The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment filed on 9-12-2025 is acknowledged. Claim has been amended. Claims 43-44 have been added. Claims 12-13 and 15 have been canceled. Claims 1-10, 14 and 16-44 are pending. Claims 1-9, 14, 16-17 and 21-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 10, 18-20 and 36-44 are currently under examination. It should be noted that claim 14 has an improper claim status indicator. A claim is either “withdrawn” or “previously presented”. Said status identifier must be corrected in any response to this action in order to be considered fully responsive.
Information Disclosure Statement
The Information Disclosure Statement filed on 9-12-2025 has been considered. An initialed copy is attached hereto.
It should be noted that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections Withdrawn
The objections to claim 10 for having an obvious grammatical error is withdrawn in light of the amendment thereto.
New Claim Objections
Claim 43 is objected to for containing an obvious typographical error. The term “stain” should read “strain”.
Claim 44 is objected to for containing an obvious typographical error. The term “stain” should read “strain”.
Claim Rejections Maintained
35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 10, 18-20 and 36-44 are rejected under 35 U.S.C. 103 as being unpatentable over Bishai et al. (WO 2016/130616 – IDS filed on 4-19-2022) and Fang (China Doctoral Dissertation Full-text Database, 2015/07, E059-41 – IDS filed on 2-7-2024) and Tullius et al. (Infection and Immunity Vol. 76, pages 5200-5214) for the reasons set forth in the previous Office action in the rejection of 10, 18-20 and 36-41.
Applicant argues:
1. Claim 10 has been amended to be directed to "[a] Th1 T cell and M1 macrophage expansion inducer comprising a strain of Mycobacteria comprising a vector comprising: (i) a nucleic acid sequence encoding a protein that makes a stimulator interferon genes (STING) agonist, wherein the protein that makes a STING agonist is a DNA integrity scanning (DisA) protein, wherein the STING agonist is a 3'-5' c-di-AMP (also known as c-di-AMP), and wherein the protein that makes the STING agonist lacks an EAL domain, and (ii) a panCD nucleic acid encoding a PanC protein and a nucleic acid sequence encoding a PanD protein, wherein the strain of Mycobacteria is Mycobacterium tuberculosis, or Mycobacterium bovis that is pantothenate-auxotroph, and wherein the Th1 T cell and the M1 macrophage are intratumoral immune cells.
2. As acknowledged by the Examiner, Bishai does not disclose or suggest a strain of Mycobacteria comprising a vector comprising a nucleic acid sequence encoding a protein that makes a STING agonist, wherein the STING agonist is a 3'-5' c-di-AMP (also known as c-di-AMP), and wherein the protein that makes the STING agonist lacks an EAL domain.
3. Bishai does not disclose or suggest a Th1 T cell and M1 macrophage expansion inducer comprising said strain of Mycobacteria, that the protein that makes a STING agonist is a DNA integrity scanning (DisA) protein, nor that the vector comprises a panCD nucleic acid encoding a PanC protein and a nucleic acid sequence encoding a PanD protein, wherein the strain of Mycobacteria is Mycobacterium tuberculosis or Mycobacterium bovis.
4. Fang clearly states that the reference is focused in elucidating the function of c-di-GMP during MTB infection (see Fang at Abstract). However, Applicants submit that Fang does not disclose or suggest a Th1 T cell and M1 macrophage expansion inducer comprising said strain of Mycobacteria comprising a vector comprising a nucleic acid sequence encoding a protein that makes a STING agonist, wherein the STING agonist is a 3'-5' c-di-AMP (also known as c-di-AMP), wherein the protein that makes the STING agonist lacks an EAL domain, wherein the protein that makes a STING agonist is a DNA integrity scanning (DisA) protein, that the vector comprises a panCD nucleic acid encoding a PanC protein and a nucleic acid sequence encoding a PanD protein, wherein the strain of Mycobacteria is Mycobacterium tuberculosis, or Mycobacterium bovis that is pantothenate-auxotroph, nor that Thi T cell and the M1 macrophage (whose expansion is induced) are intratumoral immune cells, as is presently claimed. In fact, Fang is completely silent about tumors in general, intratumoral Th1 T cells and M1 macrophages cells in particular, and notably about intratumoral immune cells expansion, and about a strain of Mycobacteria comprising a vector comprising the presently claimed nucleic acid sequences.
