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 application claims priority to the applications: CN2021/10797657.5 and PCT/CN2022/105776 with the effective filing dates of 14 July 2021 and 14 July 2022, respectively.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 11 May 2026.
Applicant's election with traverse of Group I (claims 1-17) in the reply filed on 11 May 2026 is acknowledged. Additionally, during a telephone conversation with Elizabeth Wieckowski on 28 May 2026 a provisional election was made to prosecute the invention of Example 3 (
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), claim 16. Affirmation of this election must be made by applicant in replying to this Office action. Claims 3-4, 11-14, and 19-22 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
The traversal is on the ground(s) that den Hartog (U.S. Patent No. 8,067,603; of record, see PTO-892 mailed 11 Mar 2026) does not disclose a compound of Formula (I), wherein when R4 is hydrogen, m is 0 and n is 1, which does not read on Compound 13*:
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.
Applicant’s remarks are acknowledged; however, an additional search has revealed Lee (WO 2020/240492, filed 29 May 2020, see IDS filed 9 Dec 2024). Lee teaches Compound 45:
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, which falls into Formula (I) (page 43). Mapping shown below:
18/578,195 Formula (I) components
18/578,195 Formula (I)
Compound 45 (Lee)
R1
H
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R2
Halogen = F
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n
0
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49
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m
0
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p
0
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R3
Unsubstituted C3-8 cycloalkyl
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R4
C1-4 alkyl substituted heteroaryl (methylene – substituted pyridine)
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As such, in view of the above teachings,
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is not a special technical feature. Accordingly, the restriction is proper.
Claims 3-4 and 11-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 3 specifies that n is 1, which does not read on the elected species. Claim 4 specifies that m is 1, which does not read on the elected species. Claim 11 specifies that R3 is furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, which does not read on the elected species. Claim 12 specifies that R3 is unsubstituted C3-8 cycloalkyl or substituted C3-8 cycloalkyl, which does not read on the elected species. Claim 13 specifies that R3 is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-tbutylcyclohexyl, 4-isopropylcyclohexyl, 4-ethylcyclohexyl, 4-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 2,3-dihydro-1H-inden-2yl, or 2-chlorocyclohexyl, which does not read on the elected species. Claim 14 specifies that R3 is unsubstituted C4-6 heterocycloalkyl or substituted C4-6 heterocycloalkyl, which does not read on the elected species.
Claims 19-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group (Group II: claims 19-22), there being no allowable generic or linking claim.
Claims 1-2, 5-10, and 15-17 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statements filed 10 January 2024, 9 December 2024, 4 August 2025, and 20 April 2026 and the references cited therein have been considered, unless indicated otherwise.
Claim Objections
1. Claim 16 is objected to because of the following informality: lack of comma and conjunction to separate the options. Claim 16 recites a stereoisomer, pharmaceutically acceptable salt, solvate, deuterate, metabolite, or prodrug thereof selected from one of the following compounds: Ex 1 – Ex 71 but does not separate the options via comma nor specify a conjunction (i.e. “and” or “or”).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
2. Claims 15 is rejected 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 15 recites the broad recitation R4 is selected from hydrogen, C1-3 alkyl-unsubstituted heterocycloalkyl, C1-3 alkyl-substituted heterocycloalkyl, C1-3 alkyl-substituted spiroheterocyclic alkyl, C-3 alkyl-C(O)NR5R6, C1-3 alkyl-NR7R8, C1-4 alkyl-unsubstituted heteroaryl, and C1-4 alkyl-substituted heteroaryl, and the claim also recites preferably R4 is hydrogen, 2-(morpholinyl)ethyl, 2-(1,1-dioxothiomorpholine)ethyl, 2-(4- methylpiperazin-1-yl)ethyl, 2-(4-acetylpiperazin-1-yl)ethyl, 2-(3-oxopiperazin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl, 2-(piperidin-1-yl)ethyl, 2-(N,N'-dimethylamino)ethyl, 2-(2-oxopyrrolidin- 1-yl)ethyl, N,N'-dimethylacetamide, oxiran-2-ylmethyl, or 2-(2-oxa-6-azaspiro[3.3]heptan-6- yl)ethyl,
which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
3. Claim(s) 1-2 5-7, 15, and 17* are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Lee (WO 2020/240492, filed 29 May 2020, see IDS filed 9 Dec 2024).
