DETAILED ACTION
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 instant application, filed 01/05/2024, is a national stage entry of PCT/US2022/073522, filed 07/07/2022, which claims domestic priority to provisional U.S. Application Nos. 63/354,017, filed 06/21/2022, and 63/219,160, filed 07/07/2022.
Preliminary Amendments and Claim Status
The preliminary amendment filed on 08/12/2024 is acknowledged and entered.
Claims 4, 13, 16, 19, 23, 27, 29, 33, 35, 40, 45, 46, 48-50, 59, and 60 are amended;
Claims 3, 5-12, 15, 17, 18, 20-22, 24- 26, 28, 30-32, 34, 36-39, 41-44, 47, 51-54, are cancelled;
Claims 1, 2, 4, 13, 14, 16, 19, 23, 27, 29, 33, 35, 40, 45, 46, 48- 50, 55, 56, and 58-60 are pending and are under prosecution.
Information Disclosure Statement
The Information Disclosure Statement filed on 10/01/2025 and 08/15/2024 are acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statements are considered.
Specification
The disclosure is objected to because of the following informalities:
Several instances of the inclusion of low-resolution images of insufficient quality to reflect the two-dimensional structure of the compounds instantly claimed are included. For example, pages 414-419 of the instant specification includes 2D-structures of compounds 187-196 whose image quality is very low. The images of these, and all low-resolution images must be replaced to be of sufficient quality.
The attempt to incorporate subject matter into this application by reference on page 2 of the specification is ineffective because a list of references is not included to correspond with referenced the subject matter. It is recommended that applicant include the references within and additionally filed information disclosure statement in order for the references to be formally considered. Alternatively, the specification may be amended to include a formal list of references, cited by Applicant within the specification.
Appropriate correction is required.
Drawings
The drawings filed on 01/05/2024 are found to be in compliance with 37 CFR §§ 1.121 and 1.84, and are hereby accepted.
Claim Interpretation
Claim 4 is subject to the following interpretation:
Amended claim 4 assigns the designation (C7a) to two different chemical moieties:
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Under the broadest reasonable interpretation (BRI) as set forth in MPEP § 2111, interpreted to be an error introduced by amendment. According to the instant specification, the latter chemical structure is assigned to the designation (C4b)
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, (see instant specification, page 23, line 3). As such, the designation (C7a) is interpreted to be applied uniquely only to the first structure, and the second structure is interpreted to be uniquely named (C4b).
Claim Objections
Claim 4 is objected to for including multiple duplicate naming and structural limitations:
Ring moiety C2 is included in limitations in both sections (iii) and (iv)
Ring moieties (C3b), (C7a), and (C7b) is included in limitations in both sections (iii) and (iv)
The name designation of (C7a) is attributed to two distinct structures in sections (iii)
Claim 4 is further objected to for including images of compounds with an inconsistent aspect ratio compared to the rest of the two-dimensional structure images, making the images look warped.
Claim 4, page 4, line 9: the images attributed to moiety (C7)
Claim 4, page 7, line 10: the images attributed to moiety (C7)
Claim 4, page 4, line 13: the images attributed to moiety (C2)
Claim 4, page 5, line 1: the images attributed to moieties (C5a), (C6a), and (C7a)
Claim 4, page 5, line 2: the image attributed to moiety (C7a)
Claim 4, page 5, line 4: the image attributed to moiety (C7a)
Claim 45 is objected to for use of double commas next to (D63) (page 24)
Claim 60 is objected to for the incorrect spelling of “Crohns's Disease” which should be corrected to “Crohn’s disease.”
