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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 5th, 2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Election/Restrictions
The Examiner appreciates the Applicant’s indication that 29 claims are pending and that claim 29 was omitted in the groups of inventions in the requirement for restriction. Claim 29 should have been included in Group II with claims 24-28, its exclusion amounting to a clerical error as assumed.
Applicant’s election of Group I, claims 1-23, in the reply filed on June 16th, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 24-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 16th, 2026.
Claim Summary
Claims 1-29 are pending. Claims 24-29 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-23 are under examination and discussed in this Office action.
Specification
The use of the terms such as DNeasy and PowerLyzer, which are trade names or marks used in commerce, has been noted in this application. All terms should be accompanied by the generic terminology; furthermore all terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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 7 and 8 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 7 recites the limitation "wherein one of the well and the capture probe is biotinylated and the other of the well and the capture probe is modified with streptavidin". There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 7 depends, does not introduce “a well” but instead “a surface”. Claim 8 is also rejected here for its dependence from claim 7 and not further clarifying the identified issue. It appears claim 7 was intended to depend from claim 6, which does introduce “the surface is a well of a multiwell plate”, and thus will be interpreted to depend from claim 6 for the purpose of compact prosecution.
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 1-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claims recite the abstract ideas of determining if a substrate reacts, as well as later steps of comparing substrate reactions to standards and/or controls. These abstract ideas represent mental processes, as determining if a substrate reacts and comparing to standards and/or controls can reasonably be performed in the human mind.
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe abstract ideas: the abstract ideas of determining if a substrate reacts and comparing substrate reactions to standards and/or controls.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of building a capture assay to detect a nucleic acid of interest using a surface, a capture probe, a sample, a first label probe, an enzyme label, and a substrate, and further determining a substrate reaction; wherein the nucleic acid of interest is at least a portion of a fungal gene from Histoplasma capsulatum consisting of the Hcp100 gene, the CBP1 gene, and the M antigen gene; wherein the surface is a well of a multiwell plate; wherein the capture probe is biotinylated and the well is coated with streptavidin; wherein the multiwell plate includes an electrode; wherein the sample is one of a whole blood sample, a blood plasma sample, a sputum sample, a bronchoalveolar lavage sample, and a sample derived from one or more thereof; wherein the first labeling probe is biotinylated and the enzyme label is modified with streptavidin; wherein more labeling probes may be used; wherein the enzyme label is a streptavidin- modified horseradish peroxidase conjugate; wherein the streptavidin-modified horseradish peroxidase conjugate includes five identical horseradish peroxidase homopolymer blocks, each horseradish peroxidase homopolymer block comprising 80 horseradish peroxidase monomers.; wherein the substrate comprises 3,3',5,5'- tetramethylbenzidine and wherein the substrate is accompanied by hydrogen peroxide; stopping the reaction of the substrate by the addition of an acid; wherein photonically determining if any substrate reacts in step (f) comprises detecting any colorimetric change of the substrate and comparing said colorimetric change, if any, to standards and negative or positive control samples; wherein photonically determining if any substrate reacts in step (f) comprises obtaining an absorbance reading of the substrate and comparing said absorbance reading to standards to determine the amount of any reacted substrate; wherein the surface is a well of a multiwell plate and wherein the absorbance reading is taken of any contents of the well while said contents are still in the well; wherein electrochemically determining if any substrate reacts in step (f) comprises performing chronoamperometric analysis of any reacted substrate and comparing said chronoamperometric analysis to standards to determine the amount of any reacted substrate; wherein the surface is a well of a multiwell plate, the well including an electrode, and wherein the chronoamperometric analysis is performed on any contents of the well while said contents are still in the well; and wherein the surface is a well, the method further comprising, after step (c) and before (d), after step (d) and before step (e), and after step (e) and before step (f), removing any non-specific binding from the well, the claims do not improve upon capture assay techniques, photonic measurement techniques, or electrochemical measurement techniques. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite steps as presented above, no such machines are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, like a plate reader, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, the sample is not transformed into something else by the introduction of capture and labeling probes.