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, 63/162,487 and PCT/US2022/020491, 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-80 (
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) in the reply filed on 23 February 2026 is acknowledged.
Claims 29-30 were canceled.
Claims 1-4, 8-9, 12-20, 23, and 27-28 read on the elected species. The elected species, I-80 (
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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 Palacios (Bioorg. & Med. Chem. Lett., 2018, 28, 365-370).
Information Disclosure Statement
The Information Disclosure Statements filed on 20 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 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 4-5, 9, 11, 14, 17-18, 21, 23, and 25-26 are objected to because of the following informalities: lack of comma and/or conjunction to separate the options. Claim 4 recites that CyA is selected from the group consisting of:
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, but claim 4 does not separate the options via comma nor specify a conjunction (i.e. “and” or “or”). Similarly, claim 5 recites that CyA is selected from the group consisting of
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, but claim 5 does not specify a conjunction. Thus, claims 4, 9, 11, 18, 21, 23, and 26 do not separate the options via comma nor specify a conjunction, and claims 5, 14, 17, and 25 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.
2. Claim 27 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
3. Claims 8-9 and 27 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 recites that CyB is selected from phenyl, but claim 8 depends upon claim 1, which was amended to remove the limitation that CyB is phenyl.
Similarly, claim 9 recites that CyB is selected from phenyl, and claim 9 depends upon claim 1, which no longer recites that CyB is phenyl. Further, claim 27 recites compounds that require CyB to be phenyl (e.g. Compounds: I-2 – I-4; I-9 – I-40; I-42 – I-55; I-58 – I-60; I-62; I-64 – I-65; and I-67).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
4. Claim(s) 1-2, 8-9, 13, 15, and 24-26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Palacios (Bioorg. & Med. Chem. Lett., 2018, 28, 365-370).
Palacios teaches compounds of the core scaffold:
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, wherein R is CH2morpholine, in an SAR campaign to generate NAMPT inhibitors (Figure 3, page 367; abstract; page 365, column 1, paragraph 2; page 365, column 2, paragraph 1).
Palacios specifically teaches Compounds 12, 17, 27b, and 27d – 27i (Figure 3, page 367; Table 3, page 368; Table 4, page 369).
Regarding claim 1, Palacios teaches Compound 12. Mapping shown below:
18/550,504 Formula (I) Components
18/550,504 Formula (I)
Compound 12 (Palacios)
CyB
6-membered monocyclic heteroarylene
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Rx, Rx’, Ry, Ry’
H
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R8
H
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L’
Covalent bond
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CyA
phenyl
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L
Optionally substituted C1-3 hydrocarbon chain wherein 1-3 methylene units are independently replaced with -C(O)-, -NRz-, and which is optionally substituted
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CyC
Phenyl; substituted with 1 Lc-Rc;
Lc = C1-6 aliphatic chain (CH2); Rc = 3- to 7- membered saturated monocyclic heterocyclyl (morpholine)
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, R = CH2morpholine
As such, Compound 12 (
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) reads on the genus of claim 1.
Regarding claim 2, Palacios teaches that CyC is not
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(Compound 12, Figure 3, page 367).
Regarding claim 8, Palacios teaches that CyB is a 6-membered heteroaryl (pyridine; Compound 12, Figure 3, page 367).
Regarding claim 9, Palacios teaches that CyB is
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(Compound 12, Figure 3, page 367).
Regarding claim 13, Palacios teaches that L is a substituted C1-3 hydrocarbon chain, wherein 2 methylene units are replaced with –C(O)- and -NRz-, wherein Rz is H (Compound 12, Figure 3, page 367).
Regarding claim 15, Palacios teaches that L’ is a covalent bond (Compound 12, Figure 3, page 367).
Regarding claim 24, Palacios teaches a compound of Formula (IV), wherein Y1, Y2, Y3, and Y4 are independently selected from CH (Compound 12, Figure 3, page 367).
Regarding claim 25, Palacios teaches a compound of Formula (V-a) and (V-b) (Compound 12, Figure 3, page 367; Compound 27h, Table 4, page 369).
Regarding claim 26, Palacios teaches a compound of Formula (VI), (VI-a), and (VI-b) (Compound 12, Figure 3, page 367; Compound 27h, Table 4, page 369).
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.
