DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application was filed on 07/12/2023. This application claims benefit of U.S. Provisional Patent Applications 63/389,430 filed 07/15/2022 and 63/399,544 filed 08/19/2022. The effective filing date of this instant application is 07/15/2022.
Claim Status
Claims 68-76 and 96-106 are pending and examined herein below.
Information Disclosure Statement
Five Information Disclosure Statements (IDS), filed 10/10/2023, 05/22/2024, 12/31/2024, 06/11/2025, and 10/29/2025, are acknowledged and have been considered. One U.S. Patent reference in IDS filed 10/10/2023 is stricken for the reason detailed herein. U.S. Patent Cite No. 72 is stricken because it is a duplicate of U.S. Patent Cite No. 36 in IDS filed on 10/10/2023.
Regarding NPL reference cite No. 49, Ewens, in IDS filed on 10/10/2023, the scanned document does not show page numbers. NPL reference cite No. 49, Ewens, is used as an evidentiary reference for 35 USC 101 rejection, Eligibility Step: 2B, using the page numbers applicant provided in the specification of this instant application.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 75, 102, and 104-106 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to an abstract idea without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101
(see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e.,
mathematical concepts, certain methods of organizing human activity such as a fundamental
economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application
(see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception
into a practical application, do we then look to whether the claim contains an “‘inventive
concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible
application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood,
routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to
the industry, specified at a high level of generality, to the judicial exception. See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL
EXCEPTION
Step 2A, Prong 1
Claim 75 recites “using Poisson statistical treatment,” given the broadest reasonable interpretation in light of the specification in this instant application, this treatment involves observing and counting the number of binding/dissociation events in a given time interval, which is an abstract mental process. 'The courts consider a mental process (thinking) that "can be performed in the human mind, or by a human using a pen and paper" to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work’ that are open to all.’" 654 F.3d at 1371, 99USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)). See also Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012) ("‘[M]ental processes[] and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work’" (quoting Benson, 409 U.S. at 67, 175 USPQ at 675)); Parker v. Flook, 437 U.S. 584, 589, 198 USPQ 193, 197 (1978) (same). Accordingly, the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions. See MPEP 2106.049(a)(2). Claims can recite a mental process even if they are claimed as being performed on a computer. The Supreme Court recognized this in Benson, determining that a mathematical algorithm for converting binary coded decimal to pure binary within a computer’s shift register was an abstract idea. The Court concluded that the algorithm could be performed purely mentally even though the claimed procedures "can be carried out in existing computers long in use, no new machinery being necessary." 409 U.S at 67, 175 USPQ at 675. see MPEP 2106.04(a)(2)(III)(c).
Further regarding claim 75, “counting the number of binding/dissociation events in a given time interval” is subjected to statistical analysis which is directed to mathematical calculations (spec, pg. 30, lines 7-18 and pg. 30 lines 26-30- pg. 31, lines ). See for example, MPEP 2106.04(a)(2)(I)(C), regarding examples of mathematical calculations recited in a claim, including for example, statistical analyses.
Claim 102 recites “counting a first number of changes” and “counting a second number of changes,” which involves observation and calculations that can be performed in the human mind and thus is considered an abstract mental process. Under the Alice/Mayo framework, simply counting changes without a "specific, technical improvement" to a computer or technological process is considered an abstract idea. Further, given the broadest reasonable interpretation in light of the specification in this instant application, “counting” may be performed using one or more of several different algorithms (spec pg. 24, lines 31-32 through pg. 25, lines 1-3), which are considered mathematical formulas or equations. Example of case law for how the courts have recognized mathematical algorithms as an abstract idea in Benson was set forth above. see MPEP 2106.04(a)(2)(III)(c).
Claim 104 recites “producing an intensity fluctuation map by determining an average absolute image-to-image change in intensity” involves observing, measuring, analyzing, calculating, and mapping spatial or temporal variations in pixel brightness, can may be performed by a processor (spec pg. 7, lines 27-30), is directed to a mental process and mathematical formula or equation. As discussed above, claims can recite a mental process even if they are claimed as being performed on a computer. see MPEP 2106.04(a)(2)(III)(c).