5. There is no evidence in Tullius that a pantothenate auxotroph strain of Mycobacteria would survive in vivo in the tumor microenvironment and therefore induces the expression of cytokines associated with Th1 T cell and M1 macrophage expansion.
6. As further detailed in the specification of from US Serial No. 17/797,055, (now issued as US 12,359,209, hereinafter "the '005 application") a continuation-in-part of the instant application, described herein as post-filing evidence, it is clear from the in vivo data that treatment of animal with the claimed recombinant strain of Mycobacteria induces the expression of cytokines associated with Th1 T cell and M1 macrophage expansion, undoubtedly supporting the fact an intratumoral Th1 T cell and M1 macrophage expansion inducer can include the claimed recombinant strain of Mycobacteria.
7. The instant claims are based on the discovery that a strain of Mycobacterium bovis BCG comprising the claimed vector expressing a protein that makes a STING agonist could be used to
(i) inhibit the expansion of MDSCs, (ii) reduce M2 macrophages activation, (iii) reduce levels of tumor-associated Treg cells in a tumor, and (iv) induce M1 macrophages activation and T effector cells level in a tumor, as compared to the expansion of MDSCs, M2 macrophages activation, levels of Treg cells, M1 macrophages activation in a tumor of a referenced subject not administered a pharmaceutical composition comprising the strain of Mycobacteria comprising the vector expressing a protein that makes a STING agonist (e.g., in a tumor of a referenced subject administered a pharmaceutical composition comprising the strain of Mycobacteria that does not comprise a vector expressing a protein that makes a STING agonist), which is not disclosed nor suggested in Bishai even considered in combination with Fang and Tullius.
8. One of skill in the art would not be motivated to use of a single vector encoding both a protein that makes a DisA protein and a PanCD protein, but that does not include an antibiotic gene resistance, and to express it in a pantothenate-auxotroph Mycobacterium bovis BCG
9. One of skill in the art would not expect that such a vector would remain stable in the Mycobacterium, nor that it would successfully yield a Mycobacterium that overexpresses a STING agonist, that is free of an antibiotic resistance gene, and that has the immune properties of the claimed Mycobacterium, hence rendering it useful for the claimed applications
10. Applicants submit that based on the disclosure in Sanbandamurthy, one of skills in the art would not expect that a ApanCD mutant Mycobacterium such as BCG ApanCD mutant would be unable to scavenge sufficient pantothenate to survive when placed in the urinary bladder. It is part of the discovery of the present invention that because the BCG ApanCD mutant cannot scavenge sufficient pantothenate from the urinary bladder, the present mode of complementation with the panCD-containing, disA-overexpressing plasmid is effective at locking-in the plasmid in the recombinant BCG ensuring stable overexpression of the disA gene.
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Point 1, the amendment to claim 10 is insufficient to overcome the rejection. The instant claims merely require that the claimed Mycobacterium tuberculosis or Mycobacterium bovis be a pantothenate auxotroph and that the protein that produces the 3’-5’ c-di-AMP lacks an EAL domain. Given that the 3’-5’ c-di-AMP producing Mycobacterium arising from the cited references have the same components as the Mycobacterium of the rejected claims, they both necessarily have the same biological and immunological characteristics.
