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 .
Priority
This application claims benefit of U.S. Provisional Application Nos. 63/553,071 filed 02/13/2024, This application is also a CIP of 17/830,227 filed 06/01/2022, which claims benefit of 63/195,502 filed 06/01/2021. US Patent Application No. 17/830,227 is CIP of 17/178,091 filed 02/17/2021.
This application is CIP of 17/178,091 which claims benefit of US Provisional Patent Application Nos. 62/977,637 filed 02/17/2020, 62/978,149 filed 02/18/2020, 62/988,186 filed 03/11/2020, 63/009,337 filed 04/13/2020, 63/047,846 filed 07/02/2020, 63/063,093 filed 08/07/2020, 63/111,287 filed 11/09/2020, 63/119,328 filed 11/30/2020.
US Patent Application No. 17/178,091 is CIP which claims benefit of 16/848,651 filed 04/14/2020, now US Pat. No. 11,053,532, which claims benefit of 62/924,614 filed 10/22/2019, 62/928,815 filed 10/31/2019, 62/956,923 filed 01/03/2020, 62/977,637 filed 02/17/2020, 62/978,149 filed 02/18/2020, 62/988,186 filed 03/11/2020, and 63/009,337 filed 04/13/2020.
US Patent Application No. 16/848,651 is CIP of 16/216,751 filed 12/11/2018, now abandoned, which is a CON of 15/957,780 filed 04/19/2018, now US Patent No. 10,160,991, which claims benefit of 62/487,395 filed 04/19/2017.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) and 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed applications, provisional Application Nos. 62/924614, 62/928815, 62/956923, 62/977637, 62/978149, 62/988186, 63/009337, 63/047846, 63/063093, 63/111287, 63/119328, 63/195502, 63/251433, 62/487395 and non-provisional Application Nos. 15/957780, 16/216751,16/848651, 17/335767 and PCT/US21/27336 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
None of these prior-filed applications provide disclosures for the subject matter of an instant claim in its entirety. While the applications individually cover the subject matters of genetic identification testing of a sample to identify one or more organisms of a polymicrobial infection, genetic resistance marker testing of a sample to identify one or more resistance genes that confer resistance to one or more therapeutic agents, phenotypic antibiotic resistance testing of the sample to identify one or more therapeutic targets to which therapeutic agents to which the polymicrobial infection is resistant or susceptible, and comparing the results of the testing to a database to identify therapeutic agents effective for treating polymicrobial infections, none of the applications provide in their disclosure all of these elements together with the essential element of administering the identified therapeutic agent to a patient to treat a polymicrobial infection. Therefore, there is no disclosure of the subject matter of independent claim 1 in the instant application, and independent claim 1 of the instant application does not receive the benefit of the prior-filed applications. The dependent claims 2-18 do not receive the benefit of the prior-filed applications by way of their dependency on claim 1.
Applicant’s claim for the benefit of a prior-filed application, US Application 17/178091 filed on 02/17/2021 under 35 USC 119(e) or under 35 USC 120, 121, 365(c), or 386(c) is acknowledged. The disclosure of the prior-filed application 17/178,091 provides adequate descriptive support for claims 1-18 of this application.
Accordingly, the instant claims 1-18 receive the earliest effective filing date of 02/17/2021.
Status of the claims
Claims 1-18 are pending and currently under examination.
Drawings
The drawings are objected to because the text of Fig. 11 is illegible. Also Fig. 10 and Fig. 10 Cont’d should be corrected and labeled as Fig. 10A and Fig. 10B, respectively. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:.
On pages 19-20, Table 1 is illegible.
On pages 25-26, Table 2 is illegible.
On pages 26-29, Table 3 is illegible.
On pages 29-30, Table 4 is illegible.
On pages 30-31, Table 5 is illegible.
On page 31, Table 6 is illegible.
On pages 31-32, Table 7 is illegible.
On pages 32-33, Table 8 is illegible.
On pages 33-34, Table 9 is illegible.
On page 34, Table 10 is illegible.
On pages 34-35, Table 11 is illegible.
On pages 36-37, Table 12 is illegible.
On page 40, Table 13 is illegible.
On page 41, Table 14 is illegible.
On pages 41-42, Table 15 is illegible.
On page 45, Table 16 is illegible.
The disclosure is also objected to because of the following informalities.