Claim 105 recites “generating intensity-versus-time data” which is a mathematical relationship between intensity and a unit of time. A mathematical relationship may be expressed in words or using mathematical symbols. See MPEP 2106.049(a)(2). Further, claim 105 also recites “calculating a kinetic parameter from the intensity-versus-time data” which is a mathematical formular or equation.
Claim 106 recites “identifying positive detection events using a threshold for the kinetic parameter,” which is an abstract mental process. The "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions.' See MPEP 2106.049(a)(2).
Regarding this instant claim, identifying a positive value, or judging the suitability of a value, based on comparison to a threshold is a process that can be performed in the human mind or using pen and paper, and thus amounts to an abstract idea.
Step 2A, Prong 2
This judicial exception is not integrated into a practical application because the additional elements of recording changes in signal intensities for two analytes in a single field of view (claim 103), recording a series of images of time-dependent changes in signal intensities for two analytes (claim 74), and using the data to characterize, identify, quantify, distinguish, and/or detect each analyte (claims 73, 76) are extra-solution activities, namely data collection steps, that does not add a meaningful limitation to the abstract idea. Further, a generic processor may be used as a tool to perform the recording and counting steps (claims 74, 102-103), to generate the fluctuation maps and time-dependent data (claims 104-105), calculate the kinetic parameter (claim 106), and perform the Poisson mathematical and statistical analyses (claim 75) but the claims do not recite any algorithm used to perform these activities as resulting in an improvement to the functioning of the processor or technology, and therefore does not add a meaningful limitation (spec pg. 4, lines 15-21).
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS
The claims do not include additional elements that are sufficient to amount to
significantly more than the judicial exception because recording changes in signal intensities, subjecting the data to a Poisson statistical treatment, and to characterize, quantify, identify, detect and distinguish between analytes, amount to data collection steps. The specification discloses the use of a processor to carry out these data collection steps and to perform the mathematical and statistical methods. The specification further discloses that, at the time of filing, the use of a Poisson statistical treatment of data was known, routine, and conventional in the art (spec pg. 30, lines 7-31 and see Ewens, Stochastic Processes (i): Poisson Processes and Markov Chains" in Statistics for Biology and Health - Statistical Methods in Bioinformatics (Ewens, Grant, eds.), Springer (New York, 2001), pgs. 129- , filed in IDS on 10/10/2023 as NPL cite No. 49).
Further, the additional elements of recording a series of images of a molecular kinetic event, processing the images as recited in claims 73-75 and 102-103, producing intensity fluctuation data that is used to generate intensity versus time data, calculating kinetic parameters, and using a threshold kinetic parameter to detect positive events are data collection and analysis steps well-known in the art. For instance, Chatterjee at al., in the same field of endeavor, teaches the single-molecule detection and quantification of analytes by detecting the transient interactions between immobilized analytes and fluorescent labeled probes by recording these interactions as a series of images of fluorescent signals. Chatterjee further teaches processing the images acquired which includes the use of a processor to determine intensity fluctuations in the images, calculating the intensity versus time traces, and using modelling software to determine kinetic parameters including bound and unbound states (Nb+d) and lifetimes (τbound and τunbound). Chatterjee also teaches using these kinetic parameters to differentiate between true positive events and background [Tanmay Chatterjee, et al., Ultraspecific analyte detection by direct kinetic fingerprinting of single molecules, 2020, Trends in Analytical Chemistry, 123, 115754, pg. 6, full para 1, filed in IDS on 10/10/2023 as NPL cite No. 28]. Using data acquired from processed recorded images to generate intensity-versus-time data and calculate a kinetic parameter is further shown to be routine and conventional data collection and analysis steps by Jansen et al. For instance, Jansen et al., teaches collecting a series of MRI images of benign and malignant lesions and using either institutional or commercially available software to generate volumetric regions of interest (ROI) and signal versus time curves, or kinetic curves. Jansen further teaches using the intensity-versus-time data, or a kinetic curve, to calculate a kinetic parameter to determine if these parameters are consistent for all images of malignant lesions acquired using different protocols (Jansen et al., Kinetic Curves of Malignant Lesions Are Not Consistent Across MRI Systems: Need for Improved Standardization of Breast Dynamic Contrast-Enhanced MRI Acquisition, 2009, AJR Am J Roentgenol., pg. 1, “Abstract,” and pg. 3, full para 2-3 under “Kinetic Analysis” ).