With regard to Points 2 and 3, 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). Moreover, Bishai et al disclose strains of Mycobacteria (abstract). Bishai et al. disclose that said strains can be Mycobacterium strains comprising a vector (abstract) comprising a polynucleotide sequence encoding i) a di-adenylate cyclase enzyme, which is a protein that makes a STING agonist such as c-di-AMP; ii) a polynucleotide the encodes a protein domain of phosphodiesterase or knocks out a protein domain of phosphodiesterase; and that said strains can be Mycobacterium bovis or the Mycobacterium BCG strain and further discloses polynucleotide sequences encoding domains of phosphodiesterase and the full-length phosphodiesterase. While Bishai et al. don’t disclose that the protein encoding the ci-di-AMP lacks an EAL domain or that their Mycobacterium is a pantothenate-auxotroph (i.e. lacks the panCD operon) said deficiencies are remedied by the disclosures of Fang and Tullius et al. as Fang et al. disclose the deletion of the EAL domain effectively protects c-di-GMP from degradation and the disA gene of MTb contains the same GGDEF and EAL domains as the enzyme responsible for the synthesis of c-di-GMP and Tullius et al. disclose the increased safety of vaccines comprising Mycobacterium bovis pantothenate-auxotrophs expressing different antigens.
With regard to Point 4, given that the 3’-5’ c-di-AMP producing Mycobacterium arising from the cited references have the same components as the Mycobacterium of the rejected claims, they both necessarily have the same biological and immunological characteristics.
With regard to Point 5, there is no requirement that the claimed Mycobacterium survive in vivo in the tumor microenvironment. Moreover, given that the 3’-5’ c-di-AMP producing Mycobacterium arising from the cited references have the same components as the Mycobacterium of the rejected claims, they both necessarily have the same biological and immunological characteristics.
With regard to Point 6, U.S. Patent 12,359,209 are drawn to methods of utilizing a Mycobacterium tuberculosis or Mycobacterium bovis that is a pantothenate auxotroph and has the protein that produces the 3’-5’ c-di-AMP to inhibit the expansion of MDSCs within a tumor generally or bladder cancer specifically. As set forth supra, given that the 3’-5’ c-di-AMP producing Mycobacterium arising from the cited references have the same components as the Mycobacterium of the rejected claims, they both necessarily have the same biological and immunological characteristics.
With regard to Point 7, while the various in vivo uses for the claimed Mycobacterium strain is noted. However, given the rejected claims are drawn to a composition said uses constitute “intended uses”. Applicant is reminded that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Moreover, as set forth supra, given that the 3’-5’ c-di-AMP producing Mycobacterium arising from the cited references have the same components as the Mycobacterium of the rejected claims, they both necessarily have the same biological and immunological characteristics.
With regard to Point 8, as set forth in the rejection given it is known in the art that the second messengers of MTb include c-di-AMP, c-di-GMP, cGAMP (and the like) it would be obvious for one of ordinary skill in the art to delete the EAL domain of the disA gene in the recombinant MTb disclosed by Bishai et al. in order to avoid the degradation of the second messenger c-di-AMP. It would be equally obvious for the skilled artisan to utilize the Mycobacterium bovis pantothenate-auxotroph comprising plasmids comprising nucleic acids encoding the panCD in order to take advantage of the increased safety associated with said the Mycobacterium bovis pantothenate-auxotrophs. The combining of the nucleic acids encoding both panCD and the disA gene in a single vector constitutes an obvious design choice as the combination of multiple genes in a single vector is well established in the art.
With regard to Point 9, one would have a reasonable expectation of success as Fang et al. disclose the deletion of the EAL domain effectively protects c-di-GMP from degradation and the disA gene of MTb contains the same GGDEF and EAL domains as the enzyme responsible for the synthesis of c-di-GMP and Tullius et al. disclose the increased safety of vaccines comprising Mycobacterium bovis pantothenate-auxotrophs expressing different antigens.
With regard to Point 10, there is no requirement that the claimed Mycobacterium be able to scavenge sufficient pantothenate to survive in the urinary bladder. The instant claims merely require that the claimed Mycobacterium tuberculosis or Mycobacterium bovis be a pantothenate auxotroph and that the protein that produces the 3’-5’ c-di-AMP lacks an EAL domain. Given that the 3’-5’ c-di-AMP producing Mycobacterium arising from the cited references have the same components as the Mycobacterium of the rejected claims, they both necessarily have the same biological and immunological characteristics.