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the abstract ideas of determining if a substrate reacts and comparing substrate reactions to standards and/or controls in the instant case have to do with building a capture assay to detect a nucleic acid of interest using a surface, a capture probe, a sample, a first label probe, an enzyme label, and a substrate; wherein the nucleic acid of interest is at least a portion of a fungal gene from Histoplasma capsulatum consisting of the Hcp100 gene, the CBP1 gene, and the M antigen gene; wherein the surface is a well of a multiwell plate; wherein the capture probe is biotinylated and the well is coated with streptavidin; wherein the multiwell plate includes an electrode; wherein the sample is one of a whole blood sample, a blood plasma sample, a sputum sample, a bronchoalveolar lavage sample, and a sample derived from one or more thereof; wherein the first labeling probe is biotinylated and the enzyme label is modified with streptavidin; wherein more labeling probes may be used; wherein the enzyme label is a streptavidin- modified horseradish peroxidase conjugate; wherein the streptavidin-modified horseradish peroxidase conjugate includes five identical horseradish peroxidase homopolymer blocks, each horseradish peroxidase homopolymer block comprising 80 horseradish peroxidase monomers; wherein the substrate comprises 3,3',5,5'- tetramethylbenzidine and wherein the substrate is accompanied by hydrogen peroxide; stopping the reaction of the substrate by the addition of an acid; wherein photonically determining if any substrate reacts in step (f) comprises detecting any colorimetric change of the substrate; wherein photonically determining if any substrate reacts in step (f) comprises obtaining an absorbance reading of the substrate; wherein the surface is a well of a multiwell plate and wherein the absorbance reading is taken of any contents of the well while said contents are still in the well; wherein electrochemically determining if any substrate reacts in step (f) comprises performing chronoamperometric analysis of any reacted substrate; wherein the surface is a well of a multiwell plate, the well including an electrode, and wherein the chronoamperometric analysis is performed on any contents of the well while said contents are still in the well; and wherein the surface is a well, the method further comprising, after step (c) and before (d), after step (d) and before step (e), and after step (e) and before step (f), removing any non-specific binding from the well. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exceptions are the abstract ideas of determining if a substrate reacts and comparing substrate reactions to standards and/or controls. The additional elements recited in the claims (i.e. building a capture assay to detect a nucleic acid of interest using a surface, a capture probe, a sample, a first label probe, an enzyme label, and a substrate; wherein the nucleic acid of interest is at least a portion of a fungal gene from Histoplasma capsulatum consisting of the Hcp100 gene, the CBP1 gene, and the M antigen gene; wherein the surface is a well of a multiwell plate; wherein the capture probe is biotinylated and the well is coated with streptavidin; wherein the multiwell plate includes an electrode; wherein the sample is one of a whole blood sample, a blood plasma sample, a sputum sample, a bronchoalveolar lavage sample, and a sample derived from one or more thereof; wherein the first labeling probe is biotinylated and the enzyme label is modified with streptavidin; wherein more labeling probes may be used; wherein the enzyme label is a streptavidin- modified horseradish peroxidase conjugate; wherein the streptavidin-modified horseradish peroxidase conjugate includes five identical horseradish peroxidase homopolymer blocks, each horseradish peroxidase homopolymer block comprising 80 horseradish peroxidase monomers; wherein the substrate comprises 3,3',5,5'- tetramethylbenzidine and wherein the substrate is accompanied by hydrogen peroxide; stopping the reaction of the substrate by the addition of an acid; wherein photonically determining if any substrate reacts in step (f) comprises detecting any colorimetric change of the substrate; wherein photonically determining if any substrate reacts in step (f) comprises obtaining an absorbance reading of the substrate; wherein the surface is a well of a multiwell plate and wherein the absorbance reading is taken of any contents of the well while said contents are still in the well; wherein electrochemically determining if any substrate reacts in step (f) comprises performing chronoamperometric analysis of any reacted substrate; wherein the surface is a well of a multiwell plate, the well including an electrode, and wherein the chronoamperometric analysis is performed on any contents of the well while said contents are still in the well; and wherein the surface is a well, the method further comprising, after step (c) and before (d), after step (d) and before step (e), and after step (e) and before step (f), removing any non-specific binding from the well) do amount to mere instructions to apply the judicial exceptions, since these serve as mere conventional steps taken for the purpose of gathering data to determine if a substrate reacts and further to compare substrate reactions to standards and/or controls, which any practical use of the judicial exceptions would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to performing a nucleic acid capture assay using an enzyme label that reacts with a substrate to determine substrate reactions.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the method being used to detect a nucleic acid of interest is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was routine and conventional in the prior art to perform nucleic acid capture assays with the specific components as claimed, as well as look at a fungal gene in Histoplasma capsulatum for molecular detection.
