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 .
Election/Restrictions
Applicant has elected Group II with traverse.
Applicant's election with traverse of Group II in the reply filed on 12/15/25 is acknowledged. The traversal is on the ground(s) that claims 1 and 2 share the technical feature that “the solid phase support does not need to be spatially divided to achieve a random distribution”, which eliminates the need for special treatments such as spatial division, significantly reducing detection costs. For example, in a multi-well plate, samples can be randomly and uniformly distributed across different wells without requiring regular spatial division. Applicant further states that moreover the microparticles can be randomly and uniformly distributed on the surface and/or within the solid phase support. This uniform distribution is maintained after immobilization, facilitating subsequent detection-such as analyzing and detecting biomolecules through the random distribution of microparticles and direct imaging under bright-field and dark-field conditions. Therefore, Applicant states that this technical feature simplifies the detection process, enhances stability, sensitivity, and accuracy.
Applicant argues that US 20170160292 (“Wilson”) does not disclose or suggest that “the solid phase support does not need to be spatially divided to achieve a random distribution”.
This is found persuasive regarding Groups I and II, particularly after a search of the prior art.
Thus, Group I (claims 1, 22 and 43) and Group II (claims 2, 4-9, 12, 14, 16-19, 21, 23-24 and 41-42) are rejoined.
Applicant also argues that claim 25 of Group III depends from the method of claim 2 of Group II. Applicant argues that the apparatus of claim 25 is suitable for carrying out the process of claim 2, with the technical relationship that involves the special technical feature of “the solid phase support does not need to be spatially divided to achieve a random distribution” being present between the apparatus of claim 25 and the process of claim 2. Applicant asserts that Group II and Group III are linked to form a single general inventive concept under PCT Rule 13.
This argument is not persuasive since the technical feature linking Group III and (Group I or II) is a solid phase support capable of immobilizing microparticles that are capable of binding to a molecule, which does not make a contribution over the prior art in view of Wilson (US 20170160292), as mentioned in the restriction requirement. [Examiner notes that independent claim 25 of Group III does not require the alleged technical feature mentioned by Applicant, nor does it require other features such as microparticles immobilized to a surface and/or the interior of a solid phase support.]
The restriction requirement between Group III and (Group I or II) is still deemed proper and is therefore made FINAL.
Thus, claims 25-27, 29-30, 32-35, 38-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/15/25.
Claim Objections
Claim 2 is objected to because of the following informalities: in line 4, “the microparticles is linked” should be –a microparticle is linked--. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4-9, 12, 14, 16-19, 21-24 and 41-43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites in section “(5)”, “wherein step (3) comprises removing the agglomerated/overlapped microparticles in the bright field”.
The claim lacks sufficient antecedent basis for this limitation.
For examination purposes, this limitation recited here, and in other claims as mentioned below, is interpreted to refer to the description in paragraph 0053 of the Pre-Grant Publication US 20230273198. However, clarification in the claims is required.
Claim 2 recites in section “(5)”, “wherein step (3) comprises removing the agglomerated/overlapped microparticles in the bright field”.
The claim lacks sufficient antecedent basis for this limitation.
Claim 12, line 4, recites “an organic small molecule fluorescent probe”.
The limitation’s use of the term “small” makes the limitation vague. While Applicant does give an example in paragraph 0123 of a target molecule that is “a small molecule compound with a molecular weight of less than 1000”, this is not a definition, nor is it a definition of “an organic small molecule fluorescent probe”.
Claim 24 recites: “Use of the method according to claim 2 in the preparation of a diagnostic reagent for detecting a biomolecule.”
Claim 24 is vague and indefinite since it is unclear as to what the claim requires as there is no body to the claim.
Also claim 24 does not have a term like “comprising”, and thus it is not clear if the claim is open or closed to other limitations.
Moreover, it is not clear how claim 2 is used to prepare a diagnostic reagent for detecting a biomolecule, since claim 2 is itself a “method for detecting” molecules (see preamble).
Claim 41 recites: “A non-transient computer-readable storage medium for storing a program for executing the method according to claim 2 and/or data generated by programs for executing the method and data generated by executing the method.”
Claim 41 is vague and indefinite since it is unclear as to what the claim requires as there is no body to the claim.
Also, claim 41 does not have a term like “comprising”, and thus it is not clear if the claim is open or closed to other limitations.
Claim 42 recites: “An electronic device comprising the non-transient computer-readable storage medium according to claim 41”.
However, claim 41 is vague and indefinite for the reasons set forth above, which are not remedied by claim 42.
The remaining claims are rejected since they depend from claims 1 or 2, which are rejected for the reasons set forth above, without remedying the vagueness.
Allowable Subject Matter
Claims 1 and 2 would be allowable if rewritten or amended to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action.
Claims 4-9, 14, 16-19, 21-24 and 41-43 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter.
