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 .
Claims 1-56 are cancelled.
Claims 57-76 are pending.
Applicant’s election without traverse of Group I, claims 57-57 and 74-76, as well as the species of claim 57 and its dependent claims 58-67 in the reply filed on 10/17/2025 is acknowledged.
Claims 68-76 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on10/17/2025.
Claims 57-67 are under examination on the merits.
Priority
This application is a 371 of PCT/US2020/060500, filed 11/13/2020, which claims benefit of priority to US Provisional Application No. 63/016,758, filed 04/28/2020, and claims benefit of priority to US Provisional Application No. 62/936,147, filed 11/15/2019.
IDS
The information disclosure statements (IDS) filed 11/29/2023, 05/06/2024, and 10/29/2024 have been considered, except where otherwise noted.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Interpretation
Note that a ‘portion’ is never given a closed and clear definition in the instant disclosure. Therefore, the Examiner, in the interest of advancing prosecution, is interpreting the recitations of a “portion” to mean one or more of the individual locations or a terminal portion of the solid support intended for detection.
Note that the recitation of “detecting the presence of a capture agent-molecule of interest complex at each location” in claim 57 is being interpreted to mean that detection is performed at each location and is not being interpreted to require that each location is detected as having the complex present. This interpretation appears to be most consistent with the disclosure in its entirety (see for example, paragraph 0098 at page 20 of the specification, which states that in some embodiments, isolating each capture agent and capture agent-molecule of interest-detection agent complex or subsets of agents and complexes into individual locations within a support may result in the individual locations in the support being populated with a capture agent, a capture agent-molecule of interest-detection agent complex, or neither species; see also paragraphs 0103 and 104 at page 21 of the specification which state that in some embodiments, the methods further include determining the presence or absence of the capture agent and detection agent within each of the individual locations …[where] determining the presence or absence of the capture agent may comprise detection of the magnetic bead).
Recitations of one or more “particle(s)” are being interpreted to include a magnetic bead as is consistent with paragraphs 0081 and 0113 of the instant specification.
Regarding the recitations of “determining a fraction of locations comprising both the capture agent and the detection agent,” this limitation is being interpreted as determining the number of locations comprising both the capture agent and the detection agent relative to the total number or some other number of the individual locations (see for example, paragraphs 0111-0112 of the instant specification at page 23 which are deemed to inform and support this interpretation).
Recitations of “quantifying the concentration….based on the fraction of locations…to locations comprising only capture agent,” are being interpreted as requiring quantification of the concentration of the molecule of interest based upon the number of locations found to comprise both the capture agent and the detection agent relative to the number of locations found to comprise only the capture agent (locations comprising both agents: locations comprising only capture agent) (paragraphs 011-0112 and 0159 at pages 23 and 32 are deemed to inform and support this interpretation).
Claim Objections
Claim 57 is objected to because of the following informalities: The claim drafting is unconventional in that the preamble recites ‘a method comprising’ and the claim body then proceeds to describe a product configuration for use in the method (‘providing a solid support comprising spatially identifiable locations each comprising a capture agent …’). A preamble is generally drafted such that there is a concrete purpose for a claimed method that is explicitly recited, said purpose being accomplished via the method steps of the claims. More conventional drafting of the preamble would be, e.g., a method of detecting a molecule in a sample (as supported by the specification and independent claim 74).
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 57-67 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 57 recites “[a] method…wherein each capture agent pool is isolated to a portion of the individual locations… wherein each sample is isolated to a portion of the individual locations….” A portion(s) is never provided with a closed, clear definition throughout the disclosure. Artisans are left to determine whether this recitation requires that a certain distribution of individual locations along the solid support be occupied by the recited substance or if filling 1 or more individual locations would suffice to meet the claim. Therefore, the claim is indefinite as drafted.
Claims 58-67, via dependence from claim 57, incorporate and fail to remedy this deficiency and are therefore included in this rejection as indefinite.
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.
Claim(s) 57-59 and 63-67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sheehan et al (US 20140127719 A1; citation 1 under US Published Patent Applications in the IDS dated 11/29/2023) in view of Dong et al (WIREs Nanomed Nanobiotechnol 2017, 9:e1457. doi: 10.1002/wnan.1457; citation 1 under Non-Patent Literature in the IDS dated 05/06/2024).