5. Claim(s) 1-9 and 12-28 are rejected under 35 U.S.C. 103 as being unpatentable over Palacios (Bioorg. & Med. Chem. Lett., 2018, 28, 365-370) in view of Papaioannou (WO 2019/178129, published 19 Sept 2019, see IDS filed 20 Feb 2026) and Xie (Euro. J. Med. Chem., 2020, 190(112137), 1-14).
Palacios (Bioorg. & Med. Chem. Lett., 2018, 28, 365-370) is applied as discussed in the 35 U.S.C. 102 rejection above and these teachigns/disclosures are incorporated herein by reference.
The Examiner notes the relevant teachings with respect to claims 1-2, 8-9, 13, 15, and 24-26, which are incorporated herein by reference.
Additional relevant teachings are set forth below.
Palacios teaches compounds of the core scaffold:
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, and their SAR (Table 4, page 369).
Regarding claim 3, Palacios fails to teach that CyA is a 5- to 6-membered monocyclic heteroarylene or a 7- to 12-membered bicyclic heteroarylene.
Papaioannou teaches plasma kallikrein inhibitors of the core scaffold,
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(abstract). Papaioannou specifically teaches
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(page 92).
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). Further, 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).
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 Palacios with the plasma kallikrein inhibitors of Papaioannou and Xie to obtain a compound wherein CyA is a 5- to 6-membered monocyclic heteroarylene or a 7- to 12-membered bicyclic heteroarylene, to arrive at instant claim 3. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Palacios teaches the nicotinamide derivative, Compound 12 (
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; Figure 3, page 367),
-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 CyA is a 5- to 6-membered monocyclic heteroarylenes or a 7- to 12-membered bicyclic heteroarylenes as part of the middle scaffold of plasma kallikrein inhibitors,
-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),
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (Compound 12 of Palacios) to incorporate a 5- to 6-membered monocyclic heteroarylene or a 7- to 12-membered bicyclic heteroarylene of Papaioannou and Xie to arrive at a compound wherein CyA is a 5- to 6-membered heteroarylene or a 7- to 12-membered heteroarylene.
Regarding claim 4, 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 modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyridine.
Regarding claim 5, Papaioannou teaches Compound I-5:
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(page 92). Xie teaches Compound 26:
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in a crystal complex of plasma kallikrein, wherein CyA is a pyrazole (Figure 4, page 7; Figure 11, page 12). As pyrazole is able to hydrogen bond with either Ser478 or Gly480 in the bonding pocket of plasma kallikrein, a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyrazole.
Regarding claim 6, Papaioannou teaches CyA is triazolopyridinyl and imidazopyridinyl groups ([0056]; [0058]). As triazolopyridinyl and imidazopyridinyl would participate in hydrogen bonding with Ser478 or Gly480 of plasma kallikrein, a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a triazolopyridinyl or imidazopyridinyl.
Regarding claim 7, Xie teaches that halogen incorporation on CyA either maintains or improves potency (Compound 17, Figure 4, page 7; page 6, column 2, paragraph 1; Compounds 38 and 39, Figure 5, page 8; page 8, column 1, paragraph 1). Xie also teaches maintaining potency when incorporating alkoxy substituents (e.g. ethoxy in Compounds 52-55 and 57) as well as obtaining selective inhibition for plasma kallikrein (figure 9, page 10; page 9, column 2, paragraph 1).
Regarding claim 12, 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 14, 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 16, Palacios teaches Compound 12:
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(Figure 3, page 367). Papaioannou teaches Compound I-5:
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(page 92). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). As a 9- to 10-membered aryl or heteroaryl (e.g. triazolopyridinyl and imidazopyridinyl of Papaioannou) would participate in hydrogen bonding with Ser478 or Gly480 of plasma kallikrein (as shown in Figure 11 of Xie), a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a triazolopyridinyl or imidazopyridinyl. Accordingly, the combination of Palacios, Papaioannou, and Xie teaches a compound of Formula (II).
Regarding claim 17, Palacios teaches Compound 12:
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(Figure 3, page 367). Papaioannou teaches Compounds I-3 and I-5:
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and
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(pages 89 and 92). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). As a 9- to 10-membered aryl or heteroaryl (e.g. triazolopyridinyl, imidazopyridinyl, or quinolinyl of Papaioannou) would participate in hydrogen bonding with Ser478 or Gly480 of plasma kallikrein (as shown in Figure 11 of Xie), a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a triazolopyridinyl, imidazopyridinyl, or quinolinyl. Accordingly, the combination of Palacios, Papaioannou, and Xie teaches a compound of Formula (II-a) and (II-b).
