DETAILED ACTION
Claims 1-16 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 01/26/2023 has been considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites “configured to capture a firstfor capturing an antigen or a first antibody respectively as a target in a sample addedmade on thea metal substrate”. There needs to be a space between each word, such as “first for capturing”, “added made on”, and “the a metal substrate”. Further, a single word from each needs to be selected, as “added made” is unclear and “the a metal substrate” is also unclear. “added” or “made” need to be selected and “the” or “a” need to be selected. For example, the claim can be amended to read “…respectively as a target in a sample added on the metal substrate”. Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are: “configured to” and “configured for” in claims 1, 4, 11, and 14.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim 4 recites “a counting unit for counting fluorescence spots and quantify the target antigen”. Claim 4 recites “means for” language, but does not speak to any structure, material, or actions in support. The instant specification teaches that the fluorescent counting step is carried out by one or more fields of measurement image through a fluorescent microscope ([0062]) and counting the number of fluorescent points of each color tones in the observed fluorescent image ([0063]). The instant specification also teaches that fluorescence counting means a means for selecting at least one region in the fluorescence image, a means for binarizing fluorescence points of the selected region to adopt a fluorescence point or points equal to or larger than a predetermined threshold value, and a quantitative means for counting number of the fluorescence points ([0055]). The examiner is interpreting “a counting unit for counting fluorescence spots and quantify the target antigen” to be a fluorescent microscope, or a functional variant thereof.
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.
Claims 1-6, 8-10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Hasegawa et al. (JP2016080565A) (English translation attached), in view of Hasegawa et al. (U.S. 10,215,700 B2, hereafter, “Hasegawa ‘700”).
Hasegawa teaches (a) a metal substrate and (b) an antibody or antigen solidified phase (see [0003] – [0005] teaching a plasmon metal complex and use of an antigen and antibody) that is configured to capture an antigen or a first antibody as a target in a sample (see [0006] “It can be aggregated to capture the nucleoprotein of the subject.”) that is added to the metal substrate using (i) a plasmon metal complex solution comprising plasmon metal complex quantum crystals that are dropped on the metal substrate to trap the first antibody (see [0006] “As a result, in step b), the composite aqueous solution is dropped onto a metal substrate having an electrode potential lower than the oxidation-reduction potential of the plasmon metal complex salt, and the plasmon metal quantum crystal is placed on the metal substrate together with the anti-Ebolavirus nucleoprotein monoclonal antibody”) (instant claim 9) and (ii) a buffer solution comprising the first antibody or the antigen (see [0018] “Aqueous solution preparation of standard Ebola virus antibody Purified anti-Ebola virus nucleoprotein monoclonal antibody (clone 3-3D) as an Ebola virus antibody is diluted with PBS”); wherein there is an electrode potential difference between the metal substrate and the plasmon metal complex quantum crystals (see claim 2 of ‘565 “the complex aqueous solution is dropped onto a metal substrate having an electrode potential lower than the oxidation-reduction potential of the plasmon metal complex salt to drop the anti-Ebola virus nucleus.”); wherein the plasmon metal complex quantum crystals have (a) a size in a range of 50 nm to 150 nm (see [0009] “In the present invention, the plasmon metal quantum crystal is a silver thiosulfate complex quantum crystal, and is preferably a hexagonal plate-like crystal having a particle size of 10 to 500 nm.”) and are (b) substantially free of agglomeration of coagulated plasmon metal quantum crystals with each other, wherein the first antibody or the antigen from the plasmon metal complex solution is immobilized on the metal substrate with the plasmon metal complex quantum crystals that are coagulated on the metal substrate, to form an immobilized first antibody or an immobilized antigen respectively (see [0005] – [0006] teaching the plasmon metal complex containing the antibody is dropped onto a metal substrate, resulting aggregated bound plasmon complex quantum crystals and immobilizing the first antibody) (instant claim 1). Hasegawa teaches irradiating the immobilized crystal that has captured the virus antigen with a laser beam (instant claim 10), and detecting the target and using an antigen-antibody immune reaction (see [0005]) (instant claim 1). Hasegawa teaches the use of the buffer PBS which is widely known in the art to have a pH of approximately 7.4 (instant claim 2). Hasegawa teaches the plasmon metal crystals in a complex solution to have a density of 1000-5000 ppm (see [0008] teaching 500-2000 ppm) (instant claim 3). Hasegawa teaches after capturing the virus antigen (nucleoprotein), one may further react an anti-nucleoprotein rabbit polyclonal antibody, which in turn may detect using an enzyme labeled anti-rabbit antibody to confirm the presence of the nucleoprotein in a patient material (see [0007]), thereby teaching the “sandwich” method (instant claim 13). Hasegawa teaches the target antigen is an outside protein of a virus, or the target antigen is the virus itself and wherein the target is not an entity present inside the virus and separate from the virus (see [0017], claim 1 of ‘565 “…antibody (hereinafter referred to as Ebolavirus antibody) prepared from Ebolavirus antigen containing anti-Ebolavirus nuclear protein monoclonal antibody…”) (instant claim 4). Hasegawa teaches the target antigen being an enveloped virus (see [0007] “In particular, since the Ebola virus antibody is an anti-Ebola virus nucleoprotein monoclonal antibody and can capture the nucleoprotein of the sample as the Ebola virus antigen, this nucleoprotein may be detected, but further to this nucleoprotein.”) (Instant claims 5-6).
