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 .
Election/Restrictions
Applicant’s election of Group I, further electing probe EC in the reply filed on 10/1/25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further consideration the election of species is WITHDRAWN.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 7, 9, 12, 13, 26-35 and 39, is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kaushik et al. (A. M. Kaushik, K. Hsieh, T. DiSorbo and T. -H. Wang, "Rapid Pathogen Detection and Antimicrobial Susceptibility Assessment from Urine Samples Via Amplification-Free Detection of Ribosomal RNA of Single-Bacteria," 2019 20th International Conference on Solid-State Sensors, Actuators and Microsystems & Eurosensors XXXIII (TRANSDUCERS & EUROSENSORS XXXIII), Berlin, Germany, 2019, pp. 566-569, doi: 10.1109/TRANSDUCERS.2019.8808665; cited in IDS). The rejection of claim 28 is evidenced by Halford et al. (Antimicrobial Agents and Chemotherapy, 2013, Vol. 57, No. 2, pages 936-943).
The reference teaches a method that includes forming a set of droplets that each comprise one bacterial cell from a sample, at least one antimicrobial agent, and at least one set of probes, wherein the set of probes comprises a plurality of probes that each comprise at least one nucleobase sequence that is at complementary to at least one region of at least one 16S rRNA from the bacterial cell, and wherein the probes each comprise at least one reporter moiety and at least one quencher moiety that quenches the reporter moiety at least when the plurality of probes are not hybridized to the 16S rRNA. See Figure 1, also “Overview of our platform”, p. 566.
The reference teaches a brief bacterial culture or drug exposure of 10 minutes (i.e. claimed first time period). See Figure 1, also “Overview of our platform”, p. 566.
The reference teaches hybridization of fluorescent probes to complementary rRNA for 15 minutes (i.e. claimed second time period). See Figure 1, also “Overview of our platform”, p. 566.
The reference teaches detecting a detectable single from the reporter moiety of one or more of the probes in one or more of the droplets. See Figure 1, also “Overview of our platform”, p. 566.
The reference teaches that by comparing droplets with and without antibiotic susceptibility the strength of the detectable signal indicates whether or not the bacteria are resistant to the antibiotic. See Figure 1, also “Overview of our platform”, p. 566.
Regarding claim 7, the reference teaches a urine sample, and regarding claim 9, it is inherent that urine is obtained from a subject. See Figure 1.
Regarding claim 12, the reference teaches a plurality of droplets that each comprise a single bacterium from the sample. See figure 1.
Regarding claim 13, the antimicrobial agent is an antimicrobial therapeutic agent. The reference teaches testing the platform with gentamicin and ciprofloxacin, both of which are therapeutic antibiotics. See figure 5.
Regarding claim 26, the reference detectable signal is obtained from droplets that comprise the bacterial cell and the set of probes and lack the antimicrobial agent. See Figure 4A.
Regarding claim 27, the reference teaches 4 picoliter drops. See p. 567, 2nd column.
With regard to claim 28, it is inherent to E. coli that they contain these many copies of rRNA. This is evidenced by Halford et al. which teaches that in Escherichia coli, the rRNA copy number per cell has been estimated to vary from as high as 72,000 during log phase to less than 6,800 during stationary phase (p. 936).
With regard to claims 29 and 30, the reference teaches the first time period is 10 minutes, and at a temperature of about 37C. See Figures 1 and 3 and “Detection of single-bacteria and assessment of antimicrobial susceptibility in droplets”, p. 567.
With regard to claims 31 and 32, the reference teaches the second time period is 17 minutes, and at a temperature of about 60C. See Figures 1 and 3 and “Detection of single-bacteria and assessment of antimicrobial susceptibility in droplets”, p. 567.
With regard to claims 33 and 34, the reference teaches a 2-minute thermal lysis of bacterial cells to release ribosomal RNA. The lysis is at 95C. See Figures 1 and 3, also “Overview of our platform”, p. 566.
With regard to claim 35, the reference teaches testing E. coli which is a gram-negative bacterial cell.
With regard to claim 39, the reference teaches forming the droplets in a microfluidic device, see figures 1 and 3.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kaushik et al. (previously cited).
The teachings of Kaushik et al. are given previously in this Office action and are fully incorporated here.
Kaushik does not teach administering one or more antimicrobial therapeutic agents to a subject upon identifying ad determining the antimicrobial susceptibility of the bacteria in the sample.
