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 .
Claim Status
Applicant’s amendment filed 03/10/2026 has been entered. Claims 1-19 are pending. Claims 7-12 are withdrawn. Claims 1-6 and 13-19 are currently under examination.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6 and 13-19 in the reply filed on 5/21/2025 is acknowledged.
Claims 7-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/21/2025.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 03/11/2026.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
Note: ST.26 was filed when ST.25 is required. The sequence listing filed 3/10/2026 was submitted in a US national phase application with an international filing date of 03/05/2020. Therefore, ST.25 format is required.
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is defective because the Sequence Listing filed should be in ST.25 format instead of ST.26 format. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification - withdrawn
Objection to the specification is withdrawn in view of Applicant’s amendment to remove embedded hyperlinks and to add proper symbols for trade names or marks.
Specification – new objection
The disclosure is objected to because of the following informalities: The attempt to incorporate subject matter into this application by reference to the Sequence Listing is ineffective because the Sequence Listing cited is defective as described above. Appropriate correction is required.
Claim Rejections - 35 USC § 112 - withdrawn
Rejection of claims 1-6 and 13-19 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 is withdrawn in view of Applicant’s amendment to remove “optional” for the CMI response test in claim 1 and to remove limitations starting with “preferably” in claims 5 and 15-19.
Claim Rejections - 35 USC § 103 - withdrawn
Rejection of claims 1-6 and 13-19 under 35 U.S.C. 103 as being unpatentable over Rees and Swift (referred to as “Rees”; WO2015049516A1; published 4/9/2015; cited in IDS filed 10/3/2023), in view of Wyndham-Thomas et al. (published 2/14/2015; of record) with withdrawn in view of Applicant’s amendment to remove the term “optionally” from line 15 thereby requiring the limitation “performing a Mycobacterium-specific cell-mediated immune (CMI) response test on a sample isolated from the subject to generate a positive or negative CMI response test outcome”.
Claim Rejections - 35 USC § 103 – new necessitated by amendment
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 1-6 and 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over Rees and Swift (referred to as “Rees”; WO2015049516A1; published 4/9/2015; cited in IDS filed 10/3/2023), in view of Chee et al. (Latent tuberculosis infection: Opportunities and challenges. Respirology. 2018; 23: 893–900) and Wyndham-Thomas et al. (Contribution of a heparin-binding haemagglutinin interferon-gamma release assay to the detection of Mycobacterium tuberculosis infection in HIV-infected patients: comparison with the tuberculin skin test and the QuantiFERON®-TB Gold In-tube. BMC Infect Dis; published 2/14/2015).
Rees discloses methods of testing for target Mycobacteria in a reaction mixture by using mycobacteria-specific bacteriophages and PCR (entire document).
Regarding claim 1, Rees teaches a method of diagnosing a mycobacterial infection in a human or animal subject (p. 6, lines 25-26; p. 27, lines 20-24) and that it can be before any clinical symptoms are visible (and therefore asymptomatic) (p. 7, lines 32-34). Rees teaches testing for target Mycobacteria in a reaction mixture comprising the steps of: a) providing a reaction mixture; b) admixing a bacteriophage with the reaction mixture under conditions suitable to allow the bacteriophage to infect any target Mycobacteria present in the reaction mixture; c) allowing time for the bacteriophage to lyse infected live target Mycobacteria; and e) analyzing DNA from the lysed Mycobacteria to identify the presence or absence of a signature DNA sequence that occurs in the target Mycobacterium species (p. 2, lines 24-34; claims 1-5). Rees teaches that the bacteriophage may be D29 (p. 5, lines 13-16). Rees further teaches performing PCR on DNA isolated from the admixture using forward and reverse primers specific for Mycobacterial DNA sequence (p. 5, lines 22-35; p. 6, lines 1-16). Rees further teaches that performing a cell-mediated immune response test is the clinical standard for TB, but that the sensitivity of the tests cannot distinguish between infected and vaccinated subjects (p. 1, lines 26-33).
However, Rees does not specifically teach isolating a sample of peripheral blood mononuclear cells (PBMCs) from the subject.
Chee’s disclosure is directed to diagnosing and treating LTBI as an important strategy to accelerate the decline in global TB and achieve TB elimination (abstract). Chee further teaches that the TB pathogen has the ability to persist within its host in an asymptomatic state of latency and reactivate, albeit in a minority, to active TB disease months or even decades later (Background/Epidemiology). Chee further teaches using the IGRA CMI test (p. 895, left column, para 4).