For example, Yu (EP1310565A1) teaches a method of detecting a nucleic acid of interest, the method comprising the steps of: exposing a capture probe to a sample, wherein the capture probe comprises a capture probe nucleic acid, wherein the capture probe nucleic acid is designed to hybridize with specificity to a first portion of the nucleic acid of interest and wherein, if the sample comprises the nucleic acid of interest, the first portion of the nucleic acid of interest hybridizes to the capture probe nucleic acid of the capture probe (Page 5, paragraphs [0019]-[0020] and [0022]-[0023]); providing a surface (Page 5, paragraph [0026]); securing the capture probe bound to the nucleic acid of interest to the surface (Page 5, paragraph [0026]); (d) then, adding a first labeling probe, wherein the first labeling probe comprises a first labeling nucleic acid, wherein the first labeling nucleic acid is designed to hybridize with specificity to a second portion of the nucleic acid of interest, wherein, if the nucleic acid of interest is captured, the first labeling probe hybridizes to the second portion of the captured nucleic acid of interest (Page 5, paragraph [0026] and [0028]); (e) then, adding an enzyme label, wherein the enzyme label is designed to bind to the first labeling probe, wherein, if the first labeling probe is hybridized to the captured nucleic acid of interest, the enzyme label becomes coupled to the captured nucleic acid of interest (Pages 5-6, paragraph [0028]-[0030]); (f) then, adding a substrate whose reaction is catalyzed by the enzyme label, wherein, if the enzyme label is coupled to the captured nucleic acid of interest, the substrate reacts (Page 6, paragraph [0032]); and (g) then, determining, photonically, if any substrate reacts in step (f) (Page 6, paragraph [0033]). Yu further teaches that there is no specific limitation for the nucleic acid target molecule, and that the amplification with NASBA and detection with a capture assay as included in the taught method can successfully detect fungi (Page 5, paragraph [0018]). Yu further teaches wherein the surface is a well of a multiwell plate (Page 5, paragraphs [0023]-[0024]). Yu further teaches wherein the capture probe is biotinylated and the well is coated with streptavidin (Page 5, paragraphs [0022]-[0023]). Yu further teaches wherein the sample is a sample derived from a blood plasma sample (Page 6, paragraph [0040]). Yu further teaches the method further comprising, after step (f) and before step (g), stopping the reaction of the substrate by the addition of an acid (Page 6, paragraph [0032]). Yu further teaches wherein photonically determining if any substrate reacts in step (f) comprises detecting any colorimetric change of the substrate and comparing said colorimetric change, if any, to standards and negative or positive control samples (Page 9, paragraph [0061]). Yu further teaches wherein photonically determining if any substrate reacts in step (f) comprises obtaining an absorbance reading of the substrate and comparing said absorbance reading to standards to determine the amount of any reacted substrate (Page 9, paragraph [0061]). Yu further teaches wherein the surface is a well of a multiwell plate and wherein the absorbance reading is taken of any contents of the well while said contents are still in the well (Page 9, paragraph [0061]). Yu further teaches wherein the surface is a well (Page 5, paragraphs [0023]-[0024]; Page 9, paragraph [0061]), the method further comprising, after step (c) and before (d), after step (d) and before step (e), and after step (e) and before step (f), removing any non-specific binding from the well (Page 9, paragraph [0061]).
González-González (Relevant aspects of the Hcp100 molecular marker of Histoplasma capsulatum and its potential therapeutic use in histoplasmosis, Ibero-American Journal of Mycology, 2012, 29, 115-119; originally published in Spanish, both the original article and the Google translated version are provided) teaches on the known sequence of the Hcp100 gene of Histoplasma capsulatum (Page 116, column 2, paragraphs 3-4) and the detection of at least a portion of the Hcp100 gene of Histoplasma capsulatum by molecular means (Abstract).