Regarding claim 18, Palacios teaches Compound 12:
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(Figure 3, page 367). Papaioannou teaches Compounds I-5, and I-255:
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and
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(pages 92 and 531). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). As a 9- to 10-membered aryl or heteroaryl (e.g. triazolopyridinyl and imidazopyridinyl of Papaioannou) would participate in hydrogen bonding with Ser478 or Gly480 of plasma kallikrein (as shown in Figure 11 of Xie), a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a triazolopyridinyl or imidazopyridinyl. Accordingly, the combination of Palacios, Papaioannou, and Xie teaches a compound of Formula (II-a-1) – (II-a-4).
Regarding claim 19, Papaioannou teaches Compound I-5, wherein X6 is C-Lc-Rc: wherein Lc is a covalent bond and Rc is cyclopropyl (page 92), which has a dose response of A (≤ 1.0 nM) in vitro (Table 1, page 632). Further, Papaioannou teaches that the compounds disclosed therein, most of which contain a cyclopropyl group at X6, possess activity against plasma kallikrein ([0003]). Additionally, Xie teaches incorporation of a cyclopropyl group, which was necessary for maintaining activity (page 7, column 1, paragraph 1). Accordingly, a person of ordinary skill in the art would modify Formula (II) to include a cyclopropyl group at X6.
Regarding claim 20, Papaioannou teaches Compound I-262:
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, wherein Lc is a covalent bond and Rc is
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(page 543), which has a dose response of A (≤ 1.0 nM) in vitro (Table 1, page 632). Accordingly, a person of ordinary skill in the art would modify Formula (II) to include a
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group at X8.
Regarding claim 21, Palacios teaches Compound 12:
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(Figure 3, page 367). Papaioannou teaches Compound I-3
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(page 89). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). As a 9- to 10-membered aryl or heteroaryl (e.g. quinolinyl of Papaioannou) would participate in hydrogen bonding with Ser478 or Gly480 of plasma kallikrein (as shown in Figure 11 of Xie), a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a quinolinyl. Accordingly, the combination of Palacios, Papaioannou, and Xie teaches a compound of Formula (II-b-1), (II-b-3), and (II-b-4).
Regarding claim 22, Papaioannou teaches Compound I-3
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, wherein X1, X3, X4, X5, and X7 are CH (page 89).
Regarding claim 23, Palacios teaches Compound 12:
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(Figure 3, page 367). Papaioannou teaches Compounds I-5, I-255, and I-262:
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,
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, and
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(pages 92, 531, and 543). All three compounds possess in vitro dose responses of A, which corresponds to an EC50 of ≤ 1.0 nM (Table 1, page 632). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). As a 9- to 10-membered aryl or heteroaryl (e.g. triazolopyridinyl and imidazopyridinyl of Papaioannou) would participate in hydrogen bonding with Ser478 or Gly480 of plasma kallikrein (as shown in Figure 11 of Xie), a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a triazolopyridinyl or imidazopyridinyl. Accordingly, the combination of Palacios and Papaioannou teaches a compound of Formula (III) and (III-a) – (III-c).
Regarding claim 27, Palacios teaches Compound 12:
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(Figure 3, page 367), which is a nicotinamide derivative. ). 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 pyridine of Palacios for a pyrimidine as taught by Xie, because pyrimidine has more opportunities to form a hydrogen bond with Asp572 (thus increasing the likelihood of a nitrogen being in the right proximity to form a hydrogen bond with Asp572). Additionally, 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 pyrimidine as taught by Palacios and Xie differs from the methyl-pyrimidine as taught by the claimed invention by only a methyl, 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, Xie teaches that nicotimamide scaffolds have activity against plasma kallikrein (page 8, column 2, paragraph 1). Further, Xie teaches the nicotinamide derivative, 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 phenyl of Palacios 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 12 to a pyrimidine.
Further, 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.
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. Additionally, Xie teaches incorporation of more nitrogen atoms in Compounds 37-41 for forming hydrogen bonds with Ser478 and Gly480 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, Xie teaches incorporation of more nitrogen atoms to capitalize on hydrogen bonding opportunities, a person of skill in the art would substitute the benzimidazole as taught by Papaioannou for a triazolopyridine as taught by Xie, because triazolopyridine has more opportunities to form a hydrogen bond with Ser478 and Gly480 (thus increasing the likelihood of a nitrogen being in the right proximity to form a hydrogen bond with either Ser478 or Gly480).