Claim Rejections - 35 U.S.C. § 112
The following is a quotation of the first paragraph of 35 U.S.C. § 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. § 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4, 13, 14, 16, 19, 23, 27, 29, 33, 35, 40, 45-46, 48-50, 55-56, and 58-60 are rejected under 35 U.S.C. § 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 2, 4, 13, 14, 16, 19, 23, 27, 29, 33, 35, 40, 45-46, 48-50, 55-56, and 58-60 of the instant application are drawn to compounds having following substituents:
A1 is selected from N, CH and CR3
A2 is selected from N, CH and CR4,
R1 is selected from:
phenyl optionally substituted with 1 to 3 R5,
a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaryl is optionally substituted with 1 to 3 R5
a 5 or 6 membered partially or fully saturated heterocycle having 1 to 2 heteroatoms independently selected from oxygen and nitrogen, said heterocycle may be optionally substituted with 1 to 3 R5,
a partially or fully saturated C3-6 cycloalkyl which may be optionally substituted with 1 to 3 R5,
a 7 to 9 10 membered fused heterobicyclic ring system having 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen, said heterobicylic ring system is optionally substituted with 1 to 3 R5, and
a 7 to 10 membered fused carbobicyclic ring system, said carbobicyclic ring system is optionally substituted with 1 to 3 R5;
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R3 and R4 are each independently selected from halogen, C1-4alkyl, nitrile and —OR6, wherein the C1-4alkyl is optionally substituted with C1-4alkoxy or at least one halogen;
R5 for each occurrence, is independently selected from CN, hydroxyl, C1-4 alkyl, oxo, halogen, —NR8R9, C1-4 alkoxy, —O—C1-4 alkyl, C3-6cycloalkyl, —C1-4alkyl-C3-6cycloalkyl, C(O)NR10R11, a C4-7 heterocycle, and a 5 or 6 membered heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, said C1-4 alkyl is optionally substituted with one or more substituents independently selected from CN, halo, C1-4alkoxy, and hydroxyl, said C3-6cycloalkyl and heteroaryl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C1-4 alkyl, hydroxyl and halogen; or two R5 groups together with the intervening atoms can form a ring selected from phenyl, C4-6 carbocycle, C4-6 heterocycle, or a 7-membered bridged ring system optionally having 1 heteroatom selected from nitrogen and oxygen, wherein said phenyl, C4-6 carbocycle and C4-6 heterocycle are each optionally substituted with 1 to 2 C1-4 alkyl, halogen or C1-4 haloalkyl;
R6 is hydrogen, C1-5alkyl, C3-6cycloalkyl, a 4 to 7 membered partially or fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, a 5 to 10 membered spiro carbocyclic ring and a 4 to 10 membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; wherein the C1-5alkyl represented by R6 is optionally substituted with 1 to 3 substituents R6a independently selected from halogen, hydroxyl, C1-5alkyl, C1-4alkoxy, C1-4 haloalkoxy, C3-6cycloalkyl, phenyl, a 4 to 7 membered partially or fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, and a fully saturated 5 to 8 membered bridged-heterocyclic ring system having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; wherein the C3-6cycloalkyl represented by R6 is optionally substituted with 1 to 3 substituents Rb independently selected from halogen, C1-4alky, C1-4 haloalkyl, and C1-4alkoxy; wherein the 4 to 7 membered partially or fully saturated heterocycle, the 5 to 10 membered spiro carbocyclic ring and 5 to 10 membered spiro heterobicyclic ring system represented by R6 is optionally substituted with 1 to 3 substituents R6c independently selected from C1-4alkyl and oxo; and wherein said C3-6cycloalkyl, phenyl, 4 to 7 membered partially or fully saturated heterocycle represented by R6a are optionally substituted with 1 to 3 R7;
R7 is oxo, halogen, C1-4 haloalkyl and C1-4 alkyl;
R8 and R9 are hydrogen, —C(O)C1-4 alkyl and C1-4 alkyl; or R8 and R9 may combine to form a 4 to 6 membered saturated ring optionally containing one additional heteroatom selected from nitrogen or oxygen wherein said additional nitrogen may be optionally substituted with C1-4 alkyl;
R10 and R11 are hydrogen and C1-4 alkyl;
L is a bond, C1-8 alkyl, or
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G1 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl and partially saturated 4- to 11-membered heterocycle; wherein the 6- to 10-membered aryl, 5- to 910-membered heteroaryl and partially saturated 4- to 11-membered heterocycle represented by G1 are each optionally substituted with one or more RD3,
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G2 is selected from Het1, *—NRD4-Het1-*, *—NRD4-Het1-C1-4 alkyl-*, *—C1-4 alkyl-C(RD1)=Het1-*, *—C(O)—C1-4 alkyl-Het1-*, *-Het1-C1-6 alkyl-*, *-Het1-O—*, *—C(O)—C1-4 alkyl-Het1-C(O)—*, *—C(O)-Het1-C(O)—*, *—C(O)-phenyl-C1-4 alkyl-NHC(O)—*; G2 as *—C1-4 alkyl-C(RD1)=Het1-*, *-Het1-O—*, *—C(O)—C1-4 alkyl-Het1-C(O)—*, *—C(O)-Het1-C(O)—*, *—C(O)-phenyl-C1-4 alkyl-NHC(O)—* ; G2 is *—NRD4-Het1-*, *—NRD4-Het1-C1-4 alkyl-*, *—C(O)—C1-4 alkyl-Het1-*, *-Het1-C1-6 alkyl-*
Het1 is 4- to 67-membered monocyclic heterocycle or 7- to 11-membered bicyclic heterocycle, each of which is optionally substituted with one or more RD5, or piperidine, piperazine, 1,4-diazepane, morpholine, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, or 2,6-diazaspiro[3.3]heptane, each of which is optionally substituted with 1 or 2 RD5.
