Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This Application is a 371 of PCT/US2021/047074, filed Aug. 23, 2021 and claims priority benefit of U.S. Application No. 63/069,086, filed Aug. 23, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Feb. 23, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Applicant’s election without traverse of Group II, claims 9-16, and the species, ABT-199 and MIK665/S-64315 in the reply filed on Sept. 24, 2025 is acknowledged.
Claims 21-24 are newly added and read on Group II. Claims 9-16 and 21-24 are currently pending and subject to examination.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
“A person shall be entitled to a patent unless -
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.”
Claims 9-10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Walensky & Stewart (US 2012/0172285 A1) (of record, cited in the prior office action).
Claim 9 is directed towards a method of treating a Mycobacterium tuberculosis infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a BCL-2 inhibitor and a therapeutically effective amount of a MCL-1 inhibitor.
Walensky teaches a method of treating an infectious disease (Walesnky, Specification, ¶ [0016]), including tuberculosis (id., ¶ [0250]), comprising administering an MCL-1 inhibitor (id., ¶ [0014]), in combination with a BCL-2 inhibitor (id, ¶ [0015]).
Therefore, claim 9 is anticipated.
Claim 10 is directed towards the method of claim 9, wherein the BCL-2 inhibitor is ABT-199, ABT-263, S55746, or ABT-737.
Walensky teaches the BCL-2 inhibitor is ABT-263 or ABT-737(Walesnky, Specification, ¶ [0014]).
Therefore, claim 10 is anticipated.
Claim Rejections - 35 USC § 103
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.
Claim(s) 9-11 and 13-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vince et al. (WO 2016/131100 A1).
Claim 9 is directed towards a method of treating a Mycobacterium tuberculosis infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a BCL-2 inhibitor and a therapeutically effective amount of a MCL-1 inhibitor.
It is commonly known in the art that pathogens like M. tuberculosis prevent apoptosis of host cells by upregulating prosurvival proteins such as the B-cell lymphoma-2 (Bcl-2) family proteins to promote the infectious cycle. For example, Vince teaches that:
Various types of infectious pathogens, upon infection of a host cell, upregulate the pro- survival activity of one or more proteins in the BCL2 family to prevent the host cell apoptosis, which would otherwise curtail the infectious cycle. Without being bound by theory, it is believed that by inhibiting the activity of pro-survival BCL2 proteins, and particularly BCL-XL, in infected cells a BCL2 family inhibitor restores apoptosis in such cells thereby blocking the ability of certain pathogens to replicate and infect other cells.
Vince, Specification, p. 9-10.
Accordingly, Vince teaches a method of treating an M. tuberculosis infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a BCL2 family inhibitor, wherein the inhibitor targets one or more or all of BCL-XL, BCL-2, MCL-1 or A1 of the BCL2 family of proteins:
The present inventors have found that BCL2 family inhibitors can be used to treat infections in a subject. Accordingly, in one aspect described herein is a method for treating an infection, comprising administering to a subject in need thereof a therapeutically effective amount of a BCL2 family inhibitor.
Vince, Specification, p. 1, lines 16-20;
In some embodiments the subject is suffering from tuberculosis.
Id., p. 2, line 9;
In an embodiment, the inhibitor at least targets one or more or all of BCL-XL, BCL-2, MCL-1 or A1 of the BCL2 family of proteins.
Id., p. 2, lines 26-27.
As shown in the excerpts above, Vince teaches that BCL-2 and MCL-1 inhibitors can be used to treat tuberculosis by enhancing apoptosis in infected cells. Vince also teaches that the BCL-2 family inhibitor can target both BCL-2 and MCL-1.
While Vince does not explicitly teach to administer a combination of a BCL-2 inhibitor and an MCL-1 inhibitor, one of ordinary skill in the art would have a reasonable expectation of success to administer a combination of an BCL-2 inhibitor and an MCL-1 inhibitor because Vince teaches to target BCL-2, MCL-1 or both and because it is prima facie obvious to combine two agents known for the same purpose:
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
MPEP § 2144.06.
Therefore, claim 9 was prima facie obvious at the time of filing.
Claim 10 is directed towards the method of claim 9, wherein the BCL-2 inhibitor is ABT-199, ABT-263, S55746, or ABT-737.
One of ordinary skill in the art would have a reasonable expectation of success to use a BCL-2 inhibitor wherein the BCL-2 inhibitor is ABT-199, ABT-263, S55746, or ABT-737 because Vince teaches the BCL-2 inhibitors ABT-737 and ABT-263 (Vince, Specification, p. 12-13).
Therefore, claim 10 was prima facie obvious at the time of filing.