It was not found in the prior art search a teaching or suggestion for a method for detecting one or more target molecules, comprising the following steps of:
providing a solution comprising microparticles, wherein a target molecule forms a complex by a specific binding reaction, a microparticle is liked to the complex, and the complex is labeled with a signal molecule;
immobilizing the microparticles in the solution to the surface and/or the interior of a
solid phase support; the solid phase support does not need to be spatially divided to achieve a random distribution;
(3) counting the microparticles in a selected field of view under a bright field;
(4) counting the microparticles binding to the complex in a selected field of view under a dark field;
and (5) determining the concentration of the signal molecule according to the counting results obtained in steps (3) and (4), and further determining the concentration of the target molecule.
It was also not found in the prior art search a teaching or suggestion for the benefits and advantages of such combination of limitations, such as disclosed by Applicant in the specification in paragraphs 0008, 0010, 0034, 0036, 0045, 0056, 0106, and 0110 (in PreGrant Publication US 20230273198).
A close prior art is Holmes (US 20140038206) (see further below under the “Conclusion” section).
Holmes discloses use of microparticles complexing to a target and signal molecule, as well as counting microparticles under bright field and dark field, and quantifying the target. The microparticles are disclosed as being used for visualization.
However Holmes does not teach or suggest:
immobilizing the microparticles in the solution to the surface and/or the interior of a solid phase support; the solid phase support does not need to be spatially divided to achieve a random distribution.
Another close reference is Duffy (US 20110212848) (see further below under the section “Conclusion”). While Duffy discloses determining analyte concentration or counting by using magnetic beads, as well as bright field and dark field microscopy, and fluorescently labeled analyte, Duffy does not teach that the magnetic beads are immobilized during detection.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 20140038206 (“Holmes”).
As to Applicant’s claim 2, Holmes discloses a method for detecting one or more target molecules, comprising the following steps of:
providing a solution comprising microparticles, wherein a target molecule forms a complex by a specific binding reaction, a microparticle is liked to the complex, and the complex is labeled with a signal molecule;
(3) counting the microparticles in a selected field of view under a bright field;
(4) counting the microparticles binding to the complex in a selected field of view under a dark field;
and (5) determining the concentration of the signal molecule according to the counting results obtained in steps (3) and (4), and further determining the concentration of the target molecule.
However, Holmes does not teach or suggest:
immobilizing the microparticles in the solution to the surface and/or the interior of a solid phase support; the solid phase support does not need to be spatially divided to achieve a random distribution.
More specifically, Holmes discloses the following.
Holmes in paragraph 0061 discloses that the “term “cells”…encompasses….. cells, virions,
and substances bound to small particles such as beads, nanoparticles, or microspheres”.
Holmes in paragraph 0069 discloses the following. “Optionally, prior to microscopy, a sample may be contacted with one or more binders that specifically bind to a cellular component. Binders may be directly linked to a dye or other particle for the visualization of the binder. A sample may also be contacted with a secondary binder, which binds to the binder which binds to the cellular component. A secondary binder may be directly linked to a dye or other particle for the visualization of the binder. Prior to microscopy, a sample may be assayed in a spectrophotometer. For microscopy, a biological sample containing or suspected of containing an object for microscopic analysis may be introduced into a sample holder, such as a slide or a cuvette. The sample holder containing a sample may be introduced into a device configured to perform quantitative microscopy on the sample. The microscope may be coupled with an image sensor to capture images generated through the microscope objective. In the device, multiple images of the sample may be acquired by microscopy. Any one or more of quantitative fluorescence microscopy, quantitative dark field microscopy, quantitative bright field microscopy, and quantitative phase contrast microscopy may be used to obtain images of the sample. Optionally, images of the entire sample in the sample holder may be acquired by microscopy. Multiple fields of view of the microscope may be required capture images of the entire sample in the sample holder. The sample holder may move relative to the microscope or the microscope may move relative to the sample holder in order to generate different field of views in order to examine different portions of the sample in the sample holder. Multiple images of the same field of view of the sample in the sample holder may be acquired. Optionally, multiple filters may be used with the same type of microscopy and the same field of view of the sample, in order to acquire different images of the same sample which contain different information relating to the sample. Filters that may be used include, without limitation band-pass and long pass filters. Filters may permit the passage of certain wavelengths of light, and block the passage of others. Optionally, multiple types of microscopy (e.g. fluorescence, dark field, bright field, etc.) may be used to acquire images of the same field of view of the sample, in order to acquire different images of the same sample which contain different information relating to the sample. Optionally, video may be used to collect microscopy images. Optionally, microscopy images may be collected in 3-D. For microscopy performed as described herein, the device or system may be configured to link information relating to a cell in one image of the sample to the same cell in a different image of the sample. Based on different images of the same sample and/or same cells, multiple attributes of cells in the sample may be determined. In some aspects, the combination of multiple attributes/multiple pieces of information about cells in a sample may be used to reach a clinical decision and/or to draw a conclusion about the cells that would not be possible based on information from only a single attribute of the cells.” (Para. 0069, emphasis added.)
Holmes in paragraph 0134 discloses the following.
