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 application, IN2022/11038517, with the effective filing date of 5 July 2022. The Examiner notes that it is unclear whether the priority document is a certified copy or not. Applicant is kindly requested to confirm if the priority document is a certified copy, and if not, to provide a certified copy.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 30 December 2025. Applicant’s election without traverse of Group I (claims 1-10) and 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid in the reply filed on 30 December 2025 is acknowledged.
Claims 3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 16-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group (Group II: claims 16-25), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 30 December 2025.
Claims 1-2, 4-7, and 9-10 are pending.
Information Disclosure Statement
The Information Disclosure Statements filed on 16 January 2025 and 30 December 2025 and the references cited therein have been considered, unless indicated otherwise.
The references, wherein a copy was provided, but the reference is unrelated to the claimed invention, are lined through. These references are the following: US 9,684,018 (Horanzy), US 11,859,851 (Voysey), and US 2016/0146715 (Shim).
The references, wherein a copy was not provided are lined through. These references are the following: Caira (Topics in Current Chemistry, 1998, 198, 163-208); Hancock (Pharm Res, 1995, 12(6), 799-806); Hayashi (EBioMedicine, 2018, 27, 187-199); Krawczyk (Ann Hepatol, 2012, 11(5), 710-744); Miloh (Abstract Number: 292; Proceedings of the Digestive Disease Week Meeting/107th Annual Meeting of the American-Gastroenterological Association, 2006, 130:A759-760); Pfister (Hepatol Commun, 2023, 7(4):e0092); pmda.go.jp (Pharmaceutical Affairs Bureau Notification, 2002, 568, 87); Rust (Eur J Clin Invest, 2000, 30, 135-139), Schneider (Pediatrics, 2012, 130(3), e607-e614); Shah (J Pediatr Genet, 2017, 6(2), 126-127); Simons (Clin Exp Pharmacol Physiol, 1976, 3(1), 99-101); Thompson (JHEP Rep, 2023, 5(8), 100782); Togawa (Journal of Pediatric Gastroenterology and Nutrition, 2018, 67(1):S363); and Wang (Sci Rep, 2016, 6(38180), 1-9).
The Examiner notes that due to the voluminous nature of the IDS submissions, there is a possibility that one or more relevant references may have been overlooked. The Examiner respectfully requests that Applicant kindly highlight the references they believe are most relevant to the claimed subject matter.
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. Claims 1-2, 4-7, and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Jung (U.S. Patent No. 9,890,129, issued 13 Feb 2019) in view of Surur (Arch. Pharm. Chem. Life Sci., 2019, 352(e1800248), 1-11).
Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives (abstract).
Jung specifically teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
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(column 3, lines 25-27, compound 1). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). Jung additionally teaches that the compounds therein have an asymmetric carbon center in the core scaffold and thus are present as the R and S stereoisomers and racemate (column 6, lines 1-6).
Jung fails to teach the compound: 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
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(see reply to restriction requirement, filed 30 Dec 2025).
Surur teaches that sulfur is the fifth most prevalent element in drugs of biological significance and that sulfide incorporation in drug design is a result of ease and efficiency of available assembly routes as well as sulfide properties (page 2, column 1, paragraphs 2-3; page 2, column 2, paragraphs 2-3). Surur teaches that sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur (page 2, column 2, paragraph 2). The C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens (page 2, column 2, paragraph 2). Surur further specifies that intermolecular interactions between sulfur and biological targets are well-documented: sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals (page 2, column 2, paragraph 3). Additionally, Surur teaches sulfides often exist as bridging elements, because they exhibit favorable structural characteristics over conventional ethers: sulfides feature longer bonds and narrow central bond angle (page 2, column 2, paragraph 1). Further, Surur specifies that sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits (page 3, column 2, paragraph 2).
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 simply substitute the nitrogen heteroatom for a sulfur heteroatom as taught by Surur with the scaffold of Jung to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives,
-Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
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,
-Jung teaches R6 (R2 in the instant application) is C1-C6 alkyl, which significantly overlaps with the instant application (C1-C4 alkyl),
-Surur teaches sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur,
-Surur teaches C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens,
-Surur teaches sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals,
-Surur teaches sulfides feature longer bonds and narrow central bond angle, and
-Surur teaches sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element (the nitrogen heteroatom) for another (a sulfur heteroatom) to predictably arrive at a compound of Formula (I):
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, specifically the compound: 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
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. See MPEP § 2143(B).
