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 .
Detailed Action
Summary
This is the Non-Final Office action based on the 18/289130 election response filed 06/01/2026.
Claims 63-88 are pending.
Claims 1-62 are cancelled.
Claims 63-81 are elected.
Claims 82-88 are withdrawn.
Election/Restrictions
Applicant's election with traverse of Claims 63-81 in the reply filed on 06/01/2026 is acknowledged. The traversal is on the ground(s) that applicant has instantly amended Claim 63 of group I to include “a clump at bottom inside surface of the container,” instead of what was previously claimed “a clump inside the container,” so that the claims are now linked to form a single general inventive concept because there is no prior art that has all the special technical features that independent Claim 63 has in common with independent system claim 82. Applicant states that because of the mismatch before the instant amendments of Claim 63 saying that “a clump inside the container,” of magnetic beads was measured through optical emissions and now that both Claim 63 and 82 require “a clump at bottom inside surface of the container,” of magnetic beads being measured through optical emission that the prior art does not teach of this special technical feature. The examiner disagrees and this is not found persuasive because the examiner notes that the prior art does in fact teach of this special technical feature, as instantly amended 06/01/2024. This was actually noted in the restriction requirement dated 04/01/2026 as well.
Specifically, CHEN in US 20120088691 teaches of a bioassay method (paragraph 0003), which is analogous to the instant claims (and also to the bioassay method taught by DANIELLI). CHEN further teaches of a method for analyzing a target in a sample (paragraph 0023), wherein magnetic microbeads and fluorescent reporter molecules are utilized in a microwell/container. CHEN teaches that the microbeads which are encoded can be alternatively suspended or settled, which can be interpreted as “clump,” to the bottom of the microwell by application of the magnetic field and that after each cycle, then beads are settled to the bottom (by the magnetic field), the encoded microbeads are decoded, and the fluorescence signals are monitored by optical imaging (paragraph 0031-0032).
Further, the examiner notes that as group I (elected, which includes Claim 63 and those dependent therefrom), is drawn towards a method, these claims do require the limitation applicant is arguing about, while group II (non-elected Claim 82 and those that depend therefrom) is drawn towards a system/device, so the unelected claims do not require the limitation applicant is arguing about as a limiting claim limitation since it is methodical.
The requirement is still deemed proper and is therefore made FINAL.
Claims 82-88 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 06/02/2026.
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 63- 81 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.
With respect to Claim 63, step a) is unclear. It claims that only “if excited,” that reporter molecules are connected to the beads, but it is not clear where the reporter molecules come from or how the magnetic beads are prepared so they meet the “if excited,” conditional limitation. Further, throughout Claim 63 and all dependent claims, “the beads,” fail to have proper antecedent basis as it is unclear if this is meant to refer back to “the magnetic beads,” or not. Even further for Claim 63, it is unclear if any sample suspected of containing a target molecule is added or not, since no such step is claimed.
Even further for Claim 63, step c)--- what exactly “exciting the optical emission,” means. You do not excite an emission which is a signal itself. You can use and excitation light or wavelength to excite and object when them emits or produces an emission light. Please correct to the claim to make sense.
Even further for Claim 63, steps c) & d), “the reporter molecules connected to the magnetic beads in the clump,” fails to have proper antecedent basis as this phrase was not mentioned before and the connections weren’t specified, so therefore it is unclear what “the,” refers back to.
With respect to Claim 65, “the solution,” fails to have proper antecedent basis as “solution,” was not mentioned prior to this in the claims and therefore it’s unclear what the claims are referring back to.
Further, with respect to Claim 66, it is unclear what is meant by the solution having a depth of less than 4mm above the location on the bottom surface where clump aggregates. With respect to this, it seems is claiming part of a depth of a solution in a container since what is the “bottom,” is somewhat relative. Since bottom is somewhat relative so is the part of the solution “above,” the location. Correction is required to clear up.
With respect to Claim 68, “most,” is a relative term and not defined in the claims and therefore is unclear.
Further with respect to Claim 68, “if,” and “were,” are conditional limitations that would not always occur and therefore it is not clear in the claim. What “if not.”
