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 .
Status of the Claims
Claims 1-14 and 17-22 are pending in the instant application and subject to examination herein.
Claim Rejections - 35 USC § 112(b) – Withdrawn
The prior rejection of claim 19 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in response to Applicant’s amendment of claim 19.
Claim Rejections - 35 USC § 112(d) – Withdrawn
The prior rejection of claims 17-18 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is withdrawn in response to Applicant’s amendment of claims 17-18.
Claim Rejections - 35 USC § 103 – Maintained
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.
The prior rejection of claims 1 and 9-11 under 35 U.S.C. 103 as being unpatentable over Velcicky (Velcicky, et al.; Journal of Medicinal Chemistry, v61, pp865-880; 2018)1 in view of Kumari (Kumari, et al.; Journal of Medicinal Chemistry, v63, pp12290-12358; 2020) and Certal (Certal, et al.; Journal of Medicinal Chemistry, v55, pp4788-4805; 2012) is maintained.
Applicant has traversed the rejection on the grounds that the rejection “ignores the teachings of Velcicky in its entirety.” Applicant asserts that a person of ordinary skill in the art would never select Velcicky’s compound 31 as a lead compound to explore by bioisosteric equivalent modification(s) because “Velcicky clearly points to compound 40, which has 5-fluoro-2-methylpyridin-3-yl-amide, as the lead compound selected for in vivo testing, and not the phenyl-amides” (i.e., Velcicky’s compounds 31 and 34, cited in the prior 103 rejection). Applicant points to Velcicky’s statement that Velcicky’s compound 40 “displayed the best mouse pharmacokinetic parameters measured for any SPPL2a inhibitor in this series and thus allowed for testing the compound in both mouse and rat models”, and as such, the skilled artisan would have no reason to select compound 31 or compound 34 for further modification. Applicant further asserts that some of the instantly disclosed compounds exhibit greater potency against SPPL2a than Velcicky’s compound 40 as well as greater selectivity against gamma-secretase, and therefore none of the instantly claimed compounds can be found obvious over the teaching of Velcicky in view of the teachings of Kumari and Certal.
Applicant’s traverse has been considered, but is not found persuasive, because Applicant’s argument does not consider Velcicky in its entirety: in fact the teaching of Velcicky would motivate a person to select Velcicky’s compound 31 as a lead compound for bioisosteric modification in the manner taught by Kumari and Certal, for the following reasons:
Velcicky expressly identifies compound 31 as “the most promising compound” among anilide compounds prepared and evaluated for enzymatic inhibition up to that point (i.e., prior to exploring carbamoyl-pyridinyl compounds such as 40), and proceeds to perform further in vitro as well as in vivo assays, including the following (pages 869-870):
An in vitro cellular assay of compound 31 inhibiting SPPL2a cleavage of CD74/p8 in mouse B cell line A20;
An in vitro whole blood assay of compound 31 inhibiting SPPL2a cleavage of CD74/p8;
An in vivo mouse study of compound 31 inhibiting SPPL2a cleavage, observed as accumulation of CD74/p8 in mouse splenocytes, and evaluation of Hes1 mRNA as a proxy for Notch1 inhibition in the jejunum and thymus from the same animals;
An in vitro cellular “wash out” experiment of compound 31 incubated in cells of mouse B cell line A20;
In vitro metabolic profiling of compound 31 by incubation in mouse liver microsomes (MLM) and human liver microsomes (HLM);
Velcicky identifies ortho-toluidine, “a known carcinogen suspected of causing bladder cancer”, as a metabolite formed alongside compound 31’s metabolite “m1 (25)” shown below in the cropped image of Velcicky’s Figure 3, and states “Therefore, the aromatic amine had to be replaced”.
