DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed on 10/12/2023. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The application is a 371 application, filed 10/12/2023, of PCT application PCT/EP2022/060287, filed 04/19/2022, which claims priority benefits from Foreign Application No. IT10/2021000009926, filed 04/20/2021. The effective filing date of this application is 04/20/2021, the filing date of the foreign application.
Claims Status
The amendment filed 06/09/2026 is entered.
Claims 12, 13, 15, 17, 20 are amended. Claims 1-11 are cancelled. Claims 14, 16, and 18-19 are newly cancelled.
Claims 12, 13, 15, 17, 20-26 are pending and under examination.
Response to Amendment
Withdrawn Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The previous 35 USC § 112(b) rejections for claims 16-19 are withdrawn in response to Applicant’s amendments. Claims 16, 18, and 19 are cancelled, obviating the rejections. Claim 17 is amended to clarify the subject’s treatment status.
Claim Rejections - 35 USC § 103
The previous 35 USC § 103 rejections for claims 14, 16, 18, and 19 are withdrawn in response to Applicant’s amendments. Claims 14, 16, 18, and 19 are cancelled, obviating the rejections.
Maintained Objections/Rejections
The previous 35 USC § 103 rejections for claims 12, 13, 15, 17, 20-26 are maintained and updated in response to Applicant’s amendments.
Claim Rejections - 35 USC § 103
Claims 12, 13, 15, 17, 20-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO ‘340 (WO2018189340A1; published 10/18/2018) in view of Rotte (Rotte, Combination of CTLA-4 and PD-1 blockers for treatment of cancer, J Exp Clin Cancer Res 38, 255 (2019); published 2019).
Regarding claim 12, WO ‘340 teaches a method comprising administering a combination comprising N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide (instantly referred to as Compound 8) and a PD-1 checkpoint inhibitor (e.g. Figures 2-5).
WO ‘340 further teaches a method of treating three tumor cell lines that are sensitive to PD-1 inhibition with the combination therapy in murine models (Example 27, pages 140-141). These murine cell lines are models for breast cancer, colon cancer, and triple negative breast cancer (p. 141). WO ‘340 teaches that HDAC6 inhibition could reduce PD-L1 expression (page 140). WO ‘340 further teaches that the claimed HDAC6 inhibitor (also called Compound 8) and the tested anti-PD-1 antibody similarly inhibits tumor growth in murine tumor models (Figure 3 and p. 143).
WO ‘340 further teaches that diseases associated with HDAC6 include cancer (page 1, paragraph 1) and teach the link between HDAC6 inhibition and PD-1/PD-L1 checkpoint as previously discussed. As such, the PD-1 sensitive tumors taught by WO ‘340 is a model of a HDAC6-mediated disease.
WO ‘340 does not explicitly teach N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide with a CTLA4 checkpoint inhibitor.
However, WO ‘340 further teaches each HDAC6 inhibitor compound disclosed, which includes N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide, may be used in combination with other drugs, such as CTLA4 checkpoint inhibitors. See p. 41, starting at line 3, as well as claim 5 on p. 172.
Furthermore, to support that the HDAC6 inhibitor combination with a CTLA4 inhibitor would treat the claimed cancers, Rotte teaches that CTLA-4 blockers have been approved as monotherapy for melanoma, PD-1 blockers have been approved from melanoma, renal cell carcinoma, and non-small cell lung cancer, whereas the combination of CTLA-4 and PD-1 blockers has been approved for melanoma, renal cell carcinoma, and colorectal cancer (Table 1).
