detection (LOD) around 1 pg/mL which is almost 14 times less than the LOD obtained using a conventional 96-well plate assay. Thus there is an indication that the chemiluminescent assay in a flowthrough format would produce a result that should be lower than a conventional assay.
Second, with respect to dried reagents and/or chemiluminescent substrates, here again the claims are of a scope that is not limited to any specific chemiluminescent substrate or process of producing a dried reagent. In other words it covers those substrates and lyophilization techniques that are being argued as leading to past problems of variability. Thus, the comments are not commensurate in scope with the instant claims.
With respect to the unexpected results argument, applicant is referred to the discussion of the Roda, Davidsson and Varsamis papers above showing that chemiluminescent detection of analytes using a flow through system having an immobilized enzyme capable of causing the luminescence was known. These references also show that the capability of the chemiluminescent emission being localized to a relatively small area of the channel in a continuously flowing system was known and/or would have been expected by those of skill in the art. This also provides a significant rebuttal of the above argument that the results were unexpected because of an expectation the light producing components would be carried from the detection region. At least one of these references, Varsamis, also shows that those of skill in the art would have understood how to increase the amount of chemiluminescence measured and subsequently lower the limit of detection through increasing the area of immobilized enzyme that is viewed by the detector.
Applicant’s arguments with respect to claims 105, 107, 110-112, 114-120, 122, 124, 126-128 and 130-134 filed January 21, 2026 have been fully considered but they are not persuasive. In response to the amendments and arguments the rejection under 35 U.S.C. 112(b) has been withdrawn by examiner, the reference to an anticipation rejection has been removed, a new rejection under 35 U.S.C. 112(a) has been applied against certain claims and the obviousness rejection has been modified to cover the claim changes and/or provide an indication of the treatment of the claims that contain new matter in the absence of the language responsible for the new matter. With respect to the rejection under 35 U.S.C. 112(b) and anticipation rejection the arguments are moot since the rejections have been withdrawn and/or the language pointing to such a rejection has been removed. With respect to the new rejection under 35 U.S.C. 112(a), the arguments are also moot.
With respect to the obviousness rejection, the arguments reference one of more of the declarations of Dr. Nichols, Dr. Henry, Dr. Geiss, Dr. Dandy, Dr. Call and Allison Dolence. As a result examiner has modified the reasons that these declarations are not persuasive with respect to the instant claims. With respect to the argument that Henry and Ahn have fundamental and irreconcilable operational differences, the argument appears to be based on a position that to modify the teachings of Henry, one of ordinary skill would need to bodily incorporate the structures of Ahn into the device of Henry. With respect to this point of view, the Court has held, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In this respect, paragraphs [0089]-[0090] of Henry clearly teach that the first enzyme reagent pad includes dried anti-mouse-Horse radish peroxidase (HRP) for both described assay formats while the second substrate reagent pad one of two colorimetric substrates for HRP: p-dimethylaminoazobenzene (DAB) for the serology assay and tetramethylbenzidine (TMB) for the antigen assay. Paragraph [0090] in particular teaches that the reason for the p-dimethylaminoazobenzene to tetramethylbenzidine change was that TMD provided more sensitive results compared with DAB in the antigen assay. In other words, Henry clearly would change the enzyme substrate to obtain more sensitive results. The paragraphs also teach the buffer used contained 0.01% hydrogen peroxide to activate the HRP.
Paragraph [0049] of Ahn teaches that the chemiluminescent substrate may be dried or lyophilized on a lab-on-a-chip device. The chemiluminescence substrate is obtained in 2 parts (the enhancer and the peroxide) which are to be mixed in an equal ratio to obtain the final form. The Thermo Scientific™ SuperSignal™ chemiluminescent HRP substrates offer good performance in western blotting applications, with longer light emission and stronger signal intensity than other luminol-based detection systems and were used for the experiments. The enhancer and the peroxide are available in liquid form. Vacuum may be employed as a process for removing bulk and absorbed water or solvent from a product. Paragraph [0055] of Ahn teaches that compared to colorimetric and fluorescent assays, the chemiluminescence assay involves the addition of substrate for the reaction. Thus, the lab-on-a-chip device 200 involves two parallel paths: one path incorporates the HRP labelled detection antibody in drying or lyophilization chamber 220 and the other path has the substrate drying or lyophilization chambers 230, 240. In embodiments, the two components of the chemiluminescent substrate, namely the enhancer and the peroxide, need to be dried or lyophilized individually on the lab-on-a-chip device 200. Hence, the first substrate drying or lyophilization chamber 230 and the second substrate drying or lyophilization chamber 240 are envisaged on the lab-on-a-chip device 200. The enhancer may be dried or lyophilized in the first substrate drying or lyophilization chamber 230 and the peroxide may be dried or lyophilized in the second substrate drying or lyophilization chamber 240. The HRP labelled detection antibody may be dried or lyophilized in the detection antibody drying or lyophilization chamber 220.
