Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This Office Action is in response to the papers filed on 25 November 2025.
CLAIMS UNDER EXAMINATION
Claims 1, 4, 6-7, 13-16, and 20-21 have been examined on their merits.
PRIORITY
Claim 1 has been amended to recite a tissue culture plate comprising a plurality of wells pre-loaded with a plurality of pre-determined rate-targeted concentrations of antibiotic agent. Provisional Application 62/547,361, 62/552,332 and 62/671,380 do not provide support for this limitation. Support for this limitation is found at [0032] of PCT/US2018/047075 filed on 20 August 2018.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
REJECTIONS
New grounds of rejection have been necessitated by claim amendment.
Claim Rejection - 35 U.S.C. § 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, 4, 6-7, 13-16, and 20-21 are rejected under 35 U.S.C. § 101 because the claimed invention is directed to nonstatutory subject matter.
Based on the claims as a whole, claims 1, 4, 6-7, 13-16, and 20-21 are determined to be directed to a law of nature/natural principle. The rationale for the determination is explained below.
Question 1: Is the claim to a process, machine manufacture or composition of matter? Yes, the invention recited in claim 1 is a process.
Question 2A Prong 1: Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation. Yes, claim 1 is directed to a law of nature.
(a) The limitations in the claim that set forth the law of nature is:
The 2019 PEG explains that the abstract idea exception includes the following groupings of subject matter:
Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations;
Certain methods of organizing human activity – fundamental economic principles or practices (including hedging, insurance, mitigating risk); commercial or legal interactions (including agreements in the form of contracts; legal obligations; advertising, marketing or sales activities or behaviors; business relations); managing personal behavior or relationships or interactions between people (including social activities, teaching, and following rules or instructions); and
Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion).
Claim 1 is directed to an abstract idea and a natural phenomenon. The abstract ideas are:
Step (h): determining a susceptibility of bacteria in a clinical sample to the antibiotic agent by comparing (hence, a mental process) the quantity of RNA in the test amount to the quantity of RNA in the control amount (i.e., mathematical calculations based on the amounts of RNA present in the test and control samples where the difference in amount RNA determines susceptibility). The natural phenomenon is a correlation between antibiotic susceptibility of bacteria and the amount of RNA present in the test sample (i.e., bacteria are naturally susceptible to an antibiotic agent and have a lower amount of RNA, as compared to a control sample, if the bacteria are susceptible to the antibiotic). Therefore, the above abstract idea and natural phenomenon are judicial exceptions.
Question 2A Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application? No
Steps (a)-(g) are directed to inoculating, incubating and measuring a test amount and a control amount of a clinical sample. Step (a) recites providing a culture plate comprising wells pre-loaded with pre-determined rate-targeted concentrations of the antibiotic. The plate is an insignificant extra-solution activity required to perform the judicial exceptions.
Steps (b)-(e) recite inoculating and incubating the pre-loaded wells with clinical and control samples. Testing experimental and control conditions is well known in cell culture and microbiological assay fields. Step (f) recites a step of forming a lysate comprising RNA. Forming a cell lysate to analyze cellular components is well known in cell culture and microbiological assays. Step (g) is a measuring step. Measuring is required to perform the judicial exception recited in step (h).
Steps (a)-(g) are necessary data gathering steps that are required to make the determination recited in step (h) (the judicial exception). In view of the above, steps (a)-(g) are insignificant extra solution activities.
Question 2B: Do the claims recite any additional elements? Yes.
With respect to Step 2B, limitations that were found to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include:
Improvements to another technology or technical field.
Improvements to the functioning of the computer itself.
Applying the judicial exception with, or by use of, a particular machine.
Effecting a transformation or reduction of a particular article to a different state or thing
Adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application.
Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
With respect to Step 2B, limitations that were found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include:
Adding the words ‘‘apply it’’ (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well understood, routine and conventional activities previously known to the industry
Adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea
Generally linking the use of the judicial exception to a particular technological environment or field of use.
Does the additional element result in the claim amounting to significantly more?
No. Regarding claim 1: In addition to the abstract idea discussed above, the non-abstract elements (steps a-g) are recited at a high level of generality, and were well-understood, routine and conventional practices in the art prior to the time of invention. Step (b) is a sample collection step. As evidenced by the Instant Specification, isolation of uropathogens (hence, bacteria from urine) is “known in the art” ([0004]). Step (b) and step (e) are interpreted to recite the use of positive and negative controls. As evidenced by the Instant Specification, the use of positive and negative controls “would be known to those of skill in the art” ([0529] [0530]). Regarding the incubation steps recited in steps c) and d), the specification discloses “common methods” that require incubation of bacterial pathogens in clinical specimens to test for antimicrobial susceptibility ([(0006]). PCT/US2018/045211, which the specification incorporates by reference, discloses there are many conventional lysing techniques that are known to effectively lyse Gram - negative bacteria. For example, chemical lysis using an alkaline solution has been shown to effectively release target molecules, such as 16S rRNA from Gram - negative cells ([0005]). Therefore specimen collection, negative and positive controls, incubation and RNA isolation are well known, routine and conventional in the art. As set forth above, steps (a)-(g) are insignificant extrasolution activities that are required to perform the judicial exception recited in step (h).