Furthermore, Rotte et al teaches the mechanism by which CTLA-4 blockade would act synergistically with PD-1 blockade (p. 4, col. 1, section: Rationale for combination).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to substitute the PD-1 checkpoint inhibitor with a CTLA4 checkpoint inhibitor in light of WO ‘340 teaching this as a potential substitution, that HDAC6 inhibition could reduce PD-L1 expression (page 140), and in effect, already inhibiting the PD-1/PD-L1 pathway, and that HDAC6 inhibitor has comparable efficacy in inhibiting tumor growth as the anti-PD-1 antibody. Seeing as the HDAC6 inhibitor and the anti-PD-1 antibody already inhibit similar checkpoint pathways and have similar efficacy in doing so, and that PD-1/PD-L1 and CTLA4 are the two most common checkpoint inhibition pathways targeted by immunotherapies for the treatment of cancer, substituting one checkpoint inhibitor would be the most obvious substitute for another, especially in light of Rotte teaching that a combination of CTLA-4 and PD-1 blockade can be beneficial in treating cancers in subjects that may not be responsive to monotherapies. Therefore, it would be obvious to substitute one of the two PD-1/PD-L1 pathway blockers with a CTLA-4 blocker to arrive at the claimed combination of the HDAC6 inhibitor and the anti-CTLA-4 antibody.
One skilled in the art, before the effective filing date of the instant application, would be motivated to substitute the PD-1 checkpoint inhibitor with a CTLA4 checkpoint inhibitor in the combination with N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide to potentially target both commonly targeted checkpoint inhibition pathways (i.e. PD-1/PD-L1 and CTLA4). Inhibiting both the PD-1/PD-L1 and CTLA4 pathways through combination therapy is a known and advantageous endeavor to one skilled in the art, before the effective filing date of the instant application, as taught by Rotte et al.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success since each of these elements, N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide and anti-CTLA-4 antibody has already been shown to inhibit tumor growth in vivo by themselves and can work synergistically in combination with other checkpoint inhibitors to inhibit tumor growth. Further, CTLA4 checkpoint inhibitors are well-known and well-utilized as a monotherapy and in combination therapies with PD-1/PD-L1 pathway blockers to treat cancers, and specifically the cancers claimed.
Claims 13, 15, 17, 20-26 depend on claim 12. The teachings of the references regarding parent claim are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 13, WO ‘340 further teaches the anti-CTLA4 could specifically be ipilimumab or tremelimumab (page 41).
Regarding claim 17, WO ‘340 further teaches administration of the combination to treatment-naïve BALB/c mice (Example 27; page 142 for tumor induction and treatment schedule). WO ‘340 does not explicitly teach that these subjects were not previously treated due to expected toxicity, but it also does not exclude this reason.
Regarding claim 15, WO ‘340 does not explicitly teach the subject has been previously treated with anti CTLA4, anti PD1 and/or anti PDL1 antibodies and has discontinued this treatment due to toxicity, but it also does not exclude these patients.
Furthermore, Rotte teaches a low dose CTLA-4 blockade (Ipilimumab) and regular dose PD-1 (pembrolizumab) blockade combination showed promising results in melanoma patients (p. 4, section: Pembrolizumab plus ipilimumab combination). This shows that another potential benefit of combination therapy is the ability to reduce the dose of at least one of the drugs, thereby potentially allowing administration of a drug that was once toxic at a higher dose to a patient at a reduced dose.
The method of WO ‘340 would reasonably inherently include the claimed population of subjects barring teachings otherwise. WO ‘340 further teaches that administering N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide by itself, desirably, shows greater neoantigen immune response compared to the checkpoint inhibitor antibody (Example 27, page 143) and that there are beneficial, possibly synergistic, effects from the combination of HDAC6 inhibiting compounds and the checkpoint inhibitor antibody (e.g. Figures 3-5).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that even if a subject had discontinued treatment with anti CTLA4, anti PD1 and/or anti PDL1 antibodies, if because of insufficient treatment effects or toxicity at regular doses (and not some adverse reaction to the antibody that is dose-independent) or has never been treated due to expected toxicity at the regular dose, it would not preclude a subject from subsequent treatment with the combination therapy, as the N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide, even by itself, has some better effects than a checkpoint inhibitor antibody.