*While Applicant elected a compound of Formula (I) (Example 3:
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), Lee applies to the broader genus, and thus the rejection over the broader genus is made in favor of compact prosecution. However, the Examiner notes that the full genus was not searched. The prior art applicable to the elected species (Ex 3) is found in the 35 U.S.C. 103 rejection below.
Lee teaches Compound 45:
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, which falls into Formula (I). Mapping shown below:
18/578,195 Formula (I) components
18/578,195 Formula (I)
Compound 45 (Lee)
R1
H
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R2
Halogen = F
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n
0
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m
0
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p
0
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R3
Unsubstituted C3-8 cycloalkyl
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R4
C1-4 alkyl substituted heteroaryl (methylene – substituted pyridine)
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Regarding claim 1, Lee teaches a compound of Formula (I): Compound 45 (
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; page 43).
Regarding claim 2, Lee teaches a compound of Formula (I): Compound 45 (
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; page 43), wherein n is 0, m is 0, and p is 0.
Regarding claim 5, Lee teaches a compound of Formula (I): Compound 45 (
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; page 43), wherein R1 is hydrogen and R2 is fluorine.
Regarding claim 6, Lee teaches a compound of Formula (I): Compound 45 (
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; page 43), wherein R1 is hydrogen and R2 is fluorine.
Regarding claim 7, Lee teaches a compound of Formula (I): Compound 45 (
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; page 43), wherein R1 is hydrogen and R2 is fluorine.
Regarding claim 15, Lee teaches a compound of Formula (I): Compound 45 (
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; page 43), wherein R4 is C1-4 alkyl substituted heteroaryl.
Regarding claim 17, Lee teaches a composition of the compounds therein (abstract; page 1, paragraph 2).
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.
4. Claim(s) 1-2, 5-10, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Schmid (Cell, 2017, 171, 1165-1175) in view of Kennedy (J. Med. Chem., 2018, 61, 8895-8907) and Zeng (Bioorg. & Med. Chem. Letters¸2013, 23, 6001-6003) as evidenced by FDA (“OLINVYK,” Drugs at FDA, Aug 2020, <accessdata.fda.gov/drugsatfda_docs/label/2020/210730s000lbl.pdf>, accessed 9 June 2026).
Schmid teaches benzimidazolone derivatives for biased agonism as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor targets (abstract; Table 1, page 1166). Schmid teaches that opioids such as morphine and fentanyl are highly efficacious for treating severe pain but that the number of deaths from overdose caused by respiratory distress have drastically increased over the past decade due to misuse of prescription and illicit narcotics (page 1165, column 1, paragraph 1). Schmid teaches that both the analgesic and respiratory suppressive effects of opioids are due to the activation of the mu opioid receptor (MOR), which is a G protein-coupled receptor (GPCR), which interacts with beta-arrestins, which regulate GPCR signaling (page 1165, column 1, paragraph 1). Schmid teaches that interactions between MOR and beta-arrestins are thought to drive many of the unwanted side effects of MOR activation (page 1165, column 1, paragraph 1). Schmid further suggests that activating MOR without engaging beta-arrestin2 regulation is critically important for safer opioid analgesics (page 1165, column 2, paragraph 1). Schmid teaches that biased agonism (or functional selectivity) at MOR is a promising avenue for therapeutic development as late-phase clinical studies are demonstrating encouraging effects of biased agonism in human patients (page 1165, column 2, paragraphs 2-3). Schmid teaches that clinical trials revealed that TRV-30 (a small molecule biased agonist) showed promise in humans as a potent analgesic but that the therapeutic window is not as broad as originally anticipated (page 1165, column 2, paragraph 3; page 1166, column 1, paragraph 1). Schmid specifically teaches compounds of core structure,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Compound 9), which has an EC50s of 179 ± 24 nM for GTPγS signaling (to measure MOR agonism) and >10,000 nM for beta-arrestin2 recruitment (Table 1, page 1166). Schmid teaches that Compound 9 has high bias toward G protein signaling compared to beta-arrestin2 recruitment (page 1169, column 1, paragraph 3). Additionally, Schmid teaches that Compound 9 exhibited very little respiratory suppression as compared to vehicle (page 1170, column 2, paragraph 2).
