DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 01/23/2026, in which claims 1, 22, and 24 are amended and claims 18-21 are canceled.
Claims 1-17 and 22-24 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/US2020/034794, filed on 05/28/2020, which claims domestic benefit to 62/853,273 filed on 05/28/2019.
Objection Withdrawn
Applicant’s amendment and remarks, filed 01/23/2026, with respect that claims 1-12, 15-17, and 22-24 are objected to because formula (I) is not clear enough to clearly distinguish all subscripts and superscripts of the R groups shown, has been fully considered and is persuasive, as claims 1, 22, and 24 have been amended to provide a higher resolution structure. This objection has been withdrawn.
The following are maintained grounds of rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-12, 14-17, and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Andries et al. (WO 2018/158280 Al; IDS 03/01/2022) in view of Ferro et al. (Antimicrob Agents Chemother, 2016; IDS 03/01/2022).
Andries discloses combinations of medicinal compounds that are useful for medicaments for the treatment of diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (Abstract, claim 10). Andries teaches that there exists no single agent that is effective in the clinical treatment of tuberculosis (page 1, lines 32-33) but that the combinations disclosed may be useful in the treatment of active tuberculosis and may also be useful in the treatment of latent or dormant tuberculosis (page 19, lines 17-18). Furthermore, there is a high medical need for new combination drugs that facilitate compliance in the treatment of the mycobacterial infection tuberculosis (page 1, lines 37-38).
Andries discloses a medicinal composition containing Q203, which is a compound according to formula 1 in which Y is CH and in which R2 is an unsubstituted alkyl, r is 0, R6 is a haloalkoxy, q is 0, X is N, p is 1, n is 0, m is 1, and R1 is a halogen (claim 2 and page 36, table entry 6, hereafter referred to as Q203).
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Andries discloses that the combination may further comprise additional antibacterial drugs (claim 3). These drugs are selected from a list that includes, among others, the ndh2 inhibitor clofazimine and a macrolide selected from, among others, clarithromycin (claim 5). This combination can be a medicament (claim 9). Andries teaches that the disclosed combinations are for simultaneous, separate or sequential use in the treatment of a bacterial infection (claim 16 and page 22, lines 16-20). Andries further teaches that the combinations may be formulated together, for example in a fixed dose formulation (page 22, lines 10-13). Andries teaches that the disclosed combinations may be in the form of a kit (page 22, line 33).
Andries does not expressly disclose the three-component combination of a compound of instant formula (I), clofazimine, and clarithromycin (instant claims 1, 22, and 24).
Ferro teaches that multidrug therapy is a standard practice when treating mycobacterial infections (page 1097, paragraph 2). Ferro discloses a synergistic interaction between clofazimine and clarithromycin against mycobacteria in which clarithromycin was the potent antibacterial and clofazimine prevented regrowth of the bacterial (figure 4(b) and (d) and page 1104, paragraph 2).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention to combine the prior art elements of Q203, clofazimine, and clarithromycin according to the known method of combining antibacterial drugs to yield the predictable result of a medicament with increased antimicrobial efficacy, because Andries teaches combinations of Q203 and additional antibacterial agents as antimicrobials for treating mycobacterial infection, and clarithromycin is taught as suitable macrolide and clofazimine as a preferred ndh2 inhibitor for combination of Q203. One of ordinary skill in the art would have been motivated to combine Q203 with clarithromycin and clofazimine because Ferro teaches that clarithromycin and clofazimine act synergistically against mycobacteria. One of ordinary skill in the art would have a reasonable expectation of success because Andries teaches that Q203, clofazimine, and clarithromycin are all antibacterial agents useful for combined treatment of bacterial infections such as tuberculosis.
Claims 1-7, 9, 11-13, 15-17, and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (WO 2017/049321 Al; IDS 03/01/2022) in view of Ferro et al. (Antimicrob Agents Chemother, 2016; IDS 03/01/2022).