Strom (WO2021226501A2) teaches wherein a multiwell plate includes an electrode (Page 2, lines 18-27). Strom teaches on electrochemical detection of capture probe assays (Page 2, lines 18-27). Strom teaches that the label detected can comprise enzyme labels (Page 11, lines 1-6; Page 16, lines 23-31), and wherein electrochemically determining if any substrate reacts in step (f) comprises performing chronoamperometric analysis of any reacted substrate (Page 16, lines 23-31). Strom further teaches on comparing a sample to standards (Page 10, lines 4-7; Page 12, lines 9-18), which would reasonably determine the amount of any reacted substrate (Page 23, lines 3-10). Strom further teaches wherein the surface is a well of a multiwell plate, the well including an electrode, and wherein the chronoamperometric analysis is performed on any contents of the well while said contents are still in the well (Page 2, lines 18-27).
Longiaru (US5232829A) teaches wherein an enzyme label can be modified with streptavidin (Column 8, lines 60-62). Longiaru further teaches wherein a streptavidin-modified horseradish peroxidase conjugate may be used to produce detectable color in a nucleic acid capture assay (Column 8, lines 60-62). Longiaru further teaches wherein the substrate comprises 3,3',5,5'- tetramethylbenzidine and wherein the substrate is accompanied by hydrogen peroxide (Column 9, lines 20-30).
Duffy (US20150353997A1) teaches a capture assay method comprising adding two or more labeling probes (Page 8, paragraphs [0063]-[0066]; Figure 5B).
Uptima (Streptavidin-Poly-HRP [online]. Uptima, [2019] [retrieved on July 15th, 2026]. Retrieved from: https://www.interchim.fr/ft/C/CV3681.pdf) teaches on PolyHRP products, including a streptavidin-modified horseradish peroxidase conjugate includes five identical horseradish peroxidase homopolymer blocks, each horseradish peroxidase homopolymer block comprising 80 horseradish peroxidase monomers (Page 1: Poly-HRP80).
Therefore, the additional elements beyond the judicial exceptions do not represent an inventive concept performing nucleic acid capture assays with the specific components as claimed, as well as looking at a fungal gene in Histoplasma capsulatum for molecular detection was routine, well-known and conventional.
Having considered the factors discussed in MPEP 2106.04(c)(II) and MPEP 2106.05 (a)-(c) and (e)-(h), as well as the prior art of Yu, González-González, Strom, Longiaru, Duffy, and Uptima, it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exceptions into a practical application of those exceptions in such a way as to provide meaningful limits on the use of the judicial exceptions. Therefore, claims 1-23 are rejected here under 35 U.S.C. 101.
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 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.
Claims 1, 6-8, 10, 17-23 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (EP1310565A1).
Regarding instant claim 1, Yu teaches a method of detecting a nucleic acid of interest, the method comprising the steps of: exposing a capture probe to a sample, wherein the capture probe comprises a capture probe nucleic acid, wherein the capture probe nucleic acid is designed to hybridize with specificity to a first portion of the nucleic acid of interest and wherein, if the sample comprises the nucleic acid of interest, the first portion of the nucleic acid of interest hybridizes to the capture probe nucleic acid of the capture probe (Page 5, paragraphs [0019]-[0020] and [0022]-[0023]); providing a surface (Page 5, paragraphs [0023] and [0026]); securing the capture probe bound to the nucleic acid of interest to the surface (Page 5, paragraph [0026]); (d) then, adding a first labeling probe, wherein the first labeling probe comprises a first labeling nucleic acid, wherein the first labeling nucleic acid is designed to hybridize with specificity to a second portion of the nucleic acid of interest, wherein, if the nucleic acid of interest is captured, the first labeling probe hybridizes to the second portion of the captured nucleic acid of interest (Page 5, paragraph [0026] and [0028]); (e) then, adding an enzyme label, wherein the enzyme label is designed to bind to the first labeling probe, wherein, if the first labeling probe is hybridized to the captured nucleic acid of interest, the enzyme label becomes coupled to the captured nucleic acid of interest (Pages 5-6, paragraph [0028]-[0030]); (f) then, adding a substrate whose reaction is catalyzed by the enzyme label, wherein, if the enzyme label is coupled to the captured nucleic acid of interest, the substrate reacts (Page 6, paragraph [0032]); and (g) then, determining, photonically, if any substrate reacts in step (f) (Page 6, paragraph [0033]).
The method of Yu comprises all steps of the instantly claimed claim 1. With respect to the order of steps, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Regarding instant claim 6, Yu teaches the method as claimed in claim 1. Yu further teaches wherein the surface is a well of a multiwell plate (Page 5, paragraphs [0023]-[0024]).