From this it is clear that both Henry and Ahn are using a similar enzyme placed in a microfluidic network to create the measured signal. Thus it would appear that the only change needed to go from the Henry device to the instantly claimed device is a change in the substrate from one that produces a colorimetric response to one that produces a chemiluminescent response.
Paragraph [0005] of Ahn describes standard commercially available assays as mostly using optical detection methods like luminescence, fluorescence or absorbance. Therefore, to develop lab-on-a-chip (LOC) based POCT platforms with performance comparable to commercially available gold standard assay procedures optical detection methods are preferable. Several high sensitive completely integrated “sample-to-answer” LOC based POCT platforms have been developed which employs either absorbance (colorimetric) or fluorescence-based detection methods. However, most colorimetric and fluorescence detection systems lack either the desired sensitivity or are complicated to develop as they require some excitation mechanisms. Paragraph [0006] teaches that another high sensitive detection method used for conventional ELISA is chemiluminescence. Chemiluminescent signal is generated as light by the release of energy (photon) due to a chemical reaction. Unlike absorbance, colorimetric or fluorescent measurements, ELISA reagents typically contribute little or no native background chemiluminescent signal. Detection of chemiluminescent optical signal is relatively simple as it requires only a photomultiplier or photodiode and the associated electronics. The lack of inherent background and the ability to easily measure very low and very high light intensities with simple instrumentation provide a large potential dynamic range of measurement in case of chemiluminescence based assays. Paragraphs [0087]-[0088] of Ahn teach a limit of detection (LOD) around 1 pg/mL for the chemiluminescent detection which is almost 14 times less than the LOD obtained using a conventional 96-well plate assay. Based on the above description, there is an expectation that the chemiluminescent assay has better sensitivity than a colorimetric assay or would be less complicated to develop and/or measure the result.
The fact that Henry changed the substrate to provide better sensitivity is evidence that an expectation of better sensitivity such as taught by Ahn would be plenty of reason to modify the Henry device with the teachings of Ahn to change/replace the HRP colorimetric substrate with an HRP chemiluminescent substrate.
Relative to the variations in width that applicant argues on page 9 of the response, Applicant should have read the Henry disclosure before making this argument. Paragraphs [0052] and [0073] of Henry specifically teach that by varying the length, size, and similar characteristics of the channels of the microfluidic network and including other flow control mechanisms, delivery of fluid via different channels to the testing area/detection cone may be sequenced. So, for example, delivery of reagents and washes may be alternated or otherwise sequenced to follow a particular testing protocol. In other words Henry allows for variations in channel geometries such as the channel width to provide the sequential delivery of the different reagents and washes. Examiner notes that sequential delivery of fluids and/or reagents is another similarity between the Henry and Ahn disclosures. Since Henry already is designed to produce sequential delivery of reagents and washes to the detection area, one of ordinary skill in the art would not expect that modification of Henry would be needed to provide that aspect of Ahn so that the argument is not commensurate in scope with the modification that Henry would require to provide a chemiluminescent response. With respect to the posts used by Ahn, the instant claims do not exclude their presence. Thus such a structure is within the current claim scope and the argument is not commensurate in scope with the claims.
