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, 63/162,494 and PCT/US2022/02474, with the effective filing dates of 17 March 2021 and 16 March 2022, respectively.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed,
23 February 2026.
Applicant’s election without traverse of Group I (claims 1-28) and Compound I-26 (
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) in the reply filed on 23 February 2026 is acknowledged.
Claims 16-21 were canceled.
Claims 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group (Group II: claims 29-30), there being no allowable generic or linking claim.
Claims 1-3, 6-10, 12-13, 22-24, and 27-28 read on the elected species. The elected species, I-26 (
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) is free of the prior art. Thus, the search was expanded to include all compounds of claim 27 and the genus of claim 1. The closest prior art is Papaioannou (WO2019/178129, published 19 Sept 2019, see IDS filed 17 Feb 2019).
Information Disclosure Statement
The Information Disclosure Statements filed on 17 February 2026 and the references cited therein have been considered, unless indicated otherwise.
The references, wherein a copy was not provided, are lined through. These references are the following: Database Registry RN 1027012-72-1.
The references, wherein a copy was provided but is illegible, are lined through. These references are the following: Hampton (2019, poster) and Longhurst (2019, poster).
Claim Objections
1. Claims 3, 7, 13, 22-24, and 26 are objected to because of the following informalities: lack of comma and/or conjunction to separate the options. Claim 3 recites that CyA is selected from the group consisting of:
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, but claim 3 does not separate the options via comma nor specify a conjunction (i.e. “and” or “or). Similarly, claim 13 recites that L’ is
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, but claim 13 does not specify a conjunction. Thus, claims 3, 7, 23-24, and 26 do not separate the options via comma nor specify a conjunction, and claims 13 and 22 do not specify a conjunction.
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 26-27 are 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.
Claim 26 specifies the group, R0, but does not define it. Claim 26 depends upon claim 1, which also does not define R0. Thus, it is unclear to the ordinary artisan what R0 encompasses. Accordingly, claim 26 lacks antecedent basis.
Claim 27 depends upon claim 1 and recites the compounds are selected from Compounds I-1 through I-108; however, claim 27 does not recite the names or structures of Compound I-1 through I-108 and instead refers to the specification. Accordingly, claim 27 lacks antecedent basis.
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.
3. Claim(s) 1-15 and 22-28 are rejected under 35 U.S.C. 103 as being unpatentable over Papaioannou (WO2019/178129, published 19 Sept 2019, see IDS filed 17 February 2026) in view of Xie (Euro J Med Chem, 2020, 190(112137), 1-14), Ghosh 1 (J Med Chem, 2020, 63, 2751-2788), and Ghosh 2 (J Med Chem, 2015, 58, 2895-2940).
Papaioannou teaches plasma kallikrein inhibitors of the core scaffold,
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(abstract).
Papaioannou specifically teaches
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(page 92).
Regarding claim 1, Papaioannou fails to teach a urea or carbamate (urethane) of formula (I).
Xie teaches that plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy (page 2, column 1, paragraph 1; page 2, column 2, paragraph 3; page 3, column 2, paragraph 5). Xie further teaches the SAR of several plasma kallikrein inhibitors (page 2, column 1, paragraph 3). Xie additionally teaches representative peptidomimetic plasma kallikrein inhibitors in an approximation of the binding pocket (Figure 3, page 6). Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B (Figures 11-12, page 12).
Ghosh 1 teaches incorporation of ureas in medicinal chemistry (abstract). Ghosh 1 specifies that the urea functionality is increasingly used in medicinal chemistry in order to establish key drug-target interactions and fine-tune crucial drug-like properties (abstract).
Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry (abstract). Ghosh 2 specifies that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates (page 2895, column 1, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to simply modify the scaffold of Papaioannou to incorporate a urea as taught by Ghosh 1 or a carbamate as taught by Ghosh 2 to obtain a compound of Formula (I):
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, 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:
-Papaioannou teaches compounds of a core scaffold:
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that are inhibitors of plasma kallikrein,
-Papaioannou teaches
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, wherein CyA is a 5-membered monocyclic heteroarylene,
-Papaioannou teaches that plasma kallikrein is a serine protease zymogen in blood that contributes to the innate inflammatory response and intrinsic cascade of blood coagulation ([0001]),
-Papaioannou teaches that plasma kallikrein is associated with a number of disorders, such as hereditary angioedema, an autosomal dominant disease, characterized by painful, recurrent attacks of inflammation ([0002]),
-Xie teaches plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy,
--Xie teaches the SAR of several plasma kallikrein inhibitors,
-Xie teaches nicotinamide scaffolds are potent plasma kallikrein inhibitors (Compound 42; page 8, column 2, paragraph 1),
-Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B,
-Xie teaches inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors (specifically Compound 26:
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) in a crystal complex of plasma kallikrein (Figure 4, page 7; Figure 11, page 12),
-Xie teaches CyA is a 7- to 12-membered heteroarylene as Compound 36:
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(Figure 5, page 8), which would engage in hydrogen-bonding,
-Xie teaches the middle scaffold has hydrogen-bonding opportunities with Gly 480 and Ser478 and that a heterocyclic ring in fragment A or in the middle scaffold typically forms the H-bonding bridges (page 10, column 2, paragraph 2; Figure 11B, page 12),
-Ghosh 1 teaches that urea has a central role in drug development and medicinal chemistry due to its ability to form multiple stable hydrogen bonds with protein and receptor targets and that drug-target interactions are responsible for specific biological activity, drug actions, and drug properties (page 2751, column 1, paragraph 1),
-Ghosh 1 teaches modulation of hydrogen bonding capabilities of urea via electron donating and electron withdrawing functionalities (page 2754, column 1, paragraph 1),
-Ghosh 1 teaches that water solubility is enhanced by disrupting molecular planarity of the solutes in order to reduce their crystal packing energy via introduction of a substituent onto the urea (page 2754, column 2, paragraph 2; Figure 9, page 2754),
-Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry,
-Ghosh 2 teaches that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates,
-Ghosh 2 teaches that carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry due to their chemical stability and capability to permeate cell membranes (page 2895, column 1, paragraph 1),
-Ghosh 2 teaches that carbamates are able to modulate inter- and intramolecular interactions with target enzymes or receptor and impose a degree of conformational restriction due to delocalization of non-bonded electrons on the nitrogen into the carboxyl moiety (page 2895, column 1, paragraph 1), and
-Ghosh 2 teaches that carbamates engage in hydrogen bonding (page 2895, column 1, paragraph 1).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the amide of Papaioannou) to incorporate a nitrogen or oxygen (to form the urea or carbamate) to predictably arrive at a compound of Formula (I):
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.
Regarding claim 2, Papaioannou teaches the compound,
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(page 92), in which CyA is a 5-membered monocyclic heteroarylene. Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Papaioannou teaches that Compound I-5 has an in vitro dose response of A, which corresponds to ≤ 1.0 nM (Table 1, page 632). Thus, the combination of Papaioannou and Xie teaches a compound wherein CyA is a 5- to 6-membered monocyclic heteroaryl.
Regarding claim 3, Papaioannou teaches compounds in which CyA is a pyridine,
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(Compound I-3, page 89). Additionally, Xie teaches Compounds 42 and 43:
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and
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(page 9). Pyridine is capable of hydrogen bonding, and Compounds 42-44 showed good activity as plasma kallikrein inhibitors (IC50 < 0.1 uM). Thus, a person of ordinary skill in the art would substitute the pyrazole of Papaioannou to a pyridine.