Accordingly, the combination of Palacios, Xie, and Papaioannou teaches Compound I-72:
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.
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.
6. Claim 1, 3-9, 12-14, 16, 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. 18/550,474 in view of Palacios (Bioorg. & Med. Chem. Lett., 2018, 28, 365-370) and Xie (Euro. J. Med. Chem., 2020, 190(112137), 1-14).
Although the claims at issue are not identical, they are not patentably distinct from each other.
U.S. Application No. 18/550,474 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 3- to 7-membered carbocycle or heterocycle or a heteroaryl. Further, ‘474 claims a method of treating plasma kallikrein-mediated diseases or disorders using a compound of claim 1 (claim 29).
Regarding claim 1, ‘474 fails to teach a cyclopropane in the core scaffold.
Palacios teaches compounds of the core scaffold:
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, and their SAR (Table 4, page 369), which read upon the genus of claim 1.
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 scafoold, and Fragment B (Figures 11-12, page 12).
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 ‘474 with the compounds of Palacios and Xie 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:
-‘474 teaches compounds of a core scaffold:
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that are inhibitors of plasma kallikrein,
-‘474 teaches a method of treating plasma kallikrein-mediated diseases or disorders using a compound of Formula (I),
-Palacios teaches compounds of the core scaffold:
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, and their SAR, which read upon the genus of claim 1,
-Palacios teaches the compound, Compound 12 (
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; Figure 3, page 367),
-Palacios teaches methods of accessing compounds of the core scaffold:
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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 CyA is a 5- to 6-membered monocyclic heteroarylenes or a 7- to 12-membered bicyclic heteroarylenes as part of the middle scaffold of plasma kallikrein inhibitors,
-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).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the core scaffold of ‘474) with another (the cyclopropane of Palacios in the crystal complex of Xie) to arrive at a compound of Formula (I):
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.
Regarding claim 3, ‘474 teaches the compound,
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(claim 27 of ‘474), 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 ‘474 and Xie teaches a compound wherein CyA is a 5- to 6-membered monocyclic heteroaryl.
Regarding claim 4, ‘474 teaches the compound,
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(claim 27 of ‘474). 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 modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyridine.
Regarding claim 5, Xie teaches compounds incorporating pyrazole middle scaffold:
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(Compound 33, page 8). Additionally, Xie teaches Compound 26:
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in a crystal complex of plasma kallikrein, wherein CyA is a pyrazole (Figure 4, page 7; Figure 11, page 12). As a pyrazole is able to hydrogen bond with either Ser478 or Gly480 in the bonding pocket of plasma kallikrein, a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyrazole.
Regarding claim 6, ‘474 teaches the compound,
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(claim 27 of ‘474). As a 7- to 12-membered heteroarylene (e.g. triazolopyridinyl and imidazopyridinyl) would participate in hydrogen bonding with Ser478 or Gly480 of plasma kallikrein, a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a 7- to 12-membered heteroarylene.
Regarding claim 7, Xie teaches that halogen incorporation on CyA either maintains or improves potency (Compound 17, Figure 4, page 7; page 6, column 2, paragraph 1; Compounds 38 and 39, Figure 5, page 8; page 8, column 1, paragraph 1). Xie also teaches maintaining potency when incorporating alkoxy substituents (e.g. ethoxy in Compounds 52-55 and 57) as well as obtaining selective inhibition for plasma kallikrein (figure 9, page 10; page 9, column 2, paragraph 1).
Regarding claim 8, ‘474 teaches CyB is a phenyl or a 5- to 6-membered heteroaryl having 1-3 heteroatoms selected from O, N, or S and is substituted with 0-4 Rb groups (claim 6 of ‘474).
Regarding claim 9, ‘474 teaches the compound,
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, wherein Cb is a 6-membered heteroaryl (claim 27 of ‘474). Additionally, Xie teaches compounds incorporating pyrazole middle scaffold:
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(Compound 33, page 8).
