IP Library › Granted Patent US 12,239,684
Granted Patent B2
US 12,239,684 · App. 18/204,907 · Granted Mar 4, 2025

Modulators of complement activity

Inventors: Michelle Denise Hoarty (Billerica, MA); Ketki Ashok Dhamnaskar (Foster City, CA); Daniel Elbaum (Newton, MA); Kristopher Josephson (San Carlos, CA); Kelley Cronin Larson (Quincy, MA); Zhong Ma (Lexington, MA); Nathan Ezekiel Nims (Winchester, MA); Alonso Ricardo (Winchester, MA); Kathleen Seyb (Wakefield, MA); Guo-Qing Tang (Acton, MA); Douglas A. Treco (Arlington, MA); Zhaolin Wang (Wellesley, MA); Ping Ye (Lexington, MA); Hong Zheng (New York, NY); Sarah Jacqueline Perlmutter (Urbana, IL)
Assignee: RA PHARMACEUTICALS, INC.
A61K38/10A61K39/00C07K16/36C07K2317/76
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Quick Facts
Patent No.
US 12,239,684
App. No.
18/204,907
Granted
Mar 4, 2025
Kind
B2
Abstract

The present invention provides polypeptide modulators of complement activity, including cyclic polypeptide modulators. Also provided are methods of utilizing such modulators as therapeutics.

Claims (13)

1. A method of treating a C5-complement-related disorder in a subject, the method comprising administering a polypeptide of SEQ ID NO: 194 or SEQ ID NO: 184 to the subject, wherein hemolysis in the subject is reduced by at least 50% relative to hemolysis levels previously observed in the subject.

2. The method of claim 1 , wherein the polypeptide is administered to the subject at a dose of from about 0.1 mg/kg to about 10 mg/kg.

3. The method of claim 2 , wherein the polypeptide is administered to the subject at a dose of from about 0.3 mg/kg to about 3 mg/kg.