Regarding claim 4, Xie teaches Compounds with a 7- to 12-membered bicyclic heterarylene,
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(Figure 6, page 8). Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the pyrazole of Papaioannou to a 7- to 12-membered bicyclic heteroarylene as taught by Xie.
Regarding claim 5, Papaioannou teaches incorporation of a triazolopyridinyl group ([0056]; [0058]). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the pyrazole of Papaioannou to a triazolopyridinyl as taught by Papaioannou and Xie.
Regarding claim 6, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of Papaioannou for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 7, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of Papaioannou for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 8, Xie teaches Compound 37, wherein CyB (Fragment B in pink) has Rb is a halogen:
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(page 8). Papaioannou also teaches Rb is a substituted C1-6 aliphatic (Compound I-8, page 96) or a halogen (Compound I-11, page 101). Xie teaches Compound 30, wherein addition of an F atom to the phenyl ring of CyB resulted in maintenance of activity (page 7, column 1, paragraph 1; Figure 5, page 8). Additionally, Xie teaches shifting the position of the halogen around CyB of fragment B provided compounds that maintained activity (Figure 6, page 8; page 8, column 1, paragraph 1). Further, Compound 16, which incorporated a halogen on CyB, possessed good selectivity for plasma kallikrein (page 6, column 2, paragraph 1; Figure 4, page 7).
Regarding claim 9, Xie teaches L is a substituted C1-3 hydrocarbon chain in Compounds 16:
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(Figure 4, page 7). Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Thus, a person of skill in the art would incorporate a C1-3 hydrocarbon chain from Fragment A in order to shape the compound correctly in the binding pocket to best facilitate hydrogen bonding interactions with Ser478 and Gly 480.
Regarding claim 10, Xie teaches L is *OCH2CH2 as Compound 17:
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(Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2.
Regarding claim 11, Xie teaches L is an optionally substituted 5-membered saturated heterocyclene,
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, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Thus, a person of ordinary skill in the art would make a compound wherein L is a 5-membered saturated heterocycle.
Regarding claim 12, Papaioannou teaches the compound,
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, in which L’ is an optionally substituted C1-3 hydrocarbon chain (page 92). Papaioannou teaches that Compound I-5 has an in vitro dose response of A, which corresponds to ≤ 1.0 nM (Table 1, page 632). Thus, a person of ordinary skill in the art would make a compound wherein L is a C1-3 hydrocarbon chain.
Regarding claim 13, Papaioannou teaches L’ is CH2 (Compound I-5, page 92). Additionally, Papaioannou teaches that L’ is
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(
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, Compound I-124, Example 124, page 257). Papaioannou teaches that Compounds I-5 and I-124 have an in vitro dose response of A and B, respectively, which correspond to A ≤ 1.0 nM and 1.0 nM ≤ B ≤ 10 nM (Table 1, page 632). Thus, a person of ordinary skill in the art would make a compound wherein L’ is a C1-3 hydrocarbon chain.
Regarding claim 14, Papaioannou teaches compounds having a 3- to 7-membered heterocycle as Compounds I-102 and I-265b: :
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and
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(pages 229 and 553). Both compounds have potent activity at ≤1.0 nM (Table 1, page 632). Further, Xie teaches that Fragment A has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). CyB of the claimed invention would be in Fragment B of Xie and thus has a hydrogen bonding opportunity with Asp572. Accordingly, a person of skill in the art would incorporate an azetidine or oxetane into the structure of Papaioannou in order to place Fragment B into a better position to form a hydrogen bond with Asp572.
Regarding claim 15, Papaioannou teaches compounds having a 4-membered heterocycle as Compounds I-102 and I-265b: :
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and
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(pages 229 and 553). Both compounds have potent activity at ≤1.0 nM (Table 1, page 632). Further, Xie teaches that Fragment A has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). CyB of the claimed invention would be in Fragment B of Xie and thus has a hydrogen bonding opportunity with Asp572. Accordingly, a person of skill in the art would incorporate an azetidine or oxetane into the structure of Papaioannou in order to place Fragment B into a better position to form a hydrogen bond with Asp572.
Regarding claim 22, Papaioannou teaches Compound I-5,
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(page 92). Papaioannou teaches that Compound I-5 has an in vitro dose response of A, which corresponds to ≤ 1.0 nM (Table 1, page 632). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of Papaioannou (Ghosh 1: (page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). Thus, the combination of Papaioannou, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula (II-a) and (II-b).
Regarding claim 23, Papaioannou teaches Compound I-5,
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(page 92). Papaioannou teaches that Compound I-5 has an in vitro dose response of A, which corresponds to ≤ 1.0 nM (Table 1, page 632). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of Papaioannou (Ghosh 1: (page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of Papaioannou for the pyridine and pyrimidine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of Papaioannou, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas III-a-2 – III-a-3 and Formulas III-b-2 – III-b-3.
Regarding claim 24, Papaioannou teaches Compound I-5,
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(page 92). Papaioannou further teaches CyA is a pyridine,
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(Compound I-3, page 89). Papaioannou teaches that Compounds I-5 and I-3 have an in vitro dose response of A and C, respectively, which corresponds to A ≤ 1.0 nM and 10 nM ≤ C ≤ 100 nM (Table 1, page 632). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of Papaioannou (Ghosh 1: (page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of Papaioannou for the pyridine and pyrimidine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of Papaioannou, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas IV-a-1 – IV-a-2 and Formulas IV-b-1 – IV-b-2.
Regarding claim 25, Papaioannou teaches compounds having a 4-membered heterocycle as Compounds I-102 and I-265b: :
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(pages 229 and 553). Both compounds have potent activity at ≤1.0 nM (Table 1, page 632). Further, Xie teaches that Fragment A has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). CyB of the claimed invention would be in Fragment B of Xie and thus has a hydrogen bonding opportunity with Asp572. Accordingly, a person of skill in the art would incorporate an azetidine or oxetane into the structure of Papaioannou in order to place Fragment B into a better position to form a hydrogen bond with Asp572. Further, Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of Papaioannou (Ghosh 1: (page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Accordingly, the combination of Papaioannou, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas IV-a-1 – IV-a-2 and Formulas V.
Regarding claim 26, Papaioannou teaches Compound I-5,
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(page 92). Papaioannou teaches that Compound I-5 has an in vitro dose response of A, which corresponds to ≤ 1.0 nM (Table 1, page 632). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of Papaioannou (Ghosh 1: (page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches L is *OCH2CH2 as Compound 17:
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( Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by only a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2. Additionally, Xie teaches incorporation of pyrrolidine, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Accordingly, the combination of Papaioannou, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula VI-b and VI-c.
Regarding claim 27, Papaioannou teaches Compound I-5,
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(page 92). Papaioannou teaches that Compound I-5 has an in vitro dose response of A, which corresponds to ≤ 1.0 nM (Table 1, page 632). Additionally, Xie teaches that Fragment A/the middle scaffold has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12), leading a person of ordinary skill in the art to select the cyclopropyl-benzoimidazole of I-5 from Papaioannou. CyC of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480.
Xie teaches L is an optionally substituted 5-membered saturated heterocyclene,
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, which showed good inhibitory activity and provides a similar shape to Compound 26:
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, which was potent and selective for plasma kallikrein (Figure 8, page 9; Figure 4, page 7). Thus, a person of ordinary skill in the art would select the pyrrolidone of Xie, because compounds that incorporated it showed potency against and selectivity for plasma kallikrein over FXIa.