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RD1 is selected from H, C1-6 alkyl or halogen;
RD2 is H or C1-3 alkyl;
RD3 is H, halogen, C1-4 alkyl and C1-4haloalkyl;
RD4 is H or C1-3 alkyl;
RD5 is H, halogen, hydroxyl, C1-4 alkyl, C1-4haloalkyl and C1-4 alkoxy;
Z2 is a bond or C1-4 alkyl optionally substituted with one or more halogen;
Het2 is 4- to 7-membered heterocycle optionally substituted by one or more RL1,
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G3 is C3-7 cycloalkyl or 4- to 7-membered heterocycle; wherein the C3-7 cycloalkyl and 4- to 7-membered heterocycle represented by G3 are each optionally substituted with one or more RL3;
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Z3 is C1-4 alkyl, —C(O)—, or *—C1-4 alkyl-C(O)—*,
Z4 is C1-4 alkyl optionally substituted by RL4;
RL1 is H, halogen, C1-4 alkyl and C1-4haloalkyl;
RL2 is H or C1-4 alkyl;
RL3 is H, halogen, C1-4 alkyl and C1-4haloalkyl;
RL4 is halo, —ORL5, or C1-4 alkyl optionally substituted by halogen, C3-7 cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocycle, or 5- to 6-membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocycle, and 5- to 6-membered heteroaryl are each optionally substituted with one to three substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy;
RL5 is H, C1-4 alkyl or C1-4 haloalkyl;
DSM is D1-D98;
L is
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35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111,1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert, denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Bees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); EliLilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm.,927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). An application specification may show actual reduction to practice by describing testing of the claimed invention.
In the present case, the important factors leading to a conclusion of inadequate written description is the absence of any working example of the invention as claimed, and the lack of predictability in the art.
In the instant specification, there is no disclosure of compounds having the following claimed substituents:
A1 as N;
A2 as N or CR4;
R1 as a 5 membered heteroaryl having 2 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaryl is optionally substituted with 1 to 3 R5; a 5 membered partially or fully saturated heterocycle having 2 heteroatoms independently selected from oxygen and nitrogen, said heterocycle may be optionally substituted with 1 to 3 R5, a partially or fully saturated C3-6 cycloalkyl which may be optionally substituted with 1 to 3 R5; a 7, 8, or 10 membered fused heterobicyclic ring system having 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen, said heterobicylic ring system is optionally substituted with 1 to 3 R5; or a 7 to 10 membered fused carbobicyclic ring system, said carbobicyclic ring system is optionally substituted with 1 to 3 R5;
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phenyl optionally substituted with 1 to 3 R5, 6 membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, 9 membered fused heterobicyclic ring system 3 heteroatoms independently selected from nitrogen substituted with 1 R5,
R3 as halogen, C1-4alkyl, or nitrile, wherein the C1-4alkyl is optionally substituted with C1-4alkoxy or at least one halogen;
R4 as halogen, C1-4alkyl, nitrile and —OR6, wherein the C1-4alkyl is optionally substituted with C1-4alkoxy or at least one halogen;
R5 as CN, hydroxyl, C2-4 alkyl, halogen, —NR8R9, C1-4 alkoxy, —O—C1-4 alkyl, C4-6cycloalkyl, —C1-4alkyl-C3-6cycloalkyl, C(O)NR10R11, a C4-7 heterocycle, and a 5 or 6 membered heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;