Claim 10 has been amended to recite that the Th1 T cells and M1 macrophages are intratumoral immune cells. Thus, claim 10 drawn to a strain of Mycobacteria comprising a vector comprising: i) a nucleic acid sequence encoding a protein that makes a STING agonist wherein the STING agonist is a c-di-AMP which is produced by a protein that lacks an EAL domain and ii) a panCD nucleic acid encoding a PanC protein and a nucleic acid sequence encoding a PanD protein wherein the Mycobacteria is Mycobacterium tuberculosis or Mycobacterium bovis that is a pantothenate-auxotroph. The broadest reasonable interpretation of claim 10 encompasses naturally occurring strains of Mycobacteria.
Bishai et al. discloses that the M. tuberculosis genome encodes a di-adenylate cyclase enzyme (disA, also called dacA) which is encoded by gene Rv3586 that synthesizes c-di-AMP from ATP or ADP4 (see paragraph 4 of the description). Bishai et al. further discloses that the preferred mycobacterial expression vector includes an hsp60 promoter and a DNA sequence of diadenylate cyclase (disA), or a functional part thereof, wherein the expression of di-adenylate cyclase enzyme or a functional part thereof is regulated by the hsp60 promoter (see paragraphs 14-15 of the description). Bishai et al. discloses that certain so called “second messengers” (including c-diAMP and c-di-GMP) have been shown in the prior art to have important processes in bacterial infection. “In bacteria, signaling nucleotides such as cyclic AMP… have been classically linked to carbon metabolism and the stringent response, which is caused by nutrient limitation… it has become clear that signaling nucleotides contribute to the regulation of multiple different pathways; for example, … cAMP is also involved in the regulation of both biofilm formation and virulence gene expression in many pathogenic bacteria, One of the latest signaling nucleotides-to be identified is cyclic di-AMP (c-di-AMP), which is the second cyclic dinucleotide shown to be produced by bacteria, after cyclic di-GMP (c-di-GMP) …c-di-AMP has been detected in cellular extracts from Streptococcus pyogenes, B. subtilis, Chlamydia trachomatis and Staphylococcus aureus and a DisA-type c-di-AMP -synthesizing enzyme from Mycobacterium tuberculosis has been characterized biochemically.” [see paragraphs [0004]-[0005]). Bishai et al. further disclose that “At high concentrations, c-di- AMP is expected to bind to a specific set of receptor or target proteins and allosterically alter their function or the function of downstream effector proteins, thus controlling specific cellular pathways… this nucleotide has been linked to the regulation of fatty acid synthesis in Mycobacterium smegmatis, to the growth of S. aureus in low potassium conditions, to the sensing of DNA integrity in B. subtilis and to cell wall homeostasis in multiple species. The M. tuberculosis genome encodes a di-adenylate cyclase enzyme (disA -- also called dacA; encoded by gene Rv3586 (also called MT3692) in the H37Rv genome or MT3692 in the CDC1551 genome) that synthesizes c-di-AMP from ATP or ADP4. Orthologs of disA exist in all mycobacterial genomes with the exception of M. leprae. (see paragraphs [0006]-[0007]). Moreover, Bishai et al. disclose at length: steps and processes for creating MTB strains which carry certain vectors; those vectors having various coding regions for encoding for certain proteins (disA), or portions thereof, including the deletion of domains or portions of that protein; transforming MTB with the vectors; culturing the transformed MTB; and verifying the presence or absence of the desired protein or portions thereof. Bishai et al. further disclose the M. tuberculosis genome encodes a di-adenylate cyclase enzyme (disA, also called dacA; encoded by gene Rv3586 (also called MT3692) in the H37 v genome or MT3692 in the CDC 1551 genome) that synthesizes c-di-AMP from ATP or ADP4 (see paragraph 4 of the description), pSDhsp60.MT3692 and pMH94Hyg.MT3692 (a BCG strain harboring the integrative plasmid pMH94Hyg MT3692) and that the preferred mycobacterial expression vector included an hsp60 promoter and a DNA sequence of diadenylate cyclase (disA), or a functional part thereof, wherein the expression of di-adenylate cyclase enzyme or a functional part thereof was regulated by the hsp60 promoter (see paragraphs 14-15 of the description).