Further, Xie teaches Compound 43:
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(page 9). Pyridine is capable of hydrogen bonding, and Compound 43 showed good activity as plasma kallikrein inhibitors (IC50 < 0.1 uM). Thus, a person of ordinary skill in the art would substitute the pyrazole of Papaioannou to a pyridine for CyA. Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Thus, a person of skill in the art would modify the pyridine of the middle scaffold in Compound I-5 to a pyrimidine.
Further, Ghosh 1 teaches incorporation of a urea into the core scaffold of Papaioannou to provide further hydrogen-bonding opportunities (abstract; page 2754, column 1, paragraph 1) and place Compound I-33 (
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) of the claimed invention in a similar configuration to Compound 26 (
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) of Xie (Figure 4, page 7). Thus, a person of skill in the art would modify the amide core of Compound I-5 of Papaioannou to a urea.
Additionally, Papaioannou teaches compounds having a 4-membered heterocycle as Compounds I-102 and I-265b: :
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and
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(pages 229 and 553). Both compounds have potent activity at ≤1.0 nM (Table 1, page 632). Further, Xie teaches that Fragment A has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). CyB of the claimed invention would be in Fragment B of Xie and thus has a hydrogen bonding opportunity with Asp572. Accordingly, a person of skill in the art would incorporate an azetidine or oxetane into the structure of Papaioannou in order to place Fragment B into a better position to form a hydrogen bond with Asp572.
Finally, Xie teaches CyB is a 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Further, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of Papaioannou for the pyridine of Xie, because pyridine is capable of forming a hydrogen bond with Asp572 and is smaller than benzimidazole.
Accordingly, the combination of Papaioannou, Ghosh 1, and Xie teaches Compound I-33:
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.
Thus, the combination of Papaioannou, Ghosh 1, and Xie teaches a compound of claim 27.
Regarding claim 28, Papaioannou teaches a pharmaceutical composition ([0093]).
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.
4. Claim 1-12, 22-24, 26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 27-28 of U.S. Application No. 18/550,504 in view of Xie (Euro J Med Chem, 2020, 190(112137), 1-14), Ghosh 1 (J Med Chem, 2020, 63, 2751-2788), and Ghosh 2 (J Med Chem, 2015, 58, 2895-2940).
Although the claims at issue are not identical, they are not patentably distinct from each other.
U.S. Application No. 18/550,504 claims a compound of Formula (I):
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, wherein CyA is phenylene or a heteroarylene; CyB is phenylene or heteroarylene; L is an optionally substituted C1-3 hydrocarbon chain or a 5- to 6-membered heterocyclene; X is O or NRy; L’ is a covalent bond or optionally substituted C1-3 hydrocarbon chain; R3-R7 are independently selected from hydrogen or Lc-Rc; and CyC is a 8- to 10-membered bicyclic aryl, phenyl, or a 5- to 6-membered or 7- to 10-membered heteroaryl. Further, ‘504 claims a method of treating plasma kallikrein-mediated diseases or disorders using a compound of claim 1 (claim 29).
Regarding claim 1, ‘504 fails to teach a urea in the core scaffold.
Xie teaches that plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy (page 2, column 1, paragraph 1; page 2, column 2, paragraph 3; page 3, column 2, paragraph 5). Xie further teaches the SAR of several plasma kallikrein inhibitors (page 2, column 1, paragraph 3). Xie additionally teaches representative peptidomimetic plasma kallikrein inhibitors in an approximation of the binding pocket (Figure 3, page 6). Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B (Figures 11-12, page 12).
Ghosh 1 teaches incorporation of ureas in medicinal chemistry (abstract). Ghosh 1 specifies that the urea functionality is increasingly used in medicinal chemistry in order to establish key drug-target interactions and fine-tune crucial drug-like properties (abstract).
Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry (abstract). Ghosh 2 specifies that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates (page 2895, column 1, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to simply modify the scaffold of ‘504 to incorporate a urea as taught by Ghosh 1 or a carbamate as taught by Ghosh 2 to obtain a compound of Formula (I):
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, 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:
-‘504 teaches plasma kallikrein inhibitors of Formula (I):
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,
-Xie teaches plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy,
--Xie teaches the SAR of several plasma kallikrein inhibitors,
-Xie teaches nicotinamide scaffolds are potent plasma kallikrein inhibitors (Compound 42; page 8, column 2, paragraph 1),
-Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B,
-Xie teaches inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors (specifically Compound 26:
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) in a crystal complex of plasma kallikrein (Figure 4, page 7; Figure 11, page 12),
-Xie teaches CyA is a 7- to 12-membered heteroarylene as Compound 36:
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(Figure 5, page 8), which would engage in hydrogen-bonding,
-Xie teaches the middle scaffold has hydrogen-bonding opportunities with Gly 480 and Ser478 and that a heterocyclic ring in fragment A or in the middle scaffold typically forms the H-bonding bridges (page 10, column 2, paragraph 2; Figure 11B, page 12),
-Ghosh 1 teaches that urea has a central role in drug development and medicinal chemistry due to its ability to form multiple stable hydrogen bonds with protein and receptor targets and that drug-target interactions are responsible for specific biological activity, drug actions, and drug properties (page 2751, column 1, paragraph 1),
-Ghosh 1 teaches modulation of hydrogen bonding capabilities of urea via electron donating and electron withdrawing functionalities (page 2754, column 1, paragraph 1),
-Ghosh 1 teaches that water solubility is enhanced by disrupting molecular planarity of the solutes in order to reduce their crystal packing energy via introduction of a substituent onto the urea (page 2754, column 2, paragraph 2; Figure 9, page 2754),
-Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry,
-Ghosh 2 teaches that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates,
-Ghosh 2 teaches that carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry due to their chemical stability and capability to permeate cell membranes (page 2895, column 1, paragraph 1),
-Ghosh 2 teaches that carbamates are able to modulate inter- and intramolecular interactions with target enzymes or receptor and impose a degree of conformational restriction due to delocalization of non-bonded electrons on the nitrogen into the carboxyl moiety (page 2895, column 1, paragraph 1), and
-Ghosh 2 teaches that carbamates engage in hydrogen bonding (page 2895, column 1, paragraph 1).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the amide of ‘504) to incorporate a nitrogen or oxygen (to form the urea or carbamate) to predictably arrive at a compound of Formula (I):
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.
Regarding claim 2, ‘504 teaches the compound,
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(claim 27 of ‘504), in which CyA is a 6-membered monocyclic heteroarylene. Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Thus, the combination of ‘504 and Xie teaches a compound wherein CyA is a 5- to 6-membered monocyclic heteroaryl.
Regarding claim 3, ‘504 teaches the compound,
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(claim 27 of ‘504), in which CyA is a pyridine. Additionally, Xie teaches Compounds 42 and 43:
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and
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(page 9). Pyridine is capable of hydrogen bonding, and Compounds 42-44 showed good activity as plasma kallikrein inhibitors (IC50 < 0.1 uM).
Regarding claim 4, Xie teaches Compounds with a 7- to 12-membered bicyclic heterarylene,
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(Figure 6, page 8). Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the pyridine of ‘504 to a 7- to 12-membered bicyclic heteroarylene as taught by Xie.
Regarding claim 5, ‘504 teaches incorporation of a triazolopyridinyl group:
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(Compound I-68; claim 27 of ‘504). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the pyridine of ‘504 to a triazolopyridinyl as taught by ‘504 and Xie.