Miller ‘321 discloses antibacterial benzylamine-containing heterocyclic compounds and teaches combinations useful for the treatment of diseases caused by mycobacterial infections (Abstract, claim 17). Miller ‘321 teaches that there is an urgent need for new treatments against Mycobacterial infections both as single drugs and in combination therapy, especially against resistant strains (page 1, background).
Miller ‘321 discloses a compound ND-011598, which is a compound according to instant formula (I) in which R2 is an unsubstituted alkyl, r is 0, R6 is substituted alkyl, q is 0, X is N, p is 2, n is 1, m is 1, and R1 is an unsubstituted alkyl and in which Y is N (claim 14, compound ND-011598, hereafter referred to as HT-21).
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Miller ‘321 further teaches the disclosed compounds in compositions further comprising additional antimicrobials including, among others, clarithromycin and clofazimine (page 38, paragraph 1). Miller ‘321 teaches that the disclosed compounds are suitable for use in combination with additional antimicrobials, either concurrently or with delayed administration (page 38, paragraph 1), and that drug combinations are possible (page 38, paragraph 2). Miller ‘321 further teaches that the disclosed compositions may be provided as a kit (page 42, paragraph 3).
Miller ‘321 does not expressly disclose the three-component combination of a compound of instant formula (I), clofazimine, and clarithromycin (instant claims 1, 22, and 24).
Ferro teaches that multidrug therapy is a standard practice when treating mycobacterial infections (page 1097, paragraph 2). Ferro discloses a synergistic interaction between clofazimine and clarithromycin against mycobacteria in which clarithromycin was the potent antibacterial and clofazimine prevented regrowth of the bacterial (figure 4(b) and (d) and page 1104, paragraph 2).
It would have been prima facie obvious to combine the teachings of Miller ‘321 and Ferro before the effective filing date of the claimed invention by combining HT-21 with clarithromycin and clofazimine to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify combine HT-21 with clarithromycin and clofazimine because Miller ‘321 teaches that HT-21 is useful for combination with other antimicrobials and Ferro teaches that clarithromycin and clofazimine act synergistically against mycobacteria. One of ordinary skill in the art would have a reasonable expectation of success because Miller ‘321 teaches that HT-21 is useful for combination with other antimicrobials including clarithromycin and clofazimine.
Response to Arguments
Applicant's arguments filed 01/23/2026 have been fully considered but they are not persuasive.
Applicant argues that Figure 1 of Exhibit 1, which provides studies on the antimicrobial activity of Q203 alone in an M avium mouse infection model, shows that Q203 alone does not cause a statistically significant effect in reducing the number of colony-forming units such that a person of ordinary skill in the art would understand that adding Q203 to the combination of CFZ and CAM would not induce a statistically significant effect in reducing CFU (Remarks, page 10, paragraph 1). This is not persuasive.
Applicant provides Exhibit 1, but this is new data not found in the prior art or the specification and also not presented in the form of a declaration. MPEP 716.01(c) section II states that Arguments presented by the applicant cannot take the place of evidence in the record, and that examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results. As such Exhibit 1 cannot overcome any rejection. For the purposes of compact prosecution, the Examiner notes that the statistical calculations in Figure 1 of Exhibit 1 compare treatment of Q203 with a control, rather than comparing treatment of Q203 against the claimed combination. In order to show unexpected results for these compounds, a comparison of the claimed invention to the closest prior art must be given. In this case Ferro and Andries are equally close prior art references. Thus there must be a comparison showing a statistically significant difference between the claimed invention versus combination of clarithromycin and clofazimine as taught of Ferro, as well as Q203 alone as taught by Andries. MPEP 716.02(b) states that the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. MPEP 716.02(e) states that an affidavit or declaration must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. MPEP 716.02(e)II states that showing unexpected results over one of two equally close prior art references will not rebut prima facie obviousness unless the teachings of the prior art references are sufficiently similar to each other that the testing of one showing unexpected results would provide the same information as to the other.