Regarding claim 12, ‘474 teaches the compound,
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, wherein Rb is halogen (claim 27 of ‘474). Additionally, Xie teaches Compound 37, wherein CyB has Rb is a halogen:
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(page 8). Additionally, Xie teaches Rb is a substituted C1-6 aliphatic:
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(page 10). 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 13, ‘‘474 teaches the compound,
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, wherein L is a C1-3 hydrocarbon chain (claim 27 of ‘474).
Regarding claim 14, ‘474 teaches the compound,
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, wherein L is *-NHCH2 (claim 27 of ‘474). Additionally, 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 16, ‘474 teaches the compound,
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(claim 27 of ‘474). Palacios teaches Compound 12:
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(Figure 3, page 367). Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12). As a 9- to 10-membered aryl or heteroaryl (e.g. triazolopyridinyl and imidazopyridinyl) would participate in hydrogen bonding with Ser478 or Gly480 of plasma kallikrein (as shown in Figure 11 of Xie), a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a triazolopyridinyl or imidazopyridinyl. Accordingly, the combination of ‘474, Palacios, and Xie teaches a compound of Formula (II).
Regarding claim 24, Palacios teaches a compound of Formula (IV), wherein Y1, Y2, Y3, and Y4 are independently selected from CH (Compound 12, Figure 3, page 367).
Regarding claim 25, Palacios teaches a compound of Formula (V-a) (Compound 12, Figure 3, page 367).
Regarding claim 26, Palacios teaches a compound of Formula (VI) and (VI-a) (Compound 12, Figure 3, page 367).
Regarding claim 28, ‘474 teaches a pharmaceutical composition a compound of Formula (I) (claim 28 of ‘474).
7. Claim 1 and 3-4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 31 of U.S. Application No. 18/550,306.
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 teaches the compound:
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(claim 31 of ‘306), which reads on claim 1. Mapping shown below:
18/550,504 Formula (I) Components
18/550,504 Formula (I)
Compound I-674 (‘306)
CyB
6-membered monocyclic heteroarylene
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Rx, Rx’, Ry, Ry’
H
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R8
H
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L’
Covalent bond
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CyA
pyrimidine
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L
Optionally substituted C1-3 hydrocarbon chain which is optionally substituted
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CyC
benzimidazole substituted with 2 Lc-Rc;
Lc-Rc 1 = cyclopropyl;
Lc-Rc2 = methylimide
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As such, Compound I-674 of ‘306 anticipates claim 1.
Regarding claim 3, ‘306 teaches the compound:
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(claim 31 of ‘306), which anticipates claim 3, wherein CyA is a 6-membered heteroaryl.
Regarding claim 4, ‘306 teaches the compound:
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(claim 31 of ‘306), which anticipates claim 4, wherein CyA is a pyrimidine.
Regarding claim 5, ‘306 fails to teach a pyrazole in the core scaffold.
8. Claim 1, 3-4, 7-9, 12-14, 24-26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 17-18 of U.S. Patent No. 11,787,796 in view of Palacios (Bioorg & Med Chem Lett, 2018, 28, 365-370) and Xie (Euro J Med Chem, 2020, 190(112137), 1-14).
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 cyclopropane in the middle core of the scaffold.
Palacios teaches compounds of the core scaffold:
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, and their SAR (Table 4, page 369), which read upon the genus of claim 1.
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 scafoold, and Fragment B (Figures 11-12, page 12).
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 with the compounds of Palacios and Xie 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 compounds of a core scaffold:
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,
-Palacios teaches compounds of the core scaffold:
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, and their SAR, which read upon the genus of claim 1,
-Palacios teaches the compound, Compound 12 (
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; Figure 3, page 367),
-Palacios teaches methods of accessing compounds of the core scaffold:
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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 CyA is a 5- to 6-membered monocyclic heteroarylenes or a 7- to 12-membered bicyclic heteroarylenes as part of the middle scaffold of plasma kallikrein inhibitors,
-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).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the core scaffold of ‘796) with another (the cyclopropane of Palacios in the crystal complex of Xie) to arrive at a compound of Formula (I):
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.
Regarding claim 3, ‘796 teaches the compound,
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(claim 17 of ‘796), wherein 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).
Regarding claim 4, 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 modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyridine.
Regarding claim 7, Xie teaches that halogen incorporation on CyA either maintains or improves potency (Compound 17, Figure 4, page 7; page 6, column 2, paragraph 1; Compounds 38 and 39, Figure 5, page 8; page 8, column 1, paragraph 1). Xie also teaches maintaining potency when incorporating alkoxy substituents (e.g. ethoxy in Compounds 52-55 and 57) as well as obtaining selective inhibition for plasma kallikrein (figure 9, page 10; page 9, column 2, paragraph 1).