Regarding claim 1, Chee teaches isolating PBMCs from the subject (p. 895, right column, para 1). Chee further teaches that the state of LTBI encompasses a spectrum ranging from elimination of the infection to subclinical or incipient disease that represent the earliest stages of reactivation TB during which the patient is asymptomatic but may be intermittently infectious (p. 895, left column, para 4). Chee teaches categorizing LTBI diagnostic tests conceptually as ‘persistent infection tests’ (such as the TST and IGRA) which have low PPV but high NPV and which are useful as rule-out tests, versus the (yet to be discovered) ‘incipient TB tests’, which detect mycobacterial replication and have high PPV, with these two types of tests being complementary (p. 896, right column, para 3).
Wyndham-Thomas discloses methods of diagnosing active and latent tuberculosis is HIV-infected adults using cell-mediated immune response tests (entire document).
Regarding claim 1, Wyndham-Thomas teaches methods of diagnosing human HIV-infected subjects with latent TB infections and active infections (abstract). Wyndham-Thomas teaches a method of obtaining a sample of peripheral blood mononuclear cells (PBMCs) isolated from subjects (p. 3, right column, para 2). Wyndham-Thomas further teaches a multiplex analysis of positive LTBI screening was defined as the presence of at least one positive immunological test (TST, QFT-GIT or HBHA-IGRA), and a negative LTBI screening defined as all 3 tests being negative and absence of any Mtb exposure risk factor (Figures 1 and 3; and Table 4). Wyndham-Thomas teaches that with the TST and the commercialized IGRA, a negative result does not exclude active TB (p. 10, left column, para 1). Wyndham-Thomas teaches that the study provides support for further larger studies assessing HBHA-IGRA as a complementary tool in the screening for LTBI in HIV-infected patients (p. 9, left column, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Rees’s PCR-based method for diagnosing TB by testing a subject’s blood for Mycobacterial DNA with the improved CMI methods using isolating PBMCs from subjects, as described by Chee and Wyndham-Thomas. Rees teaches PCR methods of detecting Mycobacterial DNA in subjects to diagnose TB and further teaches that performing CMI tests are the clinical standards for TB, but that the sensitivity of the tests cannot distinguish between infected and vaccinated subjects (p. 1, lines 26-33). Chee teaches categorizing LTBI diagnostic tests conceptually as ‘persistent infection tests’ (such as the TST and IGRA) which have low PPV but high NPV and which are useful as rule-out tests, versus the (yet to be discovered) ‘incipient TB tests’, which detect mycobacterial replication and have high PPV, with these two types of tests being complementary (p. 896, right column, para 3). Wyndham-Thomas teaches improved methods of diagnosing TB in HIV-infected patients and teaches that for the TST and IGRA CMI tests, a negative result does not exclude active TB (p. 11, left column, para 1; Figures 1 and 3; and Table 4). Wyndham-Thomas suggests larger studies assessing HBHA-IGRA as a complementary tool in the screening for LTBI in HIV-infected patients (p. 9, left column, para 1). One would have recognized that combining Rees’s PCR based method with the improved immune response methods of Wyndham-Thomas and the improved categorization of Chee could improve diagnosis of incipient, active, or latent TB infections and thereby patient outcomes. One would have had a reasonable expectation of success because Rees and Chee are directed to methods of detecting Mycobacteria in blood samples from subjects to diagnose TB disease and disease progression and Wyndham-Thomas improved methods of diagnosing TB in HIV-infected patients. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 2, Rees teaches the IS900 element (p. 6, lines 1-16).
Regarding claim 3 and 13, Wyndham-Thomas teaches TB-contact subjects (Table 1).
Regarding claims 4 and 14, Wyndham-Thomas teaches the screening and treatment of latent tuberculosis (TB) infection reduces the risk of progression to active disease and is currently recommended for HIV-infected patients (abstract). Wyndham-Thomas further teaches that the patients were enrolled in the study between December 2011 and December 2012 and that there were 2 TB-contact subjects (Table 1).