The use of the terms POOLED ANTIBIOTIC SUSCEPTIBILITY TEST (P-AST), GUIDANCE UTI TEST, VITEK, KINGFISHER, MAGMAX, TAQMAN, LIFE TECHNOLOGIES, SIGMA-ALDRICH, OPENARRAY and BD VACUTAINER, which are trade names or marks used in commerce, have been noted in this application in paragraphs 0010, 0015, 0048, 00116, 00130, 00167-00169, 00194-00195, 00226-00227, 00254, 00256, 00287, 00301, 00320-00321, 00324, 00327, 00341. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The preamble of claim 1 recites the limitation of “providing the therapeutic solution to treat”. There is insufficient antecedent basis for “the therapeutic solution” limitation. Claims 2-18 are further rejected as they depend from claim 1.
Claim 1(b) recites the limitation “wherein if genetic identification testing detects one or more organisms in the sample then the patient has a polymicrobial infection”. This limitation lacks clarity. It is unclear if detecting one microorganism can be characterized as a polymicrobial infection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2020/0010874, filed 09/04/2019, pub. 01/09/2020) in view of Brown et al. (U.S. 10,106,847, filed 11/30/2017, pub. 10/23/208), Schmolke et al. (US 2019/0032115, filed 01/16/2018, pub. 01/31/2019) and Rahme et al. (US 2016/0237497, filed 04/04/2016, pub. 08/08/2016).
Claim 1 is directed to a method for providing the therapeutic solution to treat a polymicrobial infection in a patient in need thereof, wherein the patient either has a polymicrobial infection or is suspected of having polymicrobial infection, said method comprises:
(a) obtaining or having obtained a sample from a source of the polymicrobial infection or suspected polymicrobial infection in the patient;
(b) subjecting or having subjected a first portion of the sample to genetic identification testing, wherein genetic identification testing detects and identifies one or more organisms in the sample; wherein if genetic identification testing detects one or more organisms in the sample then the patient has a polymicrobial infection;
(c) subsequently subjecting or having subjected a second portion of the sample to genetic resistance marker testing, wherein genetic resistance marker testing is effective for detecting and identifying one or more resistance genes that confers resistance to one or more therapeutic agents;
(d) subjecting or having subjected a third portion of the sample to a fluorescent-based pooled phenotypic antibiotic resistance testing, wherein pooled phenotypic antibiotic resistance testing either or both:
(i) identifies one or more therapeutic agents to which the polymicrobial infection is resistant, and or
(ii) identifies one or more therapeutic agents to which the polymicrobial infection is susceptible, wherein organisms in the polymicrobial infection in the third portion of the sample are not first isolated before the pooled phenotypic antibiotic resistance testing;
(e) applying results from (b), (c), and (d) to a predetermined set of thresholds in a database that indicates therapeutic agents that are effective for treating polymicrobial infections, wherein applying results from (b), (c), and (d) identifies at least one therapeutic agent that is effective for treating the polymicrobial infection in the patient; and
(f) providing the therapeutic solution to a medical professional to determine treatment for the patient.
Wang et al. describes methods for identifying antibiotic resistant bacteria, quantifying bacteria growth, and applying antibiotic susceptibility tests [abstract].
Regarding claim 1 and limitations recited in step (a) of obtaining a sample from a source of a polymicrobial infection and step (b) of subjecting a portion of the sample to genetic identification testing for detecting and identifying one or more organisms, Wang et al. teaches a method of detecting bacteria in a biological sample, such as a polymicrobial infection [para 0069] that includes “amplifying DNA of the unidentified bacteria ... using PCR … and identifying the species of the unidentified bacteria by determining a first melting curve of the unidentified bacteria and comparing it to one or more melting curves of known bacteria stored in a computer” [para 5], wherein a biological sample includes “whole blood, plasma, serum RBC fraction, urine, saliva cerebrospinal fluid, semen, sweat… [etc.]” [para 0005], which is considered to encompass obtaining a sample from a source of polymicrobial infection.
Wang et al. also describes a single-cell analysis assay wherein the method is applied to single cells in a small volume for “identifying and qualifying the growth of individual cells” [para 0053], which would be capable of identifying two or more species from a sample.