Regarding claim 1, Schmid fails to teach Example 3:
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.
Kennedy teaches MOR agonists with high G protein signaling bias (abstract). Kennedy teaches that agonists of MOR (e.g. morphine and fentanyl) are extensively used for treating moderate to severe pain due to their high efficacy but that the required dose often elicits multiple unwanted side effects, including respiratory suppression, constipation, and tolerance (page 8895, column 1, paragraph 1). Kennedy teaches that the most effective opioid pain relievers are MOR agonists (page 8895, column 1, paragraph 2). Kennedy teaches that binding to MOR initiates the dissociation of heterotrimeric G protein subunits and subsequent downstream signaling and that MOR interacts with beta-arrestins (page 8895, column 1, paragraph 2). Kennedy teaches that studies using beta-arrestin2 knockout mice strongly suggest that the interaction between MOR and beta-arrestin2 produces many of morphine’s undesirable effects in vivo and that morphine retained its analgesic properties in the beta-arrestin2 knockout mice (page 8895, column 1, paragraph 2). Kennedy teaches that a number of groups have developed biased agonist compound that preferentially activate G protein signaling over beta-arrestin2 recruitment in MOR (page 8895, column 2, paragraph 2). Kennedy teaches that TRV130 demonstrated biased MOR agonism with analgesic efficacy and a modest improvement in respiratory suppression compared to morphine (page 8895, column 2, paragraph 2). Kennedy teaches Compounds 4 and 6:
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, wherein R8 is Cl and Br, respectively (Table 1, page 8897). Kennedy teaches that Compounds 4 and 6 have EC50s of 551 ± 24 nM and 367 ± 37 nM for GTPγS signaling (to measure MOR agonism) and 7656 ± 1469 nM and 6611 ± 1076 nM for beta-arrestin2 recruitment, respectively (Table 1, page 8897). Additionally, Kennedy teaches Compounds 18, 20, and 21:
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, wherein R5 is methyl and R8 is Cl, F, and Br, respectively (Table 2, page 8898). Kennedy teaches that Compounds 18, 20, and 21 have EC50s of 16 ± 1.2 nM, 75 ± 8.3 nM, and 4.8 ± 0.41 nM for GTPγS signaling (to measure MOR agonism) and 184 ± 24 nM, 377 ± 76 nM, and 182 ± 42 nM for beta-arrestin2 recruitment, respectively (Table 1, page 8898). Kennedy teaches that Compounds 18, 20, and 21 do not seem to engage MOR well as compared to their non-methylated counterparts, Compounds 4 and 6. While Kennedy is silent to the fluorinated version of Compounds 4 and 6, a person of skill in the art would contemplate making the fluorinated analog of
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, wherein R8 is F based upon the data exhibited by Compounds 4 and 6 (Table 1, page 8897). Additionally, Kennedy teaches Compounds 30 and 31:
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, which have the EC50s of 184 and 148 nM, respectively (Table 6, page 8903).