With respect to Claims 69-70, it is unclear if applicant is referring back to a limitation from Claim 63 or not, since the claim seems to repeat a step, “exciting the optical emission,” which has the same problems as it did in Claim 63, but further it is unclear if applicant is further limiting this prior limitation or not since no “the,” is used, so it seems to have improper antecedent basis.
Claim 73 also fails to have proper antecedent basis as it is unclear if it is referring back to a “measuring the emission,” that already happened or not and therefore fails to have proper antecedent basis.
With respect to Claim 73, “fully,” is a relative term and not defined in the claims and therefore unclear.
With respect to Claim 75, “sharp,” is a relative term and not defined in the claims and therefore unclear.
With respect to Claim 78 also fails to have proper antecedent basis as it is unclear what “the solution,” is referring back to.
With respect to Claim 79, “will depend on,” and what follows it in the claim is a conditional statement and therefore is not always required. Therefore, it is unclear as claimed what the claim is limited to.
With respect to Claim 80, “most,” is a relative term not defined in the claim and therefore unclear.
Claims 64-81 are also rejected by virtue of their dependency on Claim 1.
Claim Rejections - 35 USC § 103
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 non-obviousness.
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 63, 69-75, 77-81 are rejected under U.S.C. 103 as being obvious by DANIELLI in WO 2018185672 in view of CHEN in US 20120088691.
With respect to Claim 63, DANIELLI teaches of an assay method for target molecules including:
providing a container which has a capture surface inside it (Page 10, lines 8-21).
a) exposing a capture surface of the capture surface elements to the biological sample, capturing molecules of the analyte;
b) binding the analyte molecules to fluorescent reporting molecules;
c) exposing the capture surface to excitation light from an excitation light source, the same as or different from the light source used for bleaching, after exposing the capture surface to the biological sample and binding the analyte molecules to the reporting molecules, the excitation light having a wavelength distribution that would excite the autofluorescence of the capture surface elements;
d) measuring a fluorescence signal/optical emission, emitted by the reporting molecules bound to the captured analyte molecules, in response to the excitation light, over a band of emission wavelengths; and
e) determining a presence of the analyte in the sample, a concentration of the analyte in the sample, or both, from the measured fluorescence signal (Page 7, lines 4-20).
More specifically- when the system in DANIELLI is used for a bioassay as is shown above, DANIELLI further specifies that the beads can be magnetic and magnetized through a magnetic field and field gradient on the side/part of the container which is adjacent to the magnet.
DANIELLI teaches that magnets 204 and 206 can be permanent magnets or rate earth magnets, and that the magnetic field can cause the beads to stick together in a clump, and that depending on strength, the magnetic field can cause the clump of beads to move around the container or .5 seconds. DANIELLI also teaches that the magnetic field causes the clump in .1 to 2 seconds, which reads on the claimed “less than 30 seconds) (See Figure 2 and associated description including Page 45, paragraph 2 and Page 42, paragraph 3).
Even further, DANIELLI teaches that the reporter molecules/magnetic bead combination puts out detectable emissions, and teaches of detecting these emissions (Page 45, line 11-32) (Also see flowchart 500 on Figure 5 and description of it on Page 54, lines 4- end of page and Page 6, lines 1-25).
DANIELLI teaches as shown above that the magnetic field can cause the beads to stick together in a clump, and that depending on strength, the magnetic field can cause the clump of beads to move around the container, which therefore makes detecting the clump anywhere in the container (including at the bottom inner surface as claimed) obvious.
However, since DANIELLI does not call out specifically detection of the clump at the bottom inner surface, CHEN is used to remedy this.
CHEN teaches of a bioassay method (paragraph 0003), which is analogous to the instant claims (and also to the bioassay method taught by DANIELLI). CHEN further teaches of a method for analyzing a target in a sample (paragraph 0023), wherein magnetic microbeads and fluorescent reporter molecules are utilized in a microwell/container. CHEN teaches that the microbeads which are encoded can be alternatively suspended or settled, which can be interpreted as “clump,” to the bottom of the microwell by application of the magnetic field and that after each cycle, then beads are settled to the bottom (by the magnetic field), the encoded microbeads are decoded, and the fluorescence signals are monitored by optical imaging (paragraph 0031-0032).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to detect (clumped) beads at a bottom flat surface as done in CHEN in the method of DANIELLI due to the advantage this offers in being useful for both the assay and for optical or fluorescence detection in one microwell or container (CHEN, paragraphs 0030-0032, 0040) and due to the advantage that multiple reactions and assays can be processed and monitoring by optical image processing in a single microwell (CHEN, paragraph 0240).
