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 present applications claimed priority to the applications, 63/368,124 and 63/496,840, with effective filing dates of 11 July 2022 and 18 April 2023, respectively.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 27 February 2026. Applicant’s election without traverse of Group I (claims 1-34, 53, and 54) and species (
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) in the reply filed on 27 February 2026 is acknowledged.
Claims 35-52 and 55-60 are canceled.
Claims 2, 4, 6-7, 9-11, 14, 16, 18-19, 22, 25-26, 28, 30, and 32-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim 2 specifies Cy1 is selected from Cy1-a,Cy1-b, and Cy1-c, which does not read on the elected species. Claim 4 specifies Cy1 is selected from Cy1-a, Cy1-b, and Cy1-c, which does not read on the elected species. Claim 6 specifies cy1 is selected from Cy1-a, Cy1-b, and Cy-c, which does not read on the elected species. Claim 7 specifies R2 is C1-3 alkyl, which does not read on the elected species. Claim 9 specifies Cy1 is Cy1-a, which does not read on the elected species. Claim 10 specifies Cy1 is Cy1-b, which does not read on the elected species. Claim 11 specifies Cy1 is Cy1-c, which does not read on the elected species. Claim 14 specifies n is 2, which does not read on the elected species. Claim 16 specifies R5 is halo, which does not read on the elected species. Claim 18 specifies R6 is a 5-membered heteroaryl, which does not read on the elected species. Claim 19 specifies R6 is pyrazolyl, which does not read on the elected species. Claim 22 specifies R10 is CN, which does not read on the elected species. Claim 25 specifies R60 is C(O)NRc60Rd60, which does not read on the elected species. Claim 26 specifies R60 is methyl, which does not read on the elected species. Claim 28 specifies Rc60 and Rd60 are each independently C1-3 alkyl, which does not read on the elected species. Claims 30 and 32-33 do not recite the compound and thus do not read on the elected species. Election was made without traverse in the reply filed on 27 February 2026.
Claims 1, 3, 5, 8, 12-13, 15, 17, 20-21, 23-24, 27, 29, 31, 34, and 53-54 are pending.
Information Disclosure Statement
The Information Disclosure Statements filed on 7 Sept 2023, 7 Nov 2023, and 26 Mar 2025 and the references cited therein have been considered, unless indicated otherwise.
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.
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.
1. Claim(s) 1, 3, 5, 8, 12-13, 15, 17, 20-21, 23-24, 27, 29, 31, 34, and 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu (WO 2021/211864, published 21 Oct 2021, filed 15 Apr 2021, see IDS filed 26 Mar 2026) in view of Lanman (J. Med. Chem., 2020, 63, 52-65) and Petri (Topics in Current Chemistry, 2021, 379(34), 1-46).
Zhu teaches KRAS inhibitors of Formula (I):
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(abstract; page 2, lines 11-14).
Zhu specifically teaches Example 48:
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(page 210). Additionally, Zhu teaches Examples 50 and 67:
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and
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, respectively (pages 217 and 245).
Zhu fails to teach a compound having the acetyl-pyrrolidine at R6 (
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) and thus does not teach
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(Example 5 of the claimed invention).
Lanman teaches the KRAS inhibitor,
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, and its SAR (abstract). Lanman further teaches derivatives of AMG 510, wherein the fluorophenol tail is replaced with a naphthyl alcohol and indazole in order to optimize contact with lipophilic residues (V9 and I100) and modulate polar interactions with R68 and D69 (Table 2, page 55; page 56, column 1, paragraph 2). Lanman teaches that both substituents did show enhanced activity in ERK phosphorylation and viability assays, but the analogs continued to demonstrate poor aqueous solubility and low MDCK permeability (page 56, column 1, paragraph 3). Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2).