For these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 68-73, 75-76, 96, 98, 100, and 102-106 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Walter et al., US Patent No. US 10,093,967 B2 (filed in IDS on 10/10/2023 as cite No. 36).
Walter teaches a method, kit, and systems for detecting, identifying, and quantifying one, two, or more unlabeled analytes with single-molecule resolution. Target analytes are immobilized on a solid surface by capture probes (col 2, lines 39-41 and Fig. 1A). The method taught by Walter exploits the transient binding/dissociation events between an immobilized analyte and a labeled query probe. Walter teaches the binding between analyte and query probe is a Poisson process, which means each binding event is memoryless, discrete and independent and occurs randomly in a given time with a constant rate (col 2, lines 46-50). Walter also teaches that binding kinetics between target analyte and query probe differ from the kinetics from nonspecific binding with nontargets (col 9, lines 47-56). Walter further teaches detecting binding/dissociation events via fluorescent emission signals from the labeled query probe and determining binding events from changes in signal intensity (col 3, lines 1-34; col 16, lines 51-61; col 80, lines 38-60). After statistical treatment of the collected data, binding patterns can be generated for each analyte to develop a “kinetic fingerprint” that is unique to each analyte. Kinetic fingerprints allow for discrimination between analytes and from background noise, enabling a highly sensitive and accurate method for identifying, quantifying, and characterizing analytes (col 18, lines 15-22; col 23, lines 5-11; and col 19, lines 50-67- col 20, lines 1-6).
Regarding claim 68, Walter teaches a multiplex method for detecting a plurality of analytes (col 36, line 52-59), said method comprising: stably binding a first analyte to a solid support (col 36, lines 60-67); stably binding a second analyte to the solid support; providing a first query probe comprising a first detectable label (col 36, lines 60-67), wherein the first query probe is specific for the first analyte (col 36, line 67 - col 37, lines 1-3); providing a second query probe comprising a second detectable label (col 36, line 67 - col 37, lines 1-3), wherein the second query probe is specific for the second analyte (col 36, line 67 - col 37, lines 1-3) recording a first time-dependent change in a first signal intensity of the first detectable label; and recording a second time-dependent change in a second signal intensity of the second detectable label (col 80, lines 20-21 and lines 38-60).
Regarding claim 69, Walter teaches the method of claim 68, wherein the first detectable label and the second detectable label are the same (col 37, lines 13-15).
Regarding claim 70, Walter teaches the method of claim 68, wherein the first detectable label and the second detectable label are different (col 37, lines 19-20).
Regarding claim 71, Walter teaches the method of claim 68, wherein the first analyte comprises a nucleic acid, a protein, a small molecule, a lipid, a carbohydrate, a polysaccharide, a fatty acid, a phospholipid, a glycolipid, a sphingolipid, an organic molecule, an inorganic molecule, a cofactor, a pharmaceutical, a bioactive agent, a cell, a tissue, or an organism (col 36, lines 20-30).
Regarding claim 72, Walter teaches the method of claim 68, wherein the second analyte comprises a nucleic acid, a protein, a small molecule, a lipid, a carbohydrate, a polysaccharide, a fatty acid, a phospholipid, a glycolipid, a sphingolipid, an organic molecule, an inorganic molecule, a cofactor, a pharmaceutical, a bioactive agent, a cell, a tissue, or an organism (col 36, lines 20-30 and 52-59).
Regarding claim 73, the specification of this instant application clarifies that a time-dependent change in signal intensity is produced by the repeated binding and dissociation events between an analyte and a query probe (spec pg. 2, lines 19-21). Therefore, Walter anticipates claim 73 because Walter teaches the method of claim 68, comprising using the first time-dependent change in the first signal intensity to characterize, identify, quantify, and/or detect the first analyte and using the second time-dependent change in the second signal intensity to characterize, identify, quantify, and/or detect the second analyte (col 80, lines 38-60).
Regarding claim 75, Walter teaches the method of claim 68, comprising using Poisson statistical treatment that is capable of distinguishing the first time-dependent change in the first signal intensity and the second time-dependent change in the second signal intensity (col 2, lines 46-53 and col 9, lines 53-56).