Regarding the dependent claims:
Dependent claims 4, 13 and 21 further limit the RNA. Dependent claim 6 further limits the antibiotic agent. Claim 7 further limits the bacteria. Claims 14-15 further limit the clinical sample. Claim 16 recites at least one predetermined rate-targeted concentration is below the CLSI MIC cutoff for urine for the antibiotic agent. Claim 20 further limits alkaline treatment step recited in claim 1. Each of the limitations is required to perform the judicial exception recited in step (h). These steps are insignificant extrasolution activities because they are necessary data gathering steps required to perform the judicial exception (determining a susceptibility of the bacteria to the antibiotic agent).
Regarding claim 16: As evidenced by the PG Pub of the specification, the CLSI MIC is known data ([0533]). As evidenced by Feng, MIC and drug susceptibility are determined using a chart provided by the UCLA Clinical Microbiology Laboratory using a look-up table (see page 1, second paragraph). Therefore claim 16 comprises looking at data in a chart, and choosing a concentration of antibiotic that is below the CLSI MIC. This is a mental process (and a judicial exception).
Therefore claims 1, 4, 6-7, 13-16, and 20-21 are not eligible subject matter under 35 USC 101.
RESPONE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 25 November 2025 are acknowledged.
Argument 1: The arguments state the claims are patent eligible because they improve antimicrobial susceptibility testing (AST) technology using a predetermined concentration of an antibiotic to provide faster results. The arguments state step a) applies the judicial exception by use of a particular machine (a tissue culture plate) in a particular way (preloaded with pre-determined concentrations of antibiotics). The arguments state this results in significantly more that the judicial exception.
Response to argument 1: As evidenced by Feng, “the gold standard” for antimicrobial testing comprises preparing two-fold dilutions of antibiotics (hence, different concentrations) in a liquid growth medium that is dispensed in a 96-well microtiter plate (page 1, second paragraph). The antibiotic containing wells are subsequently inoculated with bacterial suspensions from a patient (biological samples; same cited section). The lowest concentration of antibiotic that prevents growth represents the minimum inhibitory concentration (MIC). This MIC value is interpreted using a table of values that relate to the proven clinical efficacy of each antibiotic for various bacterial species (last sentence of page 1, bridging fist line of page 2). The interpretive criteria has been established by the FDA and the Clinical Laboratory Standards Institute (CLSI) (see first paragraph of page 2).
Therefore a microtiter plate (a tissue culture plate comprising multiple wells containing antibiotic) was well know, routine and conventional (hence, the “gold standard”). Selecting pre-determined concentrations that are higher or lower than known CLSI MCI data is a mental process (a judicial exception). It is emphasized the claimed plates are used to make the determination step (judicial exception) recited in step (h). Therefore step (a) is interpreted to be an insignificant extra-solution activity that does not add significantly more.
Argument 2: The Applicant argues the time recited in claim 1 was not well-understood or known in the art.
Response to Argument 2: As evidence by Super et al., AST can be performed with any incubation time. Super discloses a 180 minute incubation. The claimed time does not add significantly more to the judicial exception. The incubation time is an insignificant extra-solution activity that is required to perform the judicial exception recited in step (h): determination of susceptibility. Therefore the arguments are not persuasive.
Claim Rejections - 35 U.S.C. § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4, 6-7, 13-16 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Haake et al. (previously cited; Antibiotic susceptibility testing using probes for preribosomal rna 2015/0104789, published 4/16/2015) in view of Feng et al. (High-throughput and automated diagnosis of antimicrobial resistance using a cost-effective cellphone-based micro-plate reader. Sci Rep 6, 39203; 2016), Super et al. (Rapid antibiotic susceptibility testing. US20150064703A1) and Deck et al. (previously cited; U.S. PGPUB 2016/0281125; 9/29/2016).
Hakke teaches a method for testing and detection of antibiotic susceptibility in specimens of bodily fluid and other samples ([0003]). Therefore the art teaches an antibiotic susceptibility test (AST). The specimen can be urine (hence, a clinical sample) ([0057]). The method is performed in the presence and absence of an antibiotic (Abstract) [0006] [0007]). The specimen is contacted with an oligonucleotide probe that specifically hybridizes with a target nucleic acid sequence region of ribosomal RNA of a bacteria of interest (Abstract; [0007][0051]).