With respect to applicant’s reference of the Ghosh paper and argument that a flow system would immediately wash the chemiluminescent reactants downstream preventing prolonged signal saturation examiner notes that the device described in the Ghosh paper is a flow system. The operation of the device is described in the 2 full paragraphs on page 11 of the paper. On addition of the sample, the hydrophilic polymer surface pulls the sample (causes the sample to flow)toward both of the drying chambers. A part of the sample flowing into path-1 reconstitutes the HRP labeled detection antibody which binds to the target antigen forming the HRP–DAb-antigen complex and subsequently flows into the spiral reaction chambers. The other part of the sample flowing into path-2 reconstitutes the dried chemiluminescent substrate. The meandering channel in path-2 provides a high flow resistance and reduces the flow rate. As a result, the sample in path-1 reaches the reaction chambers first and consequently stops the flow in path-2 by trapping the air in between. The reconstituted HRP–Dab-antigen complex on reaching the test spiral chamber binds with the surface immobilized capture antibody and forms the desired capture antibody-antigen-detection antibody complex. The sample in path-1 continues to flow through the reaction chambers promoting washing of unbound reagents until the sample is drained from the left half of the sample loading chamber. The hydrophobic vent connected to path-2 is then opened which allows the reconstituted substrate to eventually reach the reaction chambers and the enzyme substrate reaction in the test chamber produces the chemiluminescent light which can be directly correlated to the antigen concentration (the only way for the reconstituted substrate to reach the reaction chambers is if it flows into and through the reaction chambers). It was observed that after the vent was opened, it took around 1 min for the initiation of the chemiluminescence signal in the test chamber which remain saturated for the next 20–25 min. Figure 7 on the same page shows the results of varying the antigen concentration between 5 ng/mL and 200 ng/mL. The description of figure 7 clearly teaches that there was a linear increase in chemiluminescence output signal (intensity) with an increase in PfHRP2 concentration from 5ng/mL to 200ng/mL. In other words, it took about 1 minute for the reconstituted substrate to flow to and reach the HRP in the test chamber for the initiation of chemiluminescence. As the reconstituted substrate continued to flow through the test chamber the chemiluminescence intensity increased to a saturation point (maximum level related to the amount of analyte/HRP in the test chamber) that was maintained for 20-25 minutes. While Ghosh does teach that the flow in the reconstituted reagent path was stopped as the reconstituted HRP–Dab-antigen complex flowed through the test chamber, Ghosh does not teach that the flow of reconstituted reagent stopped during the period the signal remained saturated (constant). Thus contrary to applicant’s argument, the Ghosh teaching actually supports examiner’s position that one can measure a chemiluminescent signal as a reconstituted chemiluminescent substrate flows past a captured enzyme label.
With respect to the above applied Ahn reference, paragraphs [0077]-[0078] clearly teach that the reconstituted HRP-conjugated detection antibodies flow into the spiral reaction chambers 760, 762, 764 before the reconstituted substrates reach the spiral reaction chambers. Also taught is the reconstituted substrates flow into the spiral reaction chambers 760, 762, 764. The reconstituted substrates (i.e., chemiluminescent substrates) react with the HRP enzyme of the HRP-conjugated detection antibodies to yield an optical signal as shown in step 4 of figure 8B. When one looks at figure 7A, it is clear that the spiral reaction chambers 760, 762, 764 are in series so that fluid cannot reach spiral reaction chamber 762 or 764 without flowing through spiral reaction chamber 760. Thus during the measurement of the chemiluminescent signal, the reconstituted substrate of Ahn is flowing through the spiral reaction chamber. Thus the signal shown in figure 14 of Ahn is occurring during fluid flow rather than with the fluid being stopped. Here again, applicant’s arguments don’t reflect what is actually happening.
With respect to the Roda, Davidsson and Varsamis papers, Henry describes and the instant claims are directed to a passive pump driven flowthrough device. Thus the fact that applicant characterizes the Roda, Davidsson and Varsamis papers as teaching pump-driven, flow-through chemiluminescent assay systems built around immobilized biological reactors means that examiner has used pump-driven, flow-through chemiluminescent assay systems to show that chemiluminescent detection of analytes using a flow through system having an immobilized enzyme capable of causing measurable luminescence were known. These are appropriate references to show that contrary to the urging of applicant and the various people that provided declarations, the capability of the chemiluminescent emission being localized to a relatively small area of the channel in a continuously flowing system was not surprising and/or would have been expected by those of skill in the art.
With respect to the argument that applicant’s capture probes are not immobilized, examiner notes that the instant claims do not exclude the presence of immobilized capture probes so that the argument is not commensurate in scope with the claims and thereby not persuasive. Furthermore, if Henry does not use immobilized capture probes, the fact that Henry does not use immobilized capture probes would show one of ordinary skill in the art that immobilization of the capture probes is not needed for a functioning device.
With respect to the washing step(s), Henry is the primary reference and teaches that the time between the arrival of the first reagent and the second reagent can be modified by changing the length and/or respective dimensions of the two paths. Henry teaches the single wash being claimed so that such a teaching is not needed from Ahn.
Incorporation of flow rates from a document that is not incorporated by reference in the originally filed description constitutes incorporation of new matter into the instant application.
For these reasons the arguments of applicant are not persuasive.
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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The additionally cited art is related to microfluidic and other structures in which the detection reagent and other agents produce colorimetric and/or chemiluminescent products.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Arlen Soderquist whose telephone number is (571)272-1265. The examiner can normally be reached 1st week Monday-Thursday, 2nd week Monday-Friday.
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/ARLEN SODERQUIST/Primary Examiner, Art Unit 1797