Thus, even if the data were in a declaration it would not be possible to determine from this data whether the instantly claimed composition provides any unexpected results in comparison to the composition of Andries, and the argument would not be persuasive.
Applicant argues that Figure 2 of Exhibit 1, provides the studies on antimicrobial activity ofHT-21 alone, the combination of CAM and CFZ, and the combination ofHT-21, CAM, and CFZ in an M avium mouse infection model. It shows that HT-21 alone does not cause a statistically significant effect in reducing the number of CFU in a vehicle control (Remarks, page 11, paragraph 1). This is not persuasive.
Applicant provides Exhibit 1, but this is new data not found in the prior art or the specification and also not presented in the form of a declaration. As such it cannot overcome any rejection.
Examiner also notes that additional compounds 1-3 in combination with clarithromycin and clofazimine were tested for CFU decrease (Declaration, paragraphs 8-10), however, these compounds were not tested alone, and so there is no way to determine whether the difference in CFU is due a synergistic effect or merely the presence of compounds 1-3 in the treatment.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Instant claims 1-7, 9, 11-13, 17, 22, and 24, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,820,767 (Miller ‘767) in view of Miller et al. (WO 2017/049321 Al; IDS 03/01/2022) and Ferro et al. (Antimicrob Agents Chemother, 2016; IDS 03/01/2022).
Miller ‘767 claims a method of treating mycobacterial infectious disease comprising administering a compound of the following structure, which is a compound of instant formula (I) in which R2 is an unsubstituted alkyl, r is 0, R6 is substituted alkyl, q is 0, X is N, p is 2, n is 1, m is 1, and R1 is an unsubstituted alkyl and in which Y is N (claim 10), (hereafter referred to as HT-21).
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Miller ‘767 does not expressly claim a three-component combination of a compound of instant formula (I), clarithromycin, and clofazimine.
Miller ‘321 discloses antibacterial benzylamine-containing heterocyclic compounds and teaches combinations useful for the treatment of diseases caused by mycobacterial infections (Abstract, claim 17). Miller ‘321 teaches that there is an urgent need for new treatments against Mycobacterial infections both as single drugs and in combination therapy, especially against resistant strains (page 1, background).
Miller ‘321 discloses a compound according to formula 1 in which R2 is an unsubstituted alkyl, r is 0, R6 is substituted alkyl, q is 0, X is N, p is 2, n is 1, m is 1, and R1 is an unsubstituted alkyl and in which Y is N (claim 14, compound ND-011598), (hereafter referred to as HT-21).
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Miller ‘321 further teaches the disclosed compounds in composition further comprising additional antimicrobials including, among others, clarithromycin and clofazimine (page 38, paragraph 1). Miller ‘321 teaches that the disclosed compounds are suitable for use in combination with additional antimicrobials, either concurrently or with delayed administration (page 38, paragraph 1), and that drug combinations are possible (page 38, paragraph 2). Miller ‘321 further teaches that the disclosed compositions may be provided as a kit (page 42, paragraph 3).
Ferro teaches that multidrug therapy is a standard practice when treating mycobacterial infections (page 1097, paragraph 2). Ferro also discloses a synergistic interaction between clofazimine and clarithromycin against mycobacteria in which clarithromycin was the potent antibacterial and clofazimine prevented regrowth of the bacterial (figure 4(b) and (d) and page 1104, paragraph 2).
It would have been prima facie obvious to combine the claims of Miller ‘767 with the teachings of Miller ‘321 and Ferro before the effective filing date of the claimed invention by combining HT-21 with clarithromycin and clofazimine to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify combine HT-21 with clarithromycin and clofazimine because Miller ‘321 teaches that HT-21 is useful for combination with other antimicrobials and Ferro teaches that clarithromycin and clofazimine act synergistically against mycobacteria. One of ordinary skill in the art would have a reasonable expectation of success because Miller ‘321 teaches that HT-21 is useful for combination with other antimicrobials including clarithromycin and clofazimine.