Regarding claim 6, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘504 for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 7, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘504 for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 8, Xie teaches Compound 37, wherein CyB (Fragment B in pink) has Rb is a halogen:
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(page 8). ‘504 teaches the compound,
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, in which Rb is a substituted C1-6 aliphatic (claim 27 of ‘504). Xie teaches Compound 30, wherein addition of an F atom to the phenyl ring of CyB resulted in maintenance of activity (page 7, column 1, paragraph 1; Figure 5, page 8). Additionally, Xie teaches shifting the position of the halogen around CyB of fragment B provided compounds that maintained activity (Figure 6, page 8; page 8, column 1, paragraph 1). Further, Compound 16, which incorporated a halogen on CyB, possessed good selectivity for plasma kallikrein (page 6, column 2, paragraph 1; Figure 4, page 7).
Regarding claim 9, Xie teaches L is a substituted C1-3 hydrocarbon chain in Compounds 16:
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(Figure 4, page 7). Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Thus, a person of skill in the art would incorporate a C1-3 hydrocarbon chain from Fragment A in order to shape the compound correctly in the binding pocket to best facilitate hydrogen bonding interactions with Ser478 and Gly 480.
Regarding claim 10, Xie teaches L is *OCH2CH2 as Compound 17:
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(Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtained compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2.
Regarding claim 11, Xie teaches L is an optionally substituted 5-membered saturated heterocyclene,
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, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Thus, a person of ordinary skill in the art would make a compound wherein L is a 5-membered saturated heterocycle.
Regarding claim 12, ‘504 teaches the compound,
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, in which L’ is an optionally substituted C1-3 hydrocarbon chain (claim 27 of ‘504). Thus, a person of ordinary skill in the art would make a compound wherein L is a C1-3 hydrocarbon chain.
Regarding claim 22, ‘504 teaches the compound,
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(claim 27 of ‘504). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘504 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). Thus, the combination of ‘504, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula (II-a) and (II-b).
Regarding claim 23, ‘504 teaches the compound,
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(claim 27 of ‘504). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘504 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘504 for the pyridine and pyrimidine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘504, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas III-a-2 – III-a-3 and Formulas III-b-2 – III-b-3.
Regarding claim 24, ‘504 teaches the compound,
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, wherein CyA is a pyrimidine (claim 27 of ‘504). ‘504 further teaches the compound, wherein CyA is a pyridine,
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(claim 27 of ‘504). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘504 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘504 for the pyridine and pyrimidine of Xie and ‘504, because pyridine and pyrimidine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘504, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas IV-a-1 – IV-a-2 and Formulas IV-b-1 – IV-b-2.
Regarding claim 26, ‘504 teaches the compound,
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, wherein CyA is a pyrimidine (claim 27 of ‘504). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘504 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches L is *OCH2CH2 as Compound 17:
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( Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2. Additionally, Xie teaches incorporation of pyrrolidine, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Accordingly, the combination of ‘504, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula VI-b and VI-c.
Regarding claim 28, ‘504 teaches a pharmaceutical composition (claim 28 of ‘504).
5. Claim 1-4, 6-12, 22-24, 26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 31-32 of U.S. Application No. [[xx]] in view of Xie (Euro J Med Chem, 2020, 190(112137), 1-14), Ghosh 1 (J Med Chem, 2020, 63, 2751-2788), and Ghosh 2 (J Med Chem, 2015, 58, 2895-2940).
Although the claims at issue are not identical, they are not patentably distinct from each other.
U.S. Application No. 18/550,306 claims a compound of Formula (I):
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, wherein CyA is phenylene or a heteroarylene; CyB is phenylene, arylene, or heteroarylene; L is an optionally substituted C1-3 hydrocarbon chain or a 5- to 6-membered heterocyclene; L’ is a covalent bond or optionally substituted C1-3 hydrocarbon chain; R3-R5 and R7 are independently selected from hydrogen or Lc-Rc; R6 is CyC; and CyC is a cyclopropyl group substituted with 0-4 Ld-Rd groups. Further, ‘306 claims a method of treating plasma kallikrein-mediated diseases or disorders using a compound of claim 1 (claim 33).
Regarding claim 1, ‘306 fails to teach a urea in the core scaffold.
Xie teaches that plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy (page 2, column 1, paragraph 1; page 2, column 2, paragraph 3; page 3, column 2, paragraph 5). Xie further teaches the SAR of several plasma kallikrein inhibitors (page 2, column 1, paragraph 3). Xie additionally teaches representative peptidomimetic plasma kallikrein inhibitors in an approximation of the binding pocket (Figure 3, page 6). Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B (Figures 11-12, page 12).
Ghosh 1 teaches incorporation of ureas in medicinal chemistry (abstract). Ghosh 1 specifies that the urea functionality is increasingly used in medicinal chemistry in order to establish key drug-target interactions and fine-tune crucial drug-like properties (abstract).
Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry (abstract). Ghosh 2 specifies that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates (page 2895, column 1, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to simply modify the scaffold of ‘306 to incorporate a urea as taught by Ghosh 1 or a carbamate as taught by Ghosh 2 to obtain a compound of Formula (I):
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, 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:
-‘306 teaches plasma kallikrein inhibitors of Formula (I):
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,
-Xie teaches plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy,
--Xie teaches the SAR of several plasma kallikrein inhibitors,
-Xie teaches nicotinamide scaffolds are potent plasma kallikrein inhibitors (Compound 42; page 8, column 2, paragraph 1),
-Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B,
-Xie teaches inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors (specifically Compound 26:
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) in a crystal complex of plasma kallikrein (Figure 4, page 7; Figure 11, page 12),
-Xie teaches CyA is a 7- to 12-membered heteroarylene as Compound 36:
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(Figure 5, page 8), which would engage in hydrogen-bonding,
-Xie teaches the middle scaffold has hydrogen-bonding opportunities with Gly 480 and Ser478 and that a heterocyclic ring in fragment A or in the middle scaffold typically forms the H-bonding bridges (page 10, column 2, paragraph 2; Figure 11B, page 12),
-Ghosh 1 teaches that urea has a central role in drug development and medicinal chemistry due to its ability to form multiple stable hydrogen bonds with protein and receptor targets and that drug-target interactions are responsible for specific biological activity, drug actions, and drug properties (page 2751, column 1, paragraph 1),
-Ghosh 1 teaches modulation of hydrogen bonding capabilities of urea via electron donating and electron withdrawing functionalities (page 2754, column 1, paragraph 1),
-Ghosh 1 teaches that water solubility is enhanced by disrupting molecular planarity of the solutes in order to reduce their crystal packing energy via introduction of a substituent onto the urea (page 2754, column 2, paragraph 2; Figure 9, page 2754),
-Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry,
-Ghosh 2 teaches that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates,
-Ghosh 2 teaches that carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry due to their chemical stability and capability to permeate cell membranes (page 2895, column 1, paragraph 1),
-Ghosh 2 teaches that carbamates are able to modulate inter- and intramolecular interactions with target enzymes or receptor and impose a degree of conformational restriction due to delocalization of non-bonded electrons on the nitrogen into the carboxyl moiety (page 2895, column 1, paragraph 1), and
-Ghosh 2 teaches that carbamates engage in hydrogen bonding (page 2895, column 1, paragraph 1).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the amide of ‘504) to incorporate a nitrogen or oxygen (to form the urea or carbamate) to predictably arrive at a compound of Formula (I):
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.
Regarding claim 2, ‘306 teaches the compound,
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(claim 31 of ‘306), in which CyA is a 6-membered monocyclic heteroarylene. Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Thus, the combination of ‘306 and Xie teaches a compound wherein CyA is a 5- to 6-membered monocyclic heteroaryl.