Zeng teaches benzimidazolone agonists and their structure activity relationships (abstract). Zeng teaches that the H3 receptor is a G-protein coupled receptor in the histamine receptor family, which was originally characterized as an auto-receptor to regulate the synthesis and release of histamine from histaminergic neurons (page 6001, column 1, paragraph 1). Zeng teaches that the H3 receptor has been shown to mediate other neurotransmitters and is a proposed target for several central nervous system indications (page 6001, column 1, paragraph 1). Zeng teaches that previous H3 receptor antagonists showed significant cytochrome P450 enzyme inhibition liability and, in the case of SCH 79687, lowered cholesterol levels in rat toxicology (page 6001, column 1, paragraph 2). Zeng teaches H3 antagonists with significantly improved enzyme profiles and pharmacokinetic properties (page 6001, column 2, paragraph 1). Zeng teaches the compounds of core scaffold:
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, wherein Compound 1f has R =
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and Y is H (Table 1, page 6002). Zeng teaches that Compound 1f showed no 3A4 inhibition (Table 1, page 6002; page 6003, column 2, paragraph 2). While Zeng teaches that Compound 1f demonstrated negligible plasma levels due to low lipophilicity, which limited absorption (page 6003, column 1, paragraph 2), Zeng teaches incorporation of a di-halo-aryl substituent (Compound 1o:
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) to increase lipophilicity and thus binding affinity and pharmacokinetics, which displayed excellent plasma concentration (page 6003, column 1, paragraph 3; page 6003, column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify Compound 9 of Schmid to 1) combine the 4-fluorophenyl and 2-chlorophenyl to generate 2-chloro-4-fluorophenyl as taught by Kennedy (Compounds 4, 6, 30, and 31) to optimize biased agonism of MOR over beta-arrestin2 recruitment; 2) incorporate a di-halo substituent (the 2-chloro-4-fluorophenyl of Kennedy) to increase lipophilicity for better pharmacokinetics as taught by Zeng; and 3) incorporate the alkyl-morpholine as taught by Zeng to optimize activity while decreasing cytochrome P450 (CYP3A4) inhibition to arrive at instant claim 1 (Ex 3:
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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:
-Schmid teaches benzimidazolone derivatives for biased agonism as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor targets,
-Schmid teaches that opioids such as morphine and fentanyl are highly efficacious for treating severe pain but that the number of deaths from overdose caused by respiratory distress have drastically increased over the past decade due to misuse of prescription and illicit narcotics,
-Schmid teaches that both the analgesic and respiratory suppressive effects of opioids are due to the activation of the mu opioid receptor (MOR), which is a G protein-coupled receptor (GPCR), which interacts with beta-arrestins, which regulate GPCR signaling,
-Schmid teaches interactions between MOR and beta-arrestins is thought to drive many of the unwanted side effects of MOR activation,
-Schmid teaches that it is suggested that activating MOR without engaging beta-arrestin2 regulation is critically important for safer opioid analgesics,
-Schmid teaches biased agonism (or functional selectivity) at MOR is a promising avenue for therapeutic development as late-phase clinical studies are demonstrating encouraging effects of biased agonism in human patients,
-Schmid teaches clinical trials revealed that TRV-30 (a small molecule biased agonist) showed promise in humans as a potent analgesic, but the therapeutic window is not as broad as originally anticipated,
-Schmid teaches compounds of core structure,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Compound 9), which has an EC50s of 179 ± 24 nM for GTPγS signaling (to measure MOR agonism) and >10,000 nM for beta-arrestin2 recruitment,
-Schmid teaches that Compound 9 has high bias toward G protein signaling compared to beta-arrestin2 recruitment,
-Schmid teaches Compound 9 exhibited very little respiratory suppression as compared to vehicle,
-Kennedy teaches MOR agonists with high G protein signaling bias,
-Kennedy teaches that agonists of MOR (e.g. morphine and fentanyl) are extensively used for treating moderate to severe pain due to their high efficacy but that the required dose often elicits multiple unwanted side effects, including respiratory suppression, constipation, and tolerance,
-Kennedy teaches that the most effective opioid pain relievers are MOR agonists,
-Kennedy teaches that binding to MOR initiates the dissociation of heterotrimeric G protein subunits and subsequent downstream signaling and that MOR interacts with beta-arrestins,
-Kennedy teaches that studies using beta-arrestin2 knockout mice strongly suggest that the interaction between MOR and beta-arrestin2 produces many of morphine’s undesirable effects in vivo and that morphine retained its analgesic properties in the beta-arrestin2 knockout mice,
