DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application claims benefits of Provision Application Number 63/211,325. The
effective filling date of the instant application is June 16, 2021.
Status of the Claims
Claims 18-20 have been added. Claims 1-20 are pending.
Claims 12-17 have been withdrawn from consideration due to an election without
traverse submitted on 10/08/2024.
Thus, claims 1-11 and 18-20 represent all claims currently under consideration.
Information Disclosure Statement
No new IDS has been submitted
Withdrawn Objections/Rejections
The objection to the specification as containing trademarks is withdrawn in view of the amendment to the specification.
The 35 USC 112 (b) rejection of claims 6-7 are with withdrawn in view of the amendments.
The rejections of claims 1-11 under 35 U.S.C. 103 as being obvious over Esfandiari (US 7,189,522) in view of Mahmoudi (Trends in Analytical Chemistry, 2019). have been withdrawn in view of Applicants arguments submitted 06/16/2025. However, upon further consideration, new grounds of rejection is made as disclosed below.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-4, 9, and 11 are rejected under 35 U.S.C. 103 as being
unpatentable over Esfandiari (US 2007/0148781) in view of Mahmoudi (Ref. V, PTO-892, 03/04/2025) and Wu (US5358852).
Regarding claim 1, Esfandiari teaches a lateral flow device. Esfandiari discloses several embodiments of a device, one of which is exemplified by Figure 1 and described in detailed in paragraph [0049], comprising:
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a testing zone (i.e. second zone 63) comprising a nitrocellulose membrane ([0049] sorbent material 30) comprising a proximal end, a distal end, and a center region.
wherein the testing zone comprises an antibody zone (63) disposed between the distal end and the center region of the testing zone.
wherein the antibody zone comprises, in order from the center region to the distal end:
a detection zone (first or filter zone 31) comprising mobilizable detection antibodies conjugated to a labeling component and spot-dried to a surface of the detection zone. See [0049] a first zone is located at the first hole 24 and extends to a second zone 33. The first zones includes filter pads on which a conjugate 39 having desired antigens or antibodies with attached colored markers is deposited.
a capture zone comprising one or more capture antibodies that are spot- dried and immobilized on a surface of the capture zone. See [0049] test zone 33 printed with a test line 50 having immobilized antigens or antibodies disposed thereon.
a control zone (35) comprising one or more anti-mobilizable detection antibodies that are spot-dried and immobilized on a surface of the control zone. See [0049], a third zone 35 is printed with a control line 60 containing antibodies to the conjugate antigens or antibodies.
a sample inlet (area 31) for receiving a sample comprising:
a first sample outlet (26) intersecting with, and in fluid communication with, the center region of the testing zone;
a second sample outlet (24) fluidly connected to a first flow channel, wherein the first flow channel is in fluid communication with the proximal end of the testing zone; and
an absorbent pad (reservoir zone 37) in fluid communication with the distal end of the testing zone serving as a wicking reservoir.
While Esfandiari does not specifically state wherein the first flow channel has a greater length than the length of the first sample outlet, it can clearly be seen that the first flow channel has a greater length than the length of the first sample outlet (61).
Esfandiari teaches the use of different labels including metal colloidal solutions, colored latex and various enzymes etc. [0080], Esfandiari differs from the claims in failing to teach a substrate component and hydrogen peroxide separately spot-dried on a surface of the testing zone between the proximal end of the testing zone and the center region of the testing zone, wherein the substrate component comprises one or more enzymatic substrates;
Mahmoudi teaches the state of the art of lateral flow assay devices.
Regarding claim 1, Mahmoudi teaches ELISA enzyme tags such as HRP. Mahmoudi teaches exposing the sample to hydrogen peroxide proximal to the testing site on the nitrocellulose strip, increasing test line visibility as taught on pg. 22, under the Enzyme/Nanozyme detection heading, first paragraph. In the following paragraph the importance of a substrate in order to facilitate color change and visualization, is taught. This substrate and hydrogen peroxide are meant to enhance enzyme based colorimetric reactions. Mahmoudi teaches on pg. 26, left col., last para, both colorimetric and enzymatic derived color changes for quantification in LFAs in which the strong color change from the substrate could further improve the sensitivity of the assay. This meets limitations in claim 1 of a substrate component which is an enzymatic substrate, and hydrogen peroxide used in a device comprising a nitrocellulose membrane.
Mahmoudi fails to teach the spot drying of the enzymatic substrate and hydrogen peroxide to the test strip surface between the proximal end of the testing zone and the center region of the testing zone.
Wu discloses an immunoassay device for the detection of an analyte.