Regarding claim 3, ‘306 teaches the compound,
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(claim 31 of ‘306), in which CyA is a pyridine. Additionally, Xie teaches Compounds 42 and 43:
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and
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(page 9). Pyridine is capable of hydrogen bonding, and Compounds 42-44 showed good activity as plasma kallikrein inhibitors (IC50 < 0.1 uM).
Regarding claim 4, Xie teaches Compounds with a 7- to 12-membered bicyclic heterarylene,
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(Figure 6, page 8). Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the pyridine of ‘306 to a 7- to 12-membered bicyclic heteroarylene as taught by Xie.
Regarding claim 6, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘306 for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 7, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘306 for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 8, Xie teaches Compound 37, wherein CyB (Fragment B in pink) has Rb is a halogen:
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(page 8). ‘306 teaches the compound,
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, in which Rb is a substituted C1-6 aliphatic (claim 31 of ‘306). Xie teaches Compound 30, wherein addition of an F atom to the phenyl ring of CyB resulted in maintenance of activity (page 7, column 1, paragraph 1; Figure 5, page 8). Additionally, Xie teaches shifting the position of the halogen around CyB of fragment B provided compounds that maintained activity (Figure 6, page 8; page 8, column 1, paragraph 1). Further, Compound 16, which incorporated a halogen on CyB, possessed good selectivity for plasma kallikrein (page 6, column 2, paragraph 1; Figure 4, page 7).
Regarding claim 9, Xie teaches L is a substituted C1-3 hydrocarbon chain in Compounds 16:
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(Figure 4, page 7). Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Thus, a person of skill in the art would incorporate a C1-3 hydrocarbon chain from Fragment A in order to shape the compound correctly in the binding pocket to best facilitate hydrogen bonding interactions with Ser478 and Gly 480.
Regarding claim 10, Xie teaches L is *OCH2CH2 as Compound 17:
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(Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2.
Regarding claim 11, Xie teaches L is an optionally substituted 5-membered saturated heterocyclene,
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, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Thus, a person of ordinary skill in the art would make a compound wherein L is a 5-membered saturated heterocycle.
Regarding claim 12, ‘306 teaches the compound,
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, in which L’ is an optionally substituted C1-3 hydrocarbon chain (claim 31 of ‘306). Thus, a person of ordinary skill in the art would make a compound wherein L is a C1-3 hydrocarbon chain.
Regarding claim 22, ‘306 teaches the compound,
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(claim 31 of ‘306). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘306 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). Thus, the combination of ‘306, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula (II-a) and (II-b).
Regarding claim 23, ‘306 teaches the compound,
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(claim 31 of ‘306). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘306 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘306 for the pyridine and pyrimidine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘306, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas III-a-2 – III-a-3 and Formulas III-b-2 – III-b-3.
Regarding claim 24, ‘306 teaches the compound,
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, wherein CyA is a pyrimidine (claim 27 of ‘504). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘306 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘306 for the pyridine and pyrimidine of Xie, because pyridine and pyrimidine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘306, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas IV-a-1 – IV-a-2 and Formulas IV-b-1 – IV-b-2.
Regarding claim 26, ‘306 teaches the compound,
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, wherein CyA is a pyrimidine (claim 31 of ‘306). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘306 (Ghosh 1: (page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches L is *OCH2CH2 as Compound 17:
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( Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2. Additionally, Xie teaches incorporation of pyrrolidine, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Accordingly, the combination of ‘306, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula VI-b and VI-c.
Regarding claim 28, ‘306 teaches a pharmaceutical composition (claim 32 of ‘306).
6. Claims 1-4, 6-12, 22-24, 26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 17-18 of U.S. Patent No. 11,787,796 in view of Xie (Euro J Med Chem, 2020, 190(112137), 1-14), Ghosh 1 (J Med Chem, 2020, 63, 2751-2788), and Ghosh 2 (J Med Chem, 2015, 58, 2895-2940).
Although the claims at issue are not identical, they are not patentably distinct from each other.
U.S. Application No. 11,787,796 claims a compound of Formula (I):
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, wherein CyA is a 5-membered monocyclic heteroaryl or a 7- to 10-membered partially unsaturated bicyclic heterocycle; L is optionally substituted C1-6 hydrocarbon chain; CyB is phenyl, a 5- to 6-membered monocyclic heteroaryl, a 7- to 10-membered partially unsaturated bicyclic carbocycle, a 10-membered bibcyclic aryl, a 7- to 10-membered bicyclic heterocycle, a 12-membered tricyclic heterocycle; R1 and R2 are independently selected from hydrogen, halogen, OR, N(R)2, and optionally substituted C1-6 aliphatic; R1 and CyA may be taken together to form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocycle; R3, R4, R5, and R7 are independently selected from hydrogren, halogen, CN, or an optionally substituted C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl, a 3- to 7-membered saturated or partially unsaturated carbocycle or heterocycle; R6 is an optionally substituted C1-6 aliphatic (claim 1).
Regarding claim 1, ‘796 fails to teach a urea in the core scaffold.
Xie teaches that plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy (page 2, column 1, paragraph 1; page 2, column 2, paragraph 3; page 3, column 2, paragraph 5). Xie further teaches the SAR of several plasma kallikrein inhibitors (page 2, column 1, paragraph 3). Xie additionally teaches representative peptidomimetic plasma kallikrein inhibitors in an approximation of the binding pocket (Figure 3, page 6). Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B (Figures 11-12, page 12).
Ghosh 1 teaches incorporation of ureas in medicinal chemistry (abstract). Ghosh 1 specifies that the urea functionality is increasingly used in medicinal chemistry in order to establish key drug-target interactions and fine-tune crucial drug-like properties (abstract).
Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry (abstract). Ghosh 2 specifies that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates (page 2895, column 1, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to simply modify the scaffold of ‘796 to incorporate a urea as taught by Ghosh 1 or a carbamate as taught by Ghosh 2 to obtain a compound of Formula (I):
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, 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:
-‘796 teaches plasma kallikrein inhibitors of Formula (I):
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,
-Xie teaches plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy,
--Xie teaches the SAR of several plasma kallikrein inhibitors,
-Xie teaches nicotinamide scaffolds are potent plasma kallikrein inhibitors (Compound 42; page 8, column 2, paragraph 1),
-Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B,
-Xie teaches inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors (specifically Compound 26:
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) in a crystal complex of plasma kallikrein (Figure 4, page 7; Figure 11, page 12),
-Xie teaches CyA is a 7- to 12-membered heteroarylene as Compound 36:
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(Figure 5, page 8), which would engage in hydrogen-bonding,
-Xie teaches the middle scaffold has hydrogen-bonding opportunities with Gly 480 and Ser478 and that a heterocyclic ring in fragment A or in the middle scaffold typically forms the H-bonding bridges (page 10, column 2, paragraph 2; Figure 11B, page 12),
-Ghosh 1 teaches that urea has a central role in drug development and medicinal chemistry due to its ability to form multiple stable hydrogen bonds with protein and receptor targets and that drug-target interactions are responsible for specific biological activity, drug actions, and drug properties (page 2751, column 1, paragraph 1),
-Ghosh 1 teaches modulation of hydrogen bonding capabilities of urea via electron donating and electron withdrawing functionalities (page 2754, column 1, paragraph 1),
-Ghosh 1 teaches that water solubility is enhanced by disrupting molecular planarity of the solutes in order to reduce their crystal packing energy via introduction of a substituent onto the urea (page 2754, column 2, paragraph 2; Figure 9, page 2754),
-Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry,
-Ghosh 2 teaches that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates,
-Ghosh 2 teaches that carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry due to their chemical stability and capability to permeate cell membranes (page 2895, column 1, paragraph 1),
-Ghosh 2 teaches that carbamates are able to modulate inter- and intramolecular interactions with target enzymes or receptor and impose a degree of conformational restriction due to delocalization of non-bonded electrons on the nitrogen into the carboxyl moiety (page 2895, column 1, paragraph 1), and
-Ghosh 2 teaches that carbamates engage in hydrogen bonding (page 2895, column 1, paragraph 1).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the amide of ‘796) to incorporate a nitrogen or oxygen (to form the urea or carbamate) to predictably arrive at a compound of Formula (I):
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.
