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
The instant application claims priority to U.S. Provisional Patent Application No. 63/287,866, filed 12/09/2021 and U.S. Provisional Patent Application No. 63/393,440, filed 07/29/2022.
Applicants have not presented arguments or evidence in response to the priority determination set forth in the prior Office action of 08/01/2025. The reasons set forth in the previous action regarding the priority of the claims remain unchanged. Accordingly the effective filing dates of the claims remain unchanged in the present action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/03/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Applicants have amended claims 1, 3, 7, 10, 13, 17, 19, and 22 to recite the definitions of E1, E3, and E7 within lettered lists. The scope of these substituents is now clear, and the previous rejection under 35 U.S.C. §112(b) is hereby withdrawn.
Applicants contend that the compound of example 80 of Kaldor is not an anticipatory compound of the instantly claimed compounds owed to claim 1's proviso when E7 is 5- or 6-membered optionally substituted heteroaryl or 5- or 6-membered optionally substituted heterocyclyl, then L1 is not taken together with R3 and the N atom to which L1 and R3 are attached form an optionally substituted heterocycle having from 4 to 7 atoms in the ring structure. Instant claims 3, 11, and 13 include similar provisos that exclude L1 and R3 being taken together with the N atom to which that are attached. Applicants' indicate that Formula I-OA contains a nitrogen atom at the ring position adjacent to X3, which is not present in Example 80 of Kaldor. Example 80 can therefore not be an anticipatory compound for I-OA. These arguments have been fully considered and are persuasive, as the proviso excludes the compounds of Kaldor from the scope of the claims and the reference can therefore not anticipate the compounds of the instant claims. The previous anticipatory rejection over the reference is hereby withdrawn.
Applicants' assumption that WO 2020/198058 (Kaldor '058) was the primary reference used in the anticipatory rejections of the Office Action of 08/01/2025 is correct. The Examiner thanks the Applicants for clarifying this point. The Applicants contend that the references used in the rejection do not provide a rationale for the selection of compound 130 from the laundry list of species of the disclosure, nor does it provide motivation for the artisan to modify the compound to arrive at those of the instant claims. These arguments have been fully considered and are not found persuasive. Applicants’ arguments concerning the absence of designating compound 130 as a lead compound are unpersuasive. Obviousness does not require the prior art to identify a compound as a “lead compound,” nor does it require a showing that the compound was uniquely preferred. Kaldor ‘058 teaches that compounds possessing the same core scaffold retain biological activity upon modification of auxiliary positions around this core, rendering similar such modifications predictable. Altana v. Teva, 566 F.3d 999, 1008–09 (Fed. Cir. 2009) teaches that more than one lead can be reasonable and that the lead need not be the “best” in vitro compound if the art points to it as a promising starting point.
Applicants’ arguments regarding B-RAF inhibitory activity are not commensurate with the scope of the claims, which are directed to the compounds per se and recite no biological or functional limitations. Functional arguments alone don’t distinguish a compound claim. For a claim to “a compound,” patentability turns on structure. If the property (activity) is inherent to close analogs, mere assertion of function is not persuasive absent unexpected results with a nexus to the structural change (MPEP § 716.02; In re Papesch, 315 F.2d 381).
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.
Claims 1 and 3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sato (EP 1505064 A1).
Sato discloses compound 23
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(pg. 28). Compound 23 has the following substitutions anticipating the Markush groups of claims 1 and 3: X1, X5,and X6 are CH; X2 and X4 are N; X3 is C-N(R4)-L3-E3, R4 is H, L3 is a direct bond, and E3 is H; R1-R3 are H; L1 is a direct bond; E1 is a halo-substituted aryl; Z is L7-Z7, L7 is a direct bond, and E7 is an alky substituted heterocycle. The reference discloses a compound having substituents that each fall within the corresponding Markush definitions recited in claims 1 and 3. Because the reference compound meets all structural limitations of the claim, it is encompassed by the claimed genus and anticipates the claims.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Horswill (Horswill, J G et al. “PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats.” British journal of pharmacology vol. 152,5 (2007): 805-14. doi:10.1038/sj.bjp.0707347).
Horswill discloses the structure of PSNCBAM-1
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(pg. 806, left col, Figure 1). PSNCBAM-1 has the following substitutions anticipating the Markush group of claim 1: X2-X6 are CH; X1 is N; R1-R3 are H; L1 is a direct bond; E1 is a halo-substituted aryl; Z is L7-E7, L7 is a direct bond, and E7 is a heterocycle. The reference discloses a compound having substituents that each fall within the corresponding Markush definitions recited in claim 1. Because the reference compound meets all structural limitations of the claim, it is encompassed by the claimed genus and anticipates the claims.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Calderon (Calderón, Félix, et al. "An invitation to open innovation in malaria drug discovery: 47 quality starting points from the TCAMS." ACS Medicinal Chemistry Letters 2.10 (2011): 741-746.).