The contacting and hybridization time is interpreted as the incubation period. Haake teaches a reduced amount of probe hybridization in the presence of the antibiotic agent relative to the amount of probe hybridization in the absence of the antibiotic agent is indicative of the susceptibility of the sample to antibiotic ([0006]).
The specimen is inoculated into a growth medium prior to the contacting of steps with and without an antibiotic agent ([0007]). Haake teaches that inoculation is preferably done in both the presence and absence of antibiotic, where the presence or amount of pathogen is then determined, typically by comparing the specimens inoculated in the presence and in the absence of antibiotic ([0062]).
Haake teaches precursor ribosomal RNA (pre-rRNA) is an intermediate stage in the formation of mature ribosomal RNA (rRNA) and is a useful marker for cellular metabolism and growth rate ([0025]). In Example 2, Haake analyzes the response of pre-rRNA to cefazolin ([0091]). FIG. 9 shows the response of pre-rRNA to cefazolin. Addition of cefazolin, a beta-lactam antibiotic, to a culture of a susceptible strain of E. coli in the log phase of growth resulted in a one-log drop in the amount pre-rRNA within 30 min compared to a culture without the antibiotic. Figure 9 illustrates an incubation time of 90 and 120 minutes.
The deficiencies of Haake are:
Haake teaches an antibiotic susceptibility test, but does not teach a tissue culture dish comprising plurality of wells pre-loaded with a plurality of pre-determined rate-targeted concentrations of antibiotic agent. Haake does not specifically teach that the predetermined rate-targeted concentration is at least 2-fold or greater than the resistant CLSI MIC cutoff for the antibiotic agent
Haake does not teach lysing the test amount comprises mechanical lysis, contacting with an alkaline material to produce a lysate composition comprising RNA and recovering the lysate.
Haake does not teach a longer incubation time (150 minutes to 240 minutes).
Feng et al. teach a high throughout antimicrobial susceptibility test (Abstract).
The art teaches “the gold standard for antimicrobial testing” comprises preparing two-fold dilutions of antibiotics in a liquid growth medium that is dispensed in a 96-well microtiter plate (page 1, second paragraph). The antibiotic containing wells are inoculated with bacterial suspensions from a patient (biological samples; same cited section). The lowest concentration of antibiotic that prevents growth represents the minimum inhibitory concentration (MIC). This MIC value must be interpreted using a table of values that relate to the proven clinical efficacy of each antibiotic for various bacterial species (last sentence of page 1, bridging fist line of page 2). The interpretive criteria has been established by the FDA and the Clinical Laboratory Standards Institute (CLSI) (see first paragraph of page 2). Feng teaches the concentration range varies with the drug, the organism tested and the site of infection (page 6, second paragraph). The MIC and drug susceptibility is determined using a chart provided by the UCLA Clinical Microbiology Laboratory using a look-up table (see page 6 “Calculation of MIC and Drug Susceptibility Interpretation”). Supplementary Table 1 discloses standard drug concentrations are populated in each well of a 96-well microtiter plate. These are interpreted to be pre-determined rate-targeted concentrations of antibiotic agents.
Super teaches a method for rapid determination of antibiotic susceptibility of a microbe within hours after a sample is collected (Abstract). The art teaches a biological sample ([0035]). The art teaches a microtiter plate comprising at least one antibiotic in a least one well ([0301]). Some wells of the microtiter plate can comprise a distinct antibiotic agents and some wells do not comprise any antibiotic agents, i.e., for use as a control or reference ([0301]). A plurality of subsamples can be cultured in growth media containing different concentrations of an antibiotic agent ([0114] [0151).
The microbial culture can be incubated in the presence or absence of an antibiotic for any period of time ([0148]). In some embodiments, the assay described herein can be performed in as a little as three hours of specimen reception ([0007]). At [0148] The art teaches 180 minutes or more. Depending on the proliferation and/or growth rate of captured microbes, one of skill in the art can determine optimum incubation duration for subsequent analysis, e.g., cell viability analysis ([0148]).
Deck teaches methods of determining whether a target bacteria is susceptible to an antimicrobial compound. The methods comprise providing a sample comprising the target bacteria, maintaining the sample in the presence of an antimicrobial compound to provide an antimicrobial compound-exposed target bacterial sample, exposing the antimicrobial compound-exposed target bacterial sample to a cell-wall disruption condition (Abstract).