One skilled in the art, before the effective filing date of the instant application, would be motivated to apply this combination therapy to those that were previously treatment-refractive because the combination therapy could provide benefits over the checkpoint inhibitor antibody monotherapy and could overcome dose-dependent toxicity, as previously explained.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success since the combination therapy of HDAC6 inhibiting compounds and checkpoint inhibitor antibody has shown benefits over checkpoint inhibitor antibody monotherapy in the tumor models taught by WO ‘ 340. Although Figure 3 shows that checkpoint inhibitor antibody monotherapy and combination therapy with compound 8 have only comparable effects on tumor volume reduction, it would still be reasonably motivated to apply the combination therapy to subjects that did not respond sufficiently to checkpoint inhibitor antibody monotherapy since compound 8 by itself seems to work independently of checkpoint inhibitor antibodies. In other words, even if the subject does not respond sufficiently to anti CTLA4, anti PD1 and/or anti PDL1 antibodies, compound 8 in the combination therapy would still reasonably have treatment effects. Furthermore, even if the patient had dose-dependent toxicity to the checkpoint inhibitor, one skilled in the art would still have reasonable expectation of success that a combination therapy comprising of an HDAC6 inhibitor and a checkpoint inhibitor could still work due to their synergistic effects potentially leading to the ability to start at a lower dose of each of the individual components.
Regarding claim 20, WO ‘340 further teaches the components of the combination are administered simultaneously, separately, or sequentially (Example 27).
Claims 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO ‘340 (WO2018189340A1; published 10/18/2018) in view of Rotte (Rotte, Combination of CTLA-4 and PD-1 blockers for treatment of cancer, J Exp Clin Cancer Res 38, 255 (2019); published 2019), as applied to claim 12 above, and further in view of Ott et al (Ott, P., et al, A phase I study to evaluate the safety and tolerability of MEDI4736, an anti- programmed cell death-ligand-1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced solid tumors, Meeting Abstract: 2015 ASCO Annual Meeting I, J Clin Oncol 33, TPS3099(2015), published 05/20/2015), as evidenced by NCT01975831 (record submitted 05/11/2015).
Claims 21-26 depend on claim 12 and 20. The teachings of the references regarding the parent claims are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
As is relevant to claims 21-26, WO ‘340 teaches that N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide is administered daily and orally (Example 27).
WO ‘340 does not explicitly teach the checkpoint inhibitor antibody administration dose and schedule as claimed. WO ‘340 does not explicitly teach that N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide is administered two to three times a day. WO ‘340 does not explicitly teach that N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide is administered in an amount ranging from 200 mg to 1000 mg BID or from 100 mg to 1000 mg TID.
However, WO ‘340 does teach administration of N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide (compound 8) at 5.2 mg/kg orally showed good oral bioavailability (Example 22 and Table 7). WO ‘340 further teaches that, although compound 8 seems to be fairly stable in human samples, it is not 100% stable in human plasma after 4 hours (Example 20 and Table 5). WO ‘340 further teaches the maximum tolerated dose for compound 8 in their murine models was 50 mg/kg once a day (Example 23). WO ‘340 further teaches N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide/compound 8 is administered orally (e.g. Examples 22 and 27).
Further, Ott et al teaches a clinical trial (NCT01975831) for treating solid tumors by administering a combination therapy of an anti-PD-L1 mAb and an anti-CTLA4 mAb, specifically tremelimumab. Ott teaches tremelimumab is administered at 3 mg/kg every 4 weeks, and the clinical trial records for NCT01975831 before the publication date of Ott et al shows that tremelimumab was administered by intravenous infusion, meeting all the limitations of CTLA4 checkpoint inhibitor antibody administration dose and schedule as claimed in claims 21-26.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to administer the anti-CTLA4 antibody at a dose and schedule that has already been taught in a clinical trial study design, particularly when used in combination with another PD-1/PD-L1 inhibiting compound, as is taught by Ott et al as evidenced by NCT01975831. It would have been obvious to one skilled in the art, before the effective filing date of the instant application, considering the teachings of WO ‘340 regarding the dosing, stability, bioavailability, and maximum tolerated dose of compound 8 to arrive at the dosing limitations claimed for N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide. First, since compound 8 does show some reduced stability after 4 hours in in vitro human plasma (Example 20, Table 5), but also shows low toxicity (Example 18), administering compound 8 more than once a day, but tempered by maximum dose and subject’s convenience, would be a reasonably obvious and motivated improvement to maintain active compound 8 throughout the day.