With respect to Claim 69, DANIELLI teaches of exposing the capture surface to excitation light from an excitation light source, the same as or different from the light source used for bleaching, after exposing the capture surface to the biological sample and binding the analyte molecules to the reporting molecules, the excitation light having a wavelength distribution that would excite the autofluorescence of the capture surface elements;
d) measuring a fluorescence signal/optical emission, emitted by the reporting molecules bound to the captured analyte molecules, in response to the excitation light, over a band of emission wavelengths; and
e) determining a presence of the analyte in the sample, a concentration of the analyte in the sample, or both, from the measured fluorescence signal (Page 7, lines 4-20).
Even further, DANIELLI teaches that the reporter molecules/magnetic bead combination puts out detectable (optical) emissions, and teaches of detecting these emissions (Page 45, line 11-32) (Also see flowchart 500 on Figure 5 and description of it on Page 54, lines 4- end of page and Page 6, lines 1-25).
Even further, DANIELLI teaches of making background (background volumes )correction and thresholding based on illumination and making corrections based on this (Figure 9, paragraph 0099, 0087, 0247).
With respect to Claim 70, see Claim 63 rejection. DANIELLI further teaches of illuminating magnetic beads in a clump with excitation light (Page 50, last paragraph and Page 51, first paragraph). DANIELLI does not call out specifically detection of the clump at the bottom inner surface, CHEN is used to remedy this.
CHEN teaches of a bioassay method (paragraph 0003), which is analogous to the instant claims (and also to the bioassay method taught by DANIELLI). CHEN further teaches of a method for analyzing a target in a sample (paragraph 0023), wherein magnetic microbeads and fluorescent reporters molecules are utilized in a microwell/container. CHEN teaches that the microbeads which are encoded can be alternatively suspended or settled, which can be interpreted as “clump,” to the bottom of the microwell by application of the magnetic field and that after each cycle, then beads are settled to the bottom (by the magnetic field), the encoded microbeads are decoded, and the fluorescence signals are monitored by optical imaging (paragraph 0031-0032).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to detect (clumped) beads at a bottom flat surface as done in CHEN in the method of DANIELLI due to the advantage this offers in being useful for both the assay and for optical or fluorescence detection in one microwell or container (CHEN, paragraphs 0030-0032, 0040) and due to the advantage that multiple reactions and assays can be processed and monitoring by optical image processing in a single microwell (CHEN, paragraph 0240).
With respect to Claim 71, DANIELLI teaches of the above, but does not call out specifically illuminating the bottom surface, or of the clump at the bottom inner surface, CHEN is used to remedy this.
CHEN teaches that the microbeads which are encoded can be alternatively suspended or settled, which can be interpreted as “clump,” to the bottom of the microwell by application of the magnetic field and that after each cycle, then beads are .settled to the bottom (by the magnetic field), the encoded microbeads are decoded, and the fluorescence signals are monitored by optical imaging—at the bottom surface (both during and after aggregation) (paragraph 0031-0032) and also of monitoring over time (Figure 3, Figure 26).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to detect (clumped) beads at a bottom flat surface as done in CHEN in the method of DANIELLI due to the advantage this offers in being useful for both the assay and for optical or fluorescence detection in one microwell or container (CHEN, paragraphs 0030-0032, 0040) and due to the advantage that multiple reactions and assays can be processed and monitoring by optical image processing in a single microwell (CHEN, paragraph 0240).
With respect to Claim 72, DANIELLI teaches that the reporter molecules/magnetic bead combination puts out detectable (optical) emissions, and teaches of detecting these emissions (Page 45, line 11-32) (Also see flowchart 500 on Figure 5 and description of it on Page 54, lines 4- end of page and Page 6, lines 1-25).
Even further, DANIELLI teaches of making background (background volumes) correction and thresholding based on illumination and making corrections based on this (Figure 9, paragraph 0099, 0087, 0247).