Regarding claim 2, Jung teaches R1 is n-butyl (compound 1, column 3, lines 25-27).
Regarding claim 4, Jung teaches R2 is n-butyl (compound 1, column 3, lines 25-27). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05. The range of the claimed invention (C1-C4 alkyl chain) significantly overlaps with the range of Jung (C1-C6 alkyl chain) and the claimed invention does not provide an unexpected result in view of Jung, who describes compounds for inhibition of liver bile acid transport to treat constipation (column 1, lines 45-55). Additionally, at the time of invention, there was a recognized problem in the art (bile acid resorption heavily affects constipation), a finite number of identified predictable potential solutions (C1-C6 alkyl), and one of ordinary skill in the art would have pursued the solution of changing the size of the eastern sidechains from butyl to ethyl as taught by Jung. Thus, Jung teaches R2 is ethyl.
Regarding claim 5, Jung teaches R3 is hydrogen, 4-methoxy, 4-hydroxy, 3-methoxy, 4-fluoro, 3-fluoro, and 3-fluoro,4-methoxy (column 3, lines 25-27, compound 1; column 4, lines 16-33, compounds 20-24).
Regarding claim 6, Jung teaches R4 is methylthio (column 3, lines 25-27, compound 1). Additionally, June suggests R4 is ethylthio, because Jung allows for variability at the 7-position of the bicyclic scaffold through specifying R5 preferably is (C1-C4alkyl)thio (column 2, line 50).
Regarding claim 7, Jung teaches R5A and R5B are hydrogen, methyl, gem-di-methyl, iso-butyl, and cyclopropyl (column 16, lines 1-24; column 17, lines 34-57; column 18, lines 1-19; column 19, lines 36-60; column 23, lines 1-19).
Regarding claim 9, Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid (compound 1, column 3, lines 25-27). Additionally, Jung suggests R2 is methyl and ethyl, because Jung allows for variability on the alkyl side chains of the 7-membered ring through specifying R6 and R7 preferably are independently C1-C6 alkyl chain (column 2, line 51). Further, Jampilek teaches simple substitution of nitrogen to sulfur for modulation of ADME properties (page 1, paragraph 1).
Regarding claim 10, Jung teaches a pharmaceutical composition (column 9, lines 8-12).
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. Claims 1-2, 4-7, and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,975,045 in view of Jung (U.S. Patent No. 9,890,129, issued 13 Feb 2019) and Surur (Arch Pharm Chem Life Sci, 2019, 352(e1800248), 1-11).
U.S. Patent No. 10,975,045 claims a compound of Formula (I):
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, wherein R1 and R2 are independently C1-C4 alkyl; R3 is independently hydrogen, halogen, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino; n is 1, 2, or 3; R4 is halogen, C1-C4 alkoxy, C1-C4 alkylthio, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino; and R5A and R5B are independently hydrogen or C1-C4 alkyl.
Regarding claim 1, ‘045 fails to teach a compound of Formula (I):
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, nor the compound, 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
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.
Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives (abstract). Jung specifically teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
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(column 3, lines 25-27, compound 1). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). Jung additionally teaches that the compounds therein have an asymmetric carbon center in the core scaffold and thus are present as the R and S stereoisomers and racemate (column 6, lines 1-6).
Surur teaches that sulfur is the fifth most prevalent element in drugs of biological significance and that sulfide incorporation in drug design is a result of ease and efficiency of available assembly routes as well as sulfide properties (page 2, column 1, paragraphs 2-3; page 2, column 2, paragraphs 2-3). Surur teaches that sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur (page 2, column 2, paragraph 2). The C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens (page 2, column 2, paragraph 2). Surur further specifies that intermolecular interactions between sulfur and biological targets are well-documented: sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals (page 2, column 2, paragraph 3). Additionally, Surur teaches sulfides often exist as bridging elements, because they exhibit favorable structural characteristics over conventional ethers: sulfides feature longer bonds and narrow central bond angle (page 2, column 2, paragraph 1). Further, Surur specifies that sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits (page 3, column 2, paragraph 2).