-Kennedy teaches that a number of groups have developed biased agonist compound that preferentially activate G protein signaling over beta-arrestin2 recruitment in MOR,
-Kennedy teaches that TRV130 demonstrated biased MOR agonism with analgesic efficacy and a modest improvement in respiratory suppression compared to morphine,
-Kennedy teaches Compounds 4 and 6:
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, wherein R8 is Cl and Br, respectively,
-Kennedy teaches that Compounds 4 and 6 have EC50s of 551 ± 24 nM and 367 ± 37 nM for GTPγS signaling (to measure MOR agonism) and 7656 ± 1469 nM and 6611 ± 1076 nM for beta-arrestin2 recruitment, respectively,
-Kennedy teaches Compounds 18, 20, and 21:
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, wherein R5 is methyl and R8 is Cl, F, and Br, respectively,
-Kennedy teaches that Compounds 18, 20, and 21 have EC50s of 16 ± 1.2 nM, 75 ± 8.3 nM, and 4.8 ± 0.41 nM for GTPγS signaling (to measure MOR agonism) and 184 ± 24 nM, 377 ± 76 nM, and 182 ± 42 nM for beta-arrestin2 recruitment, respectively,
-Kennedy teaches Compounds 18, 20, and 21 do not seem to engage MOR well as compared to their non-methylated counterparts, Compounds 4 and 6,
-While Kennedy is silent to the fluorinated version of Compounds 4 and 6, a person of skill in the art would contemplate making the fluorinated analog of
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, wherein R8 is F based upon the data exhibited by Compounds 4 and 6,
-Kennedy teaches Compounds 30 and 31:
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, which have the EC50s of 184 and 148 nM, respectively,
-Zeng teaches benzimidazolone agonists and their structure activity relationships,
-Zeng teaches that the H3 receptor is a G-protein coupled receptor in the histamine receptor family, which was originally characterized as an auto-receptor to regulate the synthesis and release of histamine from histaminergic neurons,
-Zeng teaches that the H3 receptor has been shown to mediate other neurotransmitters and is a proposed target for several central nervous system indications,
-Zeng teaches previous H3 receptor antagonists showed significant cytochrome P450 enzyme inhibition liability and, in the case of SCH 79687, lowered cholesterol levels in rat toxicology,
-Zeng teaches H3 antagonists with significantly improved enzyme profiles and pharmacokinetic properties,
-Zeng teaches the compounds of core scaffold:
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, wherein Compound 1f has R =
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and Y is H,
-Zeng teaches that Compound 1f showed no 3A4 inhibition, and
-While Zeng teaches that Compound 1f demonstrated negligible plasma levels, due to low lipophilicity, which limited absorption, Zeng teaches incorporation of a di-halo-aryl substituent (Compound 1o:
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) to increase lipophilicity and thus binding affinity and pharmacokinetics, which displayed excellent plasma concentration.
Accordingly, the combination of Schmid, Kennedy, and Zeng teaches a compound of Formula (I): Ex 3 (
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).
Regarding claim 2, Schmid teaches Compound 9,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Table 1, page 1166), wherein n is 0, m is 0, and p is 1.
Regarding claim 5, Schmid teaches Compound 9,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Table 1, page 1166), wherein R1 and R2 are each halogen (chlorine).
Regarding claim 6, Schmid teaches Compound 9,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Table 1, page 1166), wherein R1 and R2 are each chlorine.
Regarding claim 7, Schmid teaches Compound 9,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Table 1, page 1166), wherein R1 and R2 are each chlorine.
Regarding claim 8, Schmid teaches Compound 9,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Table 1, page 1166), wherein R3 is a substituted aryl (2-fluoro-4-chlorophenyl). While Kennedy is silent to the fluorinated version of Compounds 4 and 6, a person of skill in the art would contemplate making the fluorinated analog of
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, wherein R8 is F based upon the data exhibited by Compounds 4 and 6 (Table 1, page 8897). Additionally, Kennedy teaches Compounds 30 and 31:
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, which have the EC50s of 184 and 148 nM, respectively (Table 6, page 8903). Further, Zeng teaches incorporation of a di-halo-aryl substituent (Compound 1o:
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) to increase lipophilicity and thus binding affinity and pharmacokinetics, which displayed excellent plasma concentration (page 6003, column 1, paragraph 3; page 6003, column 2, paragraph 1). Thus, the combination of Schmid, Kennedy, and Zeng teaches R3 is 2-chloro-4-fluorophenyl.