Regarding claim 57, the claim recites a method comprising:
1. providing a solid support
a. comprising spatially identifiable individual locations
b. each spatially identifiable individual location comprising a capture agent from one or more capture agent pools, wherein each capture agent pool comprises at least one type of capture agent each configured to bind a single molecule of interest and be separately detected, and wherein each capture agent pool is isolated to a portion of the individual locations;
2. loading one or more samples comprising one or more of the molecules of interest onto the solid support, wherein each sample is isolated to a portion of the individual locations;
3. incubating to form capture agent-molecule of interest complexes; and
4. detecting the presence of a capture agent-molecule of interest complex at each location.
Sheehan et al teach a method for detecting a non-nucleic acid analyte in a sample, the method comprising:
providing a reaction vessel (solid support) comprising a solid substrate (such as a particle or bead) comprising a bound immobilization agent, wherein the immobilization agent comprises an anti-peptide tag antibody;
providing an antibody capture agent in solution which can bind the analyte, wherein the antibody capture agent comprises a peptide tag ligand for the anti-peptide tag antibody;
providing an antibody detectable agent in solution which can bind to the analyte;
contacting the sample, the capture agent, the detectable agent and the solid substrate in the reaction vessel (held to read upon and make obvious the recited step of loading) to allow the formation of a sandwich immunocomplex comprising the analyte, the antibody capture agent and the antibody detectable agent; and
detecting the analyte by detecting the presence of the antibody detectable agent bound to the solid substrate in the reaction vessel
(see for example, Sheehan’s claims 48 and 59-61). Sheehan et al further teach that a reaction vessel (reading on the solid support as recited in the instant claims), being for example a physical container that allows the contacting of the sample, the capture agent, the detectable agent and the solid substrate to occur in the container. Examples of reaction vessels include a test tube, a micro centrifuge tube, a well, or a flask. In some embodiments, the reaction vessel comprises a well of a multi-well plate, such as a microtitre plate, or a well or surface of a microfluidic device (see for example, paragraph 0120-0124). Sheehan et al further explain that in certain embodiments, the solid substrate is separate to the reaction vessel. In these embodiments, the solid substrate may be mobilizable and may be added to the reaction vessel. For example, the solid substrate may be a bead, such as an art-known/conventional, commercially available magnetic bead to which the immobilization agent (capture antibody binding analyte) may be covalently attached (see for example, paragraphs 0129-131). Microfluidics are discussed in further detail at paragraphs 0417-0429 of Sheehan et al.
Sheehan et al do not explicitly teach the use of the bead attached to the capture agent.
However, Dong et al teach successful adaptation of ELISA to incorporate magnetic beads and microfluidic devices/microchips (see for example, column 2 of page 2-column 1 of page 8) and digital ELISA (see for example, column 2 of page 8-column 2 of page 14; paying particular attention to Figures 7-9 and their captions). Dong et al further discuss the work of Rissin et al, through which a PSA digital ELISA was developed using magnetic beads coated in capture antibody yielding a linear relationship between the concentration of analyte (PSA) and the average number of enzyme labels per bead), extending the dynamic range of the ELISA down to a subfentomolar level in a single measurement (see for example, column 2 of page 14 at the End-Point Protein Measurement with Large Dynamic Range heading at the end of the first paragraph of the 1st column of page 15). Dong et al teach that multichannel microELISA systems are reasonably suitable for ubiquitous assays, including point-of-care testing (POCT) (see for example, column 1 of page 2 and column 2 of page 5). Dong et al are deemed to make obvious the isolation of the capture agent to a portion of the individual locations as well as detection.