Calderon discloses compound TCMDC-133193
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(pg. 743, Figure 2.). TCMDC-133193 has the following substitutions anticipating the Markush group of claim 1: X1-X6 are CH; R1-R3 are H; L1 is a direct bond; E1 is a cyano substituted aryl; Z is L7-E7, L7 is a direct bond, E7 is a heteroaryl consistent with the allowed structures disclosed in [00061] of the instant application. The reference discloses a compound having substituents that each fall within the corresponding Markush definitions recited in claim 1. Because the reference compound meets all structural limitations of the claim, it is encompassed by the claimed genus and anticipates the claims.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guo (US 8,906,944 B2).
Guo discloses example compound 146
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(Col 101). Compound 146 has the following substitutions anticipating the Markush group of claim 1: X1, and X3-6 are CH; X2 is N; R1-R3 are H; L1 is a direct bond; E1 is heteroaryl, optionally substituted with halogen and alkyl; Z is L7-E7, L7 is a direct bond, E7 is heteroaryl. The reference discloses a compound having substituents that each fall within the corresponding Markush definitions recited in claim 1. Because the reference compound meets all structural limitations of the claim, it is encompassed by the claimed genus and anticipates the claims.
Claim Rejections - 35 USC § 103 (Modified)
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 and 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Kaldor ‘058 (WO 2020/198058) in view of Silverman.
Kaldor ‘058 discloses inhibitors of the receptor tyrosine kinase effector Raf (RAF), pharmaceutical compositions comprising said compounds and methods of using these compounds in the treatment of disease [0003]. The reference teaches compounds having the structure of Formula (II) as being an embodiment of these compounds
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[0005]. Exemplary compounds of Formula (II) found within the disclosure include 86, 87, 120, 123, 126-132, 193, and 194 (see Table 1 pg. 70). Compounds bearing this core were shown to be potent RAF-1 inhibitors, each with IC50 values of less than 10nM (Table 5, pg. 262). These compounds all share the same core structure with the following substituents
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. This teaches that this core is essential for the desired biological activity and numerous compounds bearing this core would be suitable lead compounds with the desired inhibitory activity. This teaches that modifications at variable positions R6, Z1, and Z2 are suitable for tuning the desired properties of the molecules.
One example compound from the reference is Kaldor’s example compound 130
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(pg. 109), which reads on the compound of formula I of claim 1 with the following substitutions:
X1, X4, X5, and X6 are each CH
X3 is N
X2 is C-O-L2-E2
R1 is methyl
L2 is a direct bond
E2 is heterocyclyl
R3 is H
Z is L7-E7
L7 is a direct bond
E7 is heterocyclyl
L1 is a direct bond
E1 is an optionally substituted heteroaryl with haloalkyl substitution
This compound satisfies the proviso beginning on the final line of pg. 5 and continuing onto pg. 6. This proviso allows for L1-E1 to be optionally substituted heteroaryl.
Compound 130 differs from the instantly claimed compounds with regards to the methyl substitution of the pyrazole ring corresponding to E1 of the instant claims. However, such substitutions are routine in the art.
Silverman teaches that hydrogen is an isostere of fluorine (Table 2.10, entry 15).
Meanwell teaches that fluorine is routinely incorporated into molecules as part of drug design due to its ability to constructively influence conformation, pKa, potency, membrane permeability, metabolic pathways, and pharmacokinetic properties (Abstract).
The prior art discloses the same core scaffold and identifies the positions noted as Z1 and Z2 above as being a variable for tuning the properties of the molecule. Kaldor ‘058 expressly teaches that compounds of Formula (II), including compound 130, have good RAF inhibition making compound 130 a reasonable starting point among the disclosed compounds (Altana, 566 F.3d at 1008–09). Medicinal chemistry routinely substitutes F for H to tune the potency and ADME properties of promising compounds (see Silverman and Meanwell). Thus, replacing CF3 for CH3 at a site taught by the prior art to be variable is a predictable, results-effective modification that the artisan would have tried with a reasonable expectation of success (MPEP §§ 2144.05, 2144.08, 2144.09; In re Aller; KSR). Applicant’s assertion that other species had superior in vitro/in vivo activity does not foreclose selection of compound 130 as a reasonable lead (Altana), nor does functional argument alone distinguish a compound claim absent evidence of unexpected results tied to the CF3 to CH3 change (MPEP § 716.02; Papesch). Accordingly, claim 1 is obvious over Kaldor ‘058 in view of general med-chem knowledge as taught by Silverman and Meanwell.
Conclusion
Claims 1,3, and 30-32 are rejected.
Claims 36, 38, 41-43, 49-50, 52-53, 58-60, 64-66, 68, 71, 74, 76, 78, and 81-82 are objected to for being dependent upon a rejected base claim.
Claims 7, 10, 11, 13, 17, 19, and 22 are allowable.
The above claims are indicated as allowed for the following reasons:
While the references Kaldor (WO 2021/081375, found in IDS filed 08/15/2023) and Aversa (WO 2016/038582 A1, found in IDS filed 08/15/2023) teach RAF kinase inhibitors with similar structures, the references cannot be prior art due to the provisos of the claims. The compounds of the references disclose IC50 activity of RAF kinases. However, the references fail to provide sufficient motivation to perform the necessary substitutions to arrive at the instantly claimed compounds. Chemistry is an unpredictable art, and the cited references do not provide a reasonable expectation that the specific substitutions resulting from the proposed combination would retain RAF kinase inhibitory activity.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625