PATENT CLAIM ANALYSIS

Application Number: 15876880
Application Type: Utility
Filing Date: 2018-01
Publication Date: 2019-06
Patent Classification: ["546", "242000"]

Abstract:
We describe a bis-benzylidine piperidone, RA190, which covalently binds to the ubiquitin receptor RPN13 (ADRM1) in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma lines, even those resistant to bortezomib, were sensitive to RA190 via ER stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After p.o. or i.p. dosing of mice, RA190 distributed to plasma and major organs excepting brain, and potently inhibited proteasome function in skin and muscle. RA190 administration i.p. profoundly reduced growth of multiple myeloma and ovarian cancer xenografts, and oral RA190 treatment retarded HPV+ syngeneic mouse tumor growth, without impacting spontaneous HPV-specific CD8+ T cell responses, suggesting its therapeutic potential. The bis-benzylidine piperidone RA190 is a new orally-available proteasome inhibitor. Multiple myeloma, cervical and ovarian cancers are particularly sensitive to RA190.

Claim (Index 1):
A method of inhibiting proteasomes in a mammal by administering to the mammal an effective amount of a compound of formula I, wherein each pair of As is one of:\n (i) phenyl, optionally substituted with 1-5 substituents selected from the group consisting of R1, OR1, NR1R2, S(O) q R1, SO 2 NR1R2, NR1SO 2 R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF 3 , and OCF 3 , \n (ii) naphthyl, optionally substituted with 1-5 substituents selected from the consisting of R1, OR1, NR1R2, S(O) q R1, SO 2 NR1R2, NR1SO 2 R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF 3 , and OCF 3 , \n (iii) a 5 or 6 membered monocyclic heteroaryl group, having 1-3 heteroatoms selected from the group consisting of 0, N, and S, optionally substituted with 1-3 substituents selected from the group consisting of R1, OR1, NR1R2, S(O) q R1, SO 2 NR1R2, NR1SO 2 R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF 3 , and OCF 3 , and \n (iv) an 8 to 10 membered bicyclic heteroaaryl group containing 1-3 heteroatoms selected from the group consisting of O, N, and S; and the second ring is fused to the first ring using 3 to 4 carbon atoms, and the bicyclic hetero aryl group is optionally substituted with 1-3 substituents selected from the group consisting of R1, OR1, NR1R2, S(O) q R1, SO 2 NR1R2, NR1SO 2 R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1 C(O)R2, NR1C(O)OR2, CF 3 , and OCF 3 ; \n wherein X is OR1 or NP, wherein P is selected from the group consisting of R1, C(O)R1, C(O)OR1, C(O)NR1R2, S\u2014N(R1)COOR1, and S\u2014N(R1), wherein Y is selected from the group consisting of O, S, NR1 and CR1R2, wherein R1 and R2 are selected from the group consisting of hydrogen, nitro, hydroxyl, carboxy, amino, halogen, cyano and C 1 -C 14  linear or branched alkyl groups, that are optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 14  linear or branched alkyl, up to perhalo substituted C 1 -C 14  linear or branched alkyl, C 1 -C 14  alkoxy, hydrogen, nitro, hydroxyl, carboxy, amino, C 1 -C 14  alkylamino, C 1 -C 14  dialkylamino, halogen, and cyano; and wherein Z is selected from the group consisting of hydrogen; C 1  to C 14  linear, branched, or cyclic alkyls; phenyl; benzyl, 1-5 substituted benzyl, C 1  to C 3  alkyl-phenyl, wherein the alkyl moiety is optionally substituted with halogen up to perhalo; up to perhalo substituted C 1  to C 14  linear or branched alkyls; \u2014(CH 2 ) q \u2014K, where K is a 5 or 6 membered monocyclic heterocyclic ring, containing 1 to 4 atoms selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or an 8 to 10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, wherein said alkyl moiety is optionally substituted with halogen up to perhalo; and wherein the variable q is an integer ranging from 0 to 4; and wherein inhibiting the proteasomes comprises inhibiting a ubiquitin proteasome system.

Metadata:
- Claim Count in Document: 4.0
- Percentile: 86.0
- Lexical Diversity: 1.53211
- Patent Class: 546.0
- Transitional Phrase Type: closed
- Component Type: 1
- Foreign Priority: False
- Related Applications: ['14889768', '13513819', '14933671', '12669361', '12527428']

Analysis Scores:
- 35 USC 101 Eligibility (BERT): 0.7822606421597579
- 35 USC 102 Novelty (BERT): 0.5969733953508203
- Combined Prediction Score: 0.7637319174788642
- Mean Citation Score: 335.409252
- Max Citation Score: 581.3244
- Similarity Product: 421.4797462536335

Labels:
- Claim Label 101: 1
- Claim Label 102: 0
- Claim Label 103: 1
- Claim Label 112: 0
- Combined Label: 0
- Label 101 Adjusted: 1

Dataset: test