R6 as hydrogen, C1-2 or 4-5alkyl, C3-6cycloalkyl, a 4 to 7 membered partially or fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, a 5 to 10 membered spiro carbocyclic ring and a 4 to 10 membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; wherein the C1-5alkyl represented by R6 is optionally substituted with 1 to 3 substituents R6a independently selected from halogen, hydroxyl, C1-5alkyl, C1-4alkoxy, C1-4 haloalkoxy, C3-6cycloalkyl, phenyl, a 4 to 7 membered partially or fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, and a fully saturated 5 to 8 membered bridged-heterocyclic ring system having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; wherein the C3-6cycloalkyl represented by R6 is optionally substituted with 1 to 3 substituents Rb independently selected from halogen, C1-4alky, C1-4 haloalkyl, and C1-4alkoxy; wherein the 4 to 7 membered partially or fully saturated heterocycle, the 5 to 10 membered spiro carbocyclic ring and 5 to 10 membered spiro heterobicyclic ring system represented by R6 is optionally substituted with 1 to 3 substituents R6c independently selected from C1-4alkyl and oxo; and wherein said C3-6cycloalkyl, phenyl, 4 to 7 membered partially or fully saturated heterocycle represented by R6a are optionally substituted with 1 to 3 R7;
R7 as oxo, halogen, C1-4 haloalkyl and C1-4 alkyl;
R8 and R9 as hydrogen, —C(O)C1-4 alkyl and C1-4 alkyl; or R8 and R9 may combine to form a 4 to 6 membered saturated ring optionally containing one additional heteroatom selected from nitrogen or oxygen wherein said additional nitrogen may be optionally substituted with C1-4 alkyl;
R10 and R11 as hydrogen and C1-4 alkyl
L as a bond, C1-8 alkyl,
G2 as *—C1-4 alkyl-C(RD1)=Het1-*, *-Het1-O—*, *—C(O)—C1-4 alkyl-Het1-C(O)—*, *—C(O)-Het1-C(O)—*, *—C(O)-phenyl-C1-4 alkyl-NHC(O)—* ;
Het1 as 4- to 5-membered monocyclic heterocycle or 4-8 or 10-11-membered bicyclic heterocycle, each of which is optionally substituted with one or more RD5, or 2,5-diazaspiro[3.4]octane
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RD1 as C1-6 alkyl or halogen;
RD2 as C2-3 alkyl;
RD3 as C1-4 alkyl or C1-4haloalkyl;,
RD4 as C2-3 alkyl;
RD5 as C1-4 alkyl, C1-4haloalkyl and C2-4 alkoxy;
Z2 as a C2-4 alkyl optionally substituted with one or more halogen;
Het2 as 5- or 7-membered heterocycle optionally substituted by one or more RL1,
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G3 as C3-5 or C7 cycloalkyl or 4-5 or 7-membered heterocycle; wherein the C3-7 cycloalkyl and 4- to 7-membered heterocycle represented by G3 are each optionally substituted with one or more RL3;
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Z3 as C2-4 alkyl, —C(O)—, or *—C2-4 alkyl-C(O)—*,
Z4 as C2-4 alkyl optionally substituted by RL4;
RL1 as halogen, C1-4 alkyl or C1-4haloalkyl;
RL2 as C2-4 alkyl;
RL3 as halogen, C1-4 alkyl or C1-4haloalkyl;
RL4 as halo, —ORL5, or C1-4 alkyl optionally substituted by halogen, C3-7 cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocycle, or 5- to 6-membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocycle, and 5- to 6-membered heteroaryl are each optionally substituted with one to three substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy;
RL5 as H, C1-4 alkyl or C1-4 haloalkyl;
DSM as D2, D3, D8, D9, D14, D21, D27, D30, D34, D39, D42, D46, D48, D51, D52, D53, D57, D58, D59, D61, D62, D63, D66, D71, D72, DD\73, D79, D82, D91, D92 or D93; DSM is D1, D4, D5, D6, D7, D10, D11, D12, D13, D15, D16, D17, D18, D19, D20, D22, D23, D24, D25, D26, D28, D29, D31, D32, D33, D35, D36, D37, D38, D40, D41, D43, D44, D45, D47, D49, D50, D54, D55, D56, D60, D64, D65, D67, D68, D69, D70, D74, D75, D76, D77, D78, D80, D81, D83, D84, D85, D86, D87, D88, D89, D90, D94, D95, D96, D97, and D98
L as L3, L5, L6, L7, L8, L9, L10, L11;
The instant specification (pages 279-425) teaches compounds which are characterized as having only the following substituents:
A1 is CH and CR3
A2 is CH
R1 is phenyl optionally substituted with 1 to 3 R5, 6 membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, 9 membered fused heterobicyclic ring system 3 heteroatoms independently selected from nitrogen substituted with 1 R5,