Regarding instant claims 7 and 8, Yu teaches the method as claimed in claim 1. Yu further teaches wherein the capture probe is biotinylated and the well is coated with streptavidin (Page 5, paragraphs [0022]-[0023]).
Regarding instant claim 10, Yu teaches the method as claimed in claim 1. Yu further teaches wherein the sample is a sample derived from a blood plasma sample (Page 6, paragraph [0040]).
Regarding instant claim 17, Yu teaches the method as claimed in claim 1. Yu further teaches the method further comprising, after step (f) and before step (g), stopping the reaction of the substrate by the addition of an acid (Page 6, paragraph [0032]).
The method of Yu comprises all steps of the instantly claimed claim 17. With respect to the order of steps, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (see MPEP §2144.04 IV C). Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Regarding instant claim 18, Yu teaches the method as claimed in claim 1. Yu further teaches wherein photonically determining if any substrate reacts in step (f) comprises detecting any colorimetric change of the substrate and comparing said colorimetric change, if any, to standards and negative or positive control samples (Page 9, paragraph [0061]).
Regarding instant claim 19, Yu teaches the method as claimed in claim 1. Yu further teaches wherein photonically determining if any substrate reacts in step (f) comprises obtaining an absorbance reading of the substrate and comparing said absorbance reading to standards to determine the amount of any reacted substrate (Page 9, paragraph [0061]).
Regarding instant claim 20, Yu teaches the method as claimed in claim 19. Yu further teaches wherein the surface is a well of a multiwell plate and wherein the absorbance reading is taken of any contents of the well while said contents are still in the well (Page 9, paragraph [0061]).
Regarding instant claim 21, given that claim 21 serves to further limit an optional limitation of claim 1 (determining, photonically and/or electrochemically, if any substrate reacts in step (f)), this claim does not serve to further limit what has been taught by the prior art of claim 1. Claim 1 teaches on photonic determination of substrate reaction and therefore, the rejection of claim 1 also serves to reject claim 21. However, the limitations of claim 21 are also present in the prior art, and further rejection can be found below.
Regarding instant claim 22, given that claim 22 depends from claim 21, which serves to further limit an optional limitation of claim 1 (determining, photonically and/or electrochemically, if any substrate reacts in step (f)), this claim does not serve to further limit what has been taught by the prior art of claim 1. Claim 1 teaches on photonic determination of substrate reaction and therefore, the rejection of claim 1 also serves to reject claim 22. However, the limitations of claim 22 are also present in the prior art, and further rejection can be found below.
Regarding instant claim 23, Yu teaches the method as claimed in claim 1. Yu further teaches wherein the surface is a well (Page 5, paragraphs [0023]-[0024]; Page 9, paragraph [0061]), the method further comprising, after step (c) and before (d), after step (d) and before step (e), and after step (e) and before step (f), removing any non-specific binding from the well (Page 9, paragraph [0061]).
Claims 2-5 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (EP1310565A1), as applied to claims 1-2, 6-8, 10, 17-20, and 23, and further in view of González-González (Relevant aspects of the Hcp100 molecular marker of Histoplasma capsulatum and its potential therapeutic use in histoplasmosis, Ibero-American Journal of Mycology, 2012, 29, 115-119; originally published in Spanish, both the original article and the Google translated version are provided).
Regarding instant claims 2-5, Yu teaches the method as claimed in claim 1. Yu further teaches that there is no specific limitation for the nucleic acid target molecule, and that the amplification with NASBA and detection with a capture assay as included in the taught method can successfully detect fungi (Page 5, paragraph [0018]). Yu further teaches that the capture probe comprises a nucleic acid sequence complementary to at least a portion of the nucleic acid target molecule (Page 5, paragraph [0019]), and the capture probe can be synthesized based on the known sequence of the nucleic acid target molecule by a conventional method such as a chemical synthesis method (Page 5, paragraph [0020]).
Yu does not directly teach on wherein the nucleic acid of interest is at least a portion of a fungal gene. Yu does not teach wherein the fungal gene is a gene of Histoplasma capsulatum, or that the gene is specifically Hcp100.