Regarding claim 1 and the limitation recited in step (d) of subjecting a portion of the sample to pooled phenotypic antibiotic resistance testing, wherein the pooled phenotypic antibiotic resistance testing either or both:
(i) identifies one or more therapeutic agents to which the polymicrobial infection is resistant, and/or (ii) identifies one or more therapeutic agents to which the polymicrobial infection is susceptible, wherein the one or more organisms of the polymicrobial infection in the sample are not first isolated before phenotypic antibiotic resistance testing, Wang et al. teaches a method of “culturing the unidentified bacteria in a first broth comprising an antibiotic; culturing the unidentified bacteria in a second broth substantially free of the antibiotic … identifying the antibiotic sensitivity or resistance of the unidentified bacteria by comparing the bacteria growth in the first broth with the bacteria grown in the second broth" [para 5] which involves no isolation steps prior to testing, and therefore is considered to correspond to pooled antibiotic resistance testing that identifies therapeutic agents to which the polymicrobial infection is susceptible without first isolating organisms.
Wang et al. further teaches “an array of digital reaction chambers for … quantifying the growth of bacteria” wherein “the bacterial sample [and] culture medium ... comprise a fluorescent intercalation dye... After completion of culture … any bacteria-containing compartments will become brightly fluorescent... The growth of ... bacteria species is determined by the average quantification cycle (Cq) derived from the [culture] wells ... the method of determining when a bacteria is antibiotic sensitive or resistant is by comparing difference in average Cq between bacteria species grown in a broth having an antibiotic with the same bacteria species grown in a broth without an antibiotic” [para 7], and wherein “antibiotic resistance may be determined when the differences of average Cq of the bacteria derived from the first broth and the second broth are less than 1.2. Generally, antibiotic sensitivity may be determined when differences of average Cq between the bacteria derived from the first broth and the second broth are greater than 1.2” [para 7].
Wang et al. does not teach the limitations of steps (c), (e) and (f) of claim 1.
Brown et al. describes methods for detecting and identification of polymicrobial infections using PCR without purification or isolation in a sample [col 3, para 4] to allow improved patient care outcomes [col 3, para 3].
Regarding claims 1 and 5-10 and the limitation in step (c) of subjecting a portion of the sample to genetic resistance marker testing for detecting and identifying one or more resistance genes, Brown et al. teaches a method comprising an automated test for “identification of multiple potentially pathogenic gram-positive bacterial organisms and select determinants of antimicrobial resistance in positive blood culture” [col 26, lines 42-55], where a “determinant of antimicrobial resistance” is defined as “a gene responsible for the development of resistance in the bacteria which actively counteracts the effect of an antibiotic.
Particularly, genetic determinants of resistance to methicillin (mecA and mecC) and vancomycin (vanA and vanB) are envisaged. Genes associated with genetic determinants of resistance such as CTX-M, NDM, IMP, OXA, KPC, VIM are envisaged” [col 8 lines 16-23] with further description of the detection of OXA-23, CTX-1, CTX-8 and CTX-25 [Table 2, col 28]. As the methods of Brown et al. include multiplex PCR [col 3, para 4] without purification or isolation, these methods are capable of detecting one or more targets. Brown et al. further teaches limits of detection (LoD Concentrations) of organisms bearing the genetic resistance markers tested in Table 11, and methods for reducing false positive results, and therefore determining positive results compared to a predetermined threshold [col 17, para 6].
Schmolke et al. describes methods of determining an infection resistant to antimicrobial drug treatment, methods of selecting a treatment of a patient suffering from an antibiotic resistant infection, and methods of determining an antibiotic resistance profile [abstract].
Regarding claim 1 and the limitation recited in step (e) of comparing results from (b), (c), and (d) to identify at least one therapeutic agent that is effective for treating the polymicrobial infection in the patient, Schmolke et al. teaches “a method of selecting a treatment of a patient having an infection with a bacterial microorganism of Proteus species, comprising: obtaining or providing a first data set comprising a gene sequence of at least one clinical isolate of the microorganism from the patient; providing a second data set of antimicrobial drug, e.g. antibiotic, resistance of a plurality of clinical isolates of the microorganism; aligning the gene sequences of the first data set to at least one, preferably one, reference genome of the microorganism, and/or assembling the gene sequence of the first data set, at least in part; analyzing the gene sequences of the first data set for genetic variants to obtain a third data set of genetic variants of the first data set; correlating the third data set with the second data set of antimicrobial drug, e.g. antibiotic, resistance of a plurality of clinical isolates of the microorganism and statistically analyzing the correlation; determining the genetic sites in the genome of the clinical isolate of the microorganism of the first data set associated with antimicrobial drug, e.g. antibiotic, resistance; and selecting a treatment of the patient with one or more antimicrobial, e.g. antibiotic, drugs different from the ones identified in the determination of the genetic sites associated with antimicrobial drug, e.g. antibiotic, resistance is disclosed” [para 0142], therefore integrating the evaluation of genetic information (genomes and resistance markers) with phenotypic antibiotic resistance in order to select an effective antibiotic treatment for a patient.