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125
106
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R3 is —OR6;
R4 is not exemplified
R5 is CH3, CHF2, CF3, F, cyclopropyl substituted optionally with Fluoro
R6 is isopropyl
R7 is not exemplified
R8 and R9 are not exemplified
R10 and R11 are not exemplified
L is
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180
345
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G1 is s 6-membered aryl, 5- to 10-membered heteroaryl and partially saturated 9-membered heterocycle;
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1
94
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82
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155
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G2 is *—NRD4-Het1-*, *—NRD4-Het1-C1-4 alkyl-*, *—C(O)—C1-4 alkyl-Het1-*, *-Het1-C1-6 alkyl-*
Het1 is Het1 is 6- to 7-membered monocyclic heterocycle or 7- to 9-membered bicyclic heterocycle, piperidine, piperazine, 1,4-diazepane, morpholine, 2-azaspiro[3.3]heptane, d 2,7-diazaspiro[3.5]nonane, or 2,6-diazaspiro[3.3]heptane,
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RD1 is selected from H,
RD2 is H and CH3 ;
RD3 is H and halogen,
RD4 is H and CH3 ;
RD5 is H, halogen, hydroxyl, and C1 alkoxy
Z2 is a bond or CH2
Het2 is 4- or 6-membered heterocycle optionally substituted by one or more RL1,
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107
14
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107
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G3 is C6 cycloalkyl or 6-membered heterocycle;
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105
11
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96
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Z3 is CH2, —C(O)—, or *— CH2C(O)—*,
Z4 is CH2
RL1 is H
RL2 is H or CH3 alkyl;
RL3 is H
RL4 is not exemplified
RL5 is not exemplified
DSM is D1, D4, D5, D6, D7, D10, D11, D12, D13, D15, D16, D17, D18, D19, D20, D22, D23, D24, D25, D26, D28, D29, D31, D32, D33, D35, D36, D37, D38, D40, D41, D43, D44, D45, D47, D49, D50, D54, D55, D56, D60, D64, D65, D67, D68, D69, D70, D74, D75, D76, D77, D78, D80, D81, D83, D84, D85, D86, D87, D88, D89, D90, D94, D95, D96, D97, and D98
L is L1, L2, L4, L4a, L11
Therefore, the compounds described in the instant specification detail only a limited number of the total substituents claimed (see substituents 1-28, above). All working examples presented in the instant specification are related to the compounds containing a fraction of the total claimed substituents (see substituents 58-88, above).
There are no working examples in the instant specification for the wide range of substituents claimed, but for which evidence of possession has not been provided (see substituents 29-57, above). Thus the instant specification does not provide any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application.
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F. 3d 1565, 1572, 41 USPQ2d 1961, 1966(1997); In re Gosteli, 872 F.2d 1008, 1012,10 USPQ2d 1614, 1618 (Fed Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.") Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021.
Thus, since Applicant has not described in adequate detail methods to synthesize compounds containing the claimed substituents, or provided evidence that said compounds have been characterized, or that they exist, an ordinary skilled artisan could not completely envisage Applicants’ invention. Moreover, it is clear that the written description requirement has not been met since Applicant has not provided any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application. Thus, claims 1, 2, 4, 13, 14, 16, 19, 23, 27, 29, 33, 35, 40, 45-46, 48-50, 55-56, 58, and 59 of the instant application are not supported by the instant specification and thus a rejection under 35 U.S.C. § 112 (a) for failing to comply with the written description requirement is proper.