4. The method of claim 2 , wherein the polypeptide is administered to the subject at a dose of about 0.3 mg/kg.

5. The method of claim 1 , wherein the polypeptide is administered to the subject daily.

6. The method of claim 1 , wherein the polypeptide is administered to the subject for seven days.

7. The method of claim 1 , wherein the polypeptide is of SEQ ID NO: 184.

8. The method of claim 1 , wherein the polypeptide is of SEQ ID NO: 194.

9. The method of claim 1 , wherein the C5-complement-related disorder is paroxysmal nocturnal hemoglobinuria (PNH).

10. The method of claim 1 , wherein the subject has previously been treated with eculizumab.

11. The method of claim 1 , wherein the subject is also receiving treatment with eculizumab.

12. The method of claim 1 , wherein treatment with eculizumab is ineffective.

13. The method of claim 1 , wherein hemolysis in the subject is reduced by at least 90% relative to hemolysis levels previously observed in the subject.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 20, 2025
From: RA PHARMACEUTICALS, INC.
To: UCB HOLDINGS, INC.
Reel/Frame 071466/0238 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 25, 2023
From: HOARTY, MICHELLE DENISE; DHAMNASKAR, KETKI ASHOK; ELBAUM, DANIEL; JOSEPHSON, KRISTOPHER; LARSON, KELLEY CRONIN; MA, ZHONG; NIMS, NATHAN EZEKIEL; RICARDO, ALONSO; SEYB, KATHLEEN; TANG, GUO-QING; TRECO, DOUGLAS A.; WANG, ZHAOLIN; YE, PING; ZHENG, HONG; PERLMUTTER, SARAH JACQUELINE
To: RA PHARMACEUTICALS, INC.
Reel/Frame 065336/0142 →
Priority Claims (1)
WO PCT/US2015/035473 · Jun 12, 2015 · international
Continuity (8)
Continuation 17143232 · Jan 7, 2021
Continuation 16776551 · Jan 30, 2020
Continuation 16393393 · Apr 24, 2019
Continuation 15905158 · Feb 26, 2018
Continuation 15547085
Provisional Application 62185298 · Jun 26, 2015
Provisional Application 62108772 · Jan 28, 2015
Related Publication 20240156896A1 · May 16, 2024
References Cited (322)
US 4033940A · Hughes et al. · 1977 [cited by applicant]
US 4179337A · Davis et al. · 1979 [cited by applicant]
US 4216141A · Rivier et al. · 1980 [cited by applicant]
US 4271068A · Kamber et al. · 1981 [cited by applicant]
US 4301144A · Iwashita et al. · 1981 [cited by applicant]
US 4496689A · Mitra · 1985 [cited by applicant]
US 4640835A · Shimizu et al. · 1987 [cited by applicant]
US 4670417A · Iwasaki et al. · 1987 [cited by applicant]
US 4791192A · Nakagawa et al. · 1988 [cited by applicant]
US 5270170A · Schatz et al. · 1993 [cited by applicant]
US 5338665A · Schatz et al. · 1994 [cited by applicant]
US 5371109A · Engstrom et al. · 1994 [cited by applicant]
US 5427908A · Dower et al. · 1995 [cited by applicant]
US 5580717A · Dower et al. · 1996 [cited by applicant]
US 5585353A · Merrifield et al. · 1996 [cited by applicant]
US 5591828A · Bosslet et al. · 1997 [cited by applicant]
US 5596078A · Andersson et al. · 1997 [cited by applicant]
US 5618676A · Hitzeman et al. · 1997 [cited by applicant]
US 5643768A · Kawasaki · 1997 [cited by applicant]
US 5658754A · Kawasaki · 1997 [cited by applicant]
US 5726287A · Andersson et al. · 1998 [cited by applicant]
US 5750344A · Doyle · 1998 [cited by applicant]
US 5766897A · Braxton · 1998 [cited by applicant]
US 5824784A · Kinstler et al. · 1998 [cited by applicant]
US 5834318A · Buettner · 1998 [cited by applicant]
US 5837500A · Ladner et al. · 1998 [cited by applicant]
US 5843701A · Gold et al. · 1998 [cited by applicant]
US 5854018A · Hitzeman et al. · 1998 [cited by applicant]
US 5856123A · Hitzeman et al. · 1999 [cited by applicant]
US 5919651A · Hitzeman et al. · 1999 [cited by applicant]
US 5922680A · Paulsen et al. · 1999 [cited by applicant]
US 5990237A · Bentley et al. · 1999 [cited by applicant]
US 5990273A · Andersson et al. · 1999 [cited by applicant]
US 6086918A · Stern et al. · 2000 [cited by applicant]