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 simply substitute the methylene and heteroatom placements on the western side chain of ‘045 as well as substitute the nitrogen heteroatom for a sulfur heteroatom as taught by Surur with the scaffold of Jung to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-045 teaches a compound of Formula (I):
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,
-Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives,
-Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
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,
-Jung teaches R6 (R2 in the instant application) is C1-C6 alkyl, which significantly overlaps with the instant application (C1-C4 alkyl),
-Surur teaches sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur,
-Surur teaches C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens,
-Surur teaches sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals,
-Surur teaches sulfides feature longer bonds and narrow central bond angle, and
-Surur teaches sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element (the nitrogen heteroatom) for another (a sulfur heteroatom) to predictably arrive at a compound of Formula (I):
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, specifically the compound: 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
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. See MPEP § 2143(B).
Regarding claim 2, ‘045 teaches R1 is n-butyl (claim 2 of ‘045).
Regarding claim 4, ‘045 teaches R2 is ethyl (claim 4 of ‘045).
Regarding claim 5, ‘045 teaches R3 is hydrogen, halogen, hydroxy, amino, or C1-C4 alkoxy (claim 5 of ‘045).
Regarding claim 6, ‘045 teaches R4 is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, or C1-C4 alkylthio (claim 5 of ‘045).
Regarding claim 7, ‘045 teaches R5A and R5B are hydrogen or methyl (claim 6 of ‘045).
Regarding claim 9, ‘045 teaches 3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid (claim 8 of ‘045). Jung teaches the methylene and heteroatom positions adjacent to the phenyl ring on the western side chain swap (compound 1, column 3, lines 25-27). Jampilek teaches simple substitution of nitrogen to sulfur for modulation of ADME properties (page 1, paragraph 1).
Regarding claim 10, ‘045 teaches a pharmaceutical composition (claim 9 of ‘045).
3. Claims 1-2, 4-7, and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-7, and 10 of U.S. Patent No. 10,941,127 in view of Surur (Arch Pharm Chem Life Sci, 2019, 352(e1800248), 1-11).
U.S. Patent No. 10,941,127 claims a compound of Formula (I):
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, wherein R1 and R2 are independently C1-C4 alkyl; R3 is independently hydrogen, halogen, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino; n is 1, 2, or 3; R4 is halogen, C1-C4 alkoxy, C1-C4 alkylthio, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino; and R5A and R5B are independently hydrogen or C1-C4 alkyl.
Regarding claim 1, ‘127 fails to teach a compound of Formula (I):
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, nor the compound, 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
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.
Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives (abstract). Jung specifically teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
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(column 3, lines 25-27, compound 1). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). Jung additionally teaches that the compounds therein have an asymmetric carbon center in the core scaffold and thus are present as the R and S stereoisomers and racemate (column 6, lines 1-6).
Surur teaches that sulfur is the fifth most prevalent element in drugs of biological significance and that sulfide incorporation in drug design is a result of ease and efficiency of available assembly routes as well as sulfide properties (page 2, column 1, paragraphs 2-3; page 2, column 2, paragraphs 2-3). Surur teaches that sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur (page 2, column 2, paragraph 2). The C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens (page 2, column 2, paragraph 2). Surur further specifies that intermolecular interactions between sulfur and biological targets are well-documented: sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals (page 2, column 2, paragraph 3). Additionally, Surur teaches sulfides often exist as bridging elements, because they exhibit favorable structural characteristics over conventional ethers: sulfides feature longer bonds and narrow central bond angle (page 2, column 2, paragraph 1). Further, Surur specifies that sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits (page 3, column 2, paragraph 2).