Regarding claim 76, Walter teaches the method of claim 68, wherein the first time-dependent change in the first signal intensity and the second time-dependent change in the second signal intensity are distinguishable by a difference in one or more of: minimum values of Nb+d, maximum values of Nb+d, signal intensity, dwell time in the unbound state, dwell time in the bound state, kinetic dissociation constant, and/or kinetic association constant (col 37, lines 5-18; col 80 lines 38-67; and col 81, lines 1-17).
Regarding claim 96, Walter teaches the method of claim 68, wherein a repeated transient association of the first query probe with the first analyte produces the first time-dependent change in the first signal intensity of the first detectable label and a repeated transient association of the second query probe with the second analyte produces the second time- dependent change in the second signal intensity of the second detectable label (col 80, lines 38-60).
Regarding claim 98, Walter teaches the method of claim 68, wherein the solid support comprises a first immobilized capture probe and a second immobilized capture probe (col 4, lines 36-41); and stably binding the first analyte to the solid support comprises stably binding the first analyte to the first immobilized capture probe and stably binding the second analyte to the solid support comprises stably binding the second analyte to the second immobilized capture probe (col 28, lines 18-25).
Regarding claim 100, Walter teaches the method of claim 68, further comprising providing a biological sample comprising the first and/or second analyte (col 59, lines 65-67 and col 60, lines 1-10) and contacting the biological sample to the solid support (col 60, lines 56-67 and col 61, lines 1-2).
Regarding claim 102, Walter teaches the method claim 68, further comprising counting a first number of changes in the signal intensity of the first detectable label and counting a second number of changes in the signal intensity of the second detectable label (col 80, lines 38-60).
Regarding claim 103, ICCD and EMCCD are specialized and highly sensitive digital cameras that record 2D images used for time-resolved scientific imaging. Further, in the art, a collection, or a series, of 2D images is used to make a “movie” of the molecular events recorded or captured in 2D. Therefore, Walter teaches the method of claim 68, wherein recording the first time-dependent change in the first signal intensity of the first detectable label and recording the second time- dependent change in the second signal intensity of the second detectable label comprises recording a series of images (col 34, lines 20-49).
Regarding claim 104, Walter teaches the method of claim 103, further comprising producing an intensity fluctuation map by determining an average absolute image-to-image change in intensity at a number of image pixels of the series of images (col 34, line 45-49 and 56-60).
Regarding claim 105, Walter teaches the method of claim 103, further comprising generating intensity-versus-time data for the first and second analytes and calculating a kinetic parameter from the intensity-versus-time data (col 66, lines 14-32).
Regarding claim 106, Walter teaches the method of claim 105, further comprising identifying positive detection events using a threshold for the kinetic parameter (col 5, lines 24-46; col 66, lines 21-24; and col 68, lines 24-29).
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.
Claim 99 is/are rejected under 35 U.S.C. 103 as being unpatentable over Walter et al., US Patent No. US 10,093,967 B2 (filed in IDS on 10/10/2023 as cite No. 36), as applied to claim 68 above.
The teachings of Walter and the reasons why Walter anticipates claim 68 are set forth above (see Claim Rejections - 35 USC § 102).
Regarding claim 99, Walter teaches the method of claim 68, wherein the first query probe repeatedly and transiently associates with the first analyte during the recording steps (col 18, lines 15-19), but in the same embodiment Walter does not teach a second analyte.
However, in the same reference but in a different embodiment, Walter teaches a first and second query probe repeatedly and transiently associates with the first and second analyte, respectively (col 80, lines 38-67).
It would have been prima facie obvious, at the time of filing, to combine the method of recording a single analyte’s repeated and transient associations with a first query probe in one embodiment, taught by Walter, with another embodiment, in the same reference, teaching detecting the repeated and transient associations of a first and second analyte with their respective query probes. As discussed above, Walter teaches that some diseases have two or more biomarkers (Walter et al., cols 39-40, Tables 1-2). A skilled artisan would have been motivated to combine the single analyte and multiplex embodiments, taught in the same reference by Walter, and further combine with the method of recording the repeated and transient association events between each analyte and its query probe because it would allow for a more sensitive detection method of multiple analytes leading to a more accurate and specific method for detecting and diagnosing a disease associated with two biomarkers. A person having ordinary skill in the art would have a reasonable expectation of success because simply combining two embodiments of the same method taught and suggested in the same reference amounts to a predictable variation of the method with predictable results.