Rahme et al. describes methods and assays related to the treatment of infection, including diagnosis and prognosis [abstract].
Regarding claim 1 and the limitation recited in step (f) of determining a therapeutic solution and administering at least one therapeutic agent identified in (e) to the patient, wherein the at least one therapeutic agent is effective for treating the polymicrobial infection, Rahme et al. teaches the administration of antibiotics to subjects determined to be at risk of having or developing an infection [para 0012], wherein antibiotics are defined as “penicillins, cephalosporins, penems, carbapenems, monobactams, aminoglycosides, sulfonamides, macrolides, tetracyclins, lincosides, quinolones, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spectinomycin, trimethoprim, sulfamethoxazole, and the like” [para 0100].
Rahme et al. further teaches clinical characteristics and genomic signatures from patients can facilitate the determination of appropriate treatment courses, particularly in regards to antibiotic use, which can limit the complications related to unneeded antibiotics, reduce the burden of lines needed to deliver the antibiotics, and streamline hospital care [para 0293].
In view of Wang et al., Brown, Schmolke et al. and Rahme et al., it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Wang et al. by carrying out genetic marker testing targeting specific antibiotic resistance genes and specific bacterial organisms via PCR, and determine a therapeutic solution for a subsequent administration of an identified therapeutic agent as taught by Brown, with the application of antibiotic resistance testing results to identify a treatment for infection as taught by Schmolke, for the administration of said antibiotics to treat the infection, as taught by Rahme, to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to modify the method of Wang et al. because Brown et al. teaches detecting and identification polymicrobial infections with PCR allows improved patient care outcomes, Rahme et al. teaches clinical characteristics and genomic signatures from patients can facilitate the determination of appropriate treatment courses, particularly in regards to antibiotic use, which can limit the complications related to unneeded antibiotics, reduce the burden of lines needed to deliver the antibiotics, and streamline hospital care, and Schmolke et al. teaches the identification of therapeutic solutions for microbial infection from the application of testing data.
One of ordinary skill in the art would have reasonable expectation of success because Wang et al., Brown et al. and Rahme et al. teach subjecting clinical samples to genetic testing and antibiotic resistance testing for the identification of treatment of microbial infections, and Schmolke et al. and Rahme et al. teach the application of testing results to determine such treatments.
Regarding claims 2-5, Wang et al. teaches the method of detecting infectious bacteria [para 0041] in a biological sample [para 0005], wherein a biological sample includes “whole blood, plasma, serum RBC fraction, urine, saliva cerebrospinal fluid, semen, sweat… [etc.]” [para 0005], wherein the detection of infectious bacteria from urine is considered to encompass a sample from a patient with a urinary tract infection. et al. teaches the method of detecting infectious bacteria [para 0041] includes “amplifying DNA of the unidentified bacteria ... using PCR … and identifying the species of the unidentified bacteria by determining a first melting curve of the unidentified bacteria and comparing it to one or more melting curves of known bacteria stored in a computer” [para 0005].
Regarding claims 6-11, Brown et al. teaches a method comprising an automated test for “identification of multiple potentially pathogenic gram-positive bacterial organisms and select determinants of antimicrobial resistance in positive blood culture” [col 26, lines 42-55], where a “determinant of antimicrobial resistance” is defined as “a gene responsible for the development of resistance in the bacteria which actively counteracts the effect of an antibiotic. Particularly, genetic determinants of resistance to methicillin (mecA and mecC) and vancomycin (vanA and vanB) are envisaged. Genes associated with genetic determinants of resistance such as CTX-M, NDM, IMP, OXA, KPC, VIM are envisaged” [col 8 lines 16-23] with further description of the detection of OXA-23, CTX-1, CTX-8 and CTX-25 [Table 2, col 28], wherein the methods of Brown et al. include multiplex PCR [col 3, para 4].
Regarding claim 12, Brown et al. teaches that targets of a detection system include Streptococcus pyogenes, Streptococcus agalactiae, Staphylococcus aureus [Table 1, cols 27-28], Acinetobacter baumanii, and Citrobacter freundii [Table 2, cols 33-34].
Regarding claims 1(d) and 11-12, 14-17, Wang et al. teaches a method of “culturing the unidentified bacteria in a first broth comprising an antibiotic; culturing the unidentified bacteria in a second broth substantially free of the antibiotic … identifying the antibiotic sensitivity or resistance of the unidentified bacteria by comparing the bacteria growth in the first broth with the bacteria grown in the second broth" [para 5] which involves no isolation steps prior to testing.