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 simply substitute the methylene and heteroatom placements on the western side chain of ‘127 as well as substitute the nitrogen heteroatom for a sulfur heteroatom as taught by Surur with the scaffold of Jung to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘127 teaches a compound of Formula (I):
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,
-Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives,
-Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
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,
-Jung teaches R6 (R2 in the instant application) is C1-C6 alkyl, which significantly overlaps with the instant application (C1-C4 alkyl),
-Surur teaches sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur,
-Surur teaches C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens,
-Surur teaches sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals,
-Surur teaches sulfides feature longer bonds and narrow central bond angle, and
-Surur teaches sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element (the nitrogen heteroatom) for another (a sulfur heteroatom) to predictably arrive at a compound of Formula (I):
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, specifically the compound: 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
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. See MPEP § 2143(B).
Regarding claim 2, ‘127 teaches R1 is n-butyl (claim 2 of ‘127).
Regarding claim 4, ‘127 teaches R2 is ethyl (claim 4 of ‘127).
Regarding claim 5, ‘127 teaches R3 is hydrogen, halogen, hydroxy, amino, or C1-C4 alkoxy (claim 5 of ‘127).
Regarding claim 6, ‘127 teaches R4 is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, or C1-C4 alkylthio (claim 6 of ‘127).
Regarding claim 7, ‘127 teaches R5A and R5B are hydrogen or methyl (claim 7 of ‘127).
Regarding claim 9, Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid (compound 1, column 3, lines 25-27). Additionally, Jung suggests R2 is methyl and ethyl, because Jung allows for variability on the alkyl side chains of the 7-membered ring through specifying R6 and R7 preferably are independently C1-C6 alkyl chain (column 2, line 51). Further, Jampilek teaches simple substitution of nitrogen to sulfur for modulation of ADME properties (page 1, paragraph 1).
Regarding claim 10, ‘127 teaches a pharmaceutical composition (claim 10 of ‘127).
4. Claims 1-2, 4-7, and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-7, and 10 of U.S. Patent No. 11,014,898 in view of Surur (Arch Pharm Chem Life Sci, 2019, 352(e1800248), 1-11).
U.S. Patent No. 11,014,898 claims a compound of Formula (I):
PNG
media_image4.png
182
221
media_image4.png
Greyscale
, wherein R1 and R2 are independently C1-C4 alkyl; R3 is independently hydrogen, halogen, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino; n is 1, 2, or 3; and R4 is halogen, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino.
Regarding claim 1, ‘898 fails to teach a compound of Formula (I):
PNG
media_image3.png
158
213
media_image3.png
Greyscale
, nor the compound, 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
PNG
media_image2.png
224
467
media_image2.png
Greyscale
.
Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives (abstract). Jung specifically teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
PNG
media_image1.png
239
361
media_image1.png
Greyscale
(column 3, lines 25-27, compound 1). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). Jung additionally teaches that the compounds therein have an asymmetric carbon center in the core scaffold and thus are present as the R and S stereoisomers and racemate (column 6, lines 1-6).
Surur teaches that sulfur is the fifth most prevalent element in drugs of biological significance and that sulfide incorporation in drug design is a result of ease and efficiency of available assembly routes as well as sulfide properties (page 2, column 1, paragraphs 2-3; page 2, column 2, paragraphs 2-3). Surur teaches that sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur (page 2, column 2, paragraph 2). The C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens (page 2, column 2, paragraph 2). Surur further specifies that intermolecular interactions between sulfur and biological targets are well-documented: sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals (page 2, column 2, paragraph 3). Additionally, Surur teaches sulfides often exist as bridging elements, because they exhibit favorable structural characteristics over conventional ethers: sulfides feature longer bonds and narrow central bond angle (page 2, column 2, paragraph 1). Further, Surur specifies that sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits (page 3, column 2, paragraph 2).
