DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-14 are pending in this application and are being examined on the merits.
Priority
The instant application is a CIP of 17/830,227 filed 06/01/2022, which claims domestic priority to PRO 63/195,502 filed 06/01/2021, and is a CIP of 17/178,091 filed 02/17/2021. The instant application is a CIP of PCT/US22/16816 filed 02/17/2022, which claims domestic priority to PRO 63/251,433 10/01/2021, PRO 63/195,502 06/01/2021, and is a CIP of 17/178,091 filed 02/17/2021, a CIP of 17/335,767 filed 06/01/2021 (patented as U.S. 11,746,371), and a CIP of PCT/US21/27336 filed 04/14/2021).
Application 17/178,091 claims domestic priority to PRO 63/119,328 filed 11/30/2020, and PRO 63/111,287 filed 11/09/2020, PRO 63/063,093 filed 08/07/2020, PRO 63/047,846 filed 07/02/2020, PRO 63/009,337 filed 04/13/2020, PRO 62/988,186 filed 03/11/2020, PRO 62/978,149 filed 02/18/2020, and PRO 62/977,637 filed 02/17/2020, and is a CIP of 16/848,651 filed 04/14/2020 (patented as U.S. 11,053,532).
Application 16/848,651 claims domestic priority to PRO 63/009,337 filed 04/13/2020, PRO 62/988,186 filed 03/11/2020, PRO 62/978,149 filed 02/18/2020, PRO 62/977,637 filed 02/17/2020, PRO 62/956,923 filed 01/03/2020, PRO 62/928,815 filed 10/31/2019, PRO 62/924,614 filed 10/22/2019, and is a CIP of 16/216,751 filed 12/11/2018.
Application 16/216,751 is a CON of 15/957,780 filed 04/19/2018 (patented as U.S. 10,160,991) which claims domestic priority to PRO 62/487,395 filed 04/19/2017.
Application 17/335,767 is a DIV of 16/848,651 filed 04/14/2020 (patented as U.S. 11,053,532)
Application PCT/US21/27336 claims domestic priority to PRO 63/119,328 filed 11/30/2020, PRO 63/111,287 filed 11/09/2020, PRO 63/063,093 filed 08/07/2020, PRO 63/047,846 filed 07/02/2020, is a CIP of 17/178,091 filed 02/17/2021, and a CIP of 16/848,651 (patented as U.S. 11,053,532).
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 2-14 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 1-14 of this application.
Accordingly, the instant claims 1-14 receive the earliest effective filing date of 02/17/2021.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 06/06/2024, 06/06/2024 and 08/21/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs have been considered by the examiner.
Non-Patent Literature Documents 11 and 36 of the information disclosure statement filed 06/06/2024 have been lined through because there is no copy of these references in the application file that match the title and first author described in the IDS.
Objections to Specification
The disclosure is objected to because of the following informalities.
The use of the terms POOLED ANTIBIOTIC SUSCEPTIBILITY TEST, GUIDANCE UTI TEST, VITEK, KINGFISHER, MAGMAX, TAQMAN, LIFE TECHNOLOGIES, DENSICHEK, SIGMA-ALDRICH, OPENARRAY and BD VACUTAINER, which are trade names or marks used in commerce, have been noted in this application in paragraphs 0015, 0044, 0055, 0057-0058, 0073, 0095-0097, 00122-00123, 00153-00157, 00183-00185, 00216, 00230, 00249-00251, 00253, 00256-00257, 00270 and in the heading following paragraph 0073. 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.
Drawings
The drawings are objected to because there are 2 separate views of FIG.8 labeled FIG. 8 and FIG. 8 (con’t), which should instead be labeled FIG. 8A and FIG. 8B, 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.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-14 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 (claims 2-14 dependent therefrom) is indefinite for the phrase “subjecting […] the sample to genetic identification testing, wherein […] testing detects and identifies one or more organisms in the sample […] wherein if […] testing detects one or more organisms in the sample then the patient has a polymicrobial infection” in part (b). The claim encompasses genetic identification testing that identifies only one organism in the sample and it is unclear how the detection of only one organism in the sample equates to having a polymicrobial infection.
Claims 3, 5, 6 (claim 7 dependent therefrom), and 9 are indefinite for the phrases “wherein the sample comprises” in claim 3, “wherein the genetic identification comprises” in claim 5, “wherein the genetic resistance marker testing comprises” in claim 6, and “wherein genetic antibiotic resistance testing comprises” in claim 9 each followed by a list of alternatively usable members from which a choice is to be made. According to MPEP 2117(I), any claim that cites alternatively usable members, regardless of format, should be treated as a Markush claim, and a Markush grouping is a closed group of alternatives. As claims 3, 5-6 and 9 recite the open language “comprises” followed by the Markush group of alternatives, they are considered to be indefinite, as it is unclear what other alternatives are intended to be encompassed by the claims.