Claim 11 is directed towards the method of claim 9, wherein the MCL-1 inhibitor is one or more of S63845, A-1210477, MIM-1, MIK665/S-64315, 483-LM, AZD5991, AMG-176, AMG-397, UMI-77, VU661013, or JKY-5-037.
One of ordinary skill in the art would have a reasonable expectation of success to use a MCL-1 inhibitor, wherein the MCL-1 inhibitor is one or more of S63845, A-1210477, MIM-1, MIK665/S-64315, 483-LM, AZD5991, AMG-176, AMG-397, UMI-77, VU661013, or JKY-5-037 because Vince teaches MCL-1 inhibitors such as MIM-1 (Vince, Specification, p. 15).
Therefore, claim 11 was prima facie obvious at the time of filing.
Claim 13 is directed towards the method of claim 9, wherein the subject has active tuberculosis.
One of ordinary skill in the art would have a reasonable expectation of success to treat a subject with active or latent tuberculosis because Vince teaches the treatment of acute and subacute infections (Vince, Specification, p. 2, line 14) as well as latent tuberculosis (Id., p. 49, lines 34-35).
Therefore, claims 13 and 15 were prima facie obvious at the time of filing.
Claims 14 and 16 are directed towards the methods of claims 13 and 15, respectively, wherein the method further comprises administering to the subject a therapeutically effective amount of an anti-tuberculosis antibiotic.
One of ordinary skill in the art would have a reasonable expectation of success to administer to the subject a therapeutically effective amount of an anti-tuberculosis antibiotic because Vince teaches to administer a BCL2 family inhibitor with one or more bactericidal or bacteriostatic agents, including, isoniazid, ethambutol, rifampicin and streptomycin (anti-tuberculosis antibiotics) (Vince, Specification, p. 25, lines 2-9).
Therefore, claims 14 and 16 were prima facie obvious at the time of filing.
Claim(s) 9-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vince et al. (WO 2016/131100 A1), as applied to claims 9-11 and 13-16 above, and further in view of Halilovic et al. (Cancer Research, 2019; Vol. 79, Issue 13 Suppl., Abstract nr 4477).
The rejection of claims 9-11 and 13-16 above as obvious over Vince is incorporated herein by reference.
Claim 12 is directed towards the method of claim 9, wherein the BCL-2 inhibitor is venetoclax and the MCL-1 inhibitor is MIK665/S-64315.
As shown above in the rejection of claim 9, Vince teaches the treatment of tuberculosis with BCL2 family inhibitors which act to enhance apoptosis in apoptosis resistant pathogen infected cells.
While Vince does not specifically teach that the BCL2 family inhibitors are venetoclax and MIK665/S-64315, one of ordinary skill in the art would have a reasonable expectation of success to use a combination of venetoclax and MIK665/S-64315 because it is known in the art that these two agents synergize to promote apoptosis in apoptosis resistant cells.
For example, Halilovic teaches “the combination of MIK665/S64315 with BCL201/S55746 or venetoclax” and that “a strong synergy was observed with these combinations, resulting in a remarkable induction of cell death in majority of cell lines tested” (Halilovic, Abstract).
Therefore, claim 12 was prima facie obvious at the time of filing.
Claim(s) 9-11, 13-16 and 21-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vince et al. (WO 2016/131100 A1), as applied to claims 9-11 and 13-16 above, and further in view of Ufimtseva (Immunome Research, 2017, 13:1, p. 1-19).
The rejection of claims 9-11 and 13-16 above as obvious over Vince is incorporated herein by reference.
Claim 21 is directed towards the method of claim 9, wherein the Mycobacterium tuberculosis is present in a host organ granuloma.
As shown above in the rejection of claim 9, Vince teaches the treatment of tuberculosis with BCL2 family inhibitors which act to enhance apoptosis in apoptosis resistant pathogen infected cells.
While Vince does not explicitly teach that the M. tuberculosis is present in a host organ granuloma, one of ordinary skill in the art would have a reasonable expectation of success to treat tuberculosis granulomas with the combination of BCL-2 and MCL-1 inhibitors because it is known in the art that tuberculosis granulomas are also resistant to apoptosis and express increased levels of BCL-2 family proteins.