US 6194550B1 · Gold et al. · 2001 [cited by applicant]
US 6242565B1 · Kishida et al. · 2001 [cited by applicant]
US 6258558B1 · Szostak et al. · 2001 [cited by applicant]
US 6261804B1 · Szostak et al. · 2001 [cited by applicant]
US 6268343B1 · Knudsen et al. · 2001 [cited by applicant]
US 6309669B1 · Setterstrom et al. · 2001 [cited by applicant]
US 6348584B1 · Hodgson et al. · 2002 [cited by applicant]
US 6355245B1 · Evans et al. · 2002 [cited by applicant]
US 6361943B1 · Yanagawa et al. · 2002 [cited by applicant]
US 6673901B2 · Koide · 2004 [cited by applicant]
US 6716973B2 · Baskerville et al. · 2004 [cited by applicant]
US 6720472B2 · Chada et al. · 2004 [cited by applicant]
US 6844010B1 · Setterstrom et al. · 2005 [cited by applicant]
US 6962781B1 · Williams · 2005 [cited by applicant]
US 7348401B2 · Johnson et al. · 2008 [cited by applicant]
US 7744910B2 · Gschneidner et al. · 2010 [cited by applicant]
US 8101586B2 · Rock et al. · 2012 [cited by applicant]
US 8329169B2 · Fung et al. · 2012 [cited by applicant]
US 8377437B2 · Van Lookeren Campagne · 2013 [cited by applicant]
US 8652477B2 · Schwaeble et al. · 2014 [cited by applicant]
US 8703136B2 · Baas et al. · 2014 [cited by applicant]
US 8753625B2 · Fung et al. · 2014 [cited by applicant]
US 8911733B2 · Holers et al. · 2014 [cited by applicant]
US 9937222B2 · Hoarty et al. · 2018 [cited by applicant]
US 10106579B2 · Hoarty et al. · 2018 [cited by applicant]
US 10208089B2 · Hoarty et al. · 2019 [cited by applicant]
US 10328115B2 · Hoarty et al. · 2019 [cited by applicant]
US 10435438B2 · Hoarty et al. · 2019 [cited by applicant]
US 10588936B2 · Hoarty et al. · 2020 [cited by applicant]
US 10835574B2 · DeMarco et al. · 2020 [cited by applicant]
US 10918691B2 · Hoarty et al. · 2021 [cited by applicant]
US 11014965B2 · Hoarty et al. · 2021 [cited by applicant]
US 11123399B2 · Ricardo et al. · 2021 [cited by applicant]
US 20030040472A1 · Larsen et al. · 2003 [cited by applicant]
US 20050090448A1 · Johnson et al. · 2005 [cited by applicant]
US 20050191343A1 · Liang · 2005 [cited by applicant]
US 20060027059A1 · Hsien · 2006 [cited by applicant]
US 20060270590A1 · Lockwood et al. · 2006 [cited by applicant]
US 20080146490A1 · Joabsson et al. · 2008 [cited by applicant]
US 20080269318A1 · Romano · 2008 [cited by applicant]
US 20080313749A1 · Timmerman et al. · 2008 [cited by applicant]
US 20090054623A1 · DeFrees · 2009 [cited by applicant]
US 20100015139A1 · Bansal · 2010 [cited by applicant]
US 20100092493A1 · Cao · 2010 [cited by applicant]
US 20100093624A1 · Low et al. · 2010 [cited by applicant]
US 20100099113A1 · Knör et al. · 2010 [cited by applicant]
US 20100143344A1 · Baas et al. · 2010 [cited by applicant]
US 20100166748A1 · Guild et al. · 2010 [cited by applicant]
US 20110172126A1 · Brust · 2011 [cited by applicant]
US 20110190221A1 · Francois et al. · 2011 [cited by applicant]
US 20110269807A1 · Baciu · 2011 [cited by applicant]
US 20120225056A1 · Rother et al. · 2012 [cited by applicant]
US 20130029912A1 · Holers et al. · 2013 [cited by applicant]
US 20130053302A1 · Lambris et al. · 2013 [cited by applicant]
US 20130053311A1 · Kalthoff et al. · 2013 [cited by applicant]
US 20130246083A1 · Bell · 2013 [cited by applicant]
US 20130273052A1 · Gies et al. · 2013 [cited by applicant]
US 20130344082A1 · Lambris et al. · 2013 [cited by applicant]
US 20130345257A1 · Hahn et al. · 2013 [cited by applicant]
US 20140234275A1 · Williams · 2014 [cited by applicant]
US 20150011474A1 · Berghard et al. · 2015 [cited by applicant]
US 20150057342A1 · Koren et al. · 2015 [cited by applicant]
US 20150166606A1 · Wang et al. · 2015 [cited by applicant]
US 20150359900A1 · Wang et al. · 2015 [cited by applicant]
US 20160206580A1 · Los et al. · 2016 [cited by applicant]
US 20160376355A1 · Bell et al. · 2016 [cited by applicant]