Regarding claim 1, Wu discloses in col. 5 line 9-22, when an antibody is labeled with an enzymatic substance, other reactants (typically a substrate for the enzyme) are included in the assay system, i.e. integrated into a test strip. When the assay is prepared, the substrate for the enzyme may be included in the assay system, prior to the introduction of the liquid sample. The enzymatic substrate may be a material which is directly acted upon by the enzyme label, or a material that is involved in a series of reactions which involve enzymatic reaction of the label. For example, if the enzyme label is a HRP, the substrate may be hydrogen peroxide. In col. 7 line 1-9, Wu teaches the dry element of this device may be divided into two or more contiguous zones (or layers) which are fluid permeable. The zones can be "self-supporting", which means that the zones can be composed of materials which maintain their integrity when exposed to aqueous fluids, such as filter papers or microporous membranes. Wu discloses in col. 7 lines 18-23, the dry analytical elements may contain at least one other zone which contains one or more reagents needed for the assay. Such a zone is often known in the art as a reagent or registration zone, but it can also include a second porous spreading zone if desired or printed layers located on other zones. This meets the limitations in claim 1 of spot-dried reagents required for an assay, such as an enzymatic substrate component and hydrogen peroxide as a catalyst.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to have modified the device of Esfandiari to use enzymatic labeling and colorimetric changes as taught by Mahmoudi using minimal manipulation steps by integrating reagents into the device as taught by Wu. A person of ordinary skill in the art would have been motivated to modify the device of Esfandiari to use enzymatic substrates and catalysts as taught by Mahmoudi, by integrating dried elements into the test strip of the device as disclosed by Wu because this reduces human error by reducing the necessary steps while creating a strong visualization using enzyme based colorimetric changes for visualization. When creating a device to conduct an assay, one of ordinary skill in the art would have been motivated to combine these elements, which are well known in the art and work independently and in combination, to create a device combining the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately to create a device that has strong visual markers and ease of use. One of ordinary skill in the art would have had a reasonable expectation of success and the combination as discussed would have yielded predictable results, e.g. enhancing an enzymatic color reaction using antibodies conjugated to a labeling component by exposing the sample to and mixing with a spot-dried substrate and oxidizer meant for this purpose in a device based on each of these elements being well known in the art and ready to work when combined with no change in their respective functions. This use of known assay methods and reagents combined into one device allows for the convenience of using an integrated assay system without the need for multiple manipulation steps. The reduction in manipulation required to perform a test using this device would reduce the potential for errors and create an improved system.
Regarding claim 2, Esfandiari discloses as above, and discloses in col. 2 lines 6-18, an enzymatically labelled antibody and a substrate for the enzyme. The enzyme-label interacts with the substrate, causing the formation of colored products which either deposit as a precipitate onto the solid phase or produce a visible color change in the substrate solution. This meets the limitation of claim 2 of a labeling component consisting of a colorimetric agent or an enzyme.
Regarding claim 3, Esfandiari teaches as above, but fails to teach wherein the labeling component is an enzyme comprising a peroxidase enzyme or a phosphatase enzyme.
Mahmoudi teaches as above, and teaches using a horseradish peroxidase enzyme as a labeling component on pg. 22, under the enzyme/nanozyme mediated detection heading, and phosphatase as an Antibody tag or label in table 2 on pg. 25 under the Enzyme/nanozyme detection mode heading, and the investigated tag column of the table. Mahmoudi further teaches on pg. 28, right col., 4th para., the enhancements in sensitivity and accuracy were attained by both signal amplification approaches and by the development of other detection methods including enzyme/nanozyme mediated detection. This meets limitations in the claim 3 wherein the labeling component is an enzyme comprising a peroxidase enzyme or a phosphatase enzyme.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to use the device of Esfandiari as modified by Mahmoudi because they provide enhancements in sensitivity and accuracy apart from using signal amplification in visual detection test devices. The enzymatic label taught in Mahmoudi is applicable to the device of Esfandiari, and one of ordinary skill in the art would have recognized that applying the enzyme label would have yielded predictable results with improved sensitivity and accuracy as taught by Mahmoudi.
Regarding claim 4, Esfandiari teaches as above, but fails to teach one or more enzymatic substrates is a colorimetric agent.
Mahmoudi teach as applied to claim 1 above, and further teaches that a colorimetric substrate, such as peroxidase further improves the sensitivity of the assay in the presence of hydrogen peroxide, which produces an insoluble black product along the TL on pg. 26, under the Colorimetric and nanozyme mediated dual detection mode LFAs heading. Further Mahmoudi teaches on pg. 26, l. col., para. 4, colorimetric and enzymatic derived color changes for quantification in LFAs in which the strong color change from the substrate could further improve the sensitivity of the assay. This meets limitations in claim 4 that one or more enzymatic substrates is a colorimetric agent.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to modify the device of Esfandiari using the enzymatic substrate from Mahmoudi to fit the purpose of different lateral flow assay devices. The person of ordinary skill in the art would have been motivated to make these modifications to the device of Esfandiari for analyte analysis because colorimetric changes using enzymatic substrates cause strong color changes, an insoluble black line, which improve the sensitivity of devices based on visual detection. The person of ordinary skill in the art would have had a reasonable expectation of success modifying the device of Esfandiari to detect a particular enzyme label using an enzymatic substrate which is a colorimetric agent.