Instant claims 1-7, 9, 11-13, 17, 22, and 24, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, and 5 of U.S. Patent No. 10,919,888 (Miller ‘888) in view of Miller et al. (WO 2017/049321 Al; IDS 03/01/2022) and Ferro et al. (Antimicrob Agents Chemother, 2016; IDS 03/01/2022).
Miller ‘888 discloses a compound according to formula 1 in which R2 is an unsubstituted alkyl, r is 0, R6 is substituted alkyl, q is 0, X is N, p is 2, n is 1, m is 1, and R1 is an unsubstituted alkyl and in which Y is N (claim 1), (hereafter referred to as HT-21).
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Miller ‘888 further claims a method of treating mycobacterial infectious disease comprising administering HT-21 (claim 3).
Miller ‘888 does not expressly claim a three-component combination of a compound of instant formula (I), clarithromycin, and clofazimine.
Miller ‘321 discloses antibacterial benzylamine-containing heterocyclic compounds and teaches combinations useful for the treatment of diseases caused by mycobacterial infections (Abstract, claim 17). Miller ‘321 teaches that there is an urgent need for new treatments against Mycobacterial infections both as single drugs and in combination therapy, especially against resistant strains (page 1, background).
Miller ‘321 discloses a compound according to formula 1 in which R2 is an unsubstituted alkyl, r is 0, R6 is substituted alkyl, q is 0, X is N, p is 2, n is 1, m is 1, and R1 is an unsubstituted alkyl and in which Y is N (claim 14, compound ND-011598), (hereafter referred to as HT-21).
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Miller ‘321 further teaches the disclosed compounds in composition further comprising additional antimicrobials including, among others, clarithromycin and clofazimine (page 38, paragraph 1). Miller ‘321 teaches that the disclosed compounds are suitable for use in combination with additional antimicrobials, either concurrently or with delayed administration (page 38, paragraph 1), and that drug combinations are possible (page 38, paragraph 2). Miller ‘321 further teaches that the disclosed compositions may be provided as a kit (page 42, paragraph 3).
Ferro teaches that multidrug therapy is a standard practice when treating mycobacterial infections (page 1097, paragraph 2). Ferro also discloses a synergistic interaction between clofazimine and clarithromycin against mycobacteria in which clarithromycin was the potent antibacterial and clofazimine prevented regrowth of the bacterial (figure 4(b) and (d) and page 1104, paragraph 2).
It would have been prima facie obvious to combine the claims of Miller ‘888 with the teachings of Miller ‘321 and Ferro before the effective filing date of the claimed invention by combining HT-21 with clarithromycin and clofazimine to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify combine HT-21 with clarithromycin and clofazimine because Miller ‘321 teaches that HT-21 is useful for combination with other antimicrobials and Ferro teaches that clarithromycin and clofazimine act synergistically against mycobacteria. One of ordinary skill in the art would have a reasonable expectation of success because Miller ‘321 teaches that HT-21 is useful for combination with other antimicrobials including clarithromycin and clofazimine.
Response to Arguments
Applicant's arguments filed 01/23/2026 have been fully considered but they are not persuasive.
Applicant argues that for the same reasons provided in response to the rejections under 35 U.S.C. 103 the claimed combination yielded an unexpectedly synergistic effect, supporting the non-obviousness over the nonstatutory double patenting rejections (Remarks, page 11, paragraph 3). This is not persuasive.
As discussed above regarding the rejections under 35 U.S.C. 103, the data provided in Exhibit 1 cannot be considered because it is new data not found in the prior art or the specification and also not presented in the form of a declaration. As such it cannot overcome any rejection.
Conclusion
No claims are 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 extension fee 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 date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693