CTNF 18/836,272 CTNF 101351 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION Claim Status Claims 1-20 are currently pending. There are no new, amended, or canceled claims. Claims 1-20 will be examined on the merits. Priority Acknowledgement is made of applicant’s claim for foreign priority based on an application filed on February 21, 2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Information Disclosure Statement (IDS) The IDS submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-21-aia AIA Claim s 1-14, 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Jia et al. (Published 2017; hereafter Jia; PTO-892) in view of Comas et al. (Published 2011; hereafter Comas; PTO-892) . Jia teaches a novel live attenuated recombinant Listeria monocytogenes (rLm) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein (r30/antigen 85B [Ag85B]) (rLm30) as heterologous booster vaccines in animals primed with BCG . Using three attenuated L. monocytogenes vectors, L. monocytogenes Δ actA (LmI), L. monocytogenes Δ actA Δ inlB (LmII), and L. monocytogenes Δ actA Δ inlB prfA *(LmIII), which is pertinent to claims 1, 4, 6, 10-11. Jia teaches the Listeria monocytogenes Δ actA Δ inlB Δ uvrAB prfA* (G155S) strain ( L. monocytogenes Δ actA Δ inlB prfA* ), in which one amino acid substitution (G155S) is induced in PrfA (positive regulatory factor A). In wild-type L. monocytogenes , PrfA is expressed intracellularly and induces the expression of the prfA regulon, including the hly and actA genes, which is pertinent to claim 4. See for example, Figure 4. Jia teaches the two antigen expression cassettes were (i) h30, where r30 expressed from this antigen expression cassette is driven by the hly promoter, ligated in frame to the LLO signal sequence, and processed as a secreted 31-kDa fusion protein, and (ii) a30, where r30 expressed from this antigen expression cassette is driven by the actA promoter, ligated in frame to the ActA amino-terminal (N-terminal) 100 amino acids, and processed as a secreted 39-kDa fusion protein. The resulting five rLm30 vaccine candidates are designated rLmI/h30, rLmII/h30, rLmIII/h30, rLmII/a30, and rLmIII/a30. The integration of each h30 or a30 expression cassette into the L. monocytogenes chromosome, which is pertinent to claims 1, 5-6, 8. See for example, Figure 1b. Jia teaches that to evaluate the efficacies of the rLm30 booster vaccines in mice , groups of C57BL/6 mice were primed with i.d. BCG , boosted them twice i.d. with one of the three selected rLm30 vaccines (rLmI/h30, rLmIII/h30, or rLmIII/a30) at weeks 3 and 6, and challenged them at week 12 with aerosolized M. tuberculosis (average of 112 CFU delivered to the lungs of each animal). Mice sham immunized or immunized i.d. with BCG alone or primed with BCG and boosted with the LmI vector, or r30/SAF (see Fig. S2 in the supplemental material) served as controls. At 6, 10, or 15 weeks postchallenge (weeks 18, 22, and 27), mice were euthanized, and their spleens and lungs were assayed for M. tuberculosis CFU. Jia teaches that at all time points, mice primed with BCG and boosted with any of the three vaccines had significantly fewer CFU in the lungs than did sham-immunized mice ( P < 0.0001 to 0.05). Also, at all time points, BCG-rLm30 primed-boosted mice had fewer CFU than did mice immunized with only BCG, and these differences were statistically significant for all three vaccines at week 6 postchallenge ( P < 0.01 or P < 0.05), for rLmIII/h30 and rLmIII/a30 at week 10 postchallenge ( P < 0.01), and for rLmIII/a30 at 15 weeks postchallenge ( P < 0.05). Mice boosted with r30/SAF also had significantly fewer CFU than did mice administered BCG at all time points ( P < 0.001, P < 0.01, and P < 0.05 at 6, 10, and 15 weeks postchallenge, respectively), which is pertinent to claims 2, 9-14. See for example, Figure 5a; Figure 5b. Jia teaches that to evaluate the i mmunogenicities of different rLm30 vaccine candidates as booster vaccines for BCG-primed animals , we immunized C57BL/6 mice intradermally (i.d.) with phosphate-buffered saline (PBS) (sham), BCG, or BCG followed 3 and 6 weeks later by an i.d. administered booster vaccine comprising (i) r30/SAF, (ii) LmI (vector control), (iii) rLmI/h30, (iv) rLmII/a30, (v) rLmIII/a30, (vi) rLmII/h30, or (vii) rLmIII/h30, which is pertinent to claims 9, 11-14, 16. See for example, Figure 1b. However, Jia does not teach at least one fusion protein having antigenic epitopes present in at least five Mycobacterium tuberculosis proteins selected from Immunogenic protein MPT64 ("23.5/Mpt64"), ESAT-6-like