Regarding claim 9, Esfandiari teaches as above, but fails to teach the tapering of the nitrocellulose membrane.
Mahmoudi teach as applied to claim 1 above, and further teaches a taper-shaped nitrocellulose membrane which promoted color intensity via an increase in concentration of the antigen bound compounds on pg. 16, under the heading Improvements in Membrane Performance, in the left column, second paragraph, lines 14-15. This meets limitations in the claim 9 of a nitro cellulose membrane which tapers from the proximal end to the distal end of the membrane.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to modify the device of Esfandiari by making it tapered as taught by Mahmoudi because the concentration gradient in the test line was improved significantly, and the taper shaped membrane promoted the color intensity of the test line by an increase in the concentration of the antigen. This ensures better visualization of the test line, as well as observable visualization with less antigen in the sample.
Regarding claim 11, Esfandiari discloses as applied to claim 1 above, Esfandiari also teaches a second flow channel that flows from the first sample outlet to the first flow channel where they meet in the center region of the testing zone, fig. 1, numbers 30/51. This described second flow channel and first sample outlet have a combined length which is less than the first flow channel meet limitations in claim 11.
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Esfandiari in view of Mahmoudi and Wu as applied to claim 1 above, and in further view of Sun et al (Bioscience, Biotechnology, and Biochemistry, 2017).
Esfandiari, Mahmoudi and Wu teach the device of claim 1, but fail to teach the use of TRITON X-100 and polyvinylpyrrolidone (PVP) and their concentrations when describing their conjugate antibodies.
Sun teaches a novel multi-walled carbon nanotube (MWCNT)-based antibody conjugate for quantitative and semi-quantitative lateral flow assays.
Regarding claims 5-7, Sun teaches antibody conjugates (mobilization detection antibodies and MWCNT labels) are combined with a mixture containing PVP and TRITON X-100 at concentrations up to around 8% v/v in 20ml of DI water (0.375 mg/ml of conjugate to 0.0296 mg/ml of surfactant) on pg. 1875, l. col, para. 4, these solutions were used to enhance the conjugates biocompatibility and maintain separation of the conjugates with the hydrophobic part of the surfactant molecules adsorbing onto the surface of the labels, and the hydrophilic parts interacting with the aqueous medium to suppress aggregation into bundles and ropes as taught on pg. 1875, l. col., para. 1. This meets limitations in claims 5 and 6 where the mobilization detection antibodies comprise a mixture of a water-soluble polymer and surfactant, specifically the water-soluble polymer is polyvinylpyrrolidone and the surfactant is TRITON X-100. Further, this meets limitations in claim 7 wherein the mixture comprises about 1 % v/v to about 8% v/v of the polyvinylpyrrolidone and about 1 % v/v to about 8% v/v of the Triton X- 100.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to use the device as applied to claim 1 above using the solutions as taught by Sun to create an antibody and label in a mixture of PVP and TRITON X-100, to increase the sensitivity of the test by improving biocompatibility, maintaining separation of antibodies by suppressing aggregation into bundles and ropes. The person of ordinary skill in the art would have been motivated to use these modifications in order to ensure the most accurate and reliable results by allowing for precise binding of as many labeled antibodies as available. The person of ordinary skill in the art would have a reasonable expectation of success when combining the prior art teachings to achieve sensitive and specific binding in an immunoassay.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Esfandiari in view of Mahmoudi and Wu as applied to claim 1 above, and in further view of Hajizadeh et al (PTO-892, 03/04/2025).
Esfandiari, Mahmoudi, and Wu teach the device of claim 1, but fail to teach the use of proteinase K in their device.
Hajizadeh the use of enzymes to break down cellular material in order to have more accurate and rapid lateral flow assay results.
Regarding claim 8, Hajizadeh teaches a test device which has proteinase K immobilized on a support, the sample pad or flow path, and a membrane in fluid communication with the support so the proteinase K removes substantially all interfering constituents in the specification on pg. 4, left column, lines 10 – 12. This meets the limitations in claim 8 of proteinase K disposed on a surface of the sample inlet, first sample outlet, second sample outlet, first flow channel, or a combination thereof.