Claim 60 is rejected under 35 U.S.C. § 112 (a), or 35 U.S.C. § 112 (pre-AIA ) first paragraph, because the specification, while being enabling for a method of degrading IRAK4 in a subject, it does not reasonably provide enablement for a method of treating Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Cutaneous Lupus Erythematosus, Ankylosing Spondylitis, Osteoporosis, Neuromyelitis optica, Systemic sclerosis, Psoriasis, Dermatomyositis, Atopic Dermatitis, Hidradenitis Suppurativa, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease, Crohn’s Disease, Ulcerative Colitis, Hyperimmunoglobulinemia D, periodic fever syndrome, Cryopyrin-associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, Deficiency of IL-1 Receptor Antagonist, Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Cancer, an autoimmune disease, an inflammatory disease, bone diseases, metabolic diseases, neurological and neurodegenerative diseases and/or disorders, cardiovascular diseases, allergies, asthma, hormone-related diseases, Ischemic stroke, Cerebral Ischemia, hypoxia, Traumatic Brain Injury, Chronic Traumatic Encephalopathy, epilepsy, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The specification does not provide sufficient information to support the instant claims.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claim 60 of the instant application is drawn to a method of treating an IRAK4-mediated disease comprising the administration of a compound of Formula (I).
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claim. The rejected claim is extremely broad. Applicant claims that the claimed compounds can be used to treat a disease mediated by IRAK4. Thus the cited claim is deemed very broad since the claim reads on treating a long list of diseases mediated by IRAK4, and essentially any disease which implicates IRAK4.
State of the Prior Art: There are no art recognized methods that could be used to establish that the instantly claimed method can be used to treat all the instantly claimed diseases mediated by IRAK4. Additionally, the examples provided do not demonstrate the use of the claimed compounds in a broad range of diseases which are mediated by IRAK4 as there is no disclosed common disease mechanism that links IRAK4 action within the claimed disease contexts provided in the instant specification, nor by the state of the art.
Regarding the variability of IRAK4 action in in diseases, Nunes et al. (ACS Medicinal Chemistry Letters, Volume 10, Issue 8, doi: 10.1021/acsmedchemlett.9b00219, published June 14, 2019), hereinafter Nunes, maintains that a primary challenge in treating diseases by targeting IRAK4 is at the protein functions both as a kinase and structural scaffold (page 1081). While most traditional therapeutics focus on inhibiting the kinase activity of IRAK4, research indicates that this catalytic function is often dispensable for disease drug inflammatory signals in certain human cell types (page 1081). In these contexts, the physical presence of IRAK4—acting as a scaffold to recruit other signaling molecules—is sufficient to continue driving the disease pathway even if the kinase is completely blocked. For this reason, most recent approaches in targeting IRAK4 have been aimed at the complete degradation of IRAK4 using Proteolysis-Targeting Chimeras (PROTACs), according to Feng et al. (Acta Pharmaceutica Sinica, Volume 14, Issue 12, pages 5091-5105, doi: 10.1016/j.apsb.2024.09.008, published September 14, 2024), hereinafter Feng (page 5095). Feng emphasizes that while IRAK4 PROTACs are more robust than simple inhibitors because they eliminate both kinase and scaffold functions, they still face significant hurdles in achieving universal therapeutic success (page 5092). A major challenge identified is biological redundancy in structural moieties like the C-terminal domain, where related family members like IRAK1 and IRAK2 can compensate for the absence of IRAK4 to continue driving disease signaling pathways (page 5092). Furthermore, Feng teaches that because different diseases and cell types rely on IRAK4 to varying degrees, some pathological processes can bypass the troll altogether, making it impossible for a single degradation strategy to treat every IRAK4-implicated condition (page 5102). Finally, Feng highlights that while noteworthy progress has been made, no drugs targeting IRAK4 are currently available in the market, impeding the successful treatment of diseases, present day, with PROTACs (page 5102). As such, the current state-of-the-art does not support the successful treatment of any disease by degrading IRAK4 using PROTACs.