Regarding claim 2, ‘796 teaches the compound,
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(claim 27 of ‘796), in which CyA is a 6-membered monocyclic heteroarylene. Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Thus, the combination of ‘796 and Xie teaches a compound wherein CyA is a 5- to 6-membered monocyclic heteroaryl.
Regarding claim 3, ‘796 teaches the compound,
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(claim 17 of ‘796), in which CyA is a pyridine. Additionally, Xie teaches Compounds 42 and 43:
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and
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(page 9). Pyridine is capable of hydrogen bonding, and Compounds 42-44 showed good activity as plasma kallikrein inhibitors (IC50 < 0.1 uM).
Regarding claim 4, Xie teaches Compounds with a 7- to 12-membered bicyclic heterarylene,
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(Figure 6, page 8). Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the pyridine of ‘796 to a 7- to 12-membered bicyclic heteroarylene as taught by Xie.
Regarding claim 6, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would utilize a pyridine like ‘976, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 7, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would utilize a pyridine like ‘976, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 8, Xie teaches Compound 37, wherein CyB (Fragment B in pink) has Rb is a halogen:
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(page 8). ‘976 teaches the compound,
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, in which Rb is a substituted C1-6 aliphatic (claim 17 of ‘976). Xie teaches Compound 30, wherein addition of an F atom to the phenyl ring of CyB resulted in maintenance of activity (page 7, column 1, paragraph 1; Figure 5, page 8). Additionally, Xie teaches shifting the position of the halogen around CyB of fragment B provided compounds that maintained activity (Figure 6, page 8; page 8, column 1, paragraph 1). Further, Compound 16, which incorporated a halogen on CyB, possessed good selectivity for plasma kallikrein (page 6, column 2, paragraph 1; Figure 4, page 7).
Regarding claim 9, Xie teaches L is a substituted C1-3 hydrocarbon chain in Compounds 16:
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(Figure 4, page 7). Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Thus, a person of skill in the art would incorporate a C1-3 hydrocarbon chain from Fragment A in order to shape the compound correctly in the binding pocket to best facilitate hydrogen bonding interactions with Ser478 and Gly 480.
Regarding claim 10, Xie teaches L is *OCH2CH2 as Compound 17:
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(Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2.
Regarding claim 11, Xie teaches L is an optionally substituted 5-membered saturated heterocyclene,
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, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Thus, a person of ordinary skill in the art would make a compound wherein L is a 5-membered saturated heterocycle.
Regarding claim 12, ‘976 teaches the compound,
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, in which L’ is an optionally substituted C1-3 hydrocarbon chain (claim 17 of ‘976). Thus, a person of ordinary skill in the art would make a compound wherein L is a C1-3 hydrocarbon chain.
Regarding claim 22, ‘976 teaches the compound,
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(claim 17 of ‘976). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘976 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). Thus, the combination of ‘976, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula (II-a) and (II-b).
Regarding claim 23, ‘976 teaches the compound,
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(claim 17 of ‘976). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘976 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would utilize the pyridine of ‘976 for the pyridine and pyrimidine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘976, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas III-a-2 – III-a-3 and Formulas III-b-2 – III-b-3.
Regarding claim 24, ‘976 teaches the compound,
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, wherein CyA is a pyrimidine (claim 17 of ‘976). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘976 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would utilize the pyridine of ‘976 for the pyridine and pyrimidine of Xie, because pyridine and pyrimidine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘976, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas IV-a-1 – IV-a-2 and Formulas IV-b-1 – IV-b-2.
Regarding claim 26, ‘976 teaches the compound,
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, wherein CyA is a pyrimidine (claim 17 of ‘976). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘976 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches L is *OCH2CH2 as Compound 17:
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(Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2. Additionally, Xie teaches incorporation of pyrrolidine, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Accordingly, the combination of ‘976, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula VI-b and VI-c.
Regarding claim 28, ‘976 teaches a pharmaceutical composition (claim 18 of ‘976).
7. Claim 1-4, 6-12, 22-24, 26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 9, and 13-14 of U.S. Patent No. 11,370,803 in view of Xie (Euro J Med Chem, 2020, 190(112137), 1-14), Ghosh 1 (J Med Chem, 2020, 63, 2751-2788), and Ghosh 2 (J Med Chem, 2015, 58, 2895-2940).
Although the claims at issue are not identical, they are not patentably distinct from each other.
U.S. Application No. 11,370,803 claims a compound of Formula (I):
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, wherein Heterocyclic A is a 5- to 6-membered monocyclic heteroaryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle, 7- to 10-membered saturated or partially unsaturated bicyclic heterocycle, 7- to 10-membered bicyclic heteroaryl; L is optionally substituted C1-6 hydrocarbon chain; R1—R9 are independently selected from hydrogen, halogen, CN, amide, and an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; R’ and R’’ are independently selected from hydrogen, halogen, OR, NR2, and optionally substituted C1-6 aliphatic (claim 1). Further, ‘803 claims a method of treating plasma kallikrein-mediated diseases or disorders using a compound of claim 1 (claim 15).
Regarding claim 1, ‘803 fails to teach a urea in the core scaffold.
Xie teaches that plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy (page 2, column 1, paragraph 1; page 2, column 2, paragraph 3; page 3, column 2, paragraph 5). Xie further teaches the SAR of several plasma kallikrein inhibitors (page 2, column 1, paragraph 3). Xie additionally teaches representative peptidomimetic plasma kallikrein inhibitors in an approximation of the binding pocket (Figure 3, page 6). Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B (Figures 11-12, page 12).
Ghosh 1 teaches incorporation of ureas in medicinal chemistry (abstract). Ghosh 1 specifies that the urea functionality is increasingly used in medicinal chemistry in order to establish key drug-target interactions and fine-tune crucial drug-like properties (abstract).
Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry (abstract). Ghosh 2 specifies that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates (page 2895, column 1, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to simply modify the scaffold of ‘803 to incorporate a urea as taught by Ghosh 1 or a carbamate as taught by Ghosh 2 to obtain a compound of Formula (I):
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, 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:
-‘803 teaches plasma kallikrein inhibitors of Formula (I):
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,
-Xie teaches plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy,
--Xie teaches the SAR of several plasma kallikrein inhibitors,
-Xie teaches nicotinamide scaffolds are potent plasma kallikrein inhibitors (Compound 42; page 8, column 2, paragraph 1),
-Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B,
-Xie teaches inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors (specifically Compound 26:
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) in a crystal complex of plasma kallikrein (Figure 4, page 7; Figure 11, page 12),
-Xie teaches CyA is a 7- to 12-membered heteroarylene as Compound 36:
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(Figure 5, page 8), which would engage in hydrogen-bonding,
-Xie teaches the middle scaffold has hydrogen-bonding opportunities with Gly 480 and Ser478 and that a heterocyclic ring in fragment A or in the middle scaffold typically forms the H-bonding bridges (page 10, column 2, paragraph 2; Figure 11B, page 12),
-Ghosh 1 teaches that urea has a central role in drug development and medicinal chemistry due to its ability to form multiple stable hydrogen bonds with protein and receptor targets and that drug-target interactions are responsible for specific biological activity, drug actions, and drug properties (page 2751, column 1, paragraph 1),
-Ghosh 1 teaches modulation of hydrogen bonding capabilities of urea via electron donating and electron withdrawing functionalities (page 2754, column 1, paragraph 1),
-Ghosh 1 teaches that water solubility is enhanced by disrupting molecular planarity of the solutes in order to reduce their crystal packing energy via introduction of a substituent onto the urea (page 2754, column 2, paragraph 2; Figure 9, page 2754),
-Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry,
-Ghosh 2 teaches that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates,
-Ghosh 2 teaches that carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry due to their chemical stability and capability to permeate cell membranes (page 2895, column 1, paragraph 1),
-Ghosh 2 teaches that carbamates are able to modulate inter- and intramolecular interactions with target enzymes or receptor and impose a degree of conformational restriction due to delocalization of non-bonded electrons on the nitrogen into the carboxyl moiety (page 2895, column 1, paragraph 1), and
-Ghosh 2 teaches that carbamates engage in hydrogen bonding (page 2895, column 1, paragraph 1).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the amide of ‘803) to incorporate a nitrogen or oxygen (to form the urea or carbamate) to predictably arrive at a compound of Formula (I):
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.
Regarding claim 2, ‘803 teaches the compound,
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(claims 9 and 13 of ‘803), in which CyA is a 5-membered monocyclic heteroarylene. Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Thus, the combination of ‘803 and Xie teaches a compound wherein CyA is a 5- to 6-membered monocyclic heteroaryl.
Regarding claim 3, ‘803 teaches the compound,
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(claims 9 and 13 of ‘803), in which CyA is a triazole. Additionally, Xie teaches Compounds 42 and 43:
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and
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(middle scaffold; page 9). Pyridine is capable of hydrogen bonding, and Compounds 42-44 showed good activity as plasma kallikrein inhibitors (IC50 < 0.1 uM).
Regarding claim 4, Xie teaches Compounds with a 7- to 12-membered bicyclic heterarylene,
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(Figure 6, page 8). Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the triazole of ‘803 to a 7- to 12-membered bicyclic heteroarylene as taught by Xie.
Regarding claim 6, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘803 for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 7, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘803 for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 8, Xie teaches Compound 37, wherein CyB (Fragment B in pink) has Rb is a halogen:
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(page 8). ‘803 teaches the compound,
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, in which Rb is a substituted C1-6 aliphatic (claims 9 and 13 of ‘803). Xie teaches Compound 30, wherein addition of an F atom to the phenyl ring of CyB resulted in maintenance of activity (page 7, column 1, paragraph 1; Figure 5, page 8). Additionally, Xie teaches shifting the position of the halogen around CyB of fragment B provided compounds that maintained activity (Figure 6, page 8; page 8, column 1, paragraph 1). Further, Compound 16, which incorporated a halogen on CyB, possessed good selectivity for plasma kallikrein (page 6, column 2, paragraph 1; Figure 4, page 7).
Regarding claim 9, Xie teaches L is a substituted C1-3 hydrocarbon chain in Compounds 16:
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(Figure 4, page 7). Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Thus, a person of skill in the art would incorporate a C1-3 hydrocarbon chain from Fragment A in order to shape the compound correctly in the binding pocket to best facilitate hydrogen bonding interactions with Ser478 and Gly 480.
Regarding claim 10, Xie teaches L is *OCH2CH2 as Compound 17:
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(Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2.
Regarding claim 11, Xie teaches L is an optionally substituted 5-membered saturated heterocyclene,
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, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Thus, a person of ordinary skill in the art would make a compound wherein L is a 5-membered saturated heterocycle.
Regarding claim 12, ‘803 teaches the compound,
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, in which L’ is an optionally substituted C1-3 hydrocarbon chain (claims 9 and 13 of ‘803). Thus, a person of ordinary skill in the art would make a compound wherein L is a C1-3 hydrocarbon chain.
Regarding claim 22, ‘803 teaches the compound,
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(claims 9 and 13 of ‘803). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘803 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). Thus, the combination of ‘803, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula (II-a) and (II-b).
Regarding claim 23, ‘803 teaches the compound,
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(claims 9 and 13 of ‘803). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘803 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘803 for the pyridine and pyrimidine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘803, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas III-a-2 – III-a-3 and Formulas III-b-2 – III-b-3.
Regarding claim 24, ‘803 teaches the compound,
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, wherein CyA is a pyrimidine (claims 9 and 13 of ‘803). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘803 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘803 for the pyridine and pyrimidine of Xie and ‘803, because pyridine and pyrimidine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘803, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas IV-a-1 – IV-a-2 and Formulas IV-b-1 – IV-b-2.
Regarding claim 26, ‘803 teaches the compound,
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, wherein CyA is a pyrimidine (claims 9 and 13 of ‘803). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘803 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches L is *OCH2CH2 as Compound 17:
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( Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2. Additionally, Xie teaches incorporation of pyrrolidine, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Accordingly, the combination of ‘803, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula VI-b and VI-c.
Regarding claim 28, ‘803 teaches a pharmaceutical composition (claim 14 of ‘803).
8. Claim 1-12, 22-24, 26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 17-18 of U.S. Patent No. 10,730,874 in view of Xie (Euro J Med Chem, 2020, 190(112137), 1-14), Ghosh 1 (J Med Chem, 2020, 63, 2751-2788), and Ghosh 2 (J Med Chem, 2015, 58, 2895-2940).
Although the claims at issue are not identical, they are not patentably distinct from each other.
U.S. Application No. 10,730,874 claims a compound of Formula (I):
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, wherein CyA is a 5- to 6-membered monocyclic heteroaryl, a 7- to 10-membered partially unsaturated bicyclic heterocycle, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle, a 7- to 10-membered bicyclic heteroaryl; L is an optionally substituted C1-6 hydrocarbon chain; CyB is phenyl, a 5- to 6-membered monocyclic heteroaryl, a 7- to 10-membered partially unsaturated bicyclic carbocycle, a 10-membered bibcyclic aryl, a 7- to 10-membered bicyclic heterocycle, a 12-membered tricyclic heterocycle; R1—R4 are independently selected from hydrogen or optionally substituted C1-6 aliphatic; R5—R9 are independently selected from hydrogen, halogen, CN, amide, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 5- to 6-membered heteroaryl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle (claim 1).
Regarding claim 1, ‘874 fails to teach a urea in the core scaffold.
Xie teaches that plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy (page 2, column 1, paragraph 1; page 2, column 2, paragraph 3; page 3, column 2, paragraph 5). Xie further teaches the SAR of several plasma kallikrein inhibitors (page 2, column 1, paragraph 3). Xie additionally teaches representative peptidomimetic plasma kallikrein inhibitors in an approximation of the binding pocket (Figure 3, page 6). Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B (Figures 11-12, page 12).
Ghosh 1 teaches incorporation of ureas in medicinal chemistry (abstract). Ghosh 1 specifies that the urea functionality is increasingly used in medicinal chemistry in order to establish key drug-target interactions and fine-tune crucial drug-like properties (abstract).
Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry (abstract). Ghosh 2 specifies that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates (page 2895, column 1, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to simply modify the scaffold of ‘874 to incorporate a urea as taught by Ghosh 1 or a carbamate as taught by Ghosh 2 to obtain a compound of Formula (I):
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, 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:
-‘874 teaches plasma kallikrein inhibitors of Formula (I):
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,
-Xie teaches plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy,
--Xie teaches the SAR of several plasma kallikrein inhibitors,
-Xie teaches nicotinamide scaffolds are potent plasma kallikrein inhibitors (Compound 42; page 8, column 2, paragraph 1),
-Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B,
-Xie teaches inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors (specifically Compound 26:
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) in a crystal complex of plasma kallikrein (Figure 4, page 7; Figure 11, page 12),
-Xie teaches CyA is a 7- to 12-membered heteroarylene as Compound 36:
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(Figure 5, page 8), which would engage in hydrogen-bonding,
-Xie teaches the middle scaffold has hydrogen-bonding opportunities with Gly 480 and Ser478 and that a heterocyclic ring in fragment A or in the middle scaffold typically forms the H-bonding bridges (page 10, column 2, paragraph 2; Figure 11B, page 12),
-Ghosh 1 teaches that urea has a central role in drug development and medicinal chemistry due to its ability to form multiple stable hydrogen bonds with protein and receptor targets and that drug-target interactions are responsible for specific biological activity, drug actions, and drug properties (page 2751, column 1, paragraph 1),
-Ghosh 1 teaches modulation of hydrogen bonding capabilities of urea via electron donating and electron withdrawing functionalities (page 2754, column 1, paragraph 1),
-Ghosh 1 teaches that water solubility is enhanced by disrupting molecular planarity of the solutes in order to reduce their crystal packing energy via introduction of a substituent onto the urea (page 2754, column 2, paragraph 2; Figure 9, page 2754),
-Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry,
-Ghosh 2 teaches that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates,
-Ghosh 2 teaches that carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry due to their chemical stability and capability to permeate cell membranes (page 2895, column 1, paragraph 1),
-Ghosh 2 teaches that carbamates are able to modulate inter- and intramolecular interactions with target enzymes or receptor and impose a degree of conformational restriction due to delocalization of non-bonded electrons on the nitrogen into the carboxyl moiety (page 2895, column 1, paragraph 1), and
-Ghosh 2 teaches that carbamates engage in hydrogen bonding (page 2895, column 1, paragraph 1).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the amide of ‘874) to incorporate a nitrogen or oxygen (to form the urea or carbamate) to predictably arrive at a compound of Formula (I):
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.
Regarding claim 2, ‘874 teaches the compound,
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(claim 17 of ‘874), in which CyA is a 5-membered monocyclic heteroarylene. Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Thus, the combination of ‘874 and Xie teaches a compound wherein CyA is a 5- to 6-membered monocyclic heteroaryl.
Regarding claim 3, ‘874 teaches the compound,
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(claim 17 of ‘874), in which CyA is a pyrazole. Additionally, Xie teaches Compounds 42 and 43:
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and
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(page 9). Pyridine is capable of hydrogen bonding, and Compounds 42-44 showed good activity as plasma kallikrein inhibitors (IC50 < 0.1 uM).
Regarding claim 4, Xie teaches Compounds with a 7- to 12-membered bicyclic heterarylene,
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(Figure 6, page 8). Additionally, Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the pyridine of ‘874 to a 7- to 12-membered bicyclic heteroarylene as taught by Xie.
Regarding claim 5, ‘874 teaches incorporation of a triazolopyridinyl group:
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(claim 17 of ‘874). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). CyA of the claimed invention would be in Fragment A of Xie and thus has multiple hydrogen bonding opportunities with Ser478 and Gly480. Further, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 and that changing the core to have fewer nitrogen atoms resulted in a loss of potency (page 7, column 2, paragraph 1; page 8, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would substitute the pyrazole of ‘874 to a triazolopyridinyl as taught by ‘874 and Xie.
Regarding claim 6, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘874 for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 7, Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘874 for the pyridine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole.
Regarding claim 8, Xie teaches Compound 37, wherein CyB (Fragment B in pink) has Rb is a halogen:
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(page 8). Xie teaches Compound 30, wherein addition of an F atom to the phenyl ring of CyB resulted in maintenance of activity (page 7, column 1, paragraph 1; Figure 5, page 8). Additionally, Xie teaches shifting the position of the halogen around CyB of fragment B provided compounds that maintained activity (Figure 6, page 8; page 8, column 1, paragraph 1). Further, Compound 16, which incorporated a halogen on CyB, possessed good selectivity for plasma kallikrein (page 6, column 2, paragraph 1; Figure 4, page 7).
Regarding claim 9, Xie teaches L is a substituted C1-3 hydrocarbon chain in Compounds 16:
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(Figure 4, page 7). Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Thus, a person of skill in the art would incorporate a C1-3 hydrocarbon chain from Fragment A in order to shape the compound correctly in the binding pocket to best facilitate hydrogen bonding interactions with Ser478 and Gly 480.
Regarding claim 10, Xie teaches L is *OCH2CH2 as Compound 17:
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(Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2.
Regarding claim 11, Xie teaches L is an optionally substituted 5-membered saturated heterocyclene,
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, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Thus, a person of ordinary skill in the art would make a compound wherein L is a 5-membered saturated heterocycle.
Regarding claim 12, ‘874 teaches the compound,
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, in which L’ is an optionally substituted C1-3 hydrocarbon chain (claim 17 of ‘874). Thus, a person of ordinary skill in the art would make a compound wherein L is a C1-3 hydrocarbon chain.
Regarding claim 22, ‘874 teaches the compound,
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(claim 17 of ‘874). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘874 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). Thus, the combination of ‘874, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula (II-a) and (II-b).
Regarding claim 23, ‘874 teaches the compound,
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(claim 17 of ‘874). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘874 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘874 for the pyridine and pyrimidine of Xie, because pyridine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘874, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas III-a-2 – III-a-3 and Formulas III-b-2 – III-b-3.
Regarding claim 24, ‘874 teaches the compound,
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, wherein CyA is a pyrazole (claim 17 of ‘874). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘874 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches CyB is a phenyl or a 5- to 6-membered heteroaryl: Compound 42:
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(Figure 7, page 9). Additionally, Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12). Thus, to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole of ‘874 for the pyridine and pyrimidine of Xie, because pyridine and pyrimidine is capable of forming hydrogen bonds and is smaller than benzimidazole. Accordingly, the combination of ‘874, Ghosh 1, Ghosh 2, and Xie teach a compound of Formulas IV-a-1 – IV-a-2 and Formulas IV-b-1 – IV-b-2.
Regarding claim 26, ‘874 teaches the compound,
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, wherein CyA is a pyrimidine (claim 17 of ‘874). Ghosh 1 and 2 teach incorporations of a urea or a carbamate into the core scaffold of ‘874 (Ghosh 1: page 2754, column 1, paragraph 1; Ghosh 2: page 2895, column 1, paragraph 1). Xie teaches L is *OCH2CH2 as Compound 17:
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( Figure 4, page 7). Structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093-95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the linker of Xie differs from that of the linker of the claimed invention by a methylene unit, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Further, Compound 16 possessed good selectivity for plasma kallikrein over two other related enzymes: KLK1 and FXIa (page 6, column 2, paragraph 1; Figure 4, page 7). Accordingly, a person of ordinary skill in the art would synthesize the linker, *OCH2. Thus, Xie teaches L is *OCH2. Additionally, Xie teaches incorporation of pyrrolidine, which showed good inhibitory activity (Compound 45, Figure 8, page 9). Accordingly, the combination of ‘874, Ghosh 1, Ghosh 2, and Xie teaches a compound of Formula VI-b and VI-c.
Regarding claim 28, ‘874 teaches a pharmaceutical composition (claim 18 of ‘874).
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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