Regarding claim 9, Schmid teaches Compound 9,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Table 1, page 1166), wherein R3 is a substituted phenyl having 2 substituents selected from a halogen (2-fluoro-4-chlorophenyl). While Kennedy is silent to the fluorinated version of Compounds 4 and 6, a person of skill in the art would contemplate making the fluorinated analog of
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, wherein R8 is F based upon the data exhibited by Compounds 4 and 6 (Table 1, page 8897). Additionally, Kennedy teaches Compounds 30 and 31:
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, which have the EC50s of 184 and 148 nM, respectively (Table 6, page 8903). Further, Zeng teaches incorporation of a di-halo-aryl substituent (Compound 1o:
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47
60
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) to increase lipophilicity and thus binding affinity and pharmacokinetics, which displayed excellent plasma concentration (page 6003, column 1, paragraph 3; page 6003, column 2, paragraph 1). Thus, the combination of Schmid, Kennedy, and Zeng teaches R3 is 2-chloro-4-fluorophenyl.
Regarding claim 10, Schmid teaches Compound 9,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Table 1, page 1166), wherein R3 is a substituted phenyl having 2 substituents selected from a halogen (2-fluoro-4-chlorophenyl). While Kennedy is silent to the fluorinated version of Compounds 4 and 6, a person of skill in the art would contemplate making the fluorinated analog of
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, wherein R8 is F based upon the data exhibited by Compounds 4 and 6 (Table 1, page 8897). Additionally, Kennedy teaches Compounds 30 and 31:
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184
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, which have the EC50s of 184 and 148 nM, respectively (Table 6, page 8903). Further, Zeng teaches incorporation of a di-halo-aryl substituent (Compound 1o:
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47
60
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) to increase lipophilicity and thus binding affinity and pharmacokinetics, which displayed excellent plasma concentration (page 6003, column 1, paragraph 3; page 6003, column 2, paragraph 1). Thus, the combination of Schmid, Kennedy, and Zeng teaches R3 is 2-chloro-4-fluorophenyl.
Regarding claim 15, Zeng teaches Compound 1f:
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, wherein R =
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and Y is H (Table 1, page 6002), wherein R4 is C1-3 alkyl-NR7R8, wherein R7 and R8 and N connected thereto together form a C4-6 substituted azacycloalkyl (morpholine).
Regarding claim 16, Schmid teaches Compound 9,
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, wherein R1, R2, and R3 are Cl, R4 is H, R5 is F, and R6 is H (Table 1, page 1166), wherein R3 is a substituted phenyl having 2 substituents selected from a halogen (2-fluoro-4-chlorophenyl). While Kennedy is silent to the fluorinated version of Compounds 4 and 6, a person of skill in the art would contemplate making the fluorinated analog of
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116
180
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, wherein R8 is F based upon the data exhibited by Compounds 4 and 6 (Table 1, page 8897). Additionally, Kennedy teaches Compounds 30 and 31:
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154
184
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, which have the EC50s of 184 and 148 nM, respectively (Table 6, page 8903). Further, Zeng teaches incorporation of a di-halo-aryl substituent (Compound 1o:
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47
60
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) to increase lipophilicity and thus binding affinity and pharmacokinetics, which displayed excellent plasma concentration (page 6003, column 1, paragraph 3; page 6003, column 2, paragraph 1). Zeng teaches Compound 1f:
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238
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, wherein R =
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66
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and Y is H (Table 1, page 6002). Thus, the combination of Schmid, Kennedy, and Zeng teaches R3 is 2-chloro-4-fluorophenyl and R4 is
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, which is Example 3:
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.
Regarding claim 17, Kennedy teaches the MOR biased agonist, TRV-130 (aka Oliceridine) (page 8895, column 2, paragraph 2), which is a pharmaceutical composition as evidenced by FDA (page 6, item 3: oliceridine fumarate salt).
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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