With respect to Claim 72, DANIELLI teaches of an assay method for target molecules including:
providing a container which has a capture surface inside it (Page 10, lines 8-21).
a) exposing a capture surface of the capture surface elements to the biological sample, capturing molecules of the analyte;
b) binding the analyte molecules to fluorescent reporting molecules;
c) exposing the capture surface to excitation light from an excitation light source, the same as or different from the light source used for bleaching, after exposing the capture surface to the biological sample and binding the analyte molecules to the reporting molecules, the excitation light having a wavelength distribution that would excite the autofluorescence of the capture surface elements;
d) measuring a fluorescence signal/optical emission, emitted by the reporting molecules bound to the captured analyte molecules, in response to the excitation light, over a band of emission wavelengths; and
e) determining a presence of the analyte in the sample, a concentration of the analyte in the sample, or both, from the measured fluorescence signal (Page 7, lines 4-20).
DANIELLI does not call out specifically detection of the clump at the bottom inner surface, CHEN is used to remedy this.
CHEN teaches of a bioassay method (paragraph 0003), which is analogous to the instant claims (and also to the bioassay method taught by DANIELLI). CHEN further teaches of a method for analyzing a target in a sample (paragraph 0023), wherein magnetic microbeads and fluorescent reporter molecules are utilized in a microwell/container. CHEN teaches that the microbeads which are encoded can be alternatively suspended or settled, which can be interpreted as “clump,” to the bottom of the microwell by application of the magnetic field and that after each cycle, then beads are settled to the bottom (by the magnetic field), the encoded microbeads are decoded, and the fluorescence signals are monitored by optical imaging (paragraph 0031-0032).
CHEN further teaches of monitoring over time(paragraph 0031-0032, 0204, 0294). See reason for combination from Claim 63.
With respect to Claim 73, DANIELLI teaches of an assay method for target molecules as shown above.
DANIELLI does not call out specifically detection of the clump at the bottom inner surface, CHEN is used to remedy this.
CHEN teaches of a bioassay method (paragraph 0003), which is analogous to the instant claims (and also to the bioassay method taught by DANIELLI). CHEN further teaches of a method for analyzing a target in a sample (paragraph 0023), wherein magnetic microbeads and fluorescent reporter molecules are utilized in a microwell/container. CHEN teaches that the microbeads which are encoded can be alternatively suspended or settled, which can be interpreted as “fully aggregated” to the bottom of the microwell by application of the magnetic field and that after each cycle, then beads are settled to the bottom (by the magnetic field), the encoded microbeads are decoded, and the fluorescence signals/emissions are monitored for target concentration by optical imaging (paragraph 0031-0032).
CHEN further teaches of monitoring over time (paragraph 0031-0032, 0204, 0294). See reason for combination from Claim 63.
With respect to Claim 74, DANIELLI teaches of the above, but does not call out the specific claiming of measuring increased emission as claimed. CHEN is used to remedy this and teaches of measuring fluorescence (emission) increases in each cycle(paragraph 0009). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor the emission over cycles or times as is done in CHEN in the method of DANIELLI due to the advantage this has is showing probe cleavage (CHEN, paragraph 0009).
With respect to Claim 75, DANIELLI teaches of the magnets (204 and 206) having a magnetic pole tip (210 & 208) that have sharp points through broadest reasonable interpretation which are in the direction of magnetization, and the magnets with the tips are located outside the container and is part of the magnets surfaces closest to the container (See Figure 2 and Figure 2 description) (Page 42, last paragraph and Page 43, paragraphs 1-2).
With respect to Claim 77, DANIELLI teaches that the beads are placed in the container and the magnetic field gradient is on however field gradient produced by the magnet at the portion of the container are sufficiently strong to magnetically aggregate the beads and attract them to the portion of the container, when the magnet is brought closer to the portion of the container, but not strong enough to aggregate or attract the beads to the portion of the container when the magnet is further from the portion of the container (Page 15, lines 9-15).
With respect to Claim 78, DANIELLI teaches that the beads are placed in the container and the magnetic field gradient is on however field gradient produced by the magnet at the portion of the container are sufficiently strong to magnetically aggregate the beads and attract them to the portion of the container, when the magnet is brought closer to the portion of the container, but not strong enough to aggregate or attract the beads to the portion of the container when the magnet is further from the portion of the container (Page 15, lines 9-15). DANIELLI further teaches of the clumping being based on the magnetic being on for .5 seconds, so “within 10 seconds” (Page 42, last paragraph and Page 43, paragraphs 1-2).