Regarding claim 25, the claimed amount of compound 8 to administer (200-1000 mg BID or 100-1000 mg TID) is taught in the instant specification as being based on projections of human pharmacokinetics based on bioavailability, clearance, and distribution of compound 8 and human conditions, as well as the dosing regimen (page 13). The specification teaches how these human doses for ITF3756 (i.e. compound 8 in WO ‘340) were predicted using the pharmacokinetics from mice (page 11-12). As such, these dose amounts are clearly a result-effective variable that one skilled in the art would be able to calculate or estimate based on the pharmacokinetics of mice taught by WO ‘340. The dose and maximum tolerated dose would also drive the decision for number of doses to administer in a day.
One skilled in the art, before the effective filing date of the instant application, would be motivated to use reasonably predictable dosing strategies for compound 8 based on pharmacokinetic results in mice to guide the human administration. One skilled in the art, before the effective filing date of the instant application, would be motivated to use, and would have reasonable expectation of success with, known dosing strategies for an anti-CTLA4 antibody, especially in a combination therapy with analogous pathway targets and disease model. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success with determining compound 8’s dosing because the use of drug pharmacokinetics in mice to inform human dosing is a necessary, common, and obvious method to arrive at initial dosing strategies for humans.
Double Patenting
Patent No. US11351178B2
Claims 12, 13, 15, 17, 20-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US11351178B2 in view of WO ‘340 (WO2018189340A1; published 10/18/2018) and Rotte (Rotte, Combination of CTLA-4 and PD-1 blockers for treatment of cancer, J Exp Clin Cancer Res 38, 255 (2019). ; published 2019).
Claims 1-14 of Patent ‘178 are directed towards a combination comprising of a compound, selected from a list consisting of N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide, and a drug, selected from a list consisting of a CTLA4 inhibitor, and a method of using that combination in treating cancer.
Claims 1-14 of Patent ‘178 does not explicitly teach the motivation to specifically select the claimed compound and a CTLA4 inhibitor. Accordingly, claims 1-14 of Patent ‘178 does not explicitly teach the method of using that exact combination and all the specific further limitations of the method instantly claimed in claims 12, 13, 15, 17, 20-26.
However, WO ‘340 does teach all the method limitations for claims 12, 13, 15, 17, 20-26 starting from an analogous combination comprising of N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide and a PD-1 checkpoint inhibitor antibody. The rationale for why it would be obvious, motivated, and reasonably successful to arrive at the particular claimed combination and method from the similar combination claimed in WO ‘340, as discussed previously in the 35 U.S.C. 103 rejection, is the same for starting from the similar combinations for Patent ‘178, and is incorporated in its entirety here.
Claims 21-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US11351178B2 in view of WO ‘340 (WO2018189340A1; published 10/18/2018) and Rotte as applied to claim 12 above, and further in view of Ott et al (Ott, P., et al, A phase I study to evaluate the safety and tolerability of MEDI4736, an anti- programmed cell death-ligand-1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced solid tumors, Meeting Abstract: 2015 ASCO Annual Meeting I, J Clin Oncol 33, TPS3099(2015), published 05/20/2015), as evidenced by NCT01975831 (record submitted 05/11/2015).
The teachings of claims 1-14 of Patent ‘178 and WO ‘340 regarding instant claims 12 are incorporated in its entirety for the instant dependent claims.