Regarding claim 8, ‘796 teaches the compound,
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(claim 17 of ‘796), wherein CyB is a 6-membered heteroaryl.
Regarding claim 9, ‘796 teaches the compound,
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(claim 17 of ‘796), wherein CyB is a pyridine. Additionally, Xie teaches compounds incorporating pyrazole middle scaffold:
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(Compound 33, page 8).
Regarding claim 12, ‘796 teaches the compound,
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(claim 17 of ‘796), wherein Rb is a halogen or an optionally substituted C1-6 aliphatic. Additionally, Xie teaches Compound 37, wherein CyB has Rb is a halogen:
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(page 8). Additionally, Xie teaches Rb is a substituted C1-6 aliphatic:
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(page 10). 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 13, ‘796 teaches the compound,
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(claim 17 of ‘796), wherein L is an optionally substituted C1-6 hydrocarbon chain.
Regarding claim 14, 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 24, Palacios teaches a compound of Formula (IV), wherein Y1, Y2, Y3, and Y4 are independently selected from CH (Compound 12, Figure 3, page 367).
Regarding claim 25, Palacios teaches a compound of Formula (V-a) (Compound 12, Figure 3, page 367).
Regarding claim 26, Palacios teaches a compound of Formula (VI) and (VI-a) (Compound 12, Figure 3, page 367).
Regarding claim 28, ‘796 teaches a pharmaceutical composition a compound of Formula (I) (claim 18 of ‘796).
9. Claim 1, 3-4, 7, 13-14, 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 Palacios (Bioorg & Med Chem Lett, 2018, 28, 365-370) and Xie (Euro J Med Chem, 2020, 190(112137), 1-14).
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 cyclopropane in the middle core of the scaffold.
Palacios teaches compounds of the core scaffold:
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, and their SAR (Table 4, page 369), which read upon the genus of claim 1.
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 scafoold, and Fragment B (Figures 11-12, page 12).
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 with the compounds of Palacios and Xie 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 compounds of a core scaffold:
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,
-Palacios teaches compounds of the core scaffold:
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, and their SAR, which read upon the genus of claim 1,
-Palacios teaches the compound, Compound 12 (
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; Figure 3, page 367),
-Palacios teaches methods of accessing compounds of the core scaffold:
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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 CyA is a 5- to 6-membered monocyclic heteroarylenes or a 7- to 12-membered bicyclic heteroarylenes as part of the middle scaffold of plasma kallikrein inhibitors,
-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).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the core scaffold of ‘803) with another (the cyclopropane of Palacios in the crystal complex of Xie) to arrive at a compound of Formula (I):
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.
Regarding claim 3, ‘803 teaches the compound,
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(claims 9 and 13 of ‘803), wherein 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).
Regarding claim 4, 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 modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyridine.
Regarding claim 7, Xie teaches that halogen incorporation on CyA either maintains or improves potency (Compound 17, Figure 4, page 7; page 6, column 2, paragraph 1; Compounds 38 and 39, Figure 5, page 8; page 8, column 1, paragraph 1). Xie also teaches maintaining potency when incorporating alkoxy substituents (e.g. ethoxy in Compounds 52-55 and 57) as well as obtaining selective inhibition for plasma kallikrein (figure 9, page 10; page 9, column 2, paragraph 1).
Regarding claim 13, ‘803 teaches the compound,
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(claims 9 and 13 of ‘803), wherein L is an optionally substituted C1-6 hydrocarbon chain.
Regarding claim 14, 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 24, Palacios teaches a compound of Formula (IV), wherein Y1, Y2, Y3, and Y4 are independently selected from CH (Compound 12, Figure 3, page 367).
Regarding claim 25, Palacios teaches a compound of Formula (V-a) (Compound 12, Figure 3, page 367).
Regarding claim 26, Palacios teaches a compound of Formula (VI) and (VI-a) (Compound 12, Figure 3, page 367).
Regarding claim 28, ‘803 teaches a pharmaceutical composition a compound of Formula (I) (claim 14 of ‘803).
10. Claim 1, 3-4, 8-9, 12-14, 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 Palacios (Bioorg & Med Chem Lett, 2018, 28, 365-370) and Xie (Euro J Med Chem, 2020, 190(112137), 1-14).