With respect to the recitation that “each location comprising a capture agent from one or more capture agent pools, wherein each capture agent pool comprises at least one type of capture agent each configured to bind a single molecule of interest and be separately detected,” the only requirement with any bearing upon the instant method is that the location comprises a capture agent (singular). Therefore, a prepared stock of capture agent would suffice to meet the limitation of a capture agent pool, defined as comprising at least one-four capture agents (see for example, paragraph 0145 at page 30 of the instant specification). Though, with regard to a larger capture agent pool (comprising more than 1 capture agent), Sheehan et al teach that in certain embodiments, more than 1 analyte is detected (see for example, paragraph 0362). In certain embodiments the detection of more than one analyte may be achieved by providing several target-specific antibody capture agents to the reaction vessel, in combination with providing their respective detection agents (see for example, paragraph 0364).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Sheehan et al and Dong et al. The artisan would have been motivated to make and use the invention as claimed because both references teach devices compatible with methods for performing ELISA where Dong et al teach ways to modify/optimize ELISA for POCT and further teach the state of the art regarding ELISA. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 58, as defined at paragraph 0069 of the specification (see page 14 of the instant specification), a probe refers to a molecule that binds specifically or selectively to a molecule [of interest such as the analyte]. 'The probe may be a nucleic acid, an aptamer, an avimer, receptor-binding ligands, binding peptides, protein, small organic molecules, or a metal ligand. The probe may be an antibody, antibody fragment, a bispecific antibody or other antibody-based molecule or compound designed to bind to a specific biomolecule. The probe may be the same type of molecule as the biomolecule, for example, a protein biomolecule may be bound by a peptide-based probe.
Dong et al teach the use of a capture antibody immobilized on a magnetic bead in an immunoassay (see for example, column 2 of page 3 and Figure 2 and its caption at page 4).
The method of claim 58 is obvious for the same reasons that the method of claim 57 is obvious.
Regarding claim 59, as noted in the Claim Interpretation section of this Office Action above, a particle is being interpreted to encompass/include a magnetic bead. This is taught and made obvious by the combination of Sheehan et al and Dong et al (see the rejections of claims 57 and 58 above).
The method of claim 59 is obvious for the same reasons that the method of claim 57 is obvious.
Regarding claim 63, as noted above, Sheehan et al, in view of Dong et al, teach a method comprising contacting the sample, the capture agent, the detectable agent and the solid substrate in the reaction vessel to allow the formation of a sandwich immunocomplex comprising the analyte, the antibody capture agent and the antibody detectable agent and then detecting the analyte by detecting the presence of the antibody detectable agent bound to the solid substrate in the reaction vessel (see for example, claims 48, 59, and 60). Dong et al further teach that such contacting to form a capture-agent-molecule of interest-detection agent complex is well known in the art (see for example, figure 1 and its caption at page 3, figure 2 and its caption at page 4, figure 3 and its caption at page 5, and column 1 and figure 4(a) of page 6).
The method of claim 63 is obvious for the same reasons that the method of claim 57 is obvious.
Regarding claim 64, Dong et al teach that a common ELISA format comprises an enzyme-linked secondary antibody (detection agent which is a probe) configured to bind the molecule of interest and a detection moiety (where the detection moiety may be substrate for the enzyme) (see for example, column 1 of page 2, Figure 1 and its caption at page 3, and the discussion of Kim et al at column 2 of page 3-page 4 including Figure 2 and its caption).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Sheehan et al and Dong et al. The artisan would have been motivated to make and use the invention as claimed because Dong et al teach that contacting the solid support, capture agent, molecule of interest, and detection agent, to form a capture agent-molecule of interest-detection agent complex where the detection agent (a probe (a secondary antibody that is linked to an enzyme) is capable of binding the same molecule of interest as the capture agent as well as binding a detection moiety (substrate) (see paragraph 0010 at page 2 of the instant specification which supports this understanding of the scope of the claim). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 65, the recited step of using software configured to spatially identify the individual locations of the solid support to correlate the presence of capture agent and detection agent with the presence of the molecule of interest is being interpreted to encompass using software capable of measuring the various locations of the solid support to measure the detected signal from the capture agent-molecule of interest-detection agent complex which has reacted with substrate, thereby producing a detectable product/reaction. Note further that the recitation of “using software configured to spatially identify the individual locations” is being interpreted as using any software capable of performing spatial-spectral encoding (the term Applicant used repeatedly throughout the disclosure as encompassing the analysis performed. The instant specification provides descriptive definition of the term “spatial-spectral encoding” at paragraph 0138 of page 28. The Examiner believes that this section supports the Examiner’s interpretation of this limitation in light of the high-level of generality in the claim language.