Hasegawa does not teach the measuring substrate is configured for a quantitative detection of a target as a fluorescent spot via fluorescence labelling immune assay using an antigen-antibody immune reaction; and wherein the measuring substrate possess a plasmon enhancing ability for exciting the target to be labelled with a fluorescent material by irradiation of an exciting light for detecting the target antigen as the fluorescent spot through a fluorescent image.
Hasegawa ‘700 teaches the use of a plasmonic chip that comprises a metal substrate with silver complex quantum crystals (see abstract) and fluorescent imaging that quantifies the fluorescent events and results in a numerical value (see column 6 lines 1-5), where the measuring substrate possess a plasmon enhancing ability for exciting the target to be labelled with a fluorescent material by irradiation of an exciting light for detecting the target antigen as the fluorescent spot through a fluorescent image (see columns 2-3 teaching the use of a fluorescent labeling antibody that is absorbed onto the plasmon chips in order to enhance the emission of fluorescence intensity) (instant claim 1). Hasegawa ‘700 also teaches labelling fluorescence material configured to label the target antigen to form a labelled target (see column 16 “Further, it is also possible to determine the existence of cancer simply through fluorescence microscopy because the cancer-related substance with a variety of fluorescent labels can be selectively captured.”); a fluorescence imaging unit configured to make a fluorescence image of the labelled target trapped on the first antibody or antigen solidified phase as the fluorescent spot using the excitation light (see column 6 ” Although crystal of adsorbed tumor marker on the plasmonic chips cannot be visually observed, irradiation of ultraviolet, red, or green laser makes it possible to observe the crystals with a fluorescence microscope (50 times), where point-like dispersed crystalline masses can be observed. Detection of the Raman spectra therefrom by irradiating of various laser beams makes it possible to determine the cancer disease with the intensity of surface enhanced Raman scattering (SERS).”), and a counting unit for counting fluorescence spots and quantify the target antigen (see column 6 “The geometry, brightness and dimension of the fluorescence images can be quantified and the resulting numerical values are subjected to histogram processing); and wherein the system is configured to perform a fluorescence labelling immune assay (see columns 2-3 “a plasmonic chips which is easy to be mass produced, whereby cancer-related substances or fluorescent labeling marker of adsorbent material such as antibody and so on, can be absorbed onto the plasmonic chips, so that plasmons on plasmonic chips can enhance the emission of fluorescence intensity from several times to several tens of times so as to realize a diagnostic method for cancer diseases by using a diagnosed fluorescence image on the plasmonic chip.”, see column 16 “Thus, according to the present invention, the cancer related substances in blood and biological samples can be selectively detected through auto fluorescence by localized plasmon enhancement effect. Further, it is also possible to determine the existence of cancer simply through fluorescence microscopy because the cancer-related substance with a variety of fluorescent labels can be selectively captured. Furthermore, since chemical modification status of histone tails can be detected from the Raman spectrum of the crystals with or without labels, it is also possible to carry out early detection of cancer, and determination as to progress of the cancer. Therefore, summarization of the usage way according to the present invention is as follows.”) (instant claim 4). Hasegawa ‘700 teaches the plate being blown with air (see column 9 “As shown in FIG. 4, an aqueous solution containing 1000 ppm of silver thiosulfate was prepared and the 1 drop was added dropwise on a phosphor bronze plate. After standing for about 3 minutes, the solution on the plate was blown off. On the plate, quantum crystals were obtained as shown in the SEM image at the right side of FIG. 4.”) (instant claim 8).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to modify Hasegawa’s methods of using a metal substrate, monoclonal antibodies, viral antigens, and fluorescence to determine the presence of a virus, with Hasegawa ‘700’s methods of using metal complex quantum crystals and fluorescence-labels to detect a target analyte. One skilled in the art would have been motivated to substitute fluorescent labeling and detection for the enzyme-labeling with Raman detection of Hasegawa, in view of the art-recognized suitability of both fluorescence and Raman as suitable means for detecting assays performed on plasmonic substrates, as taught in Hasegawa. Hasegawa ‘700 provides motivation by teaching that using fluorescent-labeled antibodies on plasmonic chips is beneficial because the fluorescent-labeled antibodies are absorbed onto the plasmonic chips, allowing for enhanced emission of fluorescence intensity (see columns 2-3). Further, Hasegawa ‘700 provides motivation by teaching that plasmonic chips make it possible to selectively absorb related substances or markers, so the localized surface plasmon resonance makes fluorescence intensity of fluorescence image enhanced, whereby it is possible to facilitate the determination of a diagnosis from the fluorescence images (see column 4). It would have been obvious to one of ordinary skill in the art at the time of the instant application to use methods of analyte detection of Hasegawa with the methods of fluorescence-labeling taught by Hasegawa ‘700. The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Claims 11-12 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Hasegawa and Hasegawa ‘700 as applied to claims 1-6, 8-10, and 13 above, and in view of Kaneko et al., (US 20150119722A1) (effectively files on 12/10/2014).