Deck teaches that cell-wall disruption conditions include conditions that comprise at least one of a detergent, a physical means of disrupting cells, alkaline conditions, a chemical cell-wall disruption agent, and an enzyme (paragraphs 169-173).
The at least one physical means of disrupting cells comprises vortexing, sonication and homogenization (paragraphs 174 and 175; i.e., mechanical lysis). Deck also teaches that the alkaline conditions comprise a solution comprising NaOH (paragraphs 176; i.e., contacting the test sample with an alkaline material to produce a lysate composition).
The conditions taught by Deck include “at least one” of a detergent, a physical means of disrupting cells, alkaline conditions, etc., the at least one can be only the physical means of disrupting cells (e.g., vortexing, sonication and homogenization; paragraphs 174 and 175; i.e., mechanical lysis), which can be interpreted as being the first step in lysing the materials prior to any additional disruptions conditions.
It would have been obvious to use a microtiter plate comprising wells pre-loaded with a plurality of predetermined rate-targeted concentrations of the antibiotic agent in the method taught by Haake. One would have been motivated to do so since Feng teaches the gold standard of AST comprises incubating a biological sample in wells that contain different pre-determined concentrations of antibiotic. Feng teaches the use of known MIC data for an organism and an antibiotic, and two-fold serial dilutions. The skilled artisan would use at least one concentration above the MIC cutoff to confirm the lowest concentration of antibiotic that prevents bacterial growth. One would have had a reasonable expectation of success since Feng teaches the recited microtiter plate can be used for AST. One would have expected similar results since Haake and Feng are both directed to methods of determining antimicrobial susceptibility.
It would have been obvious to try increasing the incubation time taught by Haake. Haake teaches an AST comprising 120 minute incubation time and Super teaches an incubation time of three hours (180 minutes). Super teaches determining the optimum incubation time based on bacteria growth and proliferation. The skilled artisan would try increasing the incubation time based on the desired cell growth before RNA analysis. One would have had a reasonable expectation of success since Super teaches incubation times of 180 minutes or more. One would have expected similar results since both references are directed to antimicrobial susceptibility tests.
It would have been obvious to combine the teachings of Haake and Deck by mechanically lysing cells. One would have been motivated to do so since Haake teaches a method of determining the susceptibility of bacteria to a drug and Deck teaches mechanical lysis of bacteria cells to test bacteria for drug susceptibility. One would treat with an alkaline material since Deck teaches treating with NaOH to produce a lysate. One would have had a reasonable expectation of success since Deck teaches cells can be mechanically lysed and lysed with alkali. One would have expected similar results since both references are directed to methods of determining drug susceptibility. Therefore claim 1 is rendered obvious.
Haake teaches ribosomal RNA (supra). Therefore claim 4 is included in this rejection.
Haake teaches incubation with an antibiotic agent (e.g., gentamicin, ciprofloxacin, cefazolin) ([0068]). Therefore claim 6 is included in this rejection.
Haake teaches that the method for detecting antibiotic resistance is performed after first identifying and quantifying the pathogen of interest, where the method of detecting the presence of a pathogen set forth in U.S. Patent No. 7,763,426 can be used to identify the pathogen and identification of the pathogen guides the selection of antibiotic to be tested for resistance ([0062]). Therefore Haake is interpreted to teach the bacteria in the method can be an unknown bacteria. Therefore claim 7 is included in this rejection.
Haake teaches that the sample is identified as susceptible to antibiotic treatment if the amount of probe hybridization to the target sequence in the presence of antibiotic is reduced by at least 80% (or reduced by 40%) relative to the amount of probe hybridization to the target sequence in the absence of antibiotic ([0006] [0007] and [0052], claim 1). Therefore claim 13 is included in this rejection.
Haake teaches that the clinical sample is urine (a liquid mammalian cellular material, a bodily fluid; paragraph 90). Therefore claims 14-15 are included in this rejection.
Haake teaches urine can be analyzed. Haake does not teach at least one predetermined rate-targeted concentration below the CLSI for urine
It would have been obvious to use at least one predetermined rate-targeted concentration below the CLSI for urine. Feng teaches the use of known MIC data for an organism and an antibiotic, and two-fold serial dilutions. The skilled artisan would use at least one concentration below the known MIC cutoff to confirm the lowest concentration of antibiotic that prevents bacterial growth. Therefore claim 16 is included in this rejection.
Deck teaches mechanical lysis (supra). Therefore claim 20 is included in this rejection.
Haake teaches rRNA (supra). Therefore claim 21 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
RESPONE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 25 November 2025 are acknowledged. New grounds of rejection have been made to address the amended claims.
CONCLUSION
No Claims Are Allowed
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653