Claims 74 is/are rejected under 35 U.S.C. 103 as being obvious over Walter et al., US Patent No. US 10,093,967 B2 (filed in IDS on 10/10/2023 as cite No. 36) as applied to claim 68 above, and evidenced by Chatterjee et al. (Tanmay Chatterjee, et al., Ultraspecific analyte detection by direct kinetic fingerprinting of single molecules, 2020, Trends in Analytical Chemistry, 123, 115754, 1-14, filed in IDS on 10/10/2023 as NPL cite No. 28).
The teachings of Walter and the reasons why Walter anticipates claim 68 are set forth above (see Claim Rejections - 35 USC § 102).
Regarding claim 74, a time-dependent change in signal intensity is produced by the repeated binding and dissociation events between an analyte and a query probe (spec pg. 2, lines 19-21). Walter teaches the method of claim 68, wherein the first time-dependent change in the signal intensity is recorded in a single field of view for a single analyte (col 35, lines 19-22, col 36, para “D”, and claim 13), but, in the same embodiment, Walter does not teach the second time-dependent change in the second signal intensity is recorded in a single field of view.
Further, Walter teaches a separate multiplex embodiment comprising of two or more target analytes transiently associating with specific query probes and their binding events are detected as fluorescence emission signals. The multiplex embodiment taught by Walter further comprises counting time-resolved signal intensity transition events for each analyte: query probe binding/dissociation event (col 36, lines 52-67 -col 37, lines 1-12 and claim 14c). The specification of this instant application clarifies that signal intensity transitions are generated from data collected from analyte: probe binding and dissociation events (spec pg. 40, line 18). Therefore, giving the broadest reasonable interpretation, and in light of the specification of this instant application, Walter teaches a first time-dependent change and a second time-dependent change for two analytes, respectively.
It would have been prima facie obvious, at the time of filing, to combine the method of recording a time-dependent change in signal intensity for one analyte in a single field of view as taught by Walter with the method comprising detecting time-dependent changes in signal intensities for two analytes as taught by Walter in a separate embodiment in the same reference. Capturing fast transient events in a single field of view allows for more precise tracking of binding/dissociation kinetics of each molecule (see, Tanmay Chatterjee, et al., Ultraspecific analyte detection by direct kinetic fingerprinting of single molecules, 2020, Trends in Analytical Chemistry, 123, 115754, pg. 6, right-hand col, lines 1-8, filed in IDS on 10/10/2023 as NPL cite No. 28). A skilled artisan would have been motivated to combine recording of a time-dependent change in signal intensity with the multiplex embodiment because it would enable a skilled artisan to better distinguish between analytes and between analytes and background noise leading to more accurate and more sensitive detection of two different analytes. A person having ordinary skill in the art would have a reasonable expectation of success because combining two embodiments of the same method taught in the same reference amounts to a predictable variation of the method with predictable results.
Claim 97 is/are rejected under 35 U.S.C. 103 as being obvious over Walter et al., US Patent No. US 10,093,967 B2 (filed in IDS on 10/10/2023 as cite No. 36) as applied to claim 68 above, in view of Chatterjee et al. (Tanmay Chatterjee, et al., Ultraspecific analyte detection by direct kinetic fingerprinting of single molecules, 2020, Trends in Analytical Chemistry, 123, 115754, 1-14, filed in IDS on 10/10/2023 as NPL cite No. 28).
The teachings of Walter and the reasons why Walter anticipates claim 68 are set forth above (see Claim Rejections - 35 USC § 102).