Wang et al. further teaches “an array of digital reaction chambers for … quantifying the growth of bacteria” wherein “the bacterial sample [and] culture medium ... comprise a fluorescent intercalation dye... After completion of culture … any bacteria-containing compartments will become brightly fluorescent... The growth of ... bacteria species is determined by the average quantification cycle (Cq) derived from the [culture] wells ... the method of determining when a bacteria is antibiotic sensitive or resistant is by comparing difference in average Cq between bacteria species grown in a broth having an antibiotic with the same bacteria species grown in a broth without an antibiotic” [para 7], and wherein “antibiotic resistance may be determined when the differences of average Cq of the bacteria derived from the first broth and the second broth are less than 1.2. Generally, antibiotic sensitivity may be determined when differences of average Cq between the bacteria derived from the first broth and the second broth are greater than 1.2” [para 7].
Regarding claim 18, Rahme et al. teaches the administration of antibiotics to subjects determined to be at risk of having or developing an infection [para 0012], wherein antibiotics are defined as “penicillins, cephalosporins, penems, carbapenems, monobactams, aminoglycosides, sulfonamides, macrolides, tetracyclins, lincosides, quinolones, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spectinomycin, trimethoprim, sulfamethoxazole, and the like” [para 0100].
Therefore, the invention of claims 1-18 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Wojno et al. (Epub Nov 09, 2019, Urology. 136:119-126, pub. Feb 04, 2020) in view of Brown et al. (U.S. 10,106,847, filed 11/30/2017, pub. 10/23/208), Riedel et al., (2014, Journal of clinical microbiology, 52(6), pp.2216-2222), Schmolke et al. (US 2019/0032115, filed 01/16/2018, pub. 01/31/2019) and Rahme et al. (US 2016/0237497, filed 04/04/2016, pub. 08/08/2016).
Claim 1 is directed to a method for providing the therapeutic solution to treat a polymicrobial infection in a patient in need thereof, wherein the patient either has a polymicrobial infection or is suspected of having polymicrobial infection, said method comprises:
(a) obtaining or having obtained a sample from a source of the polymicrobial infection or suspected polymicrobial infection in the patient;
(b) subjecting or having subjected a first portion of the sample to genetic identification testing, wherein genetic identification testing detects and identifies one or more organisms in the sample; wherein if genetic identification testing detects one or more organisms in the sample then the patient has a polymicrobial infection;
(c) subsequently subjecting or having subjected a second portion of the sample to genetic resistance marker testing, wherein genetic resistance marker testing is effective for detecting and identifying one or more resistance genes that confers resistance to one or more therapeutic agents;
(d) subjecting or having subjected a third portion of the sample to a fluorescent-based pooled phenotypic antibiotic resistance testing, wherein pooled phenotypic antibiotic resistance testing either or both:
(i) identifies one or more therapeutic agents to which the polymicrobial infection is resistant, and or
(ii) identifies one or more therapeutic agents to which the polymicrobial infection is susceptible, wherein organisms in the polymicrobial infection in the third portion of the sample are not first isolated before the pooled phenotypic antibiotic resistance testing;
(e) applying results from (b), (c), and (d) to a predetermined set of thresholds in a database that indicates therapeutic agents that are effective for treating polymicrobial infections, wherein applying results from (b), (c), and (d) identifies at least one therapeutic agent that is effective for treating the polymicrobial infection in the patient; and
(f) providing the therapeutic solution to a medical professional to determine treatment for the patient.
Wonjo et al. (claims 1(a), 1(b), 2-4 and 12)
Regarding claim 1(a) and claim 1(b) and claims 2-4 and 12, Wonjo et al. teach polymicrobial infections are observed in about 39% of UTIs, a potential difficulty in determining appropriate treatment. Wonjo et al. notes that Khasriya found that some bacteria are detected by PCR but not by traditional urine culture and since each pathogen carries a unique pattern of antimicrobial resistance, one bacterial species can confer antimicrobial resistance on other bacterial species in a polymicrobial environment (pg 123, right col., 2nd para).
Wonjo et al. discloses that the accuracy of PCR for polymicrobial infections is an advantage that traditional urine culture does not always have (pg 123, right col., 2nd para).
Wonjo et al. is directed to a method where samples from patients presenting with symptoms of lower urinary tract infections (UTI) were tested in parallel assays using urine cultures and multiplex PCR-based molecular testing (abstract).