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 simply substitute the methylene and heteroatom placements on the western side chain of ‘898 as well as substitute the nitrogen heteroatom for a sulfur heteroatom as taught by Surur with the scaffold of Jung to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘898 teaches a compound of Formula (I):
PNG
media_image4.png
182
221
media_image4.png
Greyscale
,
-Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives,
-Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
PNG
media_image1.png
239
361
media_image1.png
Greyscale
,
-Jung teaches R6 (R2 in the instant application) is C1-C6 alkyl, which significantly overlaps with the instant application (C1-C4 alkyl),
-Surur teaches sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur,
-Surur teaches C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens,
-Surur teaches sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals,
-Surur teaches sulfides feature longer bonds and narrow central bond angle, and
-Surur teaches sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element (the nitrogen heteroatom) for another (a sulfur heteroatom) to predictably arrive at a compound of Formula (I):
PNG
media_image3.png
158
213
media_image3.png
Greyscale
, specifically the compound: 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
PNG
media_image2.png
224
467
media_image2.png
Greyscale
. See MPEP § 2143(B).
Regarding claim 2, ‘898 teaches R1 is n-butyl (claim 2 of ‘898).
Regarding claim 4, ‘898 teaches R2 is ethyl (claim 4 of ‘898).
Regarding claim 5, ‘898 teaches R3 is hydrogen, halogen, hydroxy, amino, or C1-C4 alkoxy (claim 5 of ‘898).
Regarding claim 6, ‘898 teaches R4 is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, or C1-C4 alkylthio (claim 6 of ‘898).
Regarding claim 7, Jung teaches R5A and R5B are hydrogen, methyl, gem-di-methyl, iso-butyl, and cyclopropyl (column 16, lines 1-24; column 17, lines 34-57; column 18, lines 1-19; column 19, lines 36-60; column 23, lines 1-19).
Regarding claim 9, Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid (compound 1, column 3, lines 25-27). Additionally, Jung suggests R2 is methyl and ethyl, because Jung allows for variability on the alkyl side chains of the 7-membered ring through specifying R6 and R7 preferably are independently C1-C6 alkyl chain (column 2, line 51). Further, Jampilek teaches simple substitution of nitrogen to sulfur for modulation of ADME properties (page 1, paragraph 1).
Regarding claim 10, ‘898 teaches a pharmaceutical composition (claim 10 of ‘898).
5. Claims 1-2, 4-7, and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-7, and 10 of U.S. Patent No. 11,225,466 in view of Surur (Arch Pharm Chem Life Sci, 2019, 352(e1800248), 1-11).
U.S. Patent No. 11,225,466 claims a compound of Formula (I):
PNG
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182
221
media_image4.png
Greyscale
, wherein R1 and R2 are independently C1-C4 alkyl; R3 is independently hydrogen, halogen, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino; n is 1, 2, or 3; and R4 is halogen, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino.
Regarding claim 1, ‘466 fails to teach a compound of Formula (I):
PNG
media_image3.png
158
213
media_image3.png
Greyscale
, nor the compound, 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
PNG
media_image2.png
224
467
media_image2.png
Greyscale
.
Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives (abstract). Jung specifically teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
PNG
media_image1.png
239
361
media_image1.png
Greyscale
(column 3, lines 25-27, compound 1). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). Jung additionally teaches that the compounds therein have an asymmetric carbon center in the core scaffold and thus are present as the R and S stereoisomers and racemate (column 6, lines 1-6).
Surur teaches that sulfur is the fifth most prevalent element in drugs of biological significance and that sulfide incorporation in drug design is a result of ease and efficiency of available assembly routes as well as sulfide properties (page 2, column 1, paragraphs 2-3; page 2, column 2, paragraphs 2-3). Surur teaches that sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur (page 2, column 2, paragraph 2). The C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens (page 2, column 2, paragraph 2). Surur further specifies that intermolecular interactions between sulfur and biological targets are well-documented: sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals (page 2, column 2, paragraph 3). Additionally, Surur teaches sulfides often exist as bridging elements, because they exhibit favorable structural characteristics over conventional ethers: sulfides feature longer bonds and narrow central bond angle (page 2, column 2, paragraph 1). Further, Surur specifies that sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits (page 3, column 2, paragraph 2).