Specifically, with respect to claim 10, Bishai et al disclose strains of Mycobacteria (abstract). Bishai et al. disclose that said strains can be Mycobacterium strains comprising a vector (abstract) comprising a polynucleotide sequence encoding i) a di-adenylate cyclase enzyme, which is a protein that makes a STING agonist such as c-di-AMP; ii) a polynucleotide the encodes a protein domain of phosphodiesterase or knocks out a protein domain of phosphodiesterase; and that said strains can be Mycobacterium bovis or the Mycobacterium BCG strain (abstract).
Particularly with respect to a polynucleotide sequence encoding a protein that makes a STING agonist, Bishai et al. discloses in paragraph [0006]: “The M. tuberculosis genome encodes a di-adenylate cyclase enzyme (disA, also called dacA; encoded by gene Rv3586 (also called MT3692) in the H37 v genome or the gene MT3692 in the CDC 1551 genome) that synthesizes c-di-AMP from ATP or ADP4.” C-di-AMP is an example of a STING agonist. Paragraph [0006] continues to disclose: “Orthologs of disA exist in all mycobacterial genomes with the exception of M. leprae.”
Bishai et al. further discloses polynucleotide sequences encoding domains of phosphodiesterase and the full-length phosphodiesterase and “One of the latest signaling nucleotides- to be identified is cyclic di-AMP (c-di-AMP), which is the second cyclic dinucleotide shown to be produced by bacteria, after cyclic di-GMP (c-di-GMP)(see paragraph [0004]). It has been suggested that c-di-AMP and c-di-GMP regulate very different processes.” Bishai et al. further discloses “c-di-AMP is produced from two molecules of ATP by diadenylyl cyclase (DAC) enzymes and is degraded to pApA by phosphodiesterase (PDE) enzymes.” (see paragraph [0005]). Hence, the PDE enzymes are endogenous in Mycobacteria, being encoded in the chromosome.
With respect to dependent claims 18-20, Bishai et al. discloses integrative vectors, and episomal vectors: “Another embodiment of the invention is the discovery of one or more strain(s) of Mycobacterium comprising an expression vector encoding a di-adenylate cyclase enzyme. The Mycobacterium is preferably selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium bovis, or a combination thereof…The most preferred strains are BCG- pSDhsp60.MT3692 (a BCG strain harboring the episomal plasmid pSDhsp60.MT3692), and BCG-pMH94Hyg.MT3692 (a BCG strain harboring the integrative plasmid pMH94Hyg MT3692). Many strains of BCG maybe transformed with plasmids of the present invention, pSDhsp60.MT3692 and pMH94Hyg.MT3692 to form novel pharmaceutical compositions.” (see paragraph [0015] for example).
Bishai et al. also discloses strains free of an antibiotic resistance gene: “M. tuberculosis CDC 1551” lacks a resistance gene to kanamycin. This lack is exploited by the vector system which uses a vector comprising a kanamycin resistance gene, in combination with any other genes. Under kanamycin selection, the strain must incorporate or stably maintain the vector to survive (see paragraph [0021]). Finally, Bishai et al. discloses pharmaceutical compositions of claim 10 plus a pharmaceutically acceptable carrier (see paragraphs [0012 and 0016] for example).
Bishai et al. differs from the instant invention in that they don’t discloses that the protein encoding the ci-di-AMP lacks an EAL domain or that their Mycobacterium is a pantothenate-auxotroph (i.e. lacks the panCD operon).
