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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 20th, 2026 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 20th, 2026 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.
Interview Summary
The Examiner would like to note the inclusion of the Applicant’s interview summary regarding the video conference interview on February 5th, 2026. With the inclusion of this summary, the interview record is complete.
Response to Amendment
The amendment filed February 20th, 2026 is acknowledged. Regarding the Office Action mailed August 20th, 2025:
The objections to the claims are withdrawn in view of the amendments.
The rejection set forth under 35 U.S.C. 112(b) is withdrawn in view of the amendments.
Maintained, modified, or new rejections are set forth below, as necessitated by the amendments and further considerations. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1, 4-8, 14, and 20 have been amended. Claim 3 has been canceled. Claims 1-2 and 4-31 are pending. Claims 6, 11, 12, 25, 26, and 28 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-2, 4-5, 7-10, 13-24, 27, 29, and 30-31 are under examination and discussed in this Office action.
Claim Objections - New - Necessitated by Amendment
Claims 4 and 14 are objected to because of the following informalities:
In claim 4, it recites “the antibiotic treated detected extracellular concentration value”. This wording is awkward and should be edited to align with the earlier recitation of “the detected antibiotic treated intracellular concentration value”.
In the amended section of claim 14, it recites “wherein the processing the obtained the detected antibiotic treated”. This should be edited to reflect the intended recitation, either “the obtained” or “the detected”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - New - Necessitated by Amendment and Further Considerations
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.
Claim 7 is 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 the method further comprises determining a proportionality of dead and live microorganism cells in the sample caused by the antibiotic by (i) determining an intra/extra proportion value of the sample and/or (ii) as a function of the antibiotic by determining an intra/extra proportion value of the sample, the determining a proportionality of dead and live microorganism cells performed to provide a dead/live proportion value of the microorganism cells in the sample.” It is unclear from this recitation what part (ii) of the provided and/or options means. The function of the antibiotic is not described in the instant disclosure such that it can be determined how it relates to the quantitative measure of an intra/extra proportion value of a sample. Therefore, it is unclear how this can be an option for determining a proportionality of dead and live microorganism cells in the sample caused by the antibiotic.
Claim Rejections - 35 USC § 101 - New - Necessitated by Amendment and Further Considerations
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 1-2, 4-5, 7-10, 13-24, 27, and 30-31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea 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 mathematical concept of processing nucleic acid concentration values to establish an intracellular/extracellular nucleic acid proportion value. Such mathematical concept is an abstract idea because it reasonably represents a mathematical relationship. Furthermore, claims 4-5, 7-9, 13-14, and 17-20 expand upon this mathematical concept, either with more mathematical concepts or mental steps such as determining antibiotic susceptibility or resistance, both of which constitute further judicial exceptions that are insufficient to integrate the judicial exception into a practical application.
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 an abstract idea: the mathematical concept of processing nucleic acid concentration values to establish an intracellular/extracellular nucleic acid proportion value.
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 contacting a sample with an antibiotic; performing mechanical separation by filtration and/or centrifugation of the antibiotic-treated sample into an antibiotic-treated extracellular component and an antibiotic-treated cellular component; detecting a nucleic acid concentration of the antibiotic-treated extracellular component and a nucleic acid concentration of the antibiotic-treated cellular component; processing the detected antibiotic treated intracellular nucleic acid (NA) concentration value and the detected antibiotic treated extracellular nucleic acid (NA) concentration value to establish an intracellular/extracellular nucleic acid proportion value of the sample that reduces variability in nucleic acid detection arising from confounding biological or physical events in the sample during the nucleic acid detection process; specifics about determining the intracellular/extracellular nucleic acid proportion value; determining a proportionality of dead and line microorganism cells in the sample; using a reference value indicative of intracellular/extracellular nucleic acid proportion without antibiotic treatment; determining antibiotic susceptibility or antibiotic resistance; performing a substantially equivalent method on sub-samples split by digital partitioning; specific cell numbers partitioned; pretreating the sample; the sample comprising a range of microorganism cells; a range of antibiotic contact times; detecting performed by qPCR or by DNA-seq; the antibiotic comprising a beta-lactam and or a carbapenem; the microorganism is Neisseria gonorrhoeae and/or the microorganism belongs to the family Enterobacteriaceae; and the one or more sub-samples of the plurality of sub-samples comprise a single microorganism cell, the claims do not improve upon application of antibiotics to cells, detecting nucleic acid concentrations via qPCR or DNA-seq, or the mathematics involved for determining proportion values. 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 instant claims recite steps as seen 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 particular qPCR machine or DNA sequence machine, 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, treating a sample with antibiotic does not transform the nucleic acid within the sample into something else.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the mathematical concept of processing nucleic acid concentration values to establish an intracellular/extracellular nucleic acid proportion value in the instant case have to do with nucleic acid concentration detection methods, a substantially similar method performed on sub-samples, specifics related to sub-samples, specifics related to antibiotic application time, specifics related to the antibiotic used, specifics related to the microorganism, and further mathematical concepts or mental steps such as determining antibiotic susceptibility or resistance, both of which constitute further judicial exceptions. 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 exception is the mathematical concept of processing nucleic acid concentration values to establish an intracellular/extracellular nucleic acid proportion value. The additional elements recited in the claims (i.e. nucleic acid concentration detection methods, a substantially similar method performed on sub-samples, specifics related to sub-samples, specifics related to antibiotic application time, specifics related to the antibiotic used, specifics related to the microorganism, and further mathematical concepts or mental steps such as determining antibiotic susceptibility or resistance, both of which constitute further judicial exceptions) does amount to mere instructions to apply the mathematical concept, since these additional elements serve as mere conventional steps taken for the purpose of gathering data to input into the mathematical concept, which any practical use of the mathematical concept 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 nucleic acid concentration detection methods, a substantially similar method performed on sub-samples, specifics related to sub-samples, specifics related to antibiotic application time, specifics related to the antibiotic used, specifics related to the microorganism, and further mathematical concepts or mental steps such as determining antibiotic susceptibility or resistance, both of which constitute further judicial exceptions.