“A biological sample may be dyed, or markers may be added to the sample, or the sample may be otherwise prepared for detection, visualization, or quantification of the sample… For example, a biological sample may be contacted with a solution containing a dye…..For example, a biological sample may be contacted with a solution containing an antibody or an antibody fragment. For example, a biological sample may be contacted with a solution that includes particles. Particles added to a biological sample may serve as standards (e.g., may serve as size standards, where the size or size distribution of the particles is known, or as concentration standards, where the number, amount, or concentration of the particles is known), or may serve as markers (e.g., where the particles bind or adhere to particular cells or types of cells, to particular cell markers or cellular compartments, or where the particles bind to all cells in a sample). Para. 0134 (emphasis added).
Holmes in paragraph 0142 discloses the following.
“Cytometry assays are typically used to optically, electrically, or acoustically measure characteristics of individual cells. For the purposes of this disclosure, "cells" may encompass non-cellular samples that are generally of similar sizes to individual cells, including…proteins, and substances bound to small particles such as beads or microspheres. Such characteristics include… protein content, protein modifications, nucleic acid content,…cell surface (both cellular membrane and cell wall) markers including proteins, lipids, carbohydrates, and modifications thereof. By using appropriate dyes, stains, or other labeling molecules either in pure form, conjugated with other molecules or immobilized in, or bound to nano- or micro-particles, cytometry may be used to determine the presence, quantity, and/or modifications of specific proteins, nucleic acids, lipids, carbohydrates, or other molecules. Properties that may be measured by cytometry also include measures of cellular function or activity, including but not limited to phagocytosis, antigen presentation, cytokine secretion, changes in expression of internal and surface molecules, binding to other molecules or cells or substrates, active transport of small molecules, mitosis or meiosis; protein translation, gene transcription, DNA replication, DNA repair, protein secretion, …Cytometry may also be used to determine information about a population of cells, including but not limited to cell counts, percent of total population, and variation in the sample population for any of the characteristics described above. The assays described herein may be used to measure one or more of the above characteristics for each cell, which may be advantageous to determine correlations or other relationships between different characteristics. The assays described herein may also be used to independently measure multiple populations of cells, for example by labeling a mixed cell population with antibodies specific for different cell lines. A microscopy module may permit the performance of histology, pathology, and/or morphological analysis with the device, and also facilitates the evaluation of objects based on both physical and chemical characteristics. Tissues can be homogenized, washed, deposited on a cuvette or slide, dried, stained (such as with antibodies), incubated and then imaged...” Para. 0142 (emphasis added).
2) US 20110212848 (“Duffy”) (now US Patent 8,236,574, cited in Applicant’s IDS of 8/28/24.)
This reference teaches the following.
Capture beads are used to immobilize analytes. The beads are segregated (such as into wells) for counting in order to determine the concentration of analyte (see for example paras. 0113, 0199, 0203).
The capture objects may comprise a magnetic material which “may facilitate certain aspect of the assay (e.g., washing step).” Para. 0093.
The beads may be magnetic beads. “The magnetic property of the beads may help in separating the beads from a solution (e.g., comprising a plurality of unbound analyte molecules) and/or during washing step(s) (e.g., to remove excess fluid sample, labeling agents, etc.).” Para. 0101.
The analyte may be fluorescently labeled. Para. 0176.
The same system may be used to determine the positioning of the locations containing sample (e.g., reaction vessels). The array comprising the reaction vessels containing capture objects may be illuminated with a "bright field" white light illumination….” Para. 0192 (emphasis added).
“The same system may also be used to determine which locations contain a capture object (e.g., bead). Any particular bead may or may not be associated with an analyte molecule and/or binding ligand. The array may be illuminated (e.g., using light source 473 as shown in FIG. 10A) with a "dark field" white light illumination…The collimated beam is subsequently imaged by the camera….” Para. 0193.
[While Duffy discloses magnetic beads, as well as bright field and dark field microscopy, and fluorescently labeled analyte, Duffy does not teach that the magnetic beads are immobilized during detection.]
3) US 20220178909. This reference teaches imaging a bead with fluorescent label (para. 0145) and using the bead to collect a target using a magnetic field (para. 0165) or to wash (para. 0204). [However, use of the magnetic field is not during detection, such as during dark field microscopy and/or bright field microscopy.]
4) US 20210230583. This reference teaches paramagnetic beads with fluorescent label (para.
0137). Use of a magnetic field for retrieval of beads, and then reacting (para. 0157). A magnetic field is used to deplete to enrich cells (para. 0233). Detection includes bright field, or dark field, or fluorescence microscopy (para. 0247). The particle may be a magnetic bead (para. 0250). An oscillating magnetic field may be used (para. 0121). [However, use of the magnetic field is not during detection, such as during dark field microscopy and/or bright field microscopy.]
US 20210171940. This reference teaches dark-field microscopy detection of beads in
microwells (para. 0176), partitioning beads into wells using a magnetic field (para. 0182). One or more images of microwells using bright field, dark field, and fluorescence microscopy is made (para. 0180). ). [However, use of the magnetic field is not during detection, such as during dark field microscopy and/or bright field microscopy.]
US 20160169880. This reference teaches use of one or more bright field microscopy, dark
field microscopy (para. 1361), and a magnetic field for separation or mixing (para. 1193). ). [However, use of the magnetic field is not during detection, such as during dark field microscopy and/or bright field microscopy.]
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/Ann Montgomery/Primary Examiner, Art Unit 1678