Fang discloses the study of the role of c-di-GMP secondary messenger in MTb infection and found that the MTB attenuated strain H37Ra and the virulent strain H37Rv contain only one GGDEF domain gene MRA_ 1362 and Rv1354c and one EAL domain gene MRA _ 1365 and Rv1357c, and the amino acid sequences are completely identical (see abstract). Fang further discloses that the GGDEF domain catalyzes the synthesis of c-di-GMP from GTPs, and c-di-GMP is hydrolyzed by EAL domain phosphodiacylase A (PDEA) to form the biologically inactive linear molecule 5'-pGpG (see section 1.3.1). Fang further discloses an EAL domain has an activity of degrading c-di-GMP. Moreover, Fang disclosed that the MTB attenuated strain H37Ra and the virulent strain H37Rv contain only one GGDEF domain gene (MRA_1362 and Rvl354c) and one EAL domain gene (MRA_1365 and Rvl357c) and that the encoded amino acid sequences are completely identical. “We found that there was a single GGDEF domain-containing gene, namely MRA_J362 and Rvl354c, and a single EAL domain-containing gene, namely MRA_l365 and Rv1357c respectively. The amino acid sequence is identical and the encoding product of MRA 1362 can catalyze the GTP to c-di-GMP in vitro. Then, based on the mechanism of gene homologous recombination, we deleted the genes encoding the synthesize and degrading enzymes of c-di-GMP named MRA_l362 and MRA_l365 in MTB H37Ra, respectively... Rvl 357c encodes the phosphodiesterase which degrades c-di-GMP in standard virulent MTB H37Rv strain. We deleted the Rv1357c gene and obtained ARv1357c. After 6 weeks of infecting the C57BL/6 mice, we found that the CFU in the lung of ARv1357c group was almost the same as that of the wild-type group. However, the histopathologic was analysis showed difference. Comparing with the wild-type group, the solid lesions in ARv1357c group were more obvious, and the· weight of lung were bigger. These results suggested that the inflammatory reaction and the pathogenesis of the ARv1357c group increased in infected mice. Our results demonstrate that MTB have difficulty in forming biofilm after sensing hypoxia due to increased bacterial proliferation and higher intracellular c-di-GMP level. The difficulty in forming biofilm will contribute to MTB spreading among tissues and result in more obvious inflammatory reaction. Our work showed for the first time that c-di-GMP can play a role as the second messenger in MTB by inhibiting the biofilm development in vitro and facilitating the pathogenesis in mice. C-di-GMP can also regulate the expression of some genes related to dormancy by sensing hypoxia.” (English language abstract).
Tullius et al. disclose the vaccine compositions comprising Mycobacterium bovis pantothenate-auxotrophs (see abstract and Table I) and the use of plasmids therein comprising nucleic acids encoding the panCD operon under the control of an Hsp60 promoter (see Table 1).
Given it is known in the art that the second messengers of MTb include c-di-AMP, c-di-GMP, cGAMP, and the like; it would be obvious for one of ordinary skill in the art to delete the EAL domain of the disA gene in the recombinant MTb disclosed by Bishai et al. in order to avoid the degradation of the second messenger c-di-AMP. It would be equally obvious for the skilled artisan to utilize the Mycobacterium bovis pantothenate-auxotroph comprising plasmids comprising nucleic acids encoding the panCD in order to take advantage of the increased safety associated with said the Mycobacterium bovis pantothenate-auxotrophs.
One would have a reasonable expectation of success as Fang et al. disclose the deletion of the EAL domain effectively protects c-di-GMP from degradation and the disA gene of MTb contains the same GGDEF and EAL domains as the enzyme responsible for the synthesis of c-di-GMP and Tullius et al. disclose the increased safety of vaccines comprising Mycobacterium bovis pantothenate-auxotrophs expressing different antigens. Moreover, the KSR decision sets forth “if a technique has been used to improve one device, and a person of skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill”. Given that Fang demonstrates the protection of a secondary messenger (c-di-GMP) by deleting the EAL domain and it is well established in the art that the disA gene contains an EAL domain, the deletion of the EAL domain within the disA gene is well within the capabilities of one of ordinary skill in the art. Hence, the requirements of obviousness under the KSR decision are met.