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 relating to antibiotic susceptibility of microorganisms 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 exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was known in the prior art to ascertain nucleic acid concentration in intracellular and extracellular nucleic acid fractions via DNA-seq, examine particular antibiotics and microorganisms, and examine sub-samples of a sample after splitting by digital partitioning into particular amounts of cells.
Ismagilov (WO 2019075264 A1; previously cited) teaches a method to detect a nucleic acid of a microorganism in a sample including the microorganism, the method comprising contacting the sample with an antibiotic to provide an antibiotic-treated sample (Page 40, paragraphs [00146]-[00147]; Page 41, paragraph [00151]), performing mechanical separation by filtration and/or centrifugation of the antibiotic-treated sample into an antibiotic-treated extracellular component and an antibiotic-treated cellular component (Page 40, paragraph [00149]; Page 41, paragraphs [00151]-[00153]; Page 42, paragraphs [00154]-[00155]), detecting a nucleic acid concentration of the antibiotic-treated extracellular component to obtain an antibiotic-treated extracellular nucleic acid concentration value (Page 40, paragraph [00146]), or detecting a nucleic acid concentration of the antibiotic-treated cellular component to obtain an antibiotic-treated intracellular nucleic acid concentration value (Page 40, paragraph [00147]). Ismagilov teaches wherein a reference sample is an antibiotic untreated control sample (Page 45, paragraph [00166]). Ismagilov teaches wherein the sample is pretreated to enrich said sample with the target microorganism, and/or to remove human nucleic acid or nucleic of other microorganisms, optionally by size selection (Page 31, paragraph [00114]). Ismagilov teaches wherein contacting the sample with an antibiotic is performed for up to 90 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes, or up to 5 minutes (Page 34, paragraph [00120]). Ismagilov teaches wherein the nucleic acid is DNA and the detection is performed by DNA-seq wherein the nucleic acid concentration value is provided based on the sequence data (Page 28, paragraph [00102]). Ismagilov teaches wherein the antibiotic is or comprises a beta-lactam and or a carbapenem (Page 17, paragraph [0070]). Ismagilov teaches wherein the microorganism is Neisseria gonorrhoeae and/or the microorganism belongs to the family Enterobacteriaceae (Page 65, paragraph [00252]; Page 65, paragraph [00254]).
Ismagilov II (WO 2018058078 A1; previously cited) teaches splitting a sample into a plurality of sub-samples and contacting at least one set of the plurality under at least one set of test conditions (Page 4, paragraph [0020]). Ismagilov II further teaches wherein splitting the sample is performed by digital partitioning (Page 18, paragraph [0087]). Ismagilov II teaches wherein the digital partitioning provides at least one samples of the plurality of samples not having any cells, at least one sample of the plurality of samples with less than 10 cells or less than 5 cells, and/or at least one sample of the plurality of samples having a single cell of the target microorganism (Page 29, paragraph [00124]). Ismagilov, in the same field of endeavor, teaches wherein a plurality of values can make a profile of the split sample by necessarily generating multiple detectable signals in a population of digital samples (Page 4, paragraph [0020]). Ismagilov II teaches wherein the sample comprises a number of microorganism cells lower than 100, lower than 50, lower than 25, lower than 10, or lower than 5 (Page 29, paragraph [00124]). Ismagilov II teaches wherein the sample and/or one or more sub-samples comprises a single microorganism cell (Page 29, paragraph [00124]). Ismagilov II teaches wherein the one or more sub-samples comprises a single microorganism cell (Page 29, paragraph [00124]).
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), as well as the prior art of Ismagilov and Ismagilov II, it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exception into a practical application of that exception in such a way as to provide meaningful limits on the use of the judicial exception. Therefore, claims 1-2, 4-5, 7-10, 13-24, 27, and 30-31 are rejected under 35 U.S.C. 101.
Claim Rejections – 35 USC § 103 – Modified – Necessitated by Amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 4-5, 7-10, 13, 21, 24, 27, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Ismagilov (WO 2019075264 A1; previously cited), in view of Feng et al. (A Rapid Growth-Independent Antibiotic Resistance Detection Test by SYBR Green/Propidium Iodide Viability Assay, Frontiers in Medicine, May 2018, 5, 1-11; previously cited).
Regarding instant claim 1, Ismagilov teaches a method to detect a nucleic acid of a microorganism in a sample including the microorganism, the method comprising contacting the sample with an antibiotic to provide an antibiotic-treated sample (Page 40, paragraphs [00146]-[00147]; Page 41, paragraph [00151]), performing mechanical separation of the antibiotic-treated sample into an antibiotic-treated extracellular component and an antibiotic-treated cellular component (Page 40, paragraph [00149]; Page 41, paragraphs [00151]-[00153]; Page 42, paragraphs [00154]-[00155]), detecting a nucleic acid concentration of the antibiotic-treated extracellular component to obtain an antibiotic-treated extracellular nucleic acid concentration value (Page 40, paragraph [00146]), or detecting a nucleic acid concentration of the antibiotic-treated cellular component to obtain an antibiotic-treated intracellular nucleic acid concentration value (Page 40, paragraph [00147]).