Dong et al appear to teach an ELISA for analyzing testosterone concentration where the chemiluminescent images were captured using a house-made instrument, and the images were analyzed by Image J software to calculate the testosterone concentration in samples (see for example, the first paragraph of column 2 of page 6; see also figure 10 and its caption at page 14). Dong et al further teach that Chang et al, using a digital ELISA platform, detected fluorescence of each well on a CCD camera, where the fraction of beads associated with at least one enzyme, the average fluorescent intensity of the beads, and the average number of enzyme associated with the beads in an assay were analyzed by the software (which is held to read on the recitation of using software to spatially identify the individual locations) (see for example, column 2 of page 11 of Dong et al). Dong et al appear to further show that analysis by spatially identifying individual locations on the solid support is well known in the art, whether by using software or not (see for example, Figures 7, 9, and 10 at respective pages 10, 13, and 14).
The method of claim 65 is obvious for the same reasons that the method of claims 57, 63, and 64 are obvious.
Regarding claims 66 and 67, Dong et al teach that a microfluidic system for generation and analysis of water-in-oil droplets was developed by Shim et al and was used for digital counting of enzyme molecules. This digital fluidic ELISA used PSA bound to antibody-coated beads which was then sandwiched by a biotinylated detection antibody and a streptavidin-β-galactosidase conjugate. After incubation, three types of femtodroplets, droplets containing no bead, those containing a bead without immunocomplexes, and those containing a bead with an immunocomplex were observed. The droplets exhibited a positive fluorescence signal derived of the activity of a single-enzyme molecule. The numerical ratio of wells with fluorescence signal to wells containing beads yields the concentration of the target analyte (see for example, column 2 of page 13 through column 2 of page 14, including Figure 10 and its caption at page 14). This teaches detection of the fraction (number) of wells with only capture agent and the detection of the fraction (number) of wells with capture agent-molecule of interest-detection agent complexes was known in the art and understood to be relevant for determining the concentration of analyte in the sample (for this example in Dong et al, the concentration of PSA). Where Dong et al, at the caption of figure 10 (see page 14), teach that the numerical ratio of wells containing capture agent-molecule of interest-detection agent complexes to well with only beads coated in capture agent and wells containing capture agent-molecule of interest-detection agent complexes yields the concentration of the target analyte, this is deemed to read upon the claim limitation(s) of instant claim 67 as presently drafted.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Sheehan et al and Dong et al. The artisan would have been motivated to make and use the invention as claimed because Dong et al teach that quantification of the concentration of the molecule of interest based upon the fraction of locations having an immunocomplex (complex of capture agent-molecule of interest-detection agent) is known in the art to be successful, with or without software. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 60-62 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sheehan et al and Dong et al, as applied to claims 57-59 and 63-67 above, in further view of Rissin et al (Lab Chip, 2013,13, 2902-2911; citation 51 under Non-Patent Literature in the IDS dated 11/29/2023).
Regarding claim 60, the instant specification is deemed to best describe a detectable label at paragraph 0081 (noting that this specific term is not mentioned throughout this instant specification).
Sheehan et al and Dong et al do not appear to explicitly teach labeling the beads (capture agent).