Petri teaches motivations to utilize pyrrolidine: efficient exploration of pharmacophore space due to sp3-hybridization, contribution to stereochemistry of the molecule, and increased three-dimensional coverage due to non-planarity of the ring (abstract). Petri further teaches that chemical complexity and globular three-dimensional shape offer more opportunities to improve druggability by modifying parameters such as solubility, lipophilicity, and other ADME properties (page 3, paragraph 1; page 4, paragraph 1). Petri teaches that molecules with growing hetero-aliphatic character showed an increase in aqueous solubility compared with those comprising three aromatic rings and that each portion of molecules influences the balance of the physicochemical parameters (page 4, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify Example 48 of Zhu to incorporate (1) the fluoroquinoline (Example 50) of Zhu and nitrogen placement of Lanman to optimize contact with lipophilic residues (V9 and I100) and modulate polar interactions with R68 and D69; (2) the methylpyrrolidine-substituted alkoxy (Example 67) of Zhu to incorporate a pyrrolidine for solubility and permeability purposes as taught by Petri as well as optimize binding in the H95 groove (wherein the methyl of Example 67 of Zhu is placed akin to the isopropyl of Compound 9 of Lanman, which has close contact with Y96, H95, and Q99); and (3) a pyrrolidine moiety as taught by Petri to wrap up the alkyl-amide tail of Example 48 in Zhu to increase aqueous solubility; to arrive at a compound of Formula (I):
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. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Zhu teaches KRAS inhibitors of Formula (I):
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,
-Zhu teaches Example 48:
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,
-Zhu teaches Example 48 possesses an IC50 of ≤ 100 nM (Table 2, page 269),
-Zhu teaches Examples 50 and 67:
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, and
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,
-Zhu teaches Examples 50 and 67 possess an IC50 of ≤ 100 nM (Tables 1 and 2, pages 266-269),
-Lanman teaches the KRAS inhibitor,
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, and its SAR,
-Lanman teaches derivatives of AMG 510, wherein the fluorophenol tail is replaced with a naphthyl alcohol and indazole in order to optimize contact with lipophilic residues (V9 and I100) and modulate polar interactions with R68 and D69,
-Lanman teaches that both substituents did show enhanced activity in ERK phosphorylation and viability assays, but the analogs continued to demonstrate poor aqueous solubility and low MDCK permeability,
-Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99,
-Petri teaches motivations to utilize pyrrolidine: efficient exploration of pharmacophore space due to sp3-hybridization, contribution to stereochemistry of the molecule, and increased three-dimensional coverage due to non-planarity of the ring,
-Petri teaches that chemical complexity and globular three-dimensional shape offer more opportunities to improve druggability by modifying parameters such as solubility, lipophilicity, and other ADME properties, and
-Petri teaches that molecules with growing hetero-aliphatic character showed an increase in aqueous solubility compared with those comprising three aromatic rings and that each portion of molecules influences the balance of the physicochemical parameters.
As such, an artisan having ordinary skill in the art would have been motivated to substitute
one known element for another to predictably arrive at a compound of Formula (I):
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.
Regarding claim 3, Zhu teaches the Examples 48, 50, and 67:
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,
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, and
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, respectively (pages 210, 217, and 245), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo; R60 is C(O)Rb60; and Rb60 is C1-3 alkyl. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of Zhu, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of Zhu, Lanman, and Petri teaches claim 3.
Regarding claim 5, Zhu teaches the Examples 48, 50, and 67:
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,
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, and
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, respectively (pages 210, 217, and 245), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo; and R60 is C(O)Rb60; and Rb60 is C1-3 alkyl. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of Zhu, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of Zhu, Lanman, and Petri teaches claim 5.
Regarding claim 8, Zhu teaches Example 48:
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(page 210), wherein R2 is -CH2CH2CN.
Regarding claim 12, Zhu teaches Example 50:
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(page 217). Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Accordingly, the combination of Zhu and Lanman teaches incorporation of the fluoroquinoline, Thus, the combination of Zhu and Lanman teaches claim 12.
Regarding claim 13, Zhu teaches Example 48:
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(page 210), wherein n is 1.
Regarding claim 15, Zhu teaches Example 48:
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(page 210), wherein R5 is H.
Regarding claim 17, Zhu teaches Example 48:
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(page 210), wherein R60 is C(O)Rb60 and Rb60 is C1-3 alkyl. Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of Zhu and Petri teaches R6 is the acetyl-pyrrolidine of
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. Thus, the combination of Zhu and Petri teaches claim 17.
Regarding claim 20, Zhu teaches Example 48:
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(page 210), wherein R60 is C(O)Rb60 and Rb60 is C1-3 alkyl. Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of Zhu and Petri teaches R6 is the acetyl-pyrrolidine of
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. Thus, the combination of Zhu and Petri teaches claim 20.
Regarding claim 21, Zhu teaches Example 50:
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(page 217), wherein R10 is halo.
Regarding claim 23, Zhu teaches Example 48:
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(page 210), wherein R60 is C(O)Rb60 and Rb60 is C1-3 alkyl. Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of Zhu and Petri teaches incorporation of the acetyl-pyrrolidine of
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. Thus, the combination of Zhu and Petri teaches claim 23.
Regarding claim 24, Zhu teaches Example 48:
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(page 210), wherein R60 is C(O)Rb60 and Rb60 is C1-3 alkyl. Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of Zhu and Petri teaches incorporation of the acetyl-pyrrolidine of
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. Thus, the combination of Zhu and Petri teaches claim 24.
Regarding claim 27, Zhu teaches Example 48:
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(page 210), wherein R60 is C(O)Rb60 and Rb60 is C1-3 alkyl. Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of Zhu and Petri teaches incorporation of the acetyl-pyrrolidine of
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. Thus, the combination of Zhu and Petri teaches claim 24.