Throughout the article, Chatterjee teaches the use of the single-molecule recognition through equilibrium Poisson sampling (SiMREPS) technique to monitor the transient association, over time, between fluorescent probes and target analytes immobilized, or captured, on a solid support. Chatterjee teaches that these repeated binding/dissociation events generate a pattern of detectable changes, or fluctuations, in fluorescence signals per unit time (Chatterjee et al., pg. 6, para 7). These fluctuation patterns represent the binding/dissociation patterns between captured analytes and probes. Chatterjee teaches data collection to determine fluorescent fluctuations involves recording the repeated binding/dissociation events from multiple fields of view to generate movies (Chatterjee et al., pg. 6, full paras 4-5). Chatterjee teaches that these transient interaction patterns are unique for each analyte. The unique binding/dissociation patterns between an analyte and probe is called a “kinetic fingerprint” (Chatterjee et al., pg. 6, para 5). Chatterjee further teaches the use of kinetic fingerprints to detect and quantify target analytes, distinguish between different analytes, and identify non-target molecules with non-specific, weaker associations with the surface. Chatterjee teaches how SiMREPS provides an amplification-free, sensitive method for single-molecule detection and quantification of nucleic acids and small molecules.
Regarding claim 97, Walter teaches the method of claim 68 but does not teach wherein the first and second analytes remain bound to the solid support during the recording steps.
However, Chatterjee, in the same field of endeavor, teaches an analyte remains bound to the solid support during the recording steps (pg. 6, full para 5 and Figs. 5B-C, shows data acquisition with bound analyte), but Chatterjee does not teach a second analyte.
However, in another embodiment, Walter (US10093967B2) teaches and suggests a multiplex method for binding a first and second analyte to a solid support for detection (col 36, lines 60-67).
It would have been prima facie obvious, at the time of filing, to combine both embodiments for methods of binding a first and second analyte to a solid support for detection, as taught by Walter, with the method for an analyte remaining bound to a solid support during recording steps of the detection method, as taught by Chatterjee. A skilled artisan would have been motivated to combine the two embodiments taught by Walter in the same reference because, firstly, as discussed above, diseases, like some cancers, that have two or more biomarkers, detection of multiple analytes bound to a solid support would allow for more specific, sensitive, and accurate testing and diagnosis. Further, ensuring analytes remain bound during the recording steps ensures that binding events between analyte and probe are recorded, which allows kinetic fingerprints to be generated and used to detect and quantify analytes. Therefore, a skilled artisan would be further motivated to combine the two embodiments for capturing multiple analytes on a solid support as taught by Walter with the method for an analyte remaining bound during recording steps as taught by Chatterjee because it would allow for improved detection and more accurate quantification of multiple target analytes. A person having ordinary skill in the art would have a reasonable expectation of success, first because combining two embodiments taught and suggested in the same reference amounts to a predictable variation of the method with predictable results. Further, a skilled artisan would have a reasonable expectation of success because Chatterjee teaches an analyte bound to a solid support during the recording steps, using the same methods as Walter, with success.
Claim 101 is/are rejected under 35 U.S.C. 103 as being unpatentable over Walter et al., US Patent No. US 10,093,967 B2 (filed in IDS on 10/10/2023 as cite No. 36), as applied to claim 68 above, in view of Johnson-Buck et al., WO2018165309 A1 (filed in IDS on 10/10/2023 as For. Patent cite No.30), as evidenced by Crowther (John R. Crowther, 2009, Stages in ELISA. In: The ELISA Guidebook. Methods in Molecular Biology™, vol 516. Humana Press, 43-78, filed in IDS on 10/10/2023 as NPL cite No. 49) and Chatterjee et al., (Tanmay Chatterjee, et al., Ultraspecific analyte detection by direct kinetic fingerprinting of single molecules, 2020, Trends in Analytical Chemistry, 123, 115754, 1-14, filed in IDS on 10/10/2023 as NPL cite No. 28) .