US 20170137468A1 · Arata et al. · 2017 [cited by applicant]
US 20180280530A1 · Guo et al. · 2018 [cited by applicant]
CN 101668541A · 2010 [cited by applicant]
EP 3154561A2 · 2017 [cited by applicant]
JP 2013543380A · 2013 [cited by applicant]
RU 2406507C2 · 2010 [cited by applicant]
RU 2505311C2 · 2014 [cited by applicant]
RU 2014137303A · 2016 [cited by applicant]
WO WO1993011161A1 · 1993 [cited by applicant]
WO WO1998032427A1 · 1998 [cited by applicant]
WO WO2000021559A2 · 2000 [cited by applicant]
WO WO2005023866A2 · 2005 [cited by applicant]
WO WO2006088888A2 · 2006 [cited by applicant]
WO WO2008109742A1 · 2008 [cited by applicant]
WO WO2008113834A2 · 2008 [cited by applicant]
WO WO2009014633A1 · 2009 [cited by applicant]
WO WO2009046198A2 · 2009 [cited by applicant]
WO WO2009067191A2 · 2009 [cited by applicant]
WO WO2011057158A1 · 2011 [cited by applicant]
WO WO2012044893A1 · 2012 [cited by applicant]
WO WO2012139081A3 · 2012 [cited by applicant]
WO WO2012162215A1 · 2012 [cited by applicant]
WO WO2012174055A1 · 2012 [cited by applicant]
WO WO2013037267A1 · 2013 [cited by applicant]
WO WO2013052736A2 · 2013 [cited by applicant]
WO WO2013126006A1 · 2013 [cited by applicant]
WO WO2013172954A1 · 2013 [cited by applicant]
WO WO2014078622A1 · 2014 [cited by applicant]
WO WO2015140304A1 · 2015 [cited by applicant]
WO WO2015191951A2 · 2015 [cited by applicant]
WO WO2016094834A2 · 2016 [cited by applicant]
WO WO2016123371A1 · 2016 [cited by applicant]
WO WO2017035362A1 · 2017 [cited by applicant]
WO WO2017105939A1 · 2017 [cited by applicant]
WO WO2018106859A1 · 2018 [cited by applicant]
WO WO2019051436A1 · 2019 [cited by applicant]
WO WO2019112984A1 · 2019 [cited by applicant]
WO WO2020185541A2 · 2020 [cited by applicant]
WO WO2020219822A1 · 2020 [cited by applicant]
Abuchowski, A. et al, (1977) Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase, J. Biol. Chem., 252, 3582. [cited by applicant]
Altschul et al., (1997) Gapped Blast and PSI-Blast: a new generation of protein database search programs, Nucleic Acids Res. 25(17):3389-3402. [cited by applicant]
Amara, et al., (2008) “Interaction Between the Coagulation and Complement System” in Current Topics in Complemen II, J.D. Lambris (ed.), pp. 71-79 (Adv Exp Med Biol. 2008;632:71-9). [cited by applicant]
Amara, et al., (2010) Molecular intercommunication between the complement and coagulation systems. J. Immunol. 185:5628-5636. [cited by applicant]
Anonymous: “History of Changes for Study: NCT04382755” May 8, 2020, XP055809235, Retrieved from the Internet: URL:https://www.clinicaltrials.gov/ct2/history/NCT04382755?V_I=View#StudyPage Top [retrieved on May 31, 2021]… [cited by applicant]
Anonymous: “NCT04436497: Healey ALS Platform Trial—Regimen A Zilucoplan” Jun. 17, 2020. [cited by applicant]
ARIPO Form 18 Office Action for corresponding ARIPO Application No. AP/P/2016/009612 entitled “Modulation of Complement Activity” dated Feb. 19, 2019. [cited by applicant]
Australian Examination Report for corresponding Australian Application No. 2015274482, dated Nov. 24, 2017. [cited by applicant]
Baggio, R. et al. (2002) Identification of epitope-like consensus motifs using mRNA display, J. Mol. Recog. 15:126-134. [cited by applicant]
Ballanti et al., (2013) Complement and autoimmunity. Immunol Res 56:477-491. [cited by applicant]
Banks, P. et al., (2000) Impact of a red-shifted dye label for high throughput fluorescence polarization assays of G protein-coupled receptors. J Biomol Screen. 5(5):329-34. [cited by applicant]
Baskerville, S. and Bartel, D.P. (2002) A ribozyme that ligates RNA to protein, Proc. Natl. Acad. Sci. USA 99:9154-9159. [cited by applicant]
Beauchamp C. O. et al., (1983) A new procedure for the synthesis of polyethylene glycol-protein adducts; effects on function, receptor recognition, and clearance of superoxide dismutase, lactoferrin, and alpha 2-macrogl… [cited by applicant]