Ismagilov does not teach detecting a nucleic acid concentration of the antibiotic-treated extracellular component to obtain an antibiotic-treated extracellular nucleic acid concentration value and detecting a nucleic acid concentration of the antibiotic-treated cellular component to obtain an antibiotic-treated intracellular nucleic acid concentration value from the same sample. Ismagilov also does not teach processing the detected antibiotic treated intracellular nucleic acid (NA) concentration value and the detected antibiotic treated extracellular nucleic acid (NA) concentration value to establish an intracellular/extracellular nucleic acid proportion value of the sample that reduces variability in nucleic acid detection arising from confounding biological or physical events in the sample during the nucleic acid detection process.
Feng, in a reasonably pertinent field, teaches detecting a nucleic acid concentration of the antibiotic-treated extracellular component to obtain an antibiotic-treated extracellular nucleic acid concentration value estimation. This estimation is determined from measuring fluorescent absorbance of propidium iodide, an impermeable intercalating dye that binds to DNA made accessible by the compromised cell membranes of dead and dying cells (Page 2, column 2, SYBR Green I/PI Assay; Page 2, column 1, paragraph 2). Feng also teaches detecting a nucleic acid concentration of the antibiotic-treated cellular component to obtain an antibiotic-treated intracellular nucleic acid concentration value estimation from the same sample. This estimation is determined from measuring fluorescent absorbance of SYBR Green I, a permeable intercalating dye capable of binding to DNA inside of all cells, live or dead, allowing for a live fraction to be determined through comparison with propidium iodide stains (Page 2, column 2, SYBR Green I/PI Assay; Page 2, column 1, paragraph 2). These estimations are performed on cells within the same sample (Page 2, column 2, SYBR Green I/PI Assay; Page 2, column 1, paragraph 2). Given that Feng’s estimations are based on nucleic acid concentration determined from fluorescent intensity, they are functionally equivalent to the determination of nucleic acid concentrations as already taught by Ismagilov. Feng further teaches processing the detected antibiotic treated intracellular nucleic acid (NA) concentration value and the detected antibiotic treated extracellular nucleic acid (NA) concentration value to establish an intracellular/extracellular nucleic acid proportion value of the sample that reduces variability in nucleic acid detection arising from confounding biological or physical events in the sample during the nucleic acid detection process (Page 5, column 1: the LD ratio).
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 detecting the concentration of extracellular or intracellular nucleic acid of Ismagilov with the concept of detecting both in the same sample from Feng. Since Feng teaches on antibiotic resistance detection, which is reasonably pertinent to the antibiotic susceptibility of Ismagilov, 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 assaying both components in the same sample produces results faster (Feng, Page 3, column 2, Development of a Rapid DST Using SYBR Green I/PI Assay for Fast-Growing Organisms). Furthermore, 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 detection method of Ismagilov with the comparison of intracellular and extracellular concentrations of Feng. Since Feng teaches on antibiotic resistance detection, which is reasonably pertinent to the antibiotic susceptibility of Ismagilov, 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 this type of comparison can be used to determine a microorganism’s resistance or susceptibility to an applied antibiotic (Feng, Page 5, column 1).
It is noted by the Examiner that the recitation of “to establish an intracellular/extracellular nucleic acid proportion value of the sample that reduces variability in nucleic acid detection arising from confounding biological or physical events in the sample during the nucleic acid detection process” is interpreted as an intended use of the method because it does not add further active method steps to the invention as recited.
Regarding instant claim 2, Ismagilov, in view of Feng, teaches the method of claim 1. Ismagilov further teaches wherein the mechanical separation is performed by filtration and/or centrifugation of the antibiotic treated sample (Page 40, paragraph [00149]; Page 41, paragraphs [00152]-[00153]; Page 42, paragraphs [00154]-[00155]).
Regarding instant claim 4, Ismagilov, in view of Feng, teaches the method of claim 1, which includes the idea of the antibiotic treated intracellular/extracellular nucleic acid proportion value of the sample. Ismagilov further teaches wherein the antibiotic treated intracellular/extracellular nucleic acid proportion value of the sample is a ratio of the detected antibiotic treated intracellular concentration value and a sum of the detected antibiotic treated intracellular NA concentration value and the detected antibiotic treated extracellular NA concentration value, or a mathematical equivalent thereto, or a ratio of the antibiotic treated detected extracellular concentration value and a sum of the detected antibiotic treated intracellular NA concentration value and the detected antibiotic treated extracellular NA concentration value, or a mathematical equivalent thereto (Page 44, paragraph [00164]; Page 45, paragraph [00165]).
Regarding instant claim 5, Ismagilov, in view of Feng, teaches the method of claim 1, which includes the idea of the antibiotic treated intracellular/extracellular nucleic acid proportion value of the sample. Feng further teaches the proportion value of the sample is a percentage extracellular concentration or an intracellular percentage concentration or a mathematical equivalent thereto (Page 5, column 1).
Regarding instant claim 7, Ismagilov, in view of Feng, teaches the method of claim 1. Feng further teaches wherein the method further comprises determining a proportionality of dead and live microorganism cells in the sample caused by the antibiotic by determining an intra/extra proportion value of the sample, the determining a proportionality of the dead and live microorganism cells performed to provide a dead/live proportion value of the microorganism cells in the sample (Page 5, column 1).