protein EsxH ("TB10.4/EsxH"), 6 kDa early secretory antigenic target ("ESAT6/EsxA"), ESAT-6-like protein EsxB ("CFP10/EsxB"), and diacylglycerol acyltransferase/mycolyltransferase Ag85B ("r30/Antigen 85B"); ESAT-6-like protein EsxN ("EsxN"); PPE family immunomodulator PPE68 ("PPE68"); ESX-secretion- associated protein EspA ("EspA") and low molecular weight T-cell antigen TB8.4 ("TB8.4") as claim 1. Jia also does not teach immunogenic epitopes of 23.5/Mpt64 are N-terminal to other Mycobacterium tuberculosis immunogenic epitopes disposed in the fusion protein as claim 8. Jia does not teach Mycobacterium tuberculosis immunogenic epitopes consisting essentially of immunogenic epitopes present in at least 5 Mycobacterium tuberculosis proteins selected from: immunogenic protein MPT64 ("23.5/Mpt64"), ESAT-6-like protein EsxH ("TB10.4/EsxH"), 6 kDa early secretory antigenic target ("ESAT6/EsxA"), ESAT-6-like protein EsxB ("CFP10/EsxB"), and diacylglycerol acyltransferase/mycolyltransferase Ag85B ("r30/Antigen 85B"); ESAT-6-like protein EsxN ("EsxN"); PPE family immunomodulator PPE68 ("PPE68"); ESX-1 secretion- associated protein EspA ("EspA") and low molecular weight T-cell antigen TB8.4 ("TB8.4") as claim 19. Comas teaches human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyper conserved, which is pertinent to claims 1, 3, 5-11, 17-20. Comas teaches the locus name of the antigen in the H37Rv genome, the annotation in the Immune Epitopes Database (IEDB) that recompiles all the human T cell epitopes of M. tuberculosis eliciting a positive immune response in humans reported in the literature, which is pertinent to claims 1, 3, 5-11, 17-20. Comas teaches MPT64 (Rv1980c), ESAT-6-like protein esxH (Rv0288), ESAT-6-like protein EsxB (Rv3874), 6 kDa early secretory antigenic target (Rv3875), Antigen 85 B (Rv1886c), ESAT-6-like protein EsxN ( Rv1793 ), LOW MOLECULAR WEIGHT T-CELL ANTIGEN TB8.4 (Rv1174c), ESAT-6-like protein EsxB ("CFP10/EsxB") (Rv3874), which is pertinent to claims 3, 5, 7-11, 17-20. See for example, Supplementary table 2-3, 5. Comas teaches 491 Epitopes, the reference number in the Immune Epitopes Database (IEDB) that recompiles all the human T cell epitopes of M. tuberculosis eliciting a positive immune response in humans reported in the literature, the amino acid sequence of the epitope and the antigen that contains the respective epitope, which is pertinent to 1, 3, 7-11, 17-20. See for example, the list of epitope sequences in Supplementary table 3, 5. Examples of epitopes found within SEQ ID NO: 1 (See Supplementary Table 3): 72323 - MPT64 (Rv1980c): WDQAYRKPITYDTLWQADTD 73362 - ESAT-6-like protein esxH (Rv0288): YAGTLQSLGAEIAVEQAA 3064- 6 kDa early secretory antigenic target (Rv3875): AMASTEGNV 4899- 6 kDa early secretory antigenic target (Rv3875): ATATELNNALQNLARTI 3094 - Antigen 85 B (Rv1886c): AMGDAGGYK 5623 - Antigen 85 B (Rv1886c): AVYLLDGLR 7530 - ESAT-6-like protein EsxN ( Rv1793 ): DAHGAMIRAQAASLE 326 - ESAT-6-like protein EsxB ("CFP10/EsxB") (Rv3874): AANKQKQELDEISTN 506 - ESAT-6-like protein EsxB ("CFP10/EsxB") (Rv3874): AAVVRFQEAANKQKQEL 327 - ESAT-6-like protein EsxB ("CFP10/EsxB") (Rv3874): AANKQKQELDEISTNIRQAG 328 - ESAT-6-like protein EsxB ("CFP10/EsxB") (Rv3874): AANKQKQELDEISTNIRQAGVQYSR 3934- ESAT-6-like protein EsxB (Rv3874): AQAAVVRFQEAANKQ Examples of epitopes found within SEQ ID NO: 2 (See Supplementary Table 3) 72323 - MPT64 (Rv1980c): WDQAYRKPITYDTLWQADTD 967- ESAT-6-like protein EsxN ( Rv1793 ): AEHQAIVRDVLAAGD 29574 - ESAT-6-like protein EsxN ( Rv1793 ): IYEQANAHGQKVQAA 34174 - ESAT-6-like protein EsxN ( Rv1793 ): KVQAAGNNMAQTDSA 5381 - LOW MOLECULAR WEIGHT T-CELL ANTIGEN TB8.4 (Rv1174c): AVINTTCNYGQ It would have been obvious to one of ordinary skill in the art to combine the teachings of Jia by Listeria monocytogenes Δ actA Δ inlB Δ uvrAB prfA* (G155S) strain and the hyperconserved human T cell epitopes of Mycobacterium tuberculosis of Comas, thereby arriving at the invention of claims 1, 3, 7-11, 17-20. Since the Listeria strain of Jia and the hyperconserved human T cell epitopes of Mycobacterium tuberculosis of Comas were both shown to be effective in generating an immune response against Mycobacterium tuberculosis , it would be beneficial and advantageous to generate chimeric (fused) antigens/epitopes sequences as a strategy to increase the variety of T cell epitopes sequences taught by Comas expressed by the Listeria strain of Jia, it would have been obvious to substitute these known equivalents; see MPEP 2144.06. See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination . 07-21-aia AIA Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Jia et al. (Published 2017; hereafter Jia; PTO-892) in view of Fatma et al. (Published 2021; hereafter Fatma; PTO-892) as to applied to claims 1-14, 16-20 above, and in further view of Fatma et al. (Published 2012; hereafter Fatma; PTO-892) . Jia teaches the limitations of claims 1-14, 16-20 in view of Comas as fully discussed above and incorporated herein. However, neither Jia nor Comas teaches administered subcutaneously as claim 15. Fatma teaches that chimeric protein subunit vaccines hold great potential as stand-alone vaccines or heterologous BCG prime boosters. immunological characterization of chimeras of high specificity antigens from Mycobacterium tuberculosis H37Rv. Fatma teaches that antigens expressed by actively replicating bacteria, such as Ag85 and ESAT-6, can induce protection in animal models when administered as adjuvanted proteins or as DNA , which is pertinent to claim 15. Fatma teaches multistage subunit vaccine against TB using different stage antigens, by exploring new antigens that demonstrate equal or better sensitivity and specificity to the sera of TB patients from high endemicity regions, in comparison to the prominent TB antigens like ESAT-6, CFP-10, Ag85A, and Ag85B , which is pertinent to claim 15. Fatma teaches that the chimeric protein PP31 by cloning the rv1198 gene into pET-NH6 expression vector with EcoRI and KpnI restriction sites. After that gene rv3111 was added at C-terminal of rv1198 using restriction sites KpnI and HindIII. Similarly for construction of chimeric protein PP43, the PCR product of rv1813c was digested with BamHI/EcoRI restriction sites and cloned into pET-NH6-rv1198-rv3111 vector, which is pertinent to claims 15. Fatma teaches PP31 chimeric protein was generated through a tandem fusion of individual genes of rv1198 and rv3111 using restriction site linkers in the plasmid vector pET-NH6. Similarly, PP43 chimeric protein was generated by adding Rv1813c at the N-terminal end of the PP31, which is pertinent to claim 15. Fatma also teaches that “subcutaneous route immunization of ESAT-6 was found to be better than the intramuscular route. Therefore, changing the route of administration of PP43/adjuvant from intramuscular to intravenous or subcutaneous might improve its vaccine efficacy ”, which is pertinent to claim 15. It would have been obvious to one of ordinary skill in the art to modify the teachings of Jia and Comas by adapting Fatma teachings, thereby arriving at the invention of claims 15. Since the Listeria strain of Jia and T cell epitopes of M. tuberculosis taught by Comas were both shown to be effective in generating an immune response to M. tuberculosis , it would have been obvious to substitute these known equivalents; see MPEP 2144.06. Additionally, KSR International Co. v. Teleflex Inc. , 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc. , 127 S. Ct. 1727, 1741 (2007) also discloses that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., the hyperconserved human T cell epitopes of Mycobacterium tuberculosis , live vaccines such as Listeria bacteria, strategies to maximize the variety of antigens/epitopes to increase the immune response, such as chimeric antigens/epitopes and routes for administration of vaccines) were known in the art. In addition, combining these elements yields a method/composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary. Conclusion No claims are allowable. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PRICILA HAUK TEODORO whose telephone number is (571) 272-2784. The examiner can normally be reached 6:15AM-3:15PM. 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, Heather Calamita can be reached at (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /PRICILA NMN HAUK TEODORO/Examiner, Art Unit 1645 /HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684 Application/Control Number: 18/836,272 Page 2 Art Unit: 1645 Application/Control Number: 18/836,272 Page 3 Art Unit: 1645 Application/Control Number: 18/836,272 Page 4 Art Unit: 1645 Application/Control Number: 18/836,272 Page 5 Art Unit: 1645 Application/Control Number: 18/836,272 Page 6 Art Unit: 1645 Application/Control Number: 18/836,272 Page 7 Art Unit: 1645 Application/Control Number: 18/836,272 Page 8 Art Unit: 1645 Application/Control Number: 18/836,272 Page 9 Art Unit: 1645 Application/Control Number: 18/836,272 Page 10 Art Unit: 1645 Application/Control Number: 18/836,272 Page 11 Art Unit: 1645
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