Claims 1-14 of Patent ‘178 and WO ‘340 does not explicitly teach the administration dose and schedule for the checkpoint inhibitor antibody and N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide as instantly claimed, as discussed previously in the 35 U.S.C. 103 rejection. However, the combination arrived at from Claims 1-14 of Patent ‘178 in view of WO ‘340 is the same as that instantly claimed. The further teachings of WO ‘340 and Ott et al regarding instant claims 21-26 and the rationale for why it would be obvious, motivated, and reasonably successful to arrive at the claimed limitations of the method of using this combination from these teachings, as discussed previously in the 35 U.S.C. 103 rejection, is therefore relevant and incorporated here in its entirety.
Response to Arguments
Applicant's arguments filed 06/09/2026 have been fully considered but they are not persuasive.
Applicant’s arguments and the Declaration under 37 CFR 1.132 by Gianluca Fossati filed 06/09/2026 are insufficient to overcome the rejection of claims 12, 13, 15, 17, 20-26 based upon 35 U.S.C. 103.
Regarding the Applicant’s argument about the deficiencies of the prior art teaching a method of treating specific cancers, according to the Applicant’s amendments adding specific cancers, the updated rejection in response to Applicant’s amendments teaches why the combination is obvious and newly why it would be obvious in treating the specific cancers.
Specifically, ‘340 and Rotte teaches the combination of an HDAC6 inhibitor and CTLA4 for treating cancers and Rotte additionally provides the motivation for using a combination therapy in treating cancers in subjects that may not be responsive to monotherapies. Furthermore, Rotte teaches inhibiting both the PD-1/PD-L1 and CTLA4 pathways through combination therapy is a known and advantageous endeavor and a skilled artisan would have a reasonable expectation of success since each of these elements, N-hydroxy-4-((5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide and anti-CTLA-4 antibody has already been shown to inhibit tumor growth in vivo by themselves and can work synergistically in combination with other checkpoint inhibitors to inhibit tumor growth. Further, CTLA4 checkpoint inhibitors are well-known and well-utilized as a monotherapy and in combination therapies with PD-1/PD-L1 pathway blockers to treat cancers, and specifically the cancers claimed
Regarding the Applicant’s statement regarding no experimental evidence in WO ‘340, this argument is not persuasive. The experimental data and how it supports the obvious rejection is provided in the updated rejection. In summary, the prior art teaches N-hydroxy-4-( ( 5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide and anti-CTLA-4 antibodies individually have anti-tumor effects, and by their complimentary mechanisms of action, would be expected to work together synergistically in combination therapies, similar to the rationale anti-PD1 and anti-CTLA-4 combination therapy. Also similar to anti-PD1 and anti-CTLA-4 combination therapy, it is likely possible that the dose of the individual drugs could be administered at a lower dose to lower the risk of toxicity to patient. MPEP 2143.02 teaches that obviousness does not require absolute predictability, but only a reasonable expectation of success is required. Experimental evidence showing absolute certainty of success of the claimed invention is not necessary for obviousness, since that would be anticipation; only a reasonable teaching, motivation, and expectation of success is necessary for obviousness, which is discussed in the updated rejection with WO ‘340 in view of Rotte.
Regarding the Applicant’s statement that the combination comprising N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide and an anti-PD1 antibody had a minimal increase in tumor growth reduction, the examiner is interpreting this to mean in comparison to either the N-hydroxy-4-( ( 5-(thiophen-2-yl)-1 H-tetrazol-1-yl)methyl)benzamide or anti-PD1 antibody by itself, as is congruent with the teachings of WO ‘ 340 (in Example 27 and Figure 3).
Related to the above Applicant’s statement, Applicant argues that the claimed combination of N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide and anti-CTLA-4 antibody exhibits anti-tumor effect superior to the administration of the single drugs and exhibits a synergist therapeutic effect (Arguments, p. 5, para. 1), submitting a Declaration that is claimed to support this; however, this argument and the related information in the Declaration is not persuasive.
The Examiner notes that there is not a claimed statistical difference in tumor volume between the combination and N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide, according to the Declaration (Declaration, Figure 2 and p. 5, last paragraph). The Applicant’s Arguments claims superiority of the combination over single drugs of the combination whereas the Declaration teaches superiority of the combination over only one of the drug in the combination.