Regarding claim 29, Zhu teaches the Examples 48, 50, and 67:
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, and
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, respectively (pages 210, 217, and 245), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo; R60 is C(O)Rb60; and Rb60 is C1-3 alkyl. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of Zhu, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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, which is 3-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-fluoroquinolin-5-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1 H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile. Thus, the combination of Zhu, Lanman, and Petri teaches claim 29.
Regarding claim 31, Zhu teaches the Examples 48, 50, and 67:
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, and
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, respectively (pages 210, 217, and 245), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo; R60 is C(O)Rb60; and Rb60 is C1-3 alkyl. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of Zhu, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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, which is 3-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-fluoroquinolin-5-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1 H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile. Thus, the combination of Zhu, Lanman, and Petri teaches claim 31.
Regarding claim 34, Zhu teaches pharmaceutical compositions (page 132, lines 12-18).
Regarding claim 53, Zhu teaches the Examples 48, 50, and 67:
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, and
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, respectively (pages 210, 217, and 245), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo; R60 is C(O)Rb60; and Rb60 is C1-3 alkyl. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of Zhu, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of Zhu, Lanman, and Petri teaches claim 53.
Regarding claim 54, Zhu teaches the Examples 48, 50, and 67:
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, respectively (pages 210, 217, and 245), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo; R60 is C(O)Rb60; and Rb60 is C1-3 alkyl. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of Zhu, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of Zhu, Lanman, and Petri teaches claim 54.
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.
2. Claim 1, 3, 5, 8, 12-13, 15, 17, 20-21, 23-24, 27, 29, 31, 34, and 53-54 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 37, and 42 of copending Application No. 19/242,281 (reference application) in view of Lanman (J. Med. Chem., 2020, 63, 52-65) and Petri (Topics in Current Chemistry, 2021, 379(34), 1-46). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
U.S. Application No. 19/242,281 claims a compound of Formula (I):
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, wherein Y is N or CR6; R6 is H or 4-9 heterocycloalkyl; Cy1 is 6 – 10-membered heteroaryl; R1 is H; R2 is C1-3 alkyl, C1-3 haloalkyl, optionally substituted with Rg (H, halo, CN); R7 is halo; R3 is ORf3, Rf3 is C1-3 alkyl and 4 – 6 membered heterocycloalkyl; R5 is H or C1-3 alkyl, C1-3 haloalkyl, halo; Cy2 is
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(claim 1 of ‘281). Further, ‘281 teaches a method of treating a KRAS disease (claim 43 of ‘281). Additionally, ‘281 teaches the compound:
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(claim 37 of ‘281).
Regarding claim 1, ‘281 fails to teach a quinoline as the northwestern fragment or an acetyl-pyrrolidine as the southeastern fragment.
Lanman teaches the KRAS inhibitor,
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, and its SAR (abstract). Lanman further teaches derivatives of AMG 510, wherein the fluorophenol tail is replaced with a naphthyl alcohol and indazole in order to optimize contact with lipophilic residues (V9 and I100) and modulate polar interactions with R68 and D69 (Table 2, page 55; page 56, column 1, paragraph 2). Lanman teaches that both substituents did show enhanced activity in ERK phosphorylation and viability assays, but the analogs continued to demonstrate poor aqueous solubility and low MDCK permeability (page 56, column 1, paragraph 3). Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2).
Petri teaches motivations to utilize pyrrolidine: efficient exploration of pharmacophore space due to sp3-hybridization, contribution to stereochemistry of the molecule, and increased three-dimensional coverage due to non-planarity of the ring (abstract). Petri further teaches that chemical complexity and globular three-dimensional shape offer more opportunities to improve druggability by modifying parameters such as solubility, lipophilicity, and other ADME properties (page 3, paragraph 1; page 4, paragraph 1). Petri teaches that molecules with growing hetero-aliphatic character showed an increase in aqueous solubility compared with those comprising three aromatic rings and that each portion of molecules influences the balance of the physicochemical parameters (page 4, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the compound,
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, of claim 37 of ‘281 to (1) introduce a nitrogen to make a fluoroquinoline askin to R-11 of Table 2 in Lanman to optimize contact with lipophilic residues (V9 and I100) and modulate polar interactions with R68 and D69; (2) incorporate a pyrrolidine for solubility and permeability purposes as taught by Petri given that compounds with the naphthyl or indazole core suffered from poor permeability as taught by Lanman; (3) to better optimize binding the H95 groove where the methyl of
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of ‘281 is placed akin to the isopropyl of Compound 9 of Lanman, which has close contact with Y96, H95, and Q99); and (4) add a pyrrolidine moiety as taught by Petri for solubility and permeability purposes to incorporate hetero-aliphatic character and increase aqueous solubility; to arrive at a compound of Formula (I):
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. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘281 teaches KRAS inhibitors of Formula (I):
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,
-‘281 teaches
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,
-Lanman teaches the KRAS inhibitor,
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, and its SAR,
-Lanman teaches derivatives of AMG 510, wherein the fluorophenol tail is replaced with a naphthyl alcohol and indazole in order to optimize contact with lipophilic residues (V9 and I100) and modulate polar interactions with R68 and D69,
-Lanman teaches that both substituents did show enhanced activity in ERK phosphorylation and viability assays, but the analogs continued to demonstrate poor aqueous solubility and low MDCK permeability,
-Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99,
-Petri teaches motivations to utilize pyrrolidine: efficient exploration of pharmacophore space due to sp3-hybridization, contribution to stereochemistry of the molecule, and increased three-dimensional coverage due to non-planarity of the ring,
-Petri teaches that chemical complexity and globular three-dimensional shape offer more opportunities to improve druggability by modifying parameters such as solubility, lipophilicity, and other ADME properties, and
-Petri teaches that molecules with growing hetero-aliphatic character showed an increase in aqueous solubility compared with those comprising three aromatic rings and that each portion of molecules influences the balance of the physicochemical parameters.
