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
The instant application is a U.S. national phase application PCT/JP2020/008581 filed March 2, 2020, with a foreign priority application JP2019-042297 filed March 8, 2019.
Applicant’s amendment filed November 4, 2025 is acknowledged. Claims 3-5 are canceled. Claims 1 and 7-8 are amended to change the spelling of “cephalothin” to “cefalotin”, which are the alternative name for the same compound. Currently claims 1-2 and 6-17 are pending, wherein claims 1-2, 6-7, and 15 are withdrawn.
Claims 8-14 and 16-17 are under examination.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 8-14 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Swarna, et al. (Indian Journal of Medical Research, 2015, 141(4):p 481-482, cited in PTO-892 mailed April 26, 2024, hereinafter “Swarna”) in view of Johargy (JPMA, 01 Oct 2016, 66(10):1291-1295, cited in PTO-892 mailed 10/01/2025), and Fonseca et al. (J Clin Pathol 1986;39:220-222, cited in PTO-892 mailed 10/23/2024, hereinafter “Fonseca”).
Swarna teaches performance of extended spectrum beta lactamases (ESBL) screening agar in various clinical specimens (title). Swarna teaches the clinical specimens were screened using in-house preparation of ESBL (ESA) screen agar consisting of MacConkey agar II with cefotaxime (a third-generation cephalosporin), cloxacillin, and vancomycin at 64 mg/L, which meets the limitations of the selection medium according to claims 8, 11, and 16 (pg. 481, col. 2, para 1). Although Swarna does not explicitly teach the concentration of vancomycin is greater than 128 µg/mL, ‘Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)’.
Swarna teaches the clinical specimens screened on the agar included stool (feces), inter alia, which meets the limitation of claims 10 and 13 (pg. 482, col. 1, para 2). Pseudomonas aeruginosa was detected and selected on the ESA in the various clinical specimens by subjecting the specimens to bacterial culture and identification by standard procedure using conventional methods which meets the limitations of claims 8, 9, 11, and 12 (pg. 482, col. 1, para 2; 481, col. 2, para 1). Swarna teaches that ESA is particularly useful when detection of resistance is urgently required in the patients admitted in high-risk units (pg. 482, col. 1, para 5).
Swarna does not teach the selective medium also comprises cephalothin (a first generation cephalosporin, AKA cefalotin) in a concentration greater than 16 µg/mL. Swarna also does not explicitly teach the cefotaxime is in a concentration range of 0.1-64 µg/mL as recited in claims 8 and 11 (selection medium recipe recited in claim 1), nor in a range of 0.5-32 µg/mL as recited in claim 17.
However, Johargy teaches antimicrobial susceptibility of bacterial and fungal infections among diabetic patients, and teaches P. aeruginosa was resistant to cephalothin at concentration of 30 µg (pg. 1292 col. 1, para 2; pg. 1293, col. 1, para 4), which meets the limitation of claims 8 and 11. Johargy teaches all P. aeruginosa strains were resistant to cefotaxime at concentrations of 30 µg, which falls within the ranges recited in claims 8, 11, and 17 (pg. 1292 col. 1, para 2; pg. 1293, col. 2, para 3).
Swarna does not teach the basal medium is mixed NAC (nalidixic acid, cetrimide) medium and TSA (tryptic soy agar) medium at a mass ratio of 1:1 to 1:20, respectively, in claims 8, 11, and 14.
However, Fonseca teaches inhibition of P. aeruginosa from cystic fibrosis by selective media (title). Fonseca teaches sputum specimens were collected from patients and determined the minimum inhibitory concentration of strains from cystic fibrosis (CF) patients and non-CF patients with both nalidixic acid and cetrimide (pg. 220, col. 2, para 3). Fonseca teaches nalidixic acid and cetrimide were diluted in TSA by an agar dilution method, wherein dilution concentrations ranged from 4 mg/L to 1024 mg/L (pg. 220, col. 2, para 3, Table 1). Fonseca teaches the ‘breakpoint’ concentration for nalidixic acid was 16mg/L and for cetrimide was 256mg/L, wherein 34% cystic fibrosis cultures were sensitive to nalidixic acid, and 9% to cetrimide (pg. 221, col. 2, para 1). As disclosed in the Specification, the NAC medium contains 15 mg/L nalidixic acid and 200 mg/L cetrimide (para 17). By diluting the NAC medium with TSA 1:1 – 1:20, most P. aeruginosa strains would not be significantly inhibited by the selective growth medium based on the ‘breakpoint’ concentrations taught by Fonseca. Fonseca also teaches cross-sensitivity of the CF cultures, wherein 11 of the 18 cultures sensitive to cetrimide were also sensitive to nalidixic acid (pg. 221, col. 2, para 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to utilize the methods taught by Swarna and substitute the selective medium with the mixed NAC and TSA in ratios between 1:1-1:20, which are below the breakpoint concentrations of both nalidixic acid and cetrimide for P. aeruginosa strains taught by Fonseca, as well as adjust the cefotaxime concentration to be about 30 µg/mL and add cefalothin at a concentration of about 30 µg/mL to the selective medium as taught by Johargy with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to utilize this mixed basal medium in a mixed ratio lower than the breakpoint concentrations, because some cultures of P. aeruginosa from cystic fibrosis show increased sensitivity to cell wall antibiotics (i.e. glycopeptide-based antibiotics), and suggests that cetrimide acts synergistically with ampicillin and other antibiotics against P. aeruginosa, probably by increasing the permeability of the bacterial cell, thus higher concentrations than the breakpoint of NAC would inhibit the P. aeruginosa as taught by Fonseca (pg. 222, col. 2, para 2). Furthermore, it would have been prima facie obvious to add additional antibiotics, such as a 1st generation cephalothin to the selective media, which would select for resistant P. aeruginosa, and inhibit other common clinical isolates, such as S. aureus and E. coli, as taught by Johargy (pg. 1293, Table 3). It is also a well-understood and routine laboratory practice to determine MIC to antibiotics and formulate a selective medium targeting the desired organism.