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 simply substitute the methylene and heteroatom placements on the western side chain of ‘466 as well as substitute the nitrogen heteroatom for a sulfur heteroatom as taught by Surur with the scaffold of Jung to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘466 teaches a compound of Formula (I):
PNG
media_image4.png
182
221
media_image4.png
Greyscale
,
-Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives,
-Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
PNG
media_image1.png
239
361
media_image1.png
Greyscale
,
-Jung teaches R6 (R2 in the instant application) is C1-C6 alkyl, which significantly overlaps with the instant application (C1-C4 alkyl),
-Surur teaches sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur,
-Surur teaches C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens,
-Surur teaches sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals,
-Surur teaches sulfides feature longer bonds and narrow central bond angle, and
-Surur teaches sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element (the nitrogen heteroatom) for another (a sulfur heteroatom) to predictably arrive at a compound of Formula (I):
PNG
media_image3.png
158
213
media_image3.png
Greyscale
, specifically the compound: 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
PNG
media_image2.png
224
467
media_image2.png
Greyscale
. See MPEP § 2143(B).
Regarding claim 2, ‘466 teaches R1 is n-butyl (claim 2 of ‘466).
Regarding claim 4, ‘466 teaches R2 is ethyl (claim 4 of ‘466).
Regarding claim 5, ‘466 teaches R3 is hydrogen, halogen, hydroxy, amino, or C1-C4 alkoxy (claim 5 and 6 of ‘466).
Regarding claim 6, ‘466 teaches R4 is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, or C1-C4 alkylthio (claim 7 and 8 of ‘466).
Regarding claim 7, Jung teaches R5A and R5B are hydrogen, methyl, gem-di-methyl, iso-butyl, and cyclopropyl (column 16, lines 1-24; column 17, lines 34-57; column 18, lines 1-19; column 19, lines 36-60; column 23, lines 1-19).
Regarding claim 9, Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid (compound 1, column 3, lines 25-27). Additionally, Jung suggests R2 is methyl and ethyl, because Jung allows for variability on the alkyl side chains of the 7-membered ring through specifying R6 and R7 preferably are independently C1-C6 alkyl chain (column 2, line 51). Further, Jampilek teaches simple substitution of nitrogen to sulfur for modulation of ADME properties (page 1, paragraph 1).
Regarding claim 10, ‘466 teaches a pharmaceutical composition (claim 10 of ‘466).
6. Claims 1-2, 4-7, and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-7, and 10 of U.S. Patent No. 11,377,429 in view of Surur (Arch Pharm Chem Life Sci, 2019, 352(e1800248), 1-11).
U.S. Patent No. 11,377,429 claims a compound of Formula (I):
PNG
media_image5.png
187
225
media_image5.png
Greyscale
, wherein R1 and R2 are independently C1-C4 alkyl; R3 is independently hydrogen, halogen, hydroxy, C1-C4 alkoxy; M is CH2 or NH; R4 is C1-C4 alkylthio, amino, N-(C1-C4 alkyl)amino, or N,N-di(C1-C4 alkyl)amino; R5A and R5B are independently hydrogen or C1-C4 alkyl.
Regarding claim 1, ‘429 fails to teach a compound of Formula (I):
PNG
media_image3.png
158
213
media_image3.png
Greyscale
, nor the compound, 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
PNG
media_image2.png
224
467
media_image2.png
Greyscale
.
Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives (abstract). Jung specifically teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
PNG
media_image1.png
239
361
media_image1.png
Greyscale
(column 3, lines 25-27, compound 1). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). Jung additionally teaches that the compounds therein have an asymmetric carbon center in the core scaffold and thus are present as the R and S stereoisomers and racemate (column 6, lines 1-6).
Surur teaches that sulfur is the fifth most prevalent element in drugs of biological significance and that sulfide incorporation in drug design is a result of ease and efficiency of available assembly routes as well as sulfide properties (page 2, column 1, paragraphs 2-3; page 2, column 2, paragraphs 2-3). Surur teaches that sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur (page 2, column 2, paragraph 2). The C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens (page 2, column 2, paragraph 2). Surur further specifies that intermolecular interactions between sulfur and biological targets are well-documented: sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals (page 2, column 2, paragraph 3). Additionally, Surur teaches sulfides often exist as bridging elements, because they exhibit favorable structural characteristics over conventional ethers: sulfides feature longer bonds and narrow central bond angle (page 2, column 2, paragraph 1). Further, Surur specifies that sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits (page 3, column 2, paragraph 2).