Wonjo et al. teach:
(a) obtaining or having obtained a sample from a source of the polymicrobial infection or suspected polymicrobial infection in the patient (pg 120, left col., section entitled Materials and Methods, participants” and pg 120, right col, section entitled “DNA extraction and analysis”);
(b) subjecting or having subjected a first portion of the sample to genetic identification testing, wherein genetic identification testing detects and identifies one or more organisms in the sample; wherein if genetic identification testing detects one or more organisms in the sample then the patient has a polymicrobial infection (pg 120, left col., section entitled Urine Culture” and pg 120, right col, 1st para and also section entitled “DNA extraction and analysis”).
Wonjo et al. teach use of Pathnostics Guidance UTI Test. Samples were mixed with universal PCR master mix and amplified using TaqMan technology on a Life Technologies 12K Flex OpenArray System. DNA samples were spotted in duplicate on 112-format OpenArray chips. Plasmids for each organism being tested for were used as positive controls (pg 120, right col., section entitled “DNA extraction and analysis).
Wonjo et al. teach data analysis tool developed by Pathnostics was used to sort data, assess the quality of data, summarize control sample data, identify positive assays, calculate concentrations, and generate draft reports. Probes and primers were used for the following pathogens: Bacteria: Acinetobacter baumannii, Actinobaculum schaalii, Aerococcus urinae, Alloscardovia omnicolens, Citrobacter freundii, Citrobacter koseri, Corynebacterium riegelii, Enterobacter aerogenes, Enterococcus faecalis, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Mycobacterium tuberculosis, Mycoplasma genitalium, Mycoplasma hominis, Pantoea agglomerans, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, Streptococcus agalactiae, Ureaplasma urealyticum
Bacterial Groups: Coagulase negative staphylococci (Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus lugdunesis, Staphylococcus saprophyticus); Viridans group streptococci (Streptococcus anginosus, Streptococcus oralis, Streptococcus pasteuranus)(see pg 120, right col., section entitled “DNA extraction and analysis”).
Omitted from Wonjo et al. (claims 1(c), 1(d)-1(f), 5-10, 11, 13-18)
Regarding claim 1(c), Wonjo et al. do not teach detecting and identifying one or more resistance genes that confers resistance to one or more therapeutic agents via a genetic resistance marker test.
Regarding claim 1(d) and claims, Wonjo et al. do not teach performing a fluorescent-based pooled phenotypic antibiotic resistance test to (1) identify one or more therapeutic agents to which the polymicrobial infection is resistant, and/or (2) to identify one or more therapeutic agents to which the polymicrobial infection is susceptible, wherein organisms in the polymicrobial infection in the third portion of the sample are not first isolated before the pooled phenotypic antibiotic resistance testing.
Regarding claim 1(e) and 1(f), Wonjo et al. do not teach analyzing the results of gene identification testing, genetic resistance marker testing and fluorescent-based pooled phenotypic antibiotic resistance testing using a database, and identifying at least one therapeutic agent that is effective for treating the polymicrobial infection in the patient; and providing the therapeutic solution to a medical professional to determine treatment for the patient.
Regarding claim 5, Wonjo et al. do not teach a genetic resistance marker testing detects and identifies one or more resistance genes by PCR or sequencing.
Regarding claim 6, Wonjo et al. do not teach one or more resistance genes is ErmA + Erm B, TEM, CTX-M group 1, SHV, VEB, OXA-1, CTX-M group 2, CTX-M group 9, CTX-M group 8/25, PER-1, PER-2, GES, blaNDM-1, VIM, KPC, IMP-2 group, IMP-1 group, OXA-23, IMP-16, IMP-7, OXA-72, OXA-40, OXA-58, OXA-48, NDM, blaOXA-48, QnrA, QnrB, mecA, ampC, FOX, ACC, DHA, MOX/CMY, BIL/LAT/CMY, vanA1, vanA2, vanB, vanC1, or vanC2-C3-2.
Regarding claim 7, Wonjo et al. do not teach genetic resistance marker testing comprises genetic antibiotic resistance testing.
Regarding claim 8, Wonjo et al. do not teach genetic antibiotic resistance testing detects and identifies one or more resistance genes by PCR or sequencing.
Regarding claim 9, Wonjo et al. do not teach genetic antibiotic resistance testing is effective for detecting and identifying one or more antibiotic resistance genes that confers resistance to one or more antibiotics.