With respect to Claim 79, DANIELI teaches of the invention as shown above, however they do not call out the method steps as claimed in Claim 79.
CHEN is used to remedy this and teach of preparing of a plurality of samples, each containing multiple labeled microbeads, a fluorescence probe and target molecules; each encoded microbead having a specific encoding pattern such as a barcode pattern; (b) placing each sample in one of a plurality of sample wells of a thermal cycler instrument, each sample well having a flat surface; stimulating a reaction using the thermal cycle instrument; (c) taking an optical image and a fluorescence image of the labeled microbeads when the barcode magnetic beads settling down to the flat surface of the sample wells, the thermal cycler in operating; (d) decoding the specific barcode pattern and measuring the fluorescence intensity of each encoded microbead with the barcode optical image and the fluorescence image, respectively; and (e) quantifying specific target molecules based on the fluorescence intensity on the specific labeled microbeads reacting with fluorescence probe and target molecules (paragraph 0031-0032). CHEN teaches that the reaction occurs in a sample chamber (paragraph 0242) and on a microplate where the beads are settled to the bottom (paragraph 0245). See reason for combination from Claim 63.
With respect to Claim 80, DANIELLI teaches of an assay method for target molecules including:
providing a container which has a capture surface inside it (Page 10, lines 8-21).
a) exposing a capture surface of the capture surface elements to the biological sample, capturing molecules of the analyte;
b) binding the analyte molecules to fluorescent reporting molecules;
c) exposing the capture surface to excitation light from an excitation light source, the same as or different from the light source used for bleaching, after exposing the capture surface to the biological sample and binding the analyte molecules to the reporting molecules, the excitation light having a wavelength distribution that would excite the autofluorescence of the capture surface elements;
d) measuring a fluorescence signal/optical emission, emitted by the reporting molecules bound to the captured analyte molecules, in response to the excitation light, over a band of emission wavelengths; and
e) determining a presence of the analyte in the sample, a concentration of the analyte in the sample, or both, from the measured fluorescence signal (Page 7, lines 4-20).
More specifically- when the system in DANIELLI is used for a bioassay as is shown above, DANIELLI further specifies that the beads can be magnetic and magnetized through a magnetic field and field gradient on the side/part of the container which is adjacent to the magnet.
DANIELLI teaches that magnets 204 and 206 can be permanent magnets or rate earth magnets, and that the magnetic field can cause the beads to stick together in a clump, and that depending on strength, the magnetic field can cause the clump of beads to move around the container or .5 seconds. DANIELLI also teaches that the magnetic field causes the clump in .1 to 2 seconds, which reads on the claimed “less than 30 seconds) (See Figure 2 and associated description including Page 45, paragraph 2 and Page 42, paragraph 3).
Even further, DANIELLI teaches that the reporter molecules/magnetic bead combination puts out detectable emissions, and teaches of detecting these emissions (Page 45, line 11-32) (Also see flowchart 500 on Figure 5 and description of it on Page 54, lines 4- end of page and Page 6, lines 1-25).
DANIELLI teaches as shown above that the magnetic field can cause the beads to stick together in a clump, and that depending on strength, the magnetic field can cause the clump of beads to move around the container, which therefore makes detecting the clump anywhere in the container (including at the bottom inner surface as claimed) obvious.
DANIELLI also teaches of the above happening in and around a micro-fluidic channel wherein the channel is illuminated by the light source (Page 6, paragraph 1).
However, since DANIELLI does not call out specifically detection of the clump at the bottom inner surface, CHEN is used to remedy this.
CHEN teaches of a bioassay method (paragraph 0003), which is analogous to the instant claims (and also to the bioassay method taught by DANIELLI). CHEN further teaches of a method for analyzing a target in a sample (paragraph 0023), wherein magnetic microbeads and fluorescent reporter molecules are utilized in a microwell/container. CHEN teaches that the microbeads which are encoded can be alternatively suspended or settled, which can be interpreted as “clump,” to the bottom of the microwell by application of the magnetic field and that after each cycle, then beads are settled to the bottom (by the magnetic field), the encoded microbeads are decoded, and the fluorescence signals are monitored by optical imaging (paragraph 0031-0032).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to detect (clumped) beads at a bottom flat surface as done in CHEN in the method of DANIELLI due to the advantage this offers in being useful for both the assay and for optical or fluorescence detection in one microwell or container (CHEN, paragraphs 0030-0032, 0040) and due to the advantage that multiple reactions and assays can be processed and monitoring by optical image processing in a single microwell (CHEN, paragraph 0240).