González-González, in a reasonably pertinent field, teaches on the known sequence of the Hcp100 gene of the fungus Histoplasma capsulatum (Page 116, column 2, paragraphs 3-4) and the detection of at least a portion of the Hcp100 gene of Histoplasma capsulatum by molecular means (Abstract).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yu with the detection of the Hcp100 gene from Histoplasma capsulatum from González-González. Since González-González teaches on a fungal gene for detection of a fungus, which is reasonably pertinent to the method of Yu, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because detection of Histoplasma capsulatum is important given it causes histoplasmosis, the most common system fungal infection of the respiratory system (Page 116, column 1, paragraph 1), and Hcp100 has proved to be an excellent tool for Histoplasma capsulatum molecular detection in clinical samples (Abstract).
Claims 9, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (EP1310565A1), as applied to claims 1-2, 6-8, 10, 17-20, and 23, and further in view of Strom (WO2021226501A2).
Regarding instant claim 9, Yu teaches the method as claimed in claim 6.
Yu does not teach wherein the multiwell plate includes an electrode.
Strom, in a reasonably pertinent field, teaches wherein a multiwell plate includes an electrode (Page 2, lines 18-27).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the multiwell plate of Yu with the electrode of Strom. Since Strom teaches on capture assays for markers of interest, which is reasonably pertinent to the method of Yu, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)). Strom teaches on capture assays using multiwell plates with electrodes, which could easily be substituted for the multiwell plates of Yu.
Regarding instant claim 21, Yu teaches the method as claimed in claim 1.
Yu does not teach electrochemical detection, or wherein electrochemically determining if any substrate reacts in step (f) comprises performing chronoamperometric analysis of any reacted substrate and comparing said chronoamperometric analysis to standards to determine the amount of any reacted substrate.
Strom, in a reasonably pertinent field, teaches on electrochemical detection of capture probe assays (Page 2, lines 18-27). Strom teaches that the label detected can comprise enzyme labels (Page 11, lines 1-6; Page 16, lines 23-31), and wherein electrochemically determining if any substrate reacts in step (f) comprises performing chronoamperometric analysis of any reacted substrate (Page 16, lines 23-31). Strom further teaches on comparing a sample to standards (Page 10, lines 4-7; Page 12, lines 9-18), which would reasonably determine the amount of any reacted substrate (Page 23, lines 3-10).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yu with electrochemical detection method of Strom. Since Strom teaches on capture assays for markers of interest, which is reasonably pertinent to the method of Yu, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)). The method of Strom can be used determine substrate reaction using electrochemical methods as opposed to photonic methods as done in Yu.
It is noted that claim 21 serves to further limit an optional determination method of claim 1, and therefore does not serve to further limit claim 1. However, the limitations of claim 21 have been found in the prior art and are rejected here.
Regarding instant claim 22, Yu, in view of Strom, teaches the method as claimed in claim 21. Strom further teaches wherein the surface is a well of a multiwell plate, the well including an electrode, and wherein the chronoamperometric analysis is performed on any contents of the well while said contents are still in the well (Page 2, lines 18-27).
It is noted that claim 22, given its dependence from claim 21, serves to further limit an optional determination method of claim 1, and therefore does not serve to further limit claim 1. However, the limitations of claim 22 have been found in the prior art and are rejected here.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (EP1310565A1), as applied to claims 1-2, 6-8, 10, 17-20, and 23, and further in view of Longiaru (US5232829A).
Regarding instant claims 11 and 12, Yu teaches the method as claimed in claim 1. Yu further teaches wherein the detection probe (e.g. first labeling probe) may be biotinylated (Page 5, paragraph [0022]; Page 7, paragraph [0044]).
Yu does not teach wherein the enzyme label is modified with streptavidin.
Longiaru, in the same field of endeavor, teaches wherein an enzyme label can be modified with streptavidin (Column 8, lines 60-62).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yu with the enzyme label modified with streptavidin of Longiaru. Since both Yu and Longiaru are in the same field of endeavor (e.g. target nucleic acid capture assays), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because avidin or streptavidin bind tightly to biotinylated products (Longiaru, Column 8, lines 58-62). Furthermore, this modification amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Yu (EP1310565A1), as applied to claims 1-2, 6-8, 10, 17-20, and 23, and further in view of Duffy (US20150353997A1).
Regarding instant claim 13, Yu teaches the method as claimed in claim 1.
Yu teaches the addition of detection probes after exposing capture probes to a sample and before adding an enzyme label (Pages 5-6, paragraphs [0026] and [0028]-[0030]).
Yu does not teach the aspects of additional labeling probes.