Regarding claim 10, Wonjo et al. do not teach one or more antibiotic resistance genes is ErmA + Erm B, TEM, CTX-M group 1, SHV, VEB, OXA-1, CTX-M group 2, CTX-M group 9, CTX-M group 8/25, PER-1, PER-2, GES, blaNDM-1, VIM, KPC, IMP-2 group, IMP-1 group, OXA-23, IMP-16, IMP-7, OXA-72, OXA-40, OXA-58, OXA-48, NDM, blaOXA-48, QnrA, QnrB, mecA, ampC, FOX, ACC, DHA, MOX/CMY, BIL/LAT/CMY, vanA1, vanA2, vanB, vanC1, or vanC2-C3-2.
Regarding claim 11, Wonjo et al. do not teach pooled phenotypic antibiotic resistance testing comprises introducing fractions of the third portion of the sample to one or more media samples, each media sample comprising a therapeutic agent, incubating the media samples with the fractions, and subsequently measuring viability of organisms in the media samples after incubation.
Regarding claim 13, Wonjo et al. do not teach therapeutic agent is one or a combination of a: penicillin, tetracycline, cephalosporin, quinolone, lincomycin, macrolide, sulfonamide, glycopeptide antibiotic, aminoglycoside, carbapenem, ansamycin, annamycin, lipopeptide, Fosfomycin, monobactam, nitrofuran, oxazolidinone, amphotericin B, isavuconazole, itraconazole, micafungin, Posaconazole, voriconazole, cidofovir, vidarabine, foscarnet, acyclovir, or valacyclovir.
Regarding claim 14, Wonjo et al. do not teach fluorescent-based pooled phenotypic antibiotic resistance testing uses a fluorescent probe to either or both: (i) identify one or more therapeutic agents to which the polymicrobial infection is resistant, and or (ii) identify one or more therapeutic agents to which the polymicrobial infection is susceptible.
Regarding claim 15, Wonjo et al. do not teach fluorescent probe comprises a fluorescent dye, a redox-sensitive dye, or an Alexa Fluor Dye.
Regarding claim 16, Wonjo et al. do not teach fluorescent probe comprises one or a combination of Resazurin, Dihexyloxacarbocyanine iodide (DiOC6), Acridine Orange, Rhodamine 123, Tetrazolium Salts, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), XTT (2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide), WST-1 (Water-Soluble Tetrazolium Salt). SYTO™ 9, SYTO™ 13, SYTO™ 16, Propidium Iodide (PI), 4′,6-Diamidino-2-phenylindole (DAPI), Fluorescein Diacetate (FDA), Carboxyfluorescein Diacetate (CFDA), Ethidium Bromide (EtBr), Hoechst 33342, Calcein AM, 5-Cyano-2,3-ditolyl Tetrazolium Chloride (CTC), 5-Cyano-2,3-ditolyl Tetrazolium Chloride (CTC), Tetracycline, Bisbenzimide H 33258, Sybr Green I and II, Cyto 9, or Calcein AM.
Regarding claim 17, Wonjo et al. do not teach organisms in the polymicrobial infection in the third portion of the sample are not first isolated before the pooled phenotypic antibiotic resistance testing.
Regarding claim 18, Wonjo et al. do not teach administering or having administered at least one therapeutic agent identified in d) to the patient, wherein the at least one therapeutic agent is effective for treating the polymicrobial infection.
Brown et al. (claims 1(c), 1(e)-1(f), 5-10, 11, 13)
Brown et al. describes methods for detecting and identification of polymicrobial infections using PCR without purification or isolation in a sample [col 3, para 4] to allow improved patient care outcomes [col 3, para 3].
Regarding claims 1 and 5-10 and the limitation in step (c) of subjecting a portion of the sample to genetic resistance marker testing for detecting and identifying one or more resistance genes, Brown et al. teaches a method comprising an automated test for “identification of multiple potentially pathogenic gram-positive bacterial organisms and select determinants of antimicrobial resistance in positive blood culture” [col 26, lines 42-55], where a “determinant of antimicrobial resistance” is defined as “a gene responsible for the development of resistance in the bacteria which actively counteracts the effect of an antibiotic.