Furthermore, this superiority of the combination over the single anti-CTLA-4 antibody is expected. The superior anti-tumor effect of the combination is only seen over the anti-CTLA-4 antibody monotherapy and this is expected since the combination targets an additional checkpoint pathway. This is in contrast to the combination of N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide and anti-PD-1 antibody which both work on the same PD-1 target, and so the redundancy is reasonably not expected to proffer as much benefits to the anti-PD-1 antibody.
Furthermore, the degree of superiority of the combination over the single anti-CTLA-4 antibody is expected. As seen from WO ‘340 and the Declaration, both the combination of N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide and anti-PD-1 antibody (Figure 3) and combination of N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide and anti-CTLA-4 (Figure 2) is significantly different from either the vehicle control or untreated control and the monotherapies fall somewhere in between these two groups for both combinations.
Furthermore, this superiority of the combination therapy using one drug that targets CTLA-4 and one drug that targets the PD-1/PD-L1 pathway over monotherapy of either one is expected, as explained in the Obviousness rejection. Even further, a combination therapy the targets both the CTLA-4 and PD-1/PD-L1 pathway is expected to work better than a combination therapy that redundantly targets the PD-1 pathway, and is one motivation to improve on the teachings of the prior art from a combination therapy where both drugs target PD-1 to a combination therapy that target both CTLA-4 and PD-1/PD-L1 pathway. One skilled in the art would understand that even if a combination therapy where both drugs target PD-1 (N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide and anti-PD-1) shows minimal improvement, a combination therapy that target both PD-1 and CTLA-4 (N-hydroxy-4-((5-(thiophen-2-yl)-1H-tetrazol-1-yl)methyl)benzamide and anti-CTLA-4) could further improve the therapy. Therefore, the results shown in the Declaration are expected results.
Regarding the Applicant’s argument that the instant combination exhibits a better safety profile than a combination of an anti-CTLA4 antibody and an anti-PD1 antibody or a combination of an anti-CTLA4 antibody and an anti-PDL1 antibody, while still maintaining the same efficacy on tumor growth inhibition and cites Example 3 of the instant Specification, this tolerance is an expected result. Example 3 of the instant specification teaches the tolerability of the drug combinations by induction of diabetes. Gauci teaches anti-PD-1 and anti-CTLA-4 antibodies can, albeit rarely, cause side effects such as type 1 diabetes (Abstract). Their retrospective observational analysis of patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma (Abstract) concluded that symptomatic diabetes is increasingly reported as an adverse event specifically with anti-PD-1 treatment (p. 1207, Conclusion, para. 1) (Gauci et al, published 05/28/2018). Furthermore, in the group of patients treated previously or concomitantly with anti-CTLA-4 drugs, there was a trend of increased glycemia during anti-PD-1 treatment (p. 1207). In contrast, Makkar teaches that HDAC inhibitors have an intrinsic role as a remedy for diabetes and its complications by helping to prevent beta-cell destruction and resistance to insulin (Abstract; Makkar et al, published 08/30/2019). Therefore, Gauci teaches the diabetes risk of the combination of anti-PD-1 and anti-CTLA-4 antibodies, especially anti-PD-1. However, although HDAC6 inhibitors also inhibit the PD-1/PD-L1 pathway, Makkar teaches that HDAC6 are actually remedies for diabetes. As such, the combination of an HDAC6 inhibitor and an anti-CTLA-4 antibody are expected to mitigate the risk of diabetes over the combination between an anti-PD-1 and anti-CTLA-4.
In conclusion, Applicant’s argument of the superior and unexpected effects in term of efficacy and safety are not persuasive and the Obviousness and Double Patenting rejections relying on the same obviousness rationales are maintained.
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 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.
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/BONIRATH CHHAY/Examiner, Art Unit 1645
June 22, 2026
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 25, 2026
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