However, Rissin et al teach that they developed a method that enables the multiplexed detection of proteins based on counting single molecules. Paramagnetic beads were labeled with fluorescent dyes to create optically distinct subpopulations of beads, and antibodies to specific proteins were then immobilized to individual subpopulations. Mixtures of subpopulations of beads were then incubated with a sample, and specific proteins were captured on their specific beads; these proteins were then labeled with enzymes via immunocomplex formation. The beads were suspended in enzyme substrate, loaded into arrays of femtoliter wells—or Single Molecule Arrays (Simoa)—that were integrated into a microfluidic device (the Simoa disc). The wells were then sealed with oil, and imaged fluorescently to determine: a) the location and subpopulation identity of individual beads in the femtoliter wells, and b) the presence or absence of a single enzyme associated with each bead. The images were analyzed to determine the average enzyme per bead (AEB) for each bead subpopulation that provide a quantitative parameter for determining the concentration of each protein. Rissin et al used this approach to simultaneously detect TNF-α, IL-6, IL-1α, and IL-1β in human plasma with single molecule resolution at subfemtomolar concentrations, i.e., 200- to 1000-fold more sensitive than current multiplexed immunoassays. Rissin et al teach that the simultaneous, specific, and sensitive measurement of several proteins using multiplexed digital ELISA could enable more reliable diagnoses of disease (see for example, the abstract at page 2902).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Sheehan et al, Dong et al, and Rissin et al. The artisan would have been motivated to make and use the invention as claimed because Sheehan et al, Dong et al, and Rissin et al all pertain to the adaptation and use of ELISA where Rissin et al teach that the use of dyed beads create optically distinct subpopulations of beads for later analysis of the localized subpopulations in a multiplexed immunoassay. This would, for example, make distinction of beads comprising only capture agent (not detection agent) more readily visualized for background control. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 61, Rissin et al teach that 7-μm-diameter, carboxyl-functionalized paramagnetic beads were obtained from Agilent Technologies. Alexa Fluor 488 hydrazide was obtained from Life Technologies. Cyanine-5 (cy5) hydrazide was obtained from GE Healthcare. Hilyte 750 hydrazide was obtained from Anaspec (see for example, the Materials section at column 1 of page 2903). Note that Alexa Fluor 488 hydrazide, Cyanine-5 (cy5) hydrazide, and Hilyte 750 hydrazide are known in the art as fluorophores, any one or more of which would have been obvious to include in the method of Sheehan et al, Dong et al, and Rissin et al as a detectable label on the capture agent (such as a dye on the bead to which the capture antibody is attached) which is deemed to make obvious the limitations of instant claim 61.
Claim 61 is obvious for the same reasons that claim 60 is obvious.
Regarding claim 62, Sheehan et al teach that in certain embodiments, more than 1 analyte is detected (see for example, paragraph 0362). In certain embodiments the detection of more than one analyte may be achieved by providing several target-specific antibody capture agents to the reaction vessel, in combination with providing their respective detection agents (see for example, paragraph 0364).
While the Examiner believes that the teachings of Sheehan et al in view of Dong et al would sufficiently teach and make obvious the limitations of instant claim 62, the teachings of Rissin et al more explicitly teach the limitation of loading one or more capture agent pools into the solid support.
Rissin et al teach that a Single Molecule Array (Simoa) disc composed of 24, 3 × 4 mm arrays of ∼216 000 femtoliter wells and individually addressable microfluidic manifolds was placed on the platen of a customized system developed by Stratec Biomedical for the load, seal, and imaging of the arrays. For each sample analyzed, 15 μL of the solution containing the mixture of bead subpopulations (held to read upon one or more capture pool) and RGP was pipetted manually into the inlet port of the disc (held to read upon the limitation of loading the one or more capture pools into the solid support) (see for example, column 2 of page 2903-column 1 of page 2904).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because the combined references teach multiplexed assays where the artisan would have understood the need to have multiple capture agents in order to have an agent specific for each molecule of interest. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ekins et al (US 5516635A; citation 1 under US Patents in the IDS dated 11/29/2023) is deemed relevant and discusses pre-equilibrium quenching and measurements.
Duffy et al (US9310360B2) is deemed relevant.
Link et al (US11187702B2) is deemed relevant.
Kimoto et al (Nucleic Acids Res. 2019 Sep 19;47(16):8362-8374. doi: 10.1093/nar/gkz688), Waritani et al (MethodsX. 2017 Mar 30;4:153-165. doi: 10.1016/j.mex.2017.03.002), Swanson et al (Curr Opin Microbiol. 2012 Jun;15(3):337-47. doi: 10.1016/j.mib.2012.05.015), Drummond, J. (Common ELISA Problems and Solutions, My Assays, available from: https://www.myassays.com/common-elisa-problems-and-solutions.html#:~:text=The%20B%20control%20consists%20of,the%20wash%20process%20is%20needed.; available as of 2015 as evidenced by Wayback Machine), and Mitsuno et al (Biosens Bioelectron. 2015 Mar 15; 65: 287-94) are deemed relevant to the use of a kinetic/non-saturated (preequilibrium) measurement and calculations therefrom.
WO2015109020 A1 (citation 1 under foreign patent literature on the IDS dated 10/29/2024) and Wilson et al (citation 2 under Non-Patent Literature on the IDS dated 05/06/2024) are deemed relevant.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678