Johnson-Buck teaches a method for detecting, identifying, and quantifying unlabeled analytes with single-molecule resolution. Target analytes are immobilized on a solid surface, that may be static or diffusible (pg. 2 lines 15-16 and pg. 3, lines 29-30). Target analytes may be bound by capture probes on the surface (pg. 3, line 15 ). The method taught by Johnson-Buck exploits the transient binding/dissociation events between an immobilized analyte and a labeled query probe. Johnson-Buck teaches the binding between analyte and query probe is a Poisson process, which means each binding event is memoryless, discrete and independent and occurs randomly in a given time with a constant rate (pg. 21, lines 11-17 ). Johnson-Buck also teaches that binding kinetics for target analytes differ from the kinetics from nonspecific and weak binding of nontarget molecules to the support (pg. 22, lines 7-35 and pg. 23, lines 1-12 ). Johnson-Buck further teaches detecting binding/dissociation events via fluorescent emission signals from the labeled query probe and determining binding events from changes in signal intensity (pg. 29, lines 15-31 ). Johnson-Buck also teaches that after statistical treatment of the collected data, binding patterns can be generated for each analyte to develop a “fingerprint” that is unique to each analyte. Kinetic “fingerprints” allow for discrimination between each analyte and background noise, enabling a highly sensitive and accurate method for identifying, quantifying, and characterizing analytes (pg. 30 lines 32-35; pg. 31, lines 1-7; pg., 32, lines 4-7).
The teachings of Walter and the reasons why Walter anticipates claim 68 are set forth above (see Claim Rejections - 35 USC § 102). Regarding claim 101, Walter fails to explicitly teach wherein the solid support is diffusible.
However, Johnson-Buck, in the same field of endeavor, teaches wherein the solid support is diffusible (pg. 3, lines 29-30).
It would have been prima facie obvious, at the time of filing, to substitute the solid support taught by Walter with a diffusible solid support as taught by Johnson-Buck. It is well known in the art that stationary solid supports within a fluid rely on the diffusion of analytes to interact with the solid support, which limits the amount of surface area on the support that target analytes can interact with (see Crowther, 2009, Methods in Molecular Biology™, vol 516. Humana Press, pg. 56, full para 1 and see Chatterjee et al., 2020). Interaction between the target analyte and the capture molecule on the surface occurs on a faster time scale than the diffusion and capture of the analyte on a static solid support and this results in lower signal detection and lower sensitivity (see Chatterjee et al., 2020, Trends in Analytical Chemistry, 123, 115754, pg. 13, full para 1 [section 6.2], lines 9-16). A diffusible solid support, however, mitigates this mass transfer issue by bringing target molecules in continuous contact with the solid support, maximizing interactions between analytes and capture probes on the surface. As a result, using a freely diffusible support increases efficiency of analyte capture on the support surface (see Crowther, 2009, Methods in Molecular Biology™, vol 516. Humana Press, pg. 56, full paras 1-2 and see Chatterjee et al., 2020, Trends in Analytical Chemistry, 123, 115754, pg. 13, full para 1 [section 6.2], last 6 sentences). Therefore, a skilled artisan would have been motivated to substitute the stationary solid support taught by Walter with the freely-moving solid support taught by Johnson-Buck because it would increase the concentration of target analytes captured on the solid support. A higher concentration of captured analytes would result in an increase of detectable binding events between analytes and query probes leading to an increase in detection sensitivity. A person having ordinary skill in the art would have a reasonable expectation of success because a diffusible solid support to mitigate mass transfer issues and increase detection sensitivity was taught by Johnson-Buck, at the time of filing, so this substitution would amount to a predictable variation of the method with predictable results.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 68-72, 76, 98, 99, and 102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 14 of U.S. Patent No. 10,093,967 B2 (filed in IDS on 10/10/2023 as cite No. 6) to Walter et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims 68-72, 76, 98, 99, and 102 are anticipated by the reference (patent) claim 14.
Regarding instant claim 68, reference claim 14 recites a multiplex method for detecting a plurality of analytes, said method comprising: stably binding a first analyte to a solid support (claim 14, col 80, lines 25-26 ); stably binding a second analyte to the solid support (claim 14, col 80, lines 26-28); providing a first query probe comprising a first detectable label, wherein the first query probe is specific for the first analyte; providing a second query probe comprising a second detectable label, wherein the second query probe is specific for the second analyte (claim 14, col 80, lines 34-37); recording a first time-dependent change in a first signal intensity of the first detectable label; and recording a second time-dependent change in a second signal intensity of the second detectable label (claim 13, col 80, signal intensity transitions are recorded, and claim 14, col 80, lines 38-55).
Regarding instant claim 69, reference claim 14 recites the method of claim 68, wherein the first detectable label and the second detectable label are the same (claim 14, col 80, lines 34-36).
Regarding instant claim 70, reference claim 14 recites the method of claim 68, wherein the first detectable label and the second detectable label are different (claim 14, col 80, lines 34-36).