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.
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 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2020/0010874; cited on the attached Form PTO-892; herein referred to as Wang) in view of Brown et al. (U.S. 10,106,847; cited on the attached Form PTO-892; herein referred to as Brown), Schmolke et al. (US 2019/0032115; cited on the attached Form PTO-892; herein referred to as Schmolke) and Rahme et al. (US 2016/0237497; cited in the Form PTO-892; herein referred to as Rahme).
Claim 1 is drawn to a method for treating 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) 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 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) 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.
Regarding the limitations of part (d) in claim 1, it is noted that the recitation of “and or” between steps (i) and (ii) is considered to encompass the two steps as alternatives, and as worded the limitation “wherein organisms in the polymicrobial infection in the third portion of the sample are not first isolated before the pooled phenotypic antibiotic resistance testing” is interpreted to only be associated with step (ii).
Wang 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 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 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 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 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 does not teach the limitations of steps (c), (e) and (f) of claim 1.
Brown 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 claim 1 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 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 include multiplex PCR [col 3, para 4] without purification or isolation, these methods are capable of detecting one or more targets. Brown 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 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 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 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 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 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 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, Brown, Schmolke and Rahme, 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 by carrying out genetic marker testing targeting specific antibiotic resistance genes and specific bacterial organisms via PCR, and 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 because Brown teaches detecting and identification polymicrobial infections with PCR allows improved patient care outcomes, Rahme 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 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, Brown and Rahme teach subjecting clinical samples to genetic testing and antibiotic resistance testing for the identification of treatment of microbial infections, and Schmolke and Rahme teach the application of testing results to determine such treatments.
Regarding claim 2, Schmolke 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.
Regarding claims 3-5, Wang teaches the method of detecting infectious bacteria [para 0041] in a biological sample 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 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.
Regarding claims 6-11, Brown 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 include multiplex PCR [col 3, para 4].
Regarding claim 12, Wang 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 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 13, Brown 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 claim 14, Rahme 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 1-14 would have been obvious to one of ordinary skill in the art before the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
A. Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of co-pending Application No. 17/178091 (herein “reference application”) in view of Wang, Brown, Schmolke and Rahme.
Instant claim 1 is drawn to a method for treating 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) 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 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) 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.
Regarding instant claim 1, claim 1 of the reference application recites a method for determining a therapeutic solution to treat a polymicrobial infection or suspected polymicrobial urinary tract infection in a patient, comprising subjecting portions of a urine sample to genetic identification testing to identify either or both a bacterial or fungal species, genetic resistance marker testing to identify two or more species, pooled phenotypic antibiotic resistance testing to identify one or more therapeutic agents, and comparing results from the testing to identify a therapeutic solution.
The claims of the reference application do not recite the limitations in step (f) of instant claim 1 of 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.
Wang describes methods for identifying antibiotic resistant bacteria, quantifying bacteria growth, and applying antibiotic susceptibility tests [abstract], and discloses that clinicians need to know what bacterial strain(s) is/are causing the infections, the bacterial loads, and the antibiotic resistance profile of the bacteria [para 0002], and without knowing this vital information in a timely manner, it is impossible to begin using narrow-spectrum antibiotics that can effectively treat the patients [para 0003].
Regarding instant 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 discloses a method of detecting bacteria in a biological sample 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]. Wang 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 instant 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 discloses 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 further discloses “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].
Brown describes methods for detecting and identification 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 instant claim 1 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 discloses 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 include multiplex PCR [col 3, para 4] without purification or isolation, these methods are capable of detecting one or more targets. Brown further discloses 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 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 instant 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 discloses “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 describes methods and assays related to the treatment of infection, including diagnosis and prognosis [abstract].
Regarding instant claim 1 and the limitation recited in step (f) of 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 discloses 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 further discloses 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, Brown, Schmolke and Rahme, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claim(s) of the reference application by carrying out genetic identification testing, as taught by Wang, genetic marker testing targeting specific antibiotic resistance genes and specific bacterial organisms via PCR, and 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 claims of the reference application because Wang discloses clinicians need to know what bacterial strain(s) is/are causing the infections, the bacterial loads, and the antibiotic resistance profile of the bacteria, and without knowing this vital information in a timely manner, it is impossible to begin using narrow-spectrum antibiotics that can effectively treat the patients, Brown discloses detecting and identification polymicrobial infections with PCR allows improved patient care outcomes, Rahme discloses 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 discloses 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 the reference application, Wang, Brown and Rahme disclose subjecting clinical samples to genetic testing and antibiotic resistance testing for the identification of treatment of microbial infections, and Schmolke and Rahme disclose the application of testing results to determine such treatments.
Regarding instant claim 2, Schmolke discloses “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 resista