Response to Arguments
Applicant's arguments filed November 4, 2025 have been fully considered but they are not persuasive.
Applicant argues that the combination of cited art does not disclose or suggest the embodiments as claimed. Claim 8 recites that the medium includes vancomycin in a concentration of greater than 128 µg/ml. On page 4 of the Office Action, the Examiner states that Swarna teaches... "cefotaxime (a third-generation cephalosporin), cloxacillin, and vancomycin at 64 mg/L, which meets the limitations of the selection medium according to claims 8, 11, and 16." The Examiner is correct that Swarna discloses a selection medium including 64 mg/L vancomycin (see page 1, right column). However, 64 mg/L corresponds to 64 µg/ml. Thus, Swarna discloses a vancomycin concentration which is half of that claimed. The Examiner provides no reason why it would have been obvious to double the concentration of vancomycin in the medium according to the combination of Swarna, Johargy, and Fonseca. Accordingly, Applicant respectfully submits that the combination of cited art does not disclose the embodiments as claimed for at least this reason. Additionally applicant argues Johargy does not disclose cefotaxime in a concentration of 0.1 µg/ml or more to less than 64 µg/and cephalothin in a concentration of greater than 16 µg/ml. Rather, Johargy only discloses 30 µg of these antibiotics. The Examiner states that, for example, Johargy discloses that P. aeruginosa was "resistant to cephalothin at a concentration of 30 µg". However, "30 µg" is a mass, not a concentration. As disclosed in the paragraph bridging pages 1291 and 1292 of Johargy, the reference uses the "disc diffusion method described by Bauer et al." However, the mass of antibiotics on the discs used in the disc diffusion method cannot be used to determine a concentration. Applicant discloses reference Balouiri et al. that states, “the agar disk-diffusion method is not appropriate to determine the minimum inhibitory concentration (MIC), as it is impossible to quantify the amount of the antimicrobial agent diffused into the agar medium. Nevertheless, an approximate MIC can be calculated for some microorganisms and antibiotics by comparing the inhibition zones with stored algorithms. Applicant argues even if Johargy can be used to teach the use of cefotaxime and cephalothin generally, Johargy cannot be used to make any conclusions about the concentrations of the antibiotics. Therefore, Applicant respectfully submits that the combination of cited art is silent as to the claimed concentrations of cefotaxime and cephalothin.
In response to 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). Although Applicant is correct the previous office action had a typographical error of µg/L instead of µg/mL, the recited concentrations in the referenced art fall within the scope of the limitations recited in the claims, excluding the vancomycin concentration being half of the claimed concentration. However, it is well-known in the art that glycopeptide antibiotics (vancomycin) do not penetrate the other membrane of gram-negative isolates such as P. aeruginosa, therefore not effective, as evidenced by the results taught by Johargy showing 80.6% resistance of gram-negative isolates and 95.2% susceptibility of gram-positive isolates to vancomycin (pg. 1292, Table 1). Thus it would be obvious to one of ordinary skill in the art to combine the elements of the selective media taught in the prior art, and determine effective antibiotic concentrations to exclude non-target microorganisms. Similarly, the argument can be made about the amount of antibiotics used in the disk diffusion assay as translated into concentrations effective against a particular bacteria, namely Johargy teaching the resistance of P. aeruginosa to cefotaxime and cephalothin wherein the amount is 30 µg. It would be easily conceivable for one of ordinary skill to employ well-understood and routine laboratory practices to determine the effective concentration of either of these two antibiotics that would exclude non-target isolates, and select for P. aeruginosa, therefore is not inventive.
Conclusion
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 JESSICA EDWARDS whose telephone number is (571)270-0938. The examiner can normally be reached M-F 8am-5pm EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657