Duffy, in the same field of endeavor, teaches a capture assay method comprising adding two or more labeling probes, the two or more additional labeling probes comprising a second labeling probe and a third labeling probe, wherein the second labeling probe comprises a second labeling nucleic acid and the third labeling probe comprises a third labeling nucleic acid, wherein the second labeling nucleic acid is designed to hybridize with specificity to a third portion of the nucleic acid of interest and the third labeling nucleic acid is designed to hybridize with specificity to a fourth portion of the nucleic acid of interest (Page 8, paragraphs [0063]-[0064]; Figure 5B), wherein an enzyme label is also designed to bind to the second labeling probe and the third labeling probe, and wherein (Pages 8-9, paragraphs [0065]-[0066]), if the nucleic acid of interest is captured, the second labeling probe hybridizes to the third portion of the captured nucleic acid of interest and the third labeling probe hybridizes to the fourth portion of the captured nucleic acid of interest (Page 8, paragraphs [0063]-[0064]; Figure 5B).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yu with the multiple labeling probes of Duffy. Since both Yu and Duffy are in the same field of endeavor (e.g. target nucleic acid capture assays), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because “ using multiple detection probes that each include only a single moiety which can bind an secondary binding ligand on each detection probe improves the sensitivity of the assay over using a single detection probe comprising multiple moieties, but having the same total number of moieties. Without wishing to be bound by theory, this may be due to maximizing the opportunity for the binding of the secondary binding ligand to the moiety by spatially separating the moieties without having secondary structures of using one, larger detection probe” (Duffy, Page 9, paragraph [0068]).
Claims 14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (EP1310565A1) and Duffy (US20150353997A1), as applied to claim 13, and further in view of Longiaru (US5232829A).
Regarding instant claim 14, Yu, in view of Duffy, teaches the method as claimed in claim 13. Yu further teaches wherein the signal generator may be a horseradish peroxidase enzyme (e.g. enzyme label) (Page 7, paragraph [0049]).
Neither of these references teach wherein the enzyme label is specifically a streptavidin-modified horseradish peroxidase conjugate.
Longiaru, in the same field of endeavor, teaches wherein a streptavidin-modified horseradish peroxidase conjugate may be used to produce detectable color in a nucleic acid capture assay (Column 8, lines 60-62).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yu with the enzyme label modified with streptavidin of Longiaru. Since both Yu and Longiaru are in the same field of endeavor (e.g. target nucleic acid capture assays), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because avidin or streptavidin bind tightly to biotinylated products (Longiaru, Column 8, lines 58-62). Furthermore, this modification amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)).
Regarding instant claim 16, Yu, in view of Duffy and Longiaru, teaches the method as claimed in claim 14. Longiaru further teaches wherein the substrate comprises 3,3',5,5'- tetramethylbenzidine and wherein the substrate is accompanied by hydrogen peroxide (Column 9, lines 20-30).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Yu (EP1310565A1), Duffy (US20150353997A1), and Longiaru (US5232829A), as applied to claim 14, and further in view of Uptima (Streptavidin-Poly-HRP [online]. Uptima, [2019] [retrieved on July 15th, 2026]. Retrieved from: https://www.interchim.fr/ft/C/CV3681.pdf).
Regarding instant claim 15, Yu, in view of Duffy and Longiaru, teaches The method as claimed in claim 14.
None of these references teach wherein the streptavidin-modified horseradish peroxidase conjugate includes five identical horseradish peroxidase homopolymer blocks, each horseradish peroxidase homopolymer block comprising 80 horseradish peroxidase monomers.
Uptima, in the same field of endeavor, teaches on Poly-HRP products, including a streptavidin-modified horseradish peroxidase conjugate includes five identical horseradish peroxidase homopolymer blocks, each horseradish peroxidase homopolymer block comprising 80 horseradish peroxidase monomers (Page 1: Poly-HRP80).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yu, in view of Duffy and Longiaru, with the specific streptavidin-modified horseradish peroxidase conjugate of Ultima. Since both Yu, in view of Duffy and Longiaru, and Ultima are in the same field of endeavor (e.g. using enzyme labels for detection assays), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because poly-HRP conjugates are “designed to deliver the highest sensitivity and low background in immunoassays where sample volume is limited or when the target molecule is present at low levels” (Uptima, Page 1). Furthermore, this modification amounts to simple substitution of one known element for another to obtain predictable results (see 2141(III)).
Conclusion
All claims stand rejected.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
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