However, Kaushik does teach that their method is for detection and antimicrobial susceptibility assessment of bacteria directly from urine samples of patients with urinary tract infection (UTI), p. 566, and that the method can detect the effect of antibiotics on bacterial growth after as little as 10 minutes of drug exposure. It would have been prima facie obvious to have modified the method taught by Kaushik by administering a drug identified as successfully treating a bacteria to a UTI patient in order to provide the right drug to the right patient with the best hope of successfully treating a UTI.
Claim(s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kaushik et al. in view of Mach et al. (Analyst, 2019, 144, 1565–1574).
The teachings of Kaushik et al. are given previously in this Office action and are fully incorporated here.
Kaushik et al. does not teach a method wherein the probes are selected from Table 1.
Mach teaches probes identical to those set forth in Table 1, see reference Table 1, p. 1567, and demonstrate the use of these probes for detection of bacterial targets in a microfluidic system (see Figure 5 and throughout).
It would have been obvious to have modified the method taught by Kaushik et al. so as to have employed to probes taught by Mach et al. since Kuashik et al. teach employing PNA probes of the same structure as those in Mach et al. (See figure 1 Kaushik) and for detecting the same bacterial targets detected in Mach et al. It would have been obvious to use the probes of Mach et al. to achieve the predictable outcome of detecting the target bacteria in the system taught by Kaushik.
Response to Remarks
The response argues that Kaushik does not teach or suggest producing additional 16S rRNA as the biological readout. The claims do not recite "producing additional 16S rRNA as the biological readout" or "that antimicrobial susceptibility is determined based on whether the bacterial cells "multiply and/or at least produce additional 16S rRNA during the first incubation period." In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). 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 claims require "incubating the set of droplets for a first time period under conditions sufficient for the bacterial cells in the droplets to multiply and/or to at least product additional 16S rRNA," reciting that the first time period comprises 15 minutes or less in claim 29. The reference clearly teaches a first culture period of 10 minutes, which is identical to the exemplified length of the first culture period in instant Figure 5, and therefore meets this limitation. The limitation requires that the period of time is sufficient for the cells to multiply and/or produce additional 16S rRNA, but, contrary to the argument, there is no requirement that the cells actually do so, or that "additional 16S rRNA" is a biological readout. Nonetheless, it is relevant that the reference teaches "Growing E. coli were detected" (p. 567, 2nd column) and Figure 4, and that the biological readout is 16S rRNA, that is, the reference very clearly teaches detecting 16S rRNA in higher amounts as evidence of continued cell growth, either where there is no antibiotic or where the cells are resistant to the antibiotic. It is inherent to the growth of E. coli that additional 16S rRNA is produced.
The response argues that Kaushik does not teach comparing the detectable signal with a reference detectable signal, wherein the reference detectable signal is droplets lacking antimicrobial agent. Figure 4 very clearly shows detecting the strength of a detectable signal with a strength of a reference detectable signal. In Figure 4, the reference detectable signal can be considered within panel A as the high and low peaks, or the reference signal could be considered comparing B to A, where the "reference" is the cells in A lacking antimicrobial agent. The claimed "reference detectable signal" is broad enough to encompass the comparing set forth in the reference.
Applicant argues that the reference does not teach "optionally, to artificially amplify the 16S rRNA.” This limitation is optional; the reference need not teach it for anticipation. Furthermore, it is relevant that the Seachange case, cited by applicants, states, "Teaching away is irrelevant to anticipation (citations omitted)." Seachange Int'l v. C-Cor, 413 F.3d 1361 (Fed. Cir. 2005), emphasis added.
Applicant argues that Kaushik does not teach identification of bacteria concurrent with susceptibility determination. The "concurrent" limitation is not in the claim. Kaushik teaches “the resulting color signature is used to assess the identity of the uropathogen." See p. 566, first column. There is no requirement in the claim for "species-level identification" in the claim. No language in the claim distinguishes from the identifying carried out by Kaushik.
Applicant argues that the method operates at the "single-cell level." This is a feature not claimed. "At least one bacterial cell" is broad enough to encompass an infinite number of cells, in fact. There is no upper limit. There is no claimed "single-cell determinative analysis." Furthermore, it is noted that Figure 1 of the reference illustrates a single bacterial cell per drop, and the reference teaches "Detection of rRNA from single-bacteria in droplets." See p. 567, column 2. Furthermore, Figure 4 demonstrates signals obtained from individual droplets.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. US 20080166720 A1 teaches in paragraph 44 that multiplex detection can occur in a single picoliter-sized droplet.
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/
Primary Examiner, Art Unit 1682