With respect to Claim 81, DANIELLI teaches that the beads are placed in the container and the magnetic field gradient is on however field gradient produced by the magnet at the portion of the container are sufficiently strong to magnetically aggregate the beads and attract them to the portion of the container, when the magnet is brought closer to the portion of the container, but not strong enough to aggregate or attract the beads to the portion of the container when the magnet is further from the portion of the container (Page 15, lines 9-15). DANIELLI further teaches of the clumping being based on the magnetic being on for .5 seconds, so “within 10 seconds” (Page 42, last paragraph and Page 43, paragraphs 1-2).
Claims 64-65, 76 are rejected under U.S.C. 103 as being obvious by DANIELLI in WO 2018185672 in view of CHEN in US 20120088691 and in view of SCHMALENBERG in Magnetic bead fluorescent immunoassay for the rapid detection of the novel inflammation marker YKL40 at the point-of-care (as cited on IDS dated 01/08/2024).
With respect to Claim 64, DANIELLI and CHEN teach of the invention as shown above, but do not specifically call out that the magnet is located beneath the chamber.
SCHMALENBERG is used to remedy this and teaches of a system for measuring an optical emission signal from a quantity of magnetic beads in an assay of target molecules in a sample, comprising:
a) a container configured for holding the magnetic beads in a volume of a solution ( fig. 1);
b) one or more magnets beneath the container, the magnets producing a magnetic field with a field gradient in the volume of solution that attracts the beads to form a clump at a bottom inner surface of the container adjacent to at least one of the magnets and wherein the magnetic field vector is shown going both vertically and horizontally ( fig. 1A, second and 3rd in the flow chart where the magnet is beneath the chambers, Sect. 3.1);
c-d) detection optics and a light sensing device that receives and measures the optical emission signal from the clump of magnetic beads and a recording device that outputs and/or stores data of the optical emission signal (sect. 2.2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a magnet beneath a chamber with vertical field as is done in SCHMALENBERG in the methods of DANIELLI and CHEN due to the advantage this offers for magnetically separating components (See SCHMALENBERG, Figure 1, description).
With respect to Claim 65, see Claim 64 rejection. The magnetic clumping is already taught by DANIELLI and CHEN, do not call out magnets under the chamber.
Specifically, SCHMALENBERG teaches the magnets being located below the chamber ( fig. 1A, second and 3rd in the flow chart where the magnet is beneath the chambers, Sect. 3.1);
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a magnet beneath a chamber with vertical field as is done in SCHMALENBERG in the methods of DANIELLI and CHEN due to the advantage this offers for magnetically separating components (See SCHMALENBERG, Figure 1, description).
With respect to Claim 76, DANIELLI and CHEN teach of the invention as shown above, but do not specifically call out that specifically using different sample and different wells and the positioning of each well plate tube are is over the one or more magnets.
SCHMALENBERG is used to remedy this and teaches of repeating the measurements wherein the tube scanner which has the magnet is under each tube (Page 37, column 1, last paragraph, and Figure 1, and Page 38, 3.2.2.2 & 3.2.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to repeat the measurements as done in SCMALENBERG in the method of DANIELLI and CHEN due to the advantage this would give for monitoring a time course and assay optimization for different samples (Page 37, last paragraph, Page 38, column 2, paragraph 1).
Claims 66-68 are rejected under U.S.C. 103 as being obvious by DANIELLI in WO 2018185672 in view of CHEN in US 20120088691 and in view of SCHMALENBERG in Magnetic bead fluorescent immunoassay for the rapid detection of the novel inflammation marker YKL40 at the point-of-care (as cited on IDS dated 01/08/2024) and further in view of BURG in Magnetically aggregated biosensors for sensitive detection of biomarkers at low concentrations (both as cited on IDS dated 01/08/2024).
With respect to Claim 66, DANIELLI and CHEN teach of the invention as shown above, but do not specifically call out that the solution has a depth of less than 4 mm above the location on the bottom surface where the clump aggregates.