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 simply substitute the methylene and heteroatom placements on the western side chain of ‘429 as well as substitute the nitrogen heteroatom for a sulfur heteroatom as taught by Surur with the scaffold of Jung to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘429 teaches a compound of Formula (I):
PNG
media_image5.png
187
225
media_image5.png
Greyscale
,
-Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives,
-Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
PNG
media_image1.png
239
361
media_image1.png
Greyscale
,
-Jung teaches R6 (R2 in the instant application) is C1-C6 alkyl, which significantly overlaps with the instant application (C1-C4 alkyl),
-Surur teaches sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur,
-Surur teaches C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens,
-Surur teaches sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals,
-Surur teaches sulfides feature longer bonds and narrow central bond angle, and
-Surur teaches sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element (the nitrogen heteroatom) for another (a sulfur heteroatom) to predictably arrive at a compound of Formula (I):
PNG
media_image3.png
158
213
media_image3.png
Greyscale
, specifically the compound: 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
PNG
media_image2.png
224
467
media_image2.png
Greyscale
. See MPEP § 2143(B).
Regarding claim 2, Jung teaches R1 is n-butyl (compound 1, column 3, lines 25-27).
Regarding claim 4, Jung teaches R2 is n-butyl (compound 1, column 3, lines 25-27). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05. The range of the claimed invention (C1-C4 alkyl chain) significantly overlaps with the range of Jung (C1-C6 alkyl chain) and the claimed invention does not provide an unexpected result in view of Jung, who describes compounds for inhibition of liver bile acid transport to treat constipation (column 1, lines 45-55). Additionally, at the time of invention, there was a recognized problem in the art (bile acid resportion heavily affects constipation), a finite number of identified predictable potential solutions (C1-C6 alkyl), and one of ordinary skill in the art would have pursued the solution of changing the size of the eastern sidechains from butyl to ethyl as taught by Jung. Thus, Jung teaches R2 is ethyl.
Regarding claim 5, Jung teaches R3 is hydrogen, 4-methoxy, 4-hydroxy, 3-methoxy, 4-fluoro, 3-fluoro, and 3-fluoro,4-methoxy (column 3, lines 25-27, compound 1; column 4, lines 16-33, compounds 20-24).
Regarding claim 6, Jung teaches R4 is methylthio (column 3, lines 25-27, compound 1). Additionally, June suggests R4 is ethylthio, because Jung allows for variability at the 7-position of the bicyclic scaffold through specifying R5 preferably is (C1-C4alkyl)thio (column 2, line 50).
Regarding claim 7, ‘429 teaches R5A and R5B together form a cyclopropyl ring: 1-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (claim 2 of ‘429).
Regarding claim 9, Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid (compound 1, column 3, lines 25-27). Additionally, Jung suggests R2 is methyl and ethyl, because Jung allows for variability on the alkyl side chains of the 7-membered ring through specifying R6 and R7 preferably are independently C1-C6 alkyl chain (column 2, line 51). Further, Jampilek teaches simple substitution of nitrogen to sulfur for modulation of ADME properties (page 1, paragraph 1).
Regarding claim 10, ‘429 teaches a pharmaceutical composition (claim 3 of ‘429).
7. Claims 1-2, 4-7, and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-7, and 10 of U.S. Application No. 18/164,185 in view of Surur (Arch Pharm Chem Life Sci, 2019, 352(e1800248), 1-11).
U.S. Patent No. 18/164,185 claims a compound of Formula (I):
PNG
media_image6.png
184
273
media_image6.png
Greyscale
, wherein R2 is methyl, ethyl, n-propyl, or n-butyl; R3 is independently hydrogen, halogen, hydroxy, C1-C4 alkoxy; R4 is a halogen, methoxy, ethoxy, methylthio, ethylthio, dimethylamino; R5A is hydrogen or methyl.
Regarding claim 1, ‘185 fails to teach a compound of Formula (I):
PNG
media_image3.png
158
213
media_image3.png
Greyscale
, nor the compound, 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
PNG
media_image2.png
224
467
media_image2.png
Greyscale
.
Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives (abstract). Jung specifically teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
PNG
media_image1.png
239
361
media_image1.png
Greyscale
(column 3, lines 25-27, compound 1). While Jung only exemplifies n-butyl alkyl chains, Jung teaches that the eastern side chains of R6 and R7 (R1 and R2 in the instant application) are independently a C1-C6 alkyl chain (column 2, line 51). Jung additionally teaches that the compounds therein have an asymmetric carbon center in the core scaffold and thus are present as the R and S stereoisomers and racemate (column 6, lines 1-6).
Surur teaches that sulfur is the fifth most prevalent element in drugs of biological significance and that sulfide incorporation in drug design is a result of ease and efficiency of available assembly routes as well as sulfide properties (page 2, column 1, paragraphs 2-3; page 2, column 2, paragraphs 2-3). Surur teaches that sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur (page 2, column 2, paragraph 2). The C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens (page 2, column 2, paragraph 2). Surur further specifies that intermolecular interactions between sulfur and biological targets are well-documented: sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals (page 2, column 2, paragraph 3). Additionally, Surur teaches sulfides often exist as bridging elements, because they exhibit favorable structural characteristics over conventional ethers: sulfides feature longer bonds and narrow central bond angle (page 2, column 2, paragraph 1). Further, Surur specifies that sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits (page 3, column 2, paragraph 2).
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 simply substitute the methylene and heteroatom placements on the western side chain of ‘185 as well as substitute the nitrogen heteroatom for a sulfur heteroatom as taught by Surur with the scaffold of Jung to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘185 teaches a compound of Formula (I):
PNG
media_image6.png
184
273
media_image6.png
Greyscale
,
-Jung teaches compounds and compositions of aminoalkylbenzothiazepine derivatives,
-Jung teaches 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid, which has structure:
PNG
media_image1.png
239
361
media_image1.png
Greyscale
,
-Jung teaches R6 (R2 in the instant application) is C1-C6 alkyl, which significantly overlaps with the instant application (C1-C4 alkyl),
-Surur teaches sulfides can take part in attractive non-bonding interactions, which maintain the active conformation of the molecule, due to the low-lying C-S σ* orbital on sulfur,
-Surur teaches C-S σ* orbital allows for the phenomenon known as σ-holes, which possess a positive electrostatic potential and can interact with electron donating nitrogen or oxygen atoms, and sulfur can donate electrons into the σ-holes of various halogens,
-Surur teaches sulfur-aromatic interactions are common in proteins and have significant impact on recognition and binding of pharmaceuticals,
-Surur teaches sulfides feature longer bonds and narrow central bond angle, and
-Surur teaches sulfides undergo rapid oxidative metabolism, which can be of paramount importance if the aftermath of long-lasting activity outweighs the short term benefits.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element (the nitrogen heteroatom) for another (a sulfur heteroatom) to predictably arrive at a compound of Formula (I):
PNG
media_image3.png
158
213
media_image3.png
Greyscale
, specifically the compound: 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, which has structure:
PNG
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224
467
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Greyscale
. See MPEP § 2143(B).
Regarding claim 2, ‘185 teaches R1 is n-butyl (claim 1 of ‘185).
Regarding claim 4, ‘185 teaches R2 is ethyl (claims 1, 4, and 5 of ‘185).
Regarding claim 5, ‘185 teaches R3 is hydrogen, halogen, hydroxy, or C1-C4 alkoxy (claim 2 of ‘185).
Regarding claim 6, ‘185 teaches R4 is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, N,N-di(C1-C4 alkyl)amino, or C1-C4 alkylthio (claim 2 of ‘185).
Regarding claim 7, ‘185 teaches R5A and R5B are hydrogen or methyl (claim 3 of ‘185).
Regarding claim 9, ‘185 teaches (R)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)propanoic acid (claim 9 of ‘185). Jung teaches the methylene and heteroatom positions adjacent to the phenyl ring on the western side chain swap (compound 1, column 3, lines 25-27). Jampilek teaches simple substitution of nitrogen to sulfur for modulation of ADME properties (page 1, paragraph 1).
Regarding claim 10, ‘185 teaches a pharmaceutical composition (claim 12 of ‘185).
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