As such, an artisan having ordinary skill in the art would have been motivated to substitute
one known element for another to predictably arrive at a compound of Formula (I):
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.
Regarding claim 3, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R2 is -CH2CH2CN; n is 1; R5 is H, and R10 is halo. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of ‘281, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of ‘281, Lanman, and Petri teaches claim 3.
Regarding claim 5, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R2 is -CH2CH2CN; n is 1; R5 is H, and R10 is halo. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of ‘281, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of ‘281, Lanman, and Petri teaches claim 5.
Regarding claim 8, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R2 is -CH2CH2CN.
Regarding claim 12, ‘281 teaches the compound,
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(claim 37 of ‘281). Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Accordingly, the combination of ‘281 and Lanman teaches incorporation of the fluoroquinoline, Thus, the combination of ‘281 and Lanman teaches claim 12.
Regarding claim 13, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein n is 1.
Regarding claim 15, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R5 is H.
Regarding claim 17, ‘281 teaches the compound,
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(claim 37 of ‘281). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of ‘281 and Petri teaches incorporation of the acetyl-pyrrolidine of
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. Thus, the combination of ‘281 and Petri teaches claim 17.
Regarding claim 20, ‘281 teaches the compound,
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(claim 37 of ‘281). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of ‘281 and Petri teaches incorporation of the acetyl-pyrrolidine of
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. Thus, the combination of ‘281 and Petri teaches claim 20.
Regarding claim 21, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R10 is halo.
Regarding claim 23, ‘281 teaches the compound,
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(claim 37 of ‘281). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of ‘281 and Petri teaches incorporation of the acetyl-pyrrolidine of
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. Thus, the combination of ‘281 and Petri teaches claim 23.
Regarding claim 24, ‘281 teaches the compound,
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(claim 37 of ‘281). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of ‘281 and Petri teaches incorporation of the acetyl-pyrrolidine of
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. Thus, the combination of ‘281 and Petri teaches claim 24.
Regarding claim 27, ‘281 teaches the compound,
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(claim 37 of ‘281). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Accordingly, the combination of ‘281 and Petri teaches incorporation of the acetyl-pyrrolidine of
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. Thus, the combination of ‘281 and Petri teaches claim 24.
Regarding claim 29, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of ‘281, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of ‘281, Lanman, and Petri teaches claim 29.
Regarding claim 31, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of ‘281, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of ‘281, Lanman, and Petri teaches claim 31.
Regarding claim 34, ‘281 teaches pharmaceutical compositions (claim 42 of ‘281).
Regarding claim 53, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of ‘281, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of ‘281, Lanman, and Petri teaches claim 53.
Regarding claim 54, ‘281 teaches the compound,
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(claim 37 of ‘281), wherein R2 is -CH2CH2CN; n is 1; R5 is H, R10 is halo. Lanman teaches Cy1-d is quinoline,
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, to modulate polar interactions with R68 and D69 (page 56, column 1, paragraph 2). Petri teaches that R6 is a pyrrolidinyl to optimize hetero-aliphatic character to increase aqueous solubility and optimize the pharmacokinetic profile (page 4, paragraph 1). Additionally, Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99 (page 55, column 1, paragraph 2). Accordingly, the combination of ‘281, Lanman, and Petri teaches incorporation of the fluoroquinoline, methylpyrrolidine-substituted alkoxy, and acetyl-pyrrolidine of
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. Thus, the combination of ‘281, Lanman, and Petri teaches claim 54.
Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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