Regarding instant claim 8, Ismagilov, in view of Feng, teaches the method of claim 1. Ismagilov further teaches comparing the antibiotic treated nucleic acid concentration value of the sample with a reference value indicative of a nucleic acid concentration value in the sample in absence of antibiotic treatment to obtain a treated-reference nucleic acid comparison outcome of the sample (Page 4, paragraph [0011]). Ismagilov does not specifically teach the nucleic acid concentration value is instead an intracellular/extracellular nucleic acid proportion value of the sample. However, given the combined teachings of Ismagilov and Feng making an intracellular/extracellular nucleic acid proportion value obvious, as analyzed for claim 1, combining this with the comparison as described for instant claim 8 would be an obvious combination. One of ordinary skill in the art would have been motivated to make this combination because this type of comparison can be used to determine a microorganism’s resistance or susceptibility to an applied antibiotic (Ismagilov, Page 4, paragraph [0011]).
Regarding instant claim 9, Ismagilov, in view of Feng, teaches the method of claim 8. Ismagilov further teaches wherein the reference value comprises a reference nucleic acid concentration value of a reference sample corresponding to the antibiotic treated nucleic acid concentration value of the sample (Page 4, paragraph [0011]). Ismagilov does not specifically teach the nucleic acid concentration value is instead an intracellular/extracellular nucleic acid proportion value of the sample. However, given the combined teachings of Ismagilov and Feng making an intracellular/extracellular nucleic acid proportion value obvious, as analyzed for claim 1, combining this with what constitutes a reference value as described for instant claim 9 would be an obvious combination. One of ordinary skill in the art would have been motivated to make this combination because this type of comparison can be used to determine a microorganism’s resistance or susceptibility to an applied antibiotic (Ismagilov, Page 4, paragraph [0011]).
Regarding instant claim 10, Ismagilov, in view of Feng, teaches the method of claim 9, wherein the reference sample is an antibiotic untreated control sample (Page 45, paragraph [00166]).
Regarding instant claim 13, Ismagilov, in view of Feng, teaches the method of claim 8. Feng further teaches determining antibiotic susceptibility when the treated-reference nucleic acid comparison outcome of the sample indicates an increased lysis and an increased dead/live proportion of the microorganism cells in the antibiotic-treated sample compared to a sample treated under reference conditions (Page 5, column 1)
Regarding instant claim 21, Ismagilov, in view of Feng, teaches the method of claim 1. Ismagilov further teaches wherein the sample is pretreated to enrich said sample with the target microorganism, and/or to remove human nucleic acid or nucleic of other microorganisms, optionally by size selection (Page 31, paragraph [00114]).
Regarding instant claim 24, Ismagilov, in view of Feng, teaches the method of claim 1. Ismagilov further teaches wherein contacting the sample with an antibiotic is performed for up to 90 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes, or up to 5 minutes (Page 34, paragraph [00120]).
Regarding instant claim 27, Ismagilov, in view of Feng, teaches the method of claim 1. Ismagilov further teaches wherein the nucleic acid is DNA and the detection is performed by DNA-seq wherein the nucleic acid concentration value is provided based on the sequence data (Page 28, paragraph [00102]).
Regarding instant claim 29, Ismagilov, in view of Feng, teaches the method of any one of claim 1. Ismagilov further teaches wherein the antibiotic is or comprises a beta-lactam and or a carbapenem (Page 17, paragraph [0070]).
Regarding instant claim 30, Ismagilov, in view of Feng, teaches the method of any one of claim 1. Ismagilov further teaches wherein the microorganism is Neisseria gonorrhoeae and/or the microorganism belongs to the family Enterobacteriaceae (Page 65, paragraph [00252]; Page 65, paragraph [00254]).
Claim(s) 14-20, 22-23, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Ismagilov (WO 2019075264 A1; previously cited), in view of Feng et al. (A Rapid Growth-Independent Antibiotic Resistance Detection Test by SYBR Green/Propidium Iodide Viability Assay, Frontiers in Medicine, May 2018, 5, 1-11; previously cited) and Ismagilov (WO 2018058078 A1; previously cited), hereafter referred to as Ismagilov II.
Regarding instant claim 14, Ismagilov, in view of Feng, teaches the method of claim 1, as analyzed in the above 103 rejection.
Neither Ismagilov nor Feng teach performing the method of claim 1, which is essentially repeated in claim 14, on at least one set of a plurality of sub-samples under at least one set of test conditions.
Ismagilov II, in the same field of endeavor, teaches splitting a sample into a plurality of sub-samples and contacting at least one set of the plurality under at least one set of test conditions (Page 4, paragraph [0020]).
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 Ismagilov, in view of Feng, with performing the method on a plurality of sub-samples under at least one set of test conditions of Ismagilov II. Since Ismagilov, Feng, and Ismagilov II are in the same field of endeavor, one of ordinary skill in the art would combine the teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because a plurality of sub-samples provides robustness to the assay, robustness meaning wherein a series of repeated quantitative measurements provides a set of similar measurements under varying experimental conditions (Ismagilov II, Page 50 and 51, paragraph [00211]).
Regarding instant claim 15, Ismagilov, in view of Feng and Ismagilov II, teaches the method of claim 14. Ismagilov II further teaches wherein splitting the sample is performed by digital partitioning (Page 18, paragraph [0087]).
Regarding instant claim 16, Ismagilov, in view of Feng and Ismagilov II, teaches the method of claim 15.
Neither Ismagilov, nor Feng, teach wherein the digital partitioning provides at least one samples of the plurality of samples not having any cells, at least one sample of the plurality of samples with less than 10 cells or less than 5 cells, and/or at least one sample of the plurality of samples having a single cell of the target microorganism.
Ismagilov II, in the same field of endeavor, teaches wherein the digital partitioning provides at least one samples of the plurality of samples not having any cells, at least one sample of the plurality of samples with less than 10 cells or less than 5 cells, and/or at least one sample of the plurality of samples having a single cell of the target microorganism (Page 29, paragraph [00124]).