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation includes treating any disease mediated by protein kinases. Thus, the skilled artisan would view that successfully targeting the large number of diseases mediated by protein kinases encompassed by the claims comprising the administration of the compounds, is highly unpredictable, as there are a large number of protein kinase inhibitors, as demonstrated in the teachings of Feng, above.
Moreover, one of skill in the art would recognize that it is highly unpredictable in regard to therapeutic effects, side effects and toxicity generated by administering a singular class of compounds for treating all the disorders and diseases encompassed by the claims.
Guidance of the Specification/Working Examples: Applicant has only provided working examples of IRAK4 and IZKF1 cellular degradation (pages 426-443). The instant specification further teaches that the selected compounds demonstrate acceptable pharmacokinetic profiles following both oral and intravenous administration in male Beagle dogs and cynomolgus monkeys (pages 443-450). These experiments demonstrate that the selected compounds can reduce IRAK4 protein levels in peripheral blood mononuclear cells (PBMCs). Although the specification demonstrates that selective degradation of IRAK4 protein is achievable in vitro and that IRAK4 target engagement is measurable in PBMCs of nonhuman subjects, this is not commensurate in scope with treating the diseases recited the instant claims. The specification contains no disease relevant functional data, no cytokine or inflammatory mediator suppression data, and no in vivo efficacy data in any art-recognized disease model for any of the recited conditions. Reduction of the target proteins in a healthy animal model does not demonstrate, and cannot reasonably be extrapolated to establish therapeutic efficacy across the broad and mechanistically disparate array of diseases recited in the instant claims. Thus, the specification fails to provide sufficient evidence in support the broad use of the claimed compounds for the treatment of any disease mediated by IRAK4.
The Quantitation of Experimentation Required: In order to practice Applicant’s invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the claimed compounds could be used to treat any disease mediated by IRAK4. The population of subjects could include any subject, and thus the quantitation of experimentation is unreasonably large. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. A method for treating a disease mediated by IRAK4 comprising administering the compounds as claimed is not enabled by the instant specification.
Claim Rejections - 35 U.S.C. § 112 (b)
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.
Claims 58 and 60 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 58 is rejected under U.S.C. § 112(b) for references to Examples 1 to 199 in the claim. As stated in MPEP § 2173.05 (s), claims should be complete to themselves and the reference to tables renders the claims incomplete. Claims which recite figures or tables are only permitted in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference the duplicating a drawing or table into a claim. It is suggested to amend claims 58 to list all of the desired compounds claimed.
Claim 60 is rejected under U.S.C. § 112(b) for use of a relative term. Claim 60 of the instant application claim a method of IRAK4-mediated diseases, conditions, or disorders, comprising administering to a subject in need thereof the compound or pharmaceutically acceptable salt thereof of Formula (I).
It is unclear what “IRAK4-mediated” refers to and how to determine if a disease is mediated by IRAK4. The term “IRAK4-mediated” in claim 60 is a relative term which renders the claim indefinite. The term “IRAK4-mediated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not define how to determine if a disease is mediated by IRAK4. Thus it is unclear what would be considered mediated by IRAK4 by a person of ordinary skill in the art. There are a large number of diseases that could be considered mediated by IRAK4. These diseases can range from Kidney disease to cancer. Moreover, there are diseases that could result from IRAK4 dysfunction that do not directly have IRAK4 at the center of the disease morphology. The claims, as written, do not distinctly claim the disease to which IRAK4 is related, or how the relation is made—whether it be a disease, condition, or disorder directly implicating IRAK4 dysfunction or a disease which develop as a result of diseases, conditions, or disorders that implicate IRAK4 dysfunction. Thus an ordinary skilled artisan cannot ascertain the metes and bounds of the claimed invention and thus the claims are properly rejected as being indefinite.
Correspondence
Claims 4, 45, and 60 are objected to.
Claims 1, 2, 4, 13, 14, 16, 19, 23, 27, 29, 33, 35, 40, 45-46, 48-50, 55-56, and 58-60 are rejected.
No claim is allowed.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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