However, Wyndham-Thomas does not specifically teach obtaining the PBMCs from the asymptomatic human subject within the range of 12 months to 1 month of coming into contact with a TB-infected individual.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have obtained the PBMCs from the asymptomatic human subject as soon as possible (including within a month to a year) after contact with a TB-infected individual and performed the combined diagnostic methods of Rees and Wyndham-Thomas. One would have been motivated to reduce the risk of progression of latent TB, as taught in Wyndham-Thomas (abstract). One would have had a reasonable expectation of success because directed to methods of detecting Mycobacteria in blood samples from subjects to diagnose disease and disease progression. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claims 5 and 15-19, Rees teaches incubating the admixture to permit lysis of Mycobacteria comprises incubating at 37°C for between 1.5 hours and 6 hours, teaching Applicant’s claimed range of approximately or less than 6 hours, 5 hours, 4 hours, 3.5 hours, 3 hours, 2.5 hours, 2 hours, 1.5 hours or 1 hour (p. 14, lines 10-18; p. 23, 14-25).
Regarding claim 6, Wyndham-Thomas teaches that the optional CMI response test comprises an IGRA test (entire document).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 03/10/2026 have been fully considered but they are not persuasive. Applicant argues that the present application relates to a method for diagnosis of incipient tuberculosis (TB), which has a very specific meaning separate from latent tuberculosis (LTB), otherwise known as, latent tuberculosis infection (LTBI), which defines an "asymptomatic TB that is not likely to develop into active TB due to effective clearance or containment by the immune system", see page 10, lines 4 to 5, of the PCT application as published. Applicant further argues that Drain (2018; Cite No. 4 in the IDS filed 10/3/2023), cited on page 9, lines 34-35 of the instant specification, teaches that the tuberculin skin testing (TST) and IGRAs are not specific for disease progression and that there is a need for a method of determining individuals with incipient TB, as distinct from latent TB, where there is an increased risk of progressing to active TB. Applicant argues that Rees teaches the use of a Mycobacteria-specific bacteriophage in a test for tuberculosis, but is silent about incipient tuberculosis provides no reason to suppose that the methods disclosed in Rees would be suitable for the diagnosis of incipient TB. Applicant further argues that the skilled person would have no reason to refer to the disclosure in Rees when considering the problem of identifying individuals with incipient TB and as such, the disclosure in Rees provides no reasonable expectation of successfully being able to identify incipient TB. Applicant further argues that it could not be contemplated in advance that the method disclosed in Rees would be suitable for the identification of incipient TB as a separate diagnosis from latent TB infection and, therefore, that it could predict progression to active disease with such sensitivity and accuracy as shown in the application.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the Office relies on Rees to teach diagnosing a mycobacterial infection in a human or animal subject before any clinical symptoms are visible (and therefore asymptomatic) and further that that the sensitivity of the tests cannot distinguish between infected and vaccinated subjects (see in the 103 discussion above). The Office relies on Chee to teach that ‘persistent infection tests’ (such as the TST and IGRA) versus ‘incipient TB tests’ should be categorized different and that these two types of tests being complementary (p. 896, right column, para 3). One would have recognized that combining Rees’s PCR based method with the improved immune response methods of Wyndham-Thomas and the improved categorization of Chee could improve diagnosis of incipient, active, or latent TB infections and thereby patient outcomes.
Applicant further argues that Wyndham-Thomas makes no mention of the separate diagnosis of incipient TB and that the skilled person would have no reason to refer to the disclosure in Wyndham-Thomas when considering the problem of diagnosing for incipient TB. Applicant argues that none of the cited prior art documents refer to incipient TB or relate to the subject-matter of the present invention in the diagnosis of individuals with incipient TB. Applicant further argus that Rees is the only prior art citation to consider the use of bacteriophage, however, it could not be contemplated in advance that the method disclosed in Rees would be suitable for the identification of incipient TB, compared to latent TB infection, and that it could predict progression to active disease with such sensitivity and accuracy as shown in the application and, accordingly, the subject-matter of the present invention involves an inventive step.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, the Office relies on Chee to further distinguish between the disease progression by categorizing ‘incipient TB tests’ complementary to the TST and IGRA tests (see 103 discussion above). Wyndham-Thomas teaches improved methods of diagnosing TB in HIV-infected patients. Rees and Chee teach methods of detecting Mycobacteria-specific bacteriophage. Accordingly, one would have recognized that combining Rees’s PCR based method with the improved methods of Wyndham-Thomas and Chee’s additional categorization of detecting Mycobacteria-specific bacteriophage could improve diagnosis of incipient, active, or latent TB infections and thereby patient outcomes.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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