Particularly, genetic determinants of resistance to methicillin (mecA and mecC) and vancomycin (vanA and vanB) are envisaged. Genes associated with genetic determinants of resistance such as CTX-M, NDM, IMP, OXA, KPC, VIM are envisaged” [col 8 lines 16-23] with further description of the detection of OXA-23, CTX-1, CTX-8 and CTX-25 [Table 2, col 28]. As the methods of Brown et al. include multiplex PCR [col 3, para 4] without purification or isolation, these methods are capable of detecting one or more targets. Brown et al. further teaches limits of detection (LoD Concentrations) of organisms bearing the genetic resistance markers tested in Table 11, and methods for reducing false positive results, and therefore determining positive results compared to a predetermined threshold [col 17, para 6].
Riedel et al. (claims 1(d), claims 14-17)
Riedel et al. teach antimicrobial susceptibility testing (AST) assays to determine the distribution of MICs for vancomycin and to select alternate antimicrobial agents against S. aureus (MRSA and methicillin-susceptible S. aureus [MSSA]), Enterococcus faecium, and Enterococcus faecalis and, furthermore, to determine the accuracy of various commercially available AST methods compared to the “gold standard” broth microdilution method (abstract).
Three commercial antimicrobial susceptibility testing (AST) methods were compared to broth microdilution for testing of Staphylococcus aureus and enterococci against vancomycin, daptomycin, and linezolid. Riedel et al. teach results potentially impacting definitive antimicrobial therapy for bloodstream infections due to these organisms (ABSTRACT).
Schmolke et al. (claims 1(e)-1(f), claim 18)
Schmolke et al. teaches “a method of selecting a treatment of a patient having an infection with a bacterial microorganism of Proteus species, comprising:
obtaining or providing a first data set comprising a gene sequence of at least one clinical isolate of the microorganism from the patient; providing a second data set of antimicrobial drug, e.g. antibiotic, resistance of a plurality of clinical isolates of the microorganism;
aligning the gene sequences of the first data set to at least one, preferably one, reference genome of the microorganism,
and/or assembling the gene sequence of the first data set, at least in part; analyzing the gene sequences of the first data set for genetic variants to obtain a third data set of genetic variants of the first data set; correlating the third data set with the second data set of antimicrobial drug, e.g. antibiotic, resistance of a plurality of clinical isolates of the microorganism and statistically analyzing the correlation; determining the genetic sites in the genome of the clinical isolate of the microorganism of the first data set associated with antimicrobial drug, e.g. antibiotic, resistance; and selecting a treatment of the patient with one or more antimicrobial, e.g. antibiotic, drugs different from the ones identified in the determination of the genetic sites associated with antimicrobial drug, e.g. antibiotic, resistance is disclosed” [para 0142], which is considered to correspond to compiling a dataset with one or more datapoints from results of phenotypic antibiotic sensitivity testing, results of genetic identification testing, therapeutic agents to which the polymicrobial infection is expected to have increased resistance, therapeutic agents to which the polymicrobial infection is expected to have decreased resistance, and suggested therapeutic agents.
Rahme et al. describes methods and assays related to the treatment of infection, including diagnosis and prognosis [abstract].
Regarding claim 1 and the limitation recited in step (f) of determining a therapeutic solution and administering at least one therapeutic agent identified in (e) to the patient, wherein the at least one therapeutic agent is effective for treating the polymicrobial infection, Rahme et al. teaches the administration of antibiotics to subjects determined to be at risk of having or developing an infection [para 0012], wherein antibiotics are defined as “penicillins, cephalosporins, penems, carbapenems, monobactams, aminoglycosides, sulfonamides, macrolides, tetracyclins, lincosides, quinolones, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spectinomycin, trimethoprim, sulfamethoxazole, and the like” [para 0100].
Rahme et al. further teaches clinical characteristics and genomic signatures from patients can facilitate the determination of appropriate treatment courses, particularly in regards to antibiotic use, which can limit the complications related to unneeded antibiotics, reduce the burden of lines needed to deliver the antibiotics, and streamline hospital care [para 0293].
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to combine the assays and the analysis as taught by Wonjo et al., Brown et al. and Riedel et al. who each provide assays that validate the presence of one or more antibiotic resistant or susceptible microorganisms, and provides the identification of antibiotic resistant or susceptible microorganisms represented in a sample suspected to have microorganisms causative of a polymicrobial infections to inform a therapeutic solution in a manner as taught by Schmolke et al. and/or Rahme et al.
The combination would have yielded a robust multi-process or multi-step methods useful for disease diagnosis and treatment.
Conclusion
No claims are currently allowed.
Correspondence
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OLAYINKA A. OYEYEMI
Examiner
Art Unit 1681
/OLAYINKA A OYEYEMI/Examiner, Art Unit 1681
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