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 cyclopropane in the middle core of the scaffold.
Palacios teaches compounds of the core scaffold:
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, and their SAR (Table 4, page 369), which read upon the genus of claim 1.
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 scafoold, and Fragment B (Figures 11-12, page 12).
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 with the compounds of Palacios and Xie 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 compounds of a core scaffold:
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,
-Palacios teaches compounds of the core scaffold:
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, and their SAR, which read upon the genus of claim 1,
-Palacios teaches the compound, Compound 12 (
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; Figure 3, page 367),
-Palacios teaches methods of accessing compounds of the core scaffold:
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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 CyA is a 5- to 6-membered monocyclic heteroarylenes or a 7- to 12-membered bicyclic heteroarylenes as part of the middle scaffold of plasma kallikrein inhibitors,
-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).
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element (the core scaffold of ‘874) with another (the cyclopropane of Palacios in the crystal complex of Xie) to arrive at a compound of Formula (I):
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.
Regarding claim 3, ‘874 teaches the compound,
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(claim 17 of ‘874), wherein CyA is a 5-membered monocyclic heteroarylene. Xie teaches that Fragment A has at least two hydrogen bonding opportunities with Ser478 and Gly480 (Figure 11, page 12).
Regarding claim 4, 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 modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyridine.
Regarding claim 5, ‘874 teaches the compound,
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(claim 17 of ‘874), wherein CyA is a pyrazole pyrazole. Additionally, Xie teaches compounds incorporating pyrazole middle scaffold:
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(Compound 33, page 8). Further, Xie teaches Compound 26:
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in a crystal complex of plasma kallikrein, wherein CyA is a pyrazole (Figure 4, page 7; Figure 11, page 12). As pyrazole is able to hydrogen bond with either Ser478 or Gly480 in the bonding pocket of plasma kallikrein, a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyrazole.
Regarding claim 8, ‘874 teaches the compound,
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(claim 17 of ‘874), wherein CyB is a 7- to 10-membered heteroaryl. 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 9, Xie teaches compounds incorporating pyrazole middle scaffold:
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(Compound 33, page 8). Further, Xie teaches Compound 26:
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in a crystal complex of plasma kallikrein, wherein CyA is a pyrazole (Figure 4, page 7; Figure 11, page 12). As pyrazole is able to hydrogen bond with either Ser478 or Gly480 in the bonding pocket of plasma kallikrein, a person of ordinary skill in the art would modify Compound 12 of Palacios to substitute the phenyl of CyA with a pyrazole.
Regarding claim 12, ‘874 teaches the compound,
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(claim 17 of ‘874), wherein Rb is a halogen. Additionally, 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 13, ‘874 teaches the compound,
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(claim 17 of ‘874), wherein L is a C1-3 hydrocarbon chain.
Regarding claim 14, 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 24, Palacios teaches a compound of Formula (IV), wherein Y1, Y2, Y3, and Y4 are independently selected from CH (Compound 12, Figure 3, page 367).
Regarding claim 25, Palacios teaches a compound of Formula (V-a) (Compound 12, Figure 3, page 367).
Regarding claim 26, Palacios teaches a compound of Formula (VI) and (VI-a) (Compound 12, Figure 3, page 367).
Regarding claim 28, ‘874 teaches a pharmaceutical composition a compound of Formula (I) (claim 18 of ‘874).
Allowable Subject Matter
Claims 10 and 11 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The closest prior art references to claims 10 and 11 are Palacios (Bioorg. & Med. Chem. Lett., 2018, 28, 365-370) in view of Papaioannou (WO 2019/178129, published 19 Sept 2019, see IDS filed 20 Feb 2026).
Palacios teaches nicotinamide derivatives of the core scaffold:
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, and their SAR (Table 4, page 369).
Papaioannou teaches plasma kallikrein inhibitors of the core scaffold,
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and their activity (abstract; Table 1, page 632). Papaioannou specifically teaches
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(page 92).
However, neither Palacios nor Papaioannou teach compounds having a spirocycle in the middle core of the compound (claim 10). Further, neither Palacios nor Papaioannou teach compounds having one of the specific moieties:
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(claim 11). There is no rationale to modify or motivation to combine the aforementioned prior art to arrive at the instant claims.
Conclusion
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622