Hasegawa does not teach the fluorescence image being binarized.
Kaneko teaches an image processing method (see [0017], [0113] – [0114], [0116], [0118], and [0120]) that comprises:
making a fluorescence image of a target by irradiating an exciting light (an image
acquiring step of acquiring image information representing an image acquired by irradiating a
target with excitation light, see [0017]);
observing the fluorescence image by a microscope (see [0017], [0088]),
binarizing the fluorescence image into fluorescence points (see [0113] “image determination unit 211 includes a blob analysis unit 211a that performs blob analysis based on the fluorescence intensities (luminance values) computed by the fluorescence intensity computation unit 151. Blob analysis is image processing that treats either of two values (white and black) as a lump (blob) in a binary image obtained by binarizing a processing target image, and analyzing the blob shape features such as the presence or absence, number, area, length, perimeter, and roundness.”, see [0116] “the blob analysis unit 211a provides a pixel value, one, to pixels whose luminance value is the reference value or more, and a pixel value, zero, to the other pixels, among the pixels in the fluorescence observation image, and creates a binary image”),
wherein the binarizing comprises performing an analysis condition comprising one or
more of a brightness, an area of the fluorescence image, and a circularity of the fluorescence
points (see [0113] “Blob analysis is image processing that treats either of two values (white and black) as a lump (blob) in a binary image obtained by binarizing a processing target image, and analyzing the blob shape features such as the presence or absence, number, area, length, perimeter, and roundness.”); and
wherein the counting unit is configured to binarize the fluorescence image to adopt the fluorescence spot and quantitatively count the fluorescence spot (see [0117] – [0118] “The reference value used in the binarization process is required to be obtained, for example, from the distribution of luminance value data collected in advance from fluorescence observation images of unstained specimens of normal and abnormal gland ducts, by a well-known method such as the discriminant analysis, percentile method, or mode method (reference: “Digital gazo syori (Digital Image Processing)”, Computer Graphic Arts Society, pp. 174-176). Furthermore, the blob analysis unit 211 a computes characteristic amounts illustrated below for areas (fluorescence areas) of pixels having the pixel value one in the binary image.”) (instant claims 11-12).
Kaneko teaches the use of a filter for labeling of the fluorescent material having different wave range depending on the target (see [0173] “For example, when fluorescence observation is performed by the microscope apparatus 90, used is the optical cube (fluorescence cube) 917 in which an excitation filter 920 that selectively transmits light (excitation light) in a specific wavelength band among light emitted from the epi-illumination light source 902 and passing through the epi-illumination optical system 912, a dichroic mirror 921 that reflects the excitation light selected by the excitation filter 920 and transmits fluorescence generated in a specimen S, and an absorption filter 922 that selectively transmits only light (fluorescence) in a specific wavelength band among light incident from the direction of the specimen S are combined in a cube form.”, [0177] “a plurality of narrow bandpass filters”) (instant claim 16).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to combine the methods and teachings of Hasegawa and Hasegawa ‘700 with the methods of fluorescent images being binarized and the use of filters taught by Kaneko. Kaneko provides motivation for generating binary images from fluorescent images because it allows for detection of shapes to determine the presence, number, area, length, perimeter, and roundness (see [0113]) allows for the ability to extract certain fluorescent areas for better detection (see [0125]). Kaneko provides motivation for the use of filters by teaching that filters selectively transmit light in a specific wavelength band among light that is being emitted, which allows for accurate detection (see [0173]). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Claims 7 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Hasegawa and Hasegawa ‘700 as applied to claims 1-6, 8-10, and 13 above, and in view of Li et al., “Evaluation of multiplex assay platforms for detection of influenza hemagglutinin subtype specific antibody responses.” Journal of virological methods vol. 243 (2017): 61-67. doi:10.1016/j.jviromet.2017.01.008 (2017).
Hasegawa does not teach the virus being influenza and the system being configured to detect more than one type of target antigen.
Li teaches using multiplexed (using more than one type of target antigen) fluorescence immunoassays to detect the influenza virus (see page 65 under “2.4. Multiplexed fluorescence microsphere immunoassay”) (instant claims 7 and 14-15).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to combine the methods and teachings of Hasegawa and Hasegawa ‘700 with the methods of multiplex virus detection taught by Li. It would have been obvious to one of skill in the art to detect the influenza virus (instead of Ebola virus) in order to detect and diagnose influenza virus in afflicted individuals. One of skill in the art would have reasonable expectation of success as Li reports successful detection of influenza hemagglutinin (HA) (the influenza target). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Conclusion
No claim is allowed.
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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678