Regarding instant claim 71, reference claim 14 recites the method of claim 68, wherein the first analyte comprises a nucleic acid, a protein, a small molecule, a lipid, a carbohydrate, a polysaccharide, a fatty acid, a phospholipid, a glycolipid, a sphingolipid, an organic molecule, an inorganic molecule, a cofactor, a pharmaceutical, a bioactive agent, a cell, a tissue, or an organism (claim 14, col 80, lines 22-24).
Regarding instant claim 72, reference claim 14 recites the method of claim 68, wherein the second analyte comprises a nucleic acid, a protein, a small molecule, a lipid, a carbohydrate, a polysaccharide, a fatty acid, a phospholipid, a glycolipid, a sphingolipid, an organic molecule, an inorganic molecule, a cofactor, a pharmaceutical, a bioactive agent, a cell, a tissue, or an organism (claim 14, col 80, lines 22-24).
Regarding instant claim 76, reference claim 14 recites the method of claim 68, wherein the first time-dependent change in the first signal intensity and the second time-dependent change in the second signal intensity are distinguishable by a difference in one or more of: minimum values of Nb+d, maximum values of Nb+d, signal intensity, dwell time in the unbound state, dwell time in the bound state, kinetic dissociation constant, and/or kinetic association constant (claim 14, col 80, lines 38-60 and col 81, lines 1-17 ).
Regarding instant claim 98, the reference clarifies that a discrete region of the solid support comprises a capture probe (reference claim 3, col 79, lines 37-38). Using the broadest reasonable interpretation, in a multiplex embodiment, each discrete region of the solid support would continue to comprise a capture probe. The reference therefore, anticipates claim 98 because reference claim 14 recites the method of claim 68, wherein two different analytes are immobilized on to a first and second discrete region of a solid support, respectively. Specifically, claim 14 anticipates the instant claim wherein the solid support comprises a first immobilized capture probe and a second immobilized capture probe; and stably binding the first analyte to the solid support comprises stably binding the first analyte to the first immobilized capture probe and stably binding the second analyte to the solid support comprises stably binding the second analyte to the second immobilized capture probe (claim 14, col 80, lines 25-33).
Regarding instant claim 99, the reference clarifies that signal intensity transition events detected within the discrete region are recorded (reference claim 13). Using the broadest reasonable interpretation, signal intensity transition events that are detected continue to be recorded in a multiplex embodiment in the reference. Therefore, the reference anticipates the instant claim because reference claim 14 recites the method of claim 68, wherein the first query probe repeatedly and transiently associates with the first analyte and the second query probe repeatedly and transiently associates with the second analyte during the recording step (claim 14, col 80, lines 38-60).
Regarding instant claim 102, reference claim 14 recites the method of claim 68, further comprising counting a first number of changes in the signal intensity of the first detectable label and counting a second number of changes in the signal intensity of the second detectable label (claim 14, col 80, lines 38-60).
Claim 101 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 14 of U.S. Patent No. 10,093,967 B2 (filed in IDS on 10/10/2023 as cite No. 36) to Walter et al., as applied to instant claim 68, in view of Johnson-Buck et al., PGPub 2018/0258469 A1.
Regarding instant claim 101, reference claim 14 of Walter (U.S. Patent No. 10,093,967 B2) recites all the limitation of instant claim 68 but lacks the diffusible surface limitation of instant claim 101. Johnson-Buck (PGPub 2018/0258469 A1) discloses wherein the solid support is diffusible (Johnson-Buck et al., claim 41). It would have been obvious to a skilled artisan, at the time of filing, to have substituted the static solid support, recited in claim 101 of Walter, for the diffusible solid support recited in claim 41 of Johnson-Buck to increase efficiency of analyte capture and detection sensitivity. A person having ordinary skill in the art would have a reasonable expectation of success because, at the time of filing, using a diffusible solid support to mitigate mass transfer issues and increase detection sensitivity of analytes was taught successfully, therefore, this substitution would be a predicable variation of the method with predictable results.
Conclusion
All claims (68-76 and 96-106) in this instant application have been rejected. No claims are allowed.
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/MELISSA LIZETTE LIRIANO/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 February 20, 2026