SCHMALENBERG is used to remedy this and teaches of a system for measuring an optical emission signal from a quantity of magnetic beads in an assay of target molecules in a sample, comprising:
a) a container configured for holding the magnetic beads in a volume of a solution ( fig. 1);
b) one or more magnets beneath the container, the magnets producing a magnetic field with a field gradient in the volume of solution that attracts the beads to form a clump at a bottom inner surface of the container adjacent to at least one of the magnets and wherein the magnetic field vector is shown going both vertically and horizontally ( fig. 1A, second and 3rd in the flow chart where the magnet is beneath the chambers, Sect. 3.1);
SCHMALENBERG further teaches of using PCR tubes (Page 37, column 1, paragraph 3) and of aliquoting 10ul or regent into each tube (Page 37, column 2, last paragraph). SCHMALENBERG further teaches that the tubes are less than halfway full (See figure 1A on Page 38, bottom portion of the drawing). The examiner notes that PCR tubes are small, and usually have a depth of 14 mm to 20 mm.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a magnet beneath a chamber with vertical field as is done in SCHMALENBERG in the methods of DANIELLI and CHEN due to the advantage this offers for magnetically separating components (See SCHMALENBERG, Figure 1, description).
However, SCHMALENBERG still does not call out the size of the tube.
BURG is used to remedy this teaches an assay method for target molecules in a sample using optical emission from magnetic beads (abstract), comprising: a) preparing the magnetic beads so, if excited, they produce optical emission as a consequence of contact between the beads, reporter molecules and target molecules in the sample (figs. 1 and 3; p. 111, columns-bridging para.); b) providing the prepared magnetic beads in a solution in a container, with one or more magnets producing a magnetic field inside the container that causes the beads to aggregate into a clump inside the container; c) exciting the optical emission from the magnetic beads in the clump; and d) measuring the optical emission from the magnetic beads in the clump (abstract, figs. 1(b) and 3).
BURG further teaches of using a sample cell tube that has a size of 10 by 4.5 by 23 (Page 115, column 2, paragraph 4 and Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a sample cell and solution in it of the size of BURG in the methods of SCHMALENBURG, DANIELLI and CHEN due to the advantage it offers in coming pre-made and since it works well with the biosensor assay system in BURG (Page 115, column 2, paragraph 4 and Figure 1).
With respect to Claim 67, DANIELLI teaches of the magnets (204 and 206) having a magnetic pole tip (210 & 208) that have sharp points through broadest reasonable interpretation which are in the direction of magnetization, and the magnets with the tips are located outside the container and is part of the magnets surfaces closest to the container (See Figure 2 and Figure 2 description) (Page 42, last paragraph and Page 43, paragraphs 1-2).
DANIELLI further teaches that the beads are placed in the container and the magnetic field gradient is on however field gradient produced by the magnet at the portion of the container are sufficiently strong to magnetically aggregate the beads and attract them to the portion of the container, when the magnet is brought closer to the portion of the container, but not strong enough to aggregate or attract the beads to the portion of the container when the magnet is further from the portion of the container (Page 15, lines 9-15). DANIELI further adjusting the magnetic field gradient and the magnet positions based on the desired result, which makes the gradient claimed obvious (Page 47, lines 8-25).
With respect to Claim 68, DANIELLI teaches When light beam 216 reaches container 202, it is narrower than the width of the container between the two magnetic poles, and consequently, if the clump of beads travels from one side of the container to the other, then it will only be illuminated by beam 216 over part of its path, for only part of its travel time. Optionally, the magnetic poles are positioned so that clump 212 forms close to the front of container 202, so that beam 216 has to travel through very little water in order to reach clump 212. Also, the clump is optionally much wider than beam 216, and optionally the clump is thick enough to absorb or scatter most of the light in beam 216. This has the potential advantage that there will be very little Raman scattering of beam 216 from the water in container 202, when the clump is in the path of the beam. However, in some tests performed by the inventors with a system similar to system 200, described below, the clump of beads was not much wider than the beam, and was not thick enough to absorb or scatter most of the light in beam 216 (Page 43, last 3 lines- Page 44, line 10). This makes the claimed limitations about the travel time obvious.
Conclusion
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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