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 Ismagilov and Feng with the sub-sample cell number of Ismagilov II. Since Ismagilov, Feng, and Ismagilov II are in the same field of endeavor, 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 smaller groups of cells may respond to an antibiotic faster, which would provide faster and more refined information on antibiotic susceptibility (Ismagilov II, Page 29, paragraph [00123]).
Regarding instant claim 17, Ismagilov, in view of Feng and Ismagilov II, teaches the method of claim 14.
Ismagilov does not teach comparing the detected antibiotic treated intracellular concentration value and the detected antibiotic treated extracellular nucleic acid concentration value of the at least one set of sub-samples of the plurality of sub-samples to provide an antibiotic treated intracellular/extracellular nucleic acid proportion value for each of the at least one set of sub-samples of the plurality of sub-samples.
Feng, in the same field of endeavor, teaches comparing the detected antibiotic treated intracellular nucleic acid (NA) concentration value and the detected antibiotic treated extracellular nucleic acid (NA) concentration value to provide an antibiotic treated intracellular/extracellular nucleic acid proportion value of the sample (Page 5, column 1).
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 detection method of Ismagilov, in view of Feng, with the comparison of intracellular and extracellular concentrations of Feng. Since both Ismagilov and Feng are in the same field of endeavor, 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 this type of comparison can be used to determine a microorganism’s resistance or susceptibility to an applied antibiotic (Feng, Page 5, column 1).
Feng does not teach performing the comparison using a plurality of sub-samples.
Ismagilov II, in the same field of endeavor, teaches splitting a sample into a plurality of sub-samples under at least one set of test conditions (Page 4, paragraph [0020]).
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 comparison of Ismagilov, in view of Feng, with the plurality of sub-samples of Ismagilov II. Since Ismagilov, Feng, and Ismagilov II are in the same field of endeavor, 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 a plurality of sub-samples provides robustness to the assay, robustness meaning wherein a series of repeated quantitative measurements provides a set of similar measurements under varying experimental conditions (Ismagilov II, Page 50 and 51, paragraph [00211]).
Regarding instant claim 18, Ismagilov, in view of Feng and Ismagilov II, teaches the method of claim 17.
Neither Ismagilov, nor Feng, teaches wherein the plurality of antibiotic treated intracellular/extracellular nucleic acid proportion values of the sample are used to provide an antibiotic treated intracellular/extracellular nucleic acid proportion profile of the sample.
Ismagilov II, in the same field of endeavor, teaches wherein a plurality of values can make a profile of the split sample by necessarily generating multiple detectable signals in a population of digital samples (Page 4, paragraph [0020]).
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 proportion values of Ismagilov, Feng, and Ismagilov II with the profile of Ismagilov II. Since Ismagilov, Feng, and Ismagilov II are in the same field of endeavor, 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 a plurality of sub-samples provides robustness to the assay, robustness meaning wherein a series of repeated quantitative measurements provides a set of similar measurements under varying experimental conditions (Ismagilov II, Page 50 and 51, paragraph [00211]).
Regarding instant claim 19, Ismagilov, in view of Feng and Ismagilov II, teaches the method of claim 18. Ismagilov further teaches comparing the antibiotic treated nucleic acid concentration value of the sample with a reference value indicative of a nucleic acid concentration value in the sample in absence of antibiotic treatment to obtain a treated-reference nucleic acid comparison outcome of the sample (Page 4, paragraph [0011]). Ismagilov does not specifically teach the nucleic acid concentration value is instead an intracellular/extracellular nucleic acid proportion value of the sample. However, given the combined teachings of Ismagilov, Feng, and Ismagilov II making an intracellular/extracellular nucleic acid proportion value obvious, as analyzed for claim 18, combining this with the comparison as described for instant claim 19 would be an obvious combination. One of ordinary skill in the art would have been motivated to make this combination because this type of comparison can be used to determine a microorganism’s resistance or susceptibility to an applied antibiotic (Ismagilov, Page 4, paragraph [0011]).
Regarding instant claim 20, Ismagilov, in view of Feng and Ismagilov II, teaches the method of claim 19.
Ismagilov does not teach wherein the method further comprises determining antibiotic susceptibility when the treated-reference nucleic acid comparison outcome of the sample indicates an increased lysis and an increased dead/live proportion of the microorganism cells in the antibiotic-treated sample compared to a sample treated under reference conditions; or determining antibiotic resistance when the treated-reference nucleic acid comparison outcome of the sample indicates a substantially same dead/live proportion of the microorganism cells in the antibiotic-treated sample compared to a sample treated under reference conditions.
Feng, in the same field of endeavor, teaches determining antibiotic susceptibility when the treated-reference nucleic acid comparison outcome of the sample indicates an increased lysis and an increased dead/live proportion of the microorganism cells in the antibiotic-treated sample compared to a sample treated under reference conditions (Page 5, column 1).
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 proportion value of Ismagilov, in view of Feng, with the dead/live proportion value to determine antibiotic susceptibility of Feng. Since both Ismagilov and Feng are in the same field of endeavor, 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 this type of comparison can be used to determine a microorganism’s resistance or susceptibility to an applied antibiotic (Feng, Page 5, column 1).
Regarding instant claim 22, Ismagilov, in view of Feng, teaches the method of claim 1.
Neither Ismagilov, nor Feng, teaches wherein the sample comprises a number of microorganism cells lower than 100, lower than 50, lower than 25, lower than 10, or lower than 5.
Ismagilov II, in the same field of endeavor, teaches wherein the sample comprises a number of microorganism cells lower than 100, lower than 50, lower than 25, lower than 10, or lower than 5 (Page 29, paragraph [00124]).