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130
600
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(Velcicky’s Figure 3, page 871);
The subsequent structure-activity relationship (SAR) studies on pyridinyl analogues of Velcicky’s compound 31 were explored, as explained above, to avoid the potentially carcinogenic metabolism of compound 31 by exploring structures that were bioisosteric (nitrogen for carbon atom replacement) but less toxic because o-toluidine would not be produced by their metabolism;
A person of ordinary skill in the art would envisage the alternative bioisosteric replacement of a benzimidazole replacement for the anilide moiety as this replacement would also avoid the o-toluidine metabolite, because it was known in the art, per the teaching of Kumari, that “the amide functional group is very labile in vivo,” and that “the introduction of structural motifs that mimic the physicochemical properties of the amide bond provides greater metabolic stability” (Kumari, page 12292), and that, discussed in the prior rejection, the imidazole group is a bioisosteric group for an amide bond as taught by Kumari, and that a benzimidazole is a bioisostere for an anilide, as taught by Certal.
Reiterated Rejection:
Claim 1 is drawn to a genus of compounds, designated as Formula (I), composed of fused tricyclic tetrahydropyrazolo-benzodiazepines and corresponding diazepinones bearing a pendant amido group and additional substituents as shown in the table below. Velcicky teaches a series of fused tricyclic tetrahydropyrazolo-benzodiazepines and corresponding diazepinones as inhibitors of Sppl2a, including multiple compounds within bioisosteric equivalence of instant Formula (I), including Velcicky’s compound 312, shown in the table below:
Claim Number(s) of Instant Application
Instant Application
Velcicky
1
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164
332
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wherein:
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280
418
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Velcicky’s compound 31
10
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164
398
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wherein:
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280
418
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Velcicky’s compound 31
11
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276
422
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Instant compound 1123
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280
418
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Velcicky’s compound 31
Velcicky’s compound 31 differs from the scope of instant Formula (I) in that R10 is an amide group bound to a tolyl ring, also known as an ‘acetanilide’ fragment. However, a person of ordinary skill in the art would have a reasonable expectation of success in making and using a bioisosterically equivalent derivative of Velcicky’s compound 31, wherein an imidazole ring is selected instead of the R10 amide group, thereby converting the acetanilide moiety into a benzimidazole ring as R10, as found in the instantly-claimed compound 112 (shown in the table above) and within the scope of instant Formula (I), because it was known in the art at the effective time of filing that an imidazole ring is a suitable bioisosteric substitute for an amide bond, and that a benzimidazole is bioisosterically equivalent to an acetanilide, per the teachings of Kumari and Certal.
Kumari provides a review of bioisosteric groups explored by medicinal chemists as replacements for amide bonds. Kumari teaches that one of the most frequently employed strategies in hit-to-lead and lead optimization involves the replacement of a selected fragment within a compound of interest with another fragment that is known to closely mimic the properties of the original fragment or functional group. This process of replacement or modification of functional groups, having similar properties, is known as isosteric or bioisosteric replacement and has become a mainstay of the medicinal chemist’s toolbox (page 12291). Kumari also teaches that bioisosterism can provide several beneficial effects including increased potency, enhanced selectivity, improvements in pharmacokinetic and pharmacodynamic properties, elimination or attenuation of toxicity and facilitate access to novel chemical space to attain patent protection, and distinguishes between classical and non-classical bioisosteres, the latter category being replacement groups that “possess more advanced mimicry of their emulated counterparts and do not fulfill the criteria of steric and electronic factors required for classical isosteres” (pages 12991-12292, bridging paragraph). Kumari reviews a variety of 5-membered heteroaryl rings that have been explored as bioisosteric replacements, and identifies imidazole as such an equivalent (pages 12301-12306). Kumari provides a prominent example in the discovery of Midazolam, a short-acting benzodiazepine, by the bioisosteric replacement of an imidazole ring for the amide group in the earlier-known long-acting drug Diazepam, shown in Kumari’s Figure 19 below (page 12301):
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382
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Kumari observes that the bioisosteric modification of Diazepam into Midazolam increased the basicity of the molecule due to the imidazole ring nitrogen, which allowed the formation of water soluble salts for pure aqueous injectables, and that Midazolam undergoes rapid metabolic inactivation as compared to Diazepam and the other classical benzodiazepines which is attributed mainly to the presence of the methyl group appended to the imidazole ring. This results in a short window of action allowing greater clinical management options (page 12301). Kumari does not provide a specific example wherein an anilide (amide bound to a phenyl ring) is converted into a bicyclic heteroaryl ring; however, such an example is provided by Certal.