For example, Ufimtseva teaches that Bcl-2 contributes to the viability of tuberculosis granulomas:
Tuberculosis is a leading worldwide health problem. The latent, symptom-free stage of tuberculous infection is characterized by the formation of granulomas, specific aggregates of immune cells, predominantly macrophages, containing mycobacteria. The apoptotic death of macrophages containing mycobacteria is considered the main mechanism by which animals and human organisms oppose tuberculous infection and control its development. Previously, we have compared Mycobacterium-host cell relationships in individual granuloma cells from mice with latent tuberculous infection and cells from mouse bone marrow and peritoneal cultures infected with BCG vaccine in vitro and shown that increased death rates were revealed for macrophages heavily loaded with mycobacteria after acute BCG infection in vitro. While in ex vivo cultures granuloma macrophages with large numbers of BCG mycobacteria in them were still viable and had neither apoptotic nor necrotic morphology.
Since different specific cellular responses to latent chronic and acute BCG infection in mouse cells were determined, the our aim was to analyze granulomas isolated from the lungs, spleens and bone marrow of Balb/c mice with latent BCG infection for the presence of inducers and markers of apoptotic cell death. In granuloma cells with increased levels of the inducer of apoptosis TNFα, proapoptotic proteins Вах and Ваd, death receptor Fas/ CD95 and scavenge receptor CD36, we did not observe P53 stabilization or caspase-3 activation in the cytoplasm or nuclei of macrophages and dendritic cells, irrespective of the presence or absence of acid-fast BCG mycobacteria in them. The survival receptor CD30 was detected on the cell membranes of only few granuloma macrophages. However, at later times of tuberculous infection in mice, virtually all macrophages and other granuloma cell types had considerable amounts of the antiapoptotic protein Bcl-2 in the cytoplasm and, probably, mitochondria, in contrast to macrophages from bone barrow cell cultures and peritoneal exudates infected with BCG mycobacteria in vitro. Preservation of mitochondrial ΔΨm during staining of living granuloma macrophages containing large amounts of the Bcl-2 protein was indicative of its involvement in maintaining the integrity of mitochondrial elements and the protection of granuloma cells from death, because in similar experiments the control macrophages that did not have any Bcl-2 protein in them had considerably reduced ΔΨm and exhibited morphological signs of apoptotic death. Taken together, our results suggest that the antiapoptotic protein Bcl-2 has been proposed to contribute to the viability of granulomas macrophages not only in ex vivo culture, but also in the animal organism when faced with mycobacterial, proinflammatory and proapoptotic factors operating in granulomatous inflammatory lesions at various times of latent tuberculous infection in mice.
Ufimtseva, Abstract (emphasis added).
Claim 22 is directed towards the method of claim 21, wherein the host organ granuloma is co-infected with HIV.
One of ordinary skill in the art would have a reasonable expectation of success to treat a granuloma co-infected with HIV because Vince teaches that BCL2 inhibitors are also useful to treat HIV infections (Vince, Specification, p. 2, line 2).
Therefore, claim 22 was prima facie obvious at the time of filing.
Claim(s) 9-16 and 21-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vince et al. (WO 2016/131100 A1), as applied to claims 9-11 and 13-16 above, and further in view of Ufimtseva (Immunome Research, 2017, 13:1, p. 1-19), as applied to claims 21-22 above, and further in view of Halilovic et al. (Cancer Research, 2019; Vol. 79, Issue 13 Suppl., Abstract nr 4477), as applied to claim 12 above.
The rejection of claims 9-11 and 13-16 above as obvious over Vince is incorporated herein by reference. The rejection of claims 9-16 as obvious over Vince in view of Halilovic is incorporated herein by reference. The rejection of claims 9-11, 13-16 and 21-22 as obvious over Vince in view of Ufimtseva is incorporated herein by reference.
Claim 23 is directed towards the method of claim 22, wherein the BCL-2 inhibitor is venetoclax. Claim 24 is directed towards the method of claim 22, wherein the BCL-2 inhibitor is venetoclax and the MCL-1 inhibitor is MIK665/S-64315.
As shown above in the rejection of claim 9, Vince teaches the treatment of tuberculosis with BCL2 family inhibitors which act to enhance apoptosis in apoptosis resistant pathogen infected cells. As shown above in the rejection of claim 21, Ufimtseva teaches that tuberculosis granulomas are apoptosis resistant pathogen infected cells.
While Vince does not specifically teach that the BCL2 family inhibitors are venetoclax and MIK665/S-64315, one of ordinary skill in the art would have a reasonable expectation of success to use a combination of venetoclax and MIK665/S-64315 in a tuberculosis granuloma because it is known in the art that these two agents synergize to promote apoptosis in apoptosis resistant cells.
For example, Halilovic teaches “the combination of MIK665/S64315 with BCL201/S55746 or venetoclax” and that “a strong synergy was observed with these combinations, resulting in a remarkable induction of cell death in majority of cell lines tested” (Halilovic, Abstract).
Therefore, claims 23-24 were prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629