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 Ismagilov and Feng with the cell number of Ismagilov II. Since Ismagilov, Feng, and Ismagilov II are in the same field of endeavor, 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 smaller groups of cells may respond to an antibiotic faster, which would provide faster and more refined information on antibiotic susceptibility (Ismagilov II, Page 29, paragraph [00123]).
Regarding instant claim 23, Ismagilov, in view of Feng, teaches the method of claim 1.
Neither Ismagilov, nor Feng, teaches wherein the sample comprises a single microorganism cell.
Ismagilov II, in the same field of endeavor, teaches wherein the sample and/or one or more sub-samples comprises a single microorganism cell (Page 29, paragraph [00124]).
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 Ismagilov and Feng with the cell number of Ismagilov II. Since Ismagilov, Feng, and Ismagilov II are in the same field of endeavor, 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 smaller groups of cells may respond to an antibiotic faster, which would provide faster and more refined information on antibiotic susceptibility (Ismagilov II, Page 29, paragraph [00123]).
Regarding instant claim 31, Ismagilov, in view of Feng, teaches the method of claim 1.
Neither Ismagilov, nor Feng, teaches wherein the one or more sub-samples of the plurality of sub-samples comprise a single microorganism cell.
Ismagilov II, in the same field of endeavor, teaches wherein the one or more sub-samples comprises a single microorganism cell (Page 29, paragraph [00124]).
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 Ismagilov and Feng with the cell number of Ismagilov II. Since Ismagilov, Feng, and Ismagilov II are in the same field of endeavor, 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 smaller groups of cells may respond to an antibiotic faster, which would provide faster and more refined information on antibiotic susceptibility (Ismagilov II, Page 29, paragraph [00123]).
Response to Arguments
Applicant's arguments filed February 20th, 2026 have been fully considered but they are not persuasive.
The Applicant first briefly summarizes the Examiner’s previous rejection, arguing that “the above rejections are maintained without apparently weighing or addressing the evidence and arguments provided in the Amendment, which contradict the above conclusions of obviousness according to the preponderance of the evidence (MPEP 2143, MPEP 2145)” (Page 9 of the Remarks filed February 20th, 2026). The Applicant further states that the methods of Ismagilov and Feng are based on detection of different markers of susceptibility, specifically stating that Ismagilov is based on the detection of accessible or inaccessible nucleic acid and Feng is based on the principle of cell viability (Page 9 of the Remarks filed February 20th, 2026). The Applicant states that there is no mention or analysis of this fundamental discrepancy in biomarkers, further stating that there is a failure to explain why one of ordinary skill in the art would be motivated to modify Ismagilov’s assay with Feng’s staining (Page 9 of the Remarks filed February 20th, 2026). The Applicant argues that a mere assertion that a person of ordinary skill would make such a modification fails to account for the technical incompatibility of Ismagilov and Feng (Page 10 of the Remarks filed February 20th, 2026).
The Applicant argues that Ismagilov and Feng have different principles of operation (Page 10 of the Remarks filed February 20th, 2026). The Applicant argues that Ismagilov’s method operates on nucleic acid accessibility with or without lysis and with or without mechanical separation, while Feng operates strictly on staining based cell viability (Page 10 of the Remarks filed February 20th, 2026). The Applicant provides exemplary excerpts of both references to compare their workflows (Pages 10-11 of the Remarks filed February 20th, 2026). The Applicant argues that combining these disparate methods would have required changing their core principles of operation to function as a single unit (Page 11 of the Remarks filed February 20th, 2026). The Applicant states that the Action fails to provide a technical reasoning as to why this difference in operation would not be a significant deterrent to the proposed combination, reinforcing the conclusion that the rejection is based on impermissible hindsight (Page 11 of the Remarks filed February, 20th, 2026). The Applicant states that, as discussed during the interview, the Action ignores clear indications that lead a person of ordinary skill in the art away from the conclusion of obviousness (Page 11 of the Remarks filed February 20th, 2026). The Applicant further states that the absence of a reasonable expectation of success demonstrates that the proposed modification is only possible by using the Applicant’s disclosure as a road map (Pages 11-12 of the Remarks filed February 20th, 2026).
In response to these arguments, it is noted that Ismagilov and Feng examine fundamentally equivalent biomarkers in their methods. Ismagilov analyzes nucleic acid concentrations directly. Feng’s cell staining is analyzing nucleic acid concentration through binding of intercalating dyes, which integrate with nucleic acids, and measuring the resultant fluorescent intensity. While Applicant argues that this is a fundamental discrepancy, it should be noted that both references are ultimately measuring nucleic acid concentration of both extracellular and intracellular DNA. With respect to the argument about different principles of operation, Ismagilov is relied upon to teach the method steps with regards to the claimed method of determining nucleic acid concentration for extracellular and intracellular components. Feng then provides motivation for obtaining both intracellular and extracellular concentrations from the same sample. The details of Feng’s method are provided in the above rejection to exemplify the fundamentally equivalent measurements, establish the basis for performing these measurements in the same sample, and teach the math for comparison of extracellular and intracellular fractions of nucleic acid concentration. The combination is not to combine Ismagilov’s nucleic acid concentration detection with Feng’s staining, but instead to combine Ismagilov’s separate detection of extracellular and intracellular nucleic acid concentration into the same sample with a teaching from Feng as to why with a fundamentally equivalent set of nucleic acid concentration measurements. This would not result in changing core principles of operation because the modification only results in a different way of determining the nucleic acid concentrations and calculating a ratio therefrom.