Certal teaches a study in the structure activity relationship-based discovery of inhibitors of phosphoinositide-3-kinase-β (PI3Kβ), wherein benzimidazole is explored and validated as a bioisosteric replacement for anilide (page 4789, including Figure 1):
Starting from a high-throughput screening campaign and following early hit validation and chemical exploration, we identified compound 5 (Figure 1), which presented some interesting selectivity for PI3Kβ versus other PI3K isoforms (IC50 = 2133 nM, 42 nM, 118 nM, and >10 μM on PI3Kα, β, δ, and γ, respectively) in biochemical assays. Subsequent medicinal chemistry efforts were devoted to the replacement of the potentially labile anilide moiety to bioisosteric benzimidazole or benzoxazole analogues.4 The unsubstituted benzimidazole compound 6 (IC50 >10 μM, 158 nM, 2870 nM, and >10 μM on PI3Kα, β, δ, and γ, respectively) and benzoxazole compound 715 (IC50 >10 μM, 82 nM, 779 nM, and >10 μM on PI3Kα, β, δ, and γ, respectively) displayed a remarkable level of PI3Kβ selectivity while maintaining high ligand efficiency (LE) values of 0.40 and 0.42, respectively.
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154
586
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(from Figure 1 of Certal: bioisosteric compounds 5-7).
Applicant’s invention is unpatentable over the teaching of Velciky in view of the teachings of Kumari and Certal, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in making and using an analogue of Velcicky’s compound 31 wherein a benzimidazole is selected instead of the anilide group, because the process of replacement or modification of structural groups, having similar properties, is known as isosteric or bioisosteric replacement and is a mainstay of the medicinal chemist’s toolbox, per the teaching of Kumari, and because it was known in the art that an imidazole ring is bioisosterically equivalent to an amide group, and that a benzimidazole ring is bioisosterically equivalent to an anilide group, per the teachings of Kumari and Certal.
Thus, the invention was prima facie obvious at the time of filing.
Claim 9 further limits the genus of compounds of claim 1 to a narrower genus wherein R10 is a benzimidazole group, optionally substituted with substituent(s) selected from a Markush group that includes C1-C6alkyl, and is met by the rejection above.
Claim 10 further limits the genus of compounds of claim 1 to a narrower genus having the structure of Formula (IV), shown in the table above, and is met by the rejection above based on a bioisosteric equivalent of Velcicky’s compound 31.
Claim 11 is directed to a Markush group of specific compounds that includes instant compound 1125, which is bioisosterically equivalent to Velcicky’s compound 31 as discussed in the rejection above. The Examiner notes that by the same rationale of bioisosteric equivalence between anilide/benzimidazole groups, Applicant’s compound 1146 and Velcicky’s compound 347, both shown in the table below, are bioisosterically equivalent.
Claim Number(s) of Instant Application
Instant Application
Velcicky
11
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310
430
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Instant compound 114
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310
434
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Velcicky’s compound 34
Applicant’s invention is unpatentable over the teaching of Velciky in view of the teachings of Kumari and Certal, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in making and using analogues of Velcicky’s compounds 31 and 34 wherein a benzimidazole is selected instead of the anilide group, because the process of replacement or modification of structural groups, having similar properties, is known as isosteric or bioisosteric replacement and is a mainstay of the medicinal chemist’s toolbox, per the teaching of Kumari, and because it was known in the art that an imidazole ring is bioisosterically equivalent to an amide group, and that a benzimidazole ring is bioisosterically equivalent to an anilide group, per the teachings of Kumari and Certal.
Thus, the invention was prima facie obvious at the time of filing.
Allowable Subject Matter
Claims 2-8, 12-14 and 17-22 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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 W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Cited in Applicant’s Information Disclosure Statement dated 04/11/2023.
2 (R)-2-Methyl-N1-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)-N4-(o-tolyl)succinamide
3 (R)-2-methyl-3-(7-methyl-1H-benzo[d]imidazol-2-yl)-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)propanamide
4 Emphasis added by Examiner.
5 (R)-2-methyl-3-(7-methyl-1H-benzo[d]imidazol-2-yl)-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)propanamide
6 (R)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazo1-2-yl)propanamide
7 (R)-2-methyl-N1-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)-N4-(2-(trifluoromethyl)phenyl)succinamide