Therefore, it would have been obvious, to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to further modify the device of Esfandiari by integrating proteinase K into the test strip to break down unwanted interferents and improve the results of the assay as taught by Hajizadeh. The person of ordinary skill in the art would have been motivated to make this modification to the device as taught by the combined prior art in order to prevent interference in immunological binding and ensure maximum expose of desired analytes to the testing antibodies. A person of ordinary skill in the art would have had a reasonable expectation of success in using proteinase K in the way taught by Hajizadeh to allow for more optimized results with minimal interference.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Esfandiari in view of Mahmoudi and Wu as applied to claim 1 above, and in further view of Sukumaran et al (Indian Journal of Clinical Biochemistry, 2020).
Esfandiari, Mahmoudi, and Wu teach the device of claim 1, but fail to teach a specific length of the nitrocellulose membrane.
Sukumaran teaches the development and troubleshooting in lateral flow immunochromatography assays.
Regarding claim 10, Sukumaran teaches on pg. 9, r. col. Para. 3, - pg. 210 l. col. , para1, and shows in fig. 1b, Normally 20–25 mm is the length for NC membrane with 3–4 mm width. The test line coating should be minimum 7 mm distance from sample pad and the distance between test lines and control line should have minimum of 5 mm. These minimums are equal to 12mm with no additional factors taken into account such as depth of the control and test lines, the number and makeup of reagent spots, and the time it takes for sample fluid to migrate. In the case of the application, the Applicant discloses an ideal length of “about 15 mm to about 35 mm in length such that the required number of reagents (e.g., water- soluble polymer, surfactant), labeling component (e.g., an antibody), and substrate components (e.g., a colorimetric agent) may be spot-dried to the surface of the nitrocellulose membrane without interacting or unintendedly mixing with one another”. Finding this would require routine experimentation and optimization to find the ideal nitrocellulose membrane length.
Where the general conditions of the claim is taught by the prior art, discovering a workable or optimum range requires routine skills in the art. In this case, the general conditions of the claim is taught by the prior art as discussed above, and the recited 20-25 mm nitrocellulose length falls within a workable or optimum range, and therefore its discovery requires routine skills in the art. This meets limitations in claim 10 of a nitrocellulose membrane of about 15mm to 35 mm in length. See MPEP 2144.05 and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to use routine experimentation to find the ideal length of membrane for their device. The person of ordinary skill in the art would have been motivated to find membrane lengths similar to those taught by Sukumaran to achieve optimum results for their assay. The person of ordinary skill in the art would have had a reasonable expectation of success in finding the ideal length of a test membrane using routine experimentation when combined with prior art teachings.
Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Esfandiari in view of Mahmoudi and Wu as applied to claim 1 above, and in further view of Sun, and Sigal et al (Journal of Clinical Microbiology, 2018).
Esfandiari, Mahmoudi, Wu, and Sun teach a device as above, but fail to teach the device detecting antibodies specifically binding to Mycobacterium tuberculosis antigens.
Sigal teaches a novel sensitive immunoassay targeting a lipoarabinomannan epitope which meets the WHO’s performance target for Tuberculosis diagnosis.
Regarding claims 18-20, Sigal teaches on pg.1 in the introduction that Tuberculosis (TB) is the number one cause of death due to infectious disease. In 2016, 10.4 million people fell ill with TB and 1.7 million died from the disease. Most of the deaths from TB could have been prevented by an early diagnosis. Globally, there was a gap of 4.1 million cases between the estimated incident and the reported TB cases. Sigal also teaches in fig. 1b all Ab used in testing the identify lipoarabinomannan in samples as capture or detection antibodies. This meets limitations in claims 18-19 of detection antibodies specifically bind to one or more Mycobacterium tuberculosis antigens such as lipoarabinomannan, and in claim 20 of the above taught device detecting said antigens.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to use the device disclosed by Esfandiari and modified as above, which is generic to which specific reagents are used and which antigens are targeted, and find the appropriate reagent, specifically a detection antibody, to diagnose a disease that has a high incidence and fatality rate and can be prevented by an early diagnosis. A person of ordinary skill in the art would have been motivated to use anti-lipoarabinomannan antibodies as detection antibodies, as taught by Sigal, to diagnose a serious disease, the patients of which would benefit from rapid diagnosis. The person or ordinary skill in the art would have had a reasonable expectation of success using said antibodies in an microfluidic immunoassay to diagnose Tuberculosis.
Therefore, the combination of prior art renders these claims, as written, obvious.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIM ATWELL, D.Sc., M.S., MLS whose telephone number is (571)272-0890. The examiner can normally be reached Generally Mon-Thurs: 7:30-5:00 EST and every other Fri: 7:30-4:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIM ATWELL/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 10, 2025