In response to the Applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it is also noted that the Supreme Court ruling for KSR Int’l Co. v. Teleflex, Inc. (No 04-1350 (US 30 April 2007) forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See Ex parte Smith (USPQ2d, slip op. at 20 (Bd. Pat. App. & Interf. June 25, 2007). Reasons for combining have been clearly articulated in the rejections above.
Furthermore, in response to the Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). While the Applicant may assert that the methods are incompatible and therefore obviousness rests on hindsight assumptions (see Page 10 of the Remarks filed February 20th, 2026), both are still ultimately measuring nucleic acid concentration and represent fundamentally equivalent methods of doing so. The combination was within the level of ordinary skill as articulated in the above rejection.
The Applicant argues that the marker of susceptibility of Ismagilov II has a marker of susceptibility and a principle of operation that differ from Ismagilov’s and Feng’s (Page 12 of the Remarks filed February 20th, 2026). The Applicant provides exemplary excerpts of all three references to compare their workflows (Pages 12-14 of the Remarks filed February 20th, 2026). The Applicant argues that the Action fails to explain how a person of ordinary skill in the art would be motivated to combine the workflows of Ismagilov, Feng, and Ismagilov II (Page 14 of the Remarks filed February 20th, 2026). The Applicant further argues that there is no specific information on how Ismagilov II provides a technical bridge to Ismagilov or Feng, the current rejection overlooks passages that lead away from the proposed combination, and, absent a technical reasoning for why fundamental differences wouldn’t be a deterrent, the proposed combination remains hindsight-driven reconstruction that overlooks evidence leading away from the conclusion of obviousness (Page 14 of the Remarks filed February 20th, 2026).
In response to the Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is noted that it is not the specific method of Ismagilov II that is pertinent to what is taught, but instead aspects of sample handling and types of samples. As indicated above, Ismagilov teaches the method as claimed, while Feng provides the context for detecting both an intracellular and extracellular component in the same sample, as well as providing relevant math when both components are detected. Ismagilov II teaches that a sample may be split into a population of samples (e.g. sub-samples) for robustness of experimentation, but is not relied upon for the specific method of experimentation because this has already been obviated by Ismagilov. It would be obvious to one of ordinary skill in the art that the sample handling of Ismagilov II is not directly tied to the later steps for determining antibiotic susceptibility because the sample handling occurs before the determination step occurs (Page 4, paragraph [0020]). The method of Ismagilov could be substituted after the sample handling steps of Ismagilov II by one of ordinary skill in the art, as is intended by the combination of teachings.
In response to the Applicant’s further assertion argument that there is no teaching, suggestion, or motivation to combine the references, it is noted that the reasons for combining are clearly articulated in the rejections above.
Also, in response to the Applicant's reiteration that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it is noted that this has been addressed above.
Furthermore, in response to the argument that passages that lead away from the proposed combination, it is noted that the MPEP states “[h]owever, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).” (see MPEP 2141.02(VI)).
The Applicant next provides passages from the Examiner’s previous Response to Arguments section (Pages 14-15 of the Remarks filed February 20th, 2026). The Applicant argues that the line of reasoning provided by these arguments does not consider each reference as a whole, extracting discrete components while ignoring the underlying principles of operation constituting impermissible cherry picking of the cited documents (Page 15 of the Remarks filed February 20th, 2026). The Applicant argues that the response essentially ignores the technical barriers described in the Amendment and outlined in the previous sections (Page 15 of the Remarks filed February 20th, 2026). The Applicant argues that “one cannot simply extract a "motivation for providing relevant math" from Feng while disregarding the fact that said math is intrinsically tied to cell viability dyes, nor can one "easily substitute" the sample handling of Ismagilov Il without accounting for the fact that its entire workflow is optimized for biomass replication rather than accessibility.” (Pages 15-16 of the Remarks filed February 20th, 2026). The Applicant provides more arguments directed to evaluation of the references as a whole, concluding that the references utilize incompatible biomarkers and operational principles, and if the references are viewed as integrated technical solutions rather than a menu of pertinent aspects, non-obviousness is the only supported conclusion (Page 16 of the Remarks filed February 20th, 2026).
In response to these arguments, it is again noted that the MPEP states “[h]owever, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." (see MPEP 2141.02(VI)). The references have been considered as a whole, and their relevance noted as presented in the above responses. Furthermore, there is no explicit indication in the references that teaches away from the proposed combination.
The Applicant provides the amendment to claim 1, stating that, as discussed during the interview, there is no teaching of the claim as currently amended (Pages 16-17 of the Remarks filed February 20th, 2026). The Applicant further provides reasoning for this conclusion (Page 17 of the Remarks filed February 20th, 2026). The Applicant then provides passages from the specification to support claim 1 as currently claimed (Pages 17-19 of the Remarks filed February 20th, 2026). The Applicant states that the processing of claim 1 provides a specific technical solution to the biological noise associated with the detection process (Page 19 of the Remarks filed February 20th, 2026). The Applicant also refers to Examples from the specification related to the amended processing aspect of claim 1 (Pages 19-20 of the Remarks filed February 20th, 2026). The Applicant notes that the “proportion value” is configured to minimize the impact of events introducing variability in the nucleic acid detection and thus improves the signal-to-noise ratio (Page 20 of the Remarks filed February 20th, 2026). The Applicant argues that the cited references fail to teach the unified processing step (Page 20 of the Remarks filed February 20th, 2026).
In response to the provided citations from the specification, the Examiner acknowledges their relevance, and also reminds the Applicant that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The Applicant provides the amended claim 1 again, followed by relevant MPEP citations for providing adequate support from an obviousness rejection (Pages 20-22 of the Remarks filed February 20th, 2026). These citations are acknowledged and arguments related to their contents have already been addressed above.