In KSR Int 'l v. Teleflex, the Supreme Court, in rejecting the rigid application of the teaching, suggestion, and motivation test by the Federal Circuit, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Applying the KSR standard of obviousness to the cited references, it is deemed that the creation of an MTB strain carrying a vector comprising a STING agonist ci-di-AMP which lacks an EAL domain would have been the use of a known technique to improve similar methods. The nature of the problem to be solved may lead inventors to look at references relating to possible solutions to that problem. The nature of the problem was the creation of an MTB with a vector that encodes proteins which can make a STING agonist, where the agonist is ci-di-AMP, and the protein making the ci-di-AMP lacks an EAL domain. Bishai et al. provides MTB harboring a vector which encode proteins which can make a STING agonist, di-adenylate-cyclase enzyme. The M. tuberculosis genome encoded a di-adenylate cyclase enzyme (disA, also called dacA; encoded by gene Rv3586 (also called MT3692) in the H37 v genome or MT3692 in the CDC 1551 genome) that synthesized c-di-AMP from ATP or ADP4 (see paragraph 4 of the description). Bishai et al. also provides a preferred mycobacterial expression vector including an hsp60 promoter and a DNA sequence of diadenylate cyclase (disA), or a functional part thereof, wherein the expression of di-adenylate cyclase enzyme or a functional part thereof was regulated by the hsp60 promoter (see paragraphs 14-15 of the description). Fang provides analysis of a highly similar second messenger nucleotide ci-di-GMP, including vectors encoding proteins which encode a STING antagonist c-di-GMP, which has a single EAL domain, and which lack an EAL domain. MTB harboring the vector lacking the EAL domain were shown by Fang to have difficulty in forming biofilms after sensing hypoxia due to increased bacterial proliferation and higher intracellular c-di-GMP level. The difficulty in forming biofilm contributed to MTB spreading among tissues and result in more obvious inflammatory reaction. A more obvious inflammatory reaction can possibly lead to increased clearance of MTB by the immune system. One of skill in molecular biology at the time of the filing would have had motivation to have identified the EAL domain in disA in MTB, and deleted it, to have obtained MTB harboring a vector encoding proteins (disA) which can make a STING agonist (ci-di-AMP) where the encoded protein lacked an EAL domain for the observation of whether the lack of an EAL domain affected pathogenesis of MTB, and whether this strain would have had any protective effect against wild type MTB. Both Bishai et al. and Fang provide the details for identification of the protein which can make the STING agonist. Fang provides the EAL domain in the protein which can make a STING agonist and created vectors which encode those proteins with and without an EAL domain. While the c-di-GMP of Fang is a differing STING agonist from that of the claims (c-di AMP), the EAL domains in the proteins which could have made c-di-AMP or c-di-GMP were found to be identical. Utilizing bioinformatics techniques as those disclosed in Fang to identify the coding sequence for the protein which has or lacks the EAL domain would have been well within the level of one of skill in the art of molecular biology. Carrying out the creation of the vector with or without the desired EAL domain, the transformation of MTB with the appropriate vector, and the culturing of the transformed MTB strain are all routine steps in molecular biology and bacteriology. Therefore, it would have been obvious to one of ordinary skill in the art at the time of filing to have created a strain of Mycobacteria comprising a vector comprising a nucleic acid sequence encoding a protein which makes a STING agonist (c-di-SMP) and lacks an EAL domain, absent evidence to the contrary.
With regard to the sequence recited in claim 41 (i.e. SEQ ID NO:7), it is deemed in absence of the contrary, that said sequence would necessarily result from the combination of the cited references.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT A ZEMAN whose telephone number is (571)272-0866. The examiner can normally be reached Monday thru Friday; 6:30 am - 3pm EST.
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, Daniel Kolker can be reached on 571-272-3181. 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.
/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 January 13, 2026