Double Patenting - New - Necessitated by Further Considerations
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-5, 7-10, 13-24, 27, 29, and 30-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 11827944B2, in view of Ismagilov (WO 2019075264 A1; previously cited), Feng et al. (A Rapid Growth-Independent Antibiotic Resistance Detection Test by SYBR Green/Propidium Iodide Viability Assay, Frontiers in Medicine, May 2018, 5, 1-11; previously cited) and Ismagilov (WO 2018058078 A1; previously cited).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘944 patent and the instant application claim a method to detect a nucleic acid of a microorganism in a sample including the microorganism, the method comprising contacting a sample with an antibiotic to provide an antibiotic treated sample (instant claim 1, reference claim 1); quantitatively detecting in the treated sample an accessible nucleic acid of the microorganism to obtain an accessible nucleic acid concentration (instant claim 1, reference claim 1); mechanical separation of nucleic acid fractions by filtration (instant claim 3; reference claim 14); comparing antibiotic treated sample concentrations with reference values (instant claim 8; reference claim 3); the reference sample being an untreated control sample (instant claim 10; reference claim 5); times for contacting the sample with an antibiotic including up to 90 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes; and up to 5 minutes (instant claim 24; reference claims 19-23); the nucleic acid being DNA and quantitatively detecting via DNA-seq (instant claim 27; reference claims 9, 12, and 18); the antibiotic being a beta-lactam or a carbapenem (instant claim 29; reference claims 25-26); and the microorganism being Neisseria gonorrhoeae or being from the family Enterobacteriaceae (instant claim 30; reference claims 28-29).
The ‘944 claims do not require detecting an extracellular and intracellular nucleic acid concentration of the antibiotic-treated sample; establishing an intracellular/extracellular proportion value; the proportion value being a ratio of either the detected intracellular concentration and the sum of the intracellular and extracellular concentration values or the detected extracellular concentration and the sum of the intracellular and extracellular concentration values; the proportion value being a percent extracellular concentration or intracellular concentration; determining a proportionality od dead and live microorganism cells in the sample by determining an intra/extra proportion value; a reference value comprising a reference intracellular/extracellular nucleic acid proportion value of a reference sample; determining antibiotic susceptibility or determining antibiotic resistance based on the intracellular/extracellular proportion value compared to a reference; performing substantially the same method as detailed on sub-samples; splitting the sub-samples by digital partitioning into particular amounts of cells; and pretreating to enrich the sample with the target microorganism and/or to remove nucleic acids from other organism. However, Ismagilov, Feng, and Ismagilov II teach the claimed limitations as discussed in the above 103 rejections, obviating these variations to the claims of the ‘944 patent. Any additional limitations of the claims of U.S. Patent No. 11827944B2 are encompassed by the open claim language “comprising” found in the instant claims.
Claims 1-2, 4-5, 7-10, 13-24, 27, 29, and 30-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 12448655B2, in view of Ismagilov (WO 2019075264 A1; previously cited), Feng et al. (A Rapid Growth-Independent Antibiotic Resistance Detection Test by SYBR Green/Propidium Iodide Viability Assay, Frontiers in Medicine, May 2018, 5, 1-11; previously cited) and Ismagilov (WO 2018058078 A1; previously cited).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘655 patent and the instant application claim a method to detect a nucleic acid of a microorganism in a sample including the microorganism, the method comprising contacting a sample with an antibiotic to provide an antibiotic treated sample (instant claim 1, reference claim 1); quantitatively detecting in the treated sample an accessible nucleic acid of the microorganism to obtain an accessible nucleic acid concentration (instant claim 1, reference claim 1); mechanical separation of nucleic acid fractions by filtration or centrifugation (instant claim 3; reference claims 2-3); comparing antibiotic treated sample concentrations with reference values (instant claim 8; reference claim 12); the reference sample being an untreated control sample (instant claim 10; reference claim 15); pretreating to enrich the sample with the target microorganism and/or to remove nucleic acids from other organism (instant claim 21; reference claim 30); times for contacting the sample with an antibiotic including up to 90 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes; and up to 5 minutes (instant claim 24; reference claim 4); the nucleic acid being DNA and quantitatively detecting via qPCR (instant claim 27; reference claims 5, 20, and 22); the antibiotic being a beta-lactam or a carbapenem (instant claim 29; reference claims 28); and the microorganism being from the family Enterobacteriaceae (instant claim 30; reference claims 29).
The ‘655 claims do not require detecting an extracellular and intracellular nucleic acid concentration of the antibiotic-treated sample; establishing an intracellular/extracellular proportion value; the proportion value being a ratio of either the detected intracellular concentration and the sum of the intracellular and extracellular concentration values or the detected extracellular concentration and the sum of the intracellular and extracellular concentration values; the proportion value being a percent extracellular concentration or intracellular concentration; determining a proportionality od dead and live microorganism cells in the sample by determining an intra/extra proportion value; a reference value comprising a reference intracellular/extracellular nucleic acid proportion value of a reference sample; determining antibiotic susceptibility or determining antibiotic resistance based on the intracellular/extracellular proportion value compared to a reference; performing substantially the same method as detailed on sub-samples; and splitting the sub-samples by digital partitioning into particular amounts of cells. However, Ismagilov, Feng, and Ismagilov II teach the claimed limitations as discussed in the above 103 rejections, obviating these variations to the claims of the ‘655 patent. Any additional limitations of the claims of U.S. Patent No. 12448655B2 are encompassed by the open claim language “comprising” found in the instant claims.
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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