Bergseth, G. et al., (2013) An international serum standard for application in assays to detect human complement activation products. Mol Immunol. 56:232-9. [cited by applicant]
Berman, H.M. et al., (2000) The Protein Data Bank, Nucleic Acids Research, 28: 235-242. [cited by applicant]
Blackwell, H. E. and Grubbs, R. H. (1998) Highly Efficient Synthesis of Covalently Cross-Linked Peptide Helices by Ring-Closing Metathesis, Angew. Chem., Int. Ed. 37, 3281-3284. [cited by applicant]
Bracken, et al.(1994) Synthesis and Nuclear Magnetic Resonance Structure Determination of an .alpha.-Helical, Bicyclic, Lactam-Bridged Hexapeptide, J. Am. Chem. Soc., 116, 6431-6432. [cited by applicant]
Brodsky (2014) Paroxysmal nocturnal hemoglobinuria. Blood 2014;124:2804-2811. [cited by applicant]
Canadian Examination Report for corresponding Canadian Application No. 2949985, dated Oct. 26, 2017. [cited by applicant]
Cantel et al. (2008) Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide-alkyne 1,3-dipolar cycloaddition, J. Org. Chem., 73 (15), 5663-5674. [cited by applicant]
Cazander G., et al., (2012) Complement activation and inhibition in wound healing. Clin Dev Immunol, 2012:534291. [cited by applicant]
Chang, Kyeong-Ok Characterization and inhibition of norovirus proteases of genogroups I and II using a fluorescence resonance energy transfer assay. Virology, 2012, 423(2), 125-133. [cited by applicant]
Cheng et al. Chromatographic separtion and Tandem MS identification of active peptides in potato protein hydrolysate that inhibit autoxidation of soybean oil-in-water emulsions. Journal of Agricultural and Food Chemistr… [cited by applicant]
Chinese Office Action for corresponding Chinese Application No. 2015800313418 dated Dec. 21, 2018. [cited by applicant]
Cichewicz et al. Cutaneous delivery of alpha-tocopherol and lipoic acid using microemulsions: influence of composition and charge J Pharm Pharmacol. Jun. 2013, vol. 65, No. 6, pp. 817-826. [cited by applicant]
Coin, I et al. (2007) Solid-phase peptide synthesis: from standard procedures to the synthesis of difficult sequences, Nature Protcols 2(12):3247-56. [cited by applicant]
Coto, Y. et al. (2008) Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides, ACS Chem. Biol. 3:120-129. [cited by applicant]
Cwirla, S.E. et al. (1990) Peptides on phage: a vast library of peptides for identifying ligands, Proc. Natl. Acad. Sci. U.S.A. 87:6378-6382. [cited by applicant]
De Boer J.P., et al., (1993) Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of [cited by applicant]
Deangelis RA., et al., (2012) Targeted complement inhibition as a promising strategy for preventing inflammatory complications in hemodialysis.,Immunobiology, 217(11): 1097-1105. [cited by applicant]
Declercq et al: “Zilucoplan in patients with acute hypoxic respiratory failure due to COVID-19 (Zilucov): a structured summary of a study protocol for a randomised controlled trial”, Trials, vol. 21, No. 1, Dec. 1, 2020. [cited by applicant]
Dedkova, L. et al. (2003) Enhanced D-amino acid incorporation into protein by modified ribosomes, J. Am. Chem. Soc. 125: 6616-6617. [cited by applicant]
Dennis et al. (2002) Albumin binding as a general strategy for improving the pharmokinetics of proteins. J Biol Chem. 277(38):35035-43. [cited by applicant]
Devlin, J.J., et. al., (1990). Random peptide libraries: a source of specific protein binding molecules, Science 249, 404-406. [cited by applicant]
Diurno et al: “Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience”, Apr. 1, 2020 (Apr. 1, 2020). [cited by applicant]
Engelhardt, et al., (2002) Severe cold hemagglutinin disease (CHD) successfully treated with rituximab., Blood, 100(5):1922-23. [cited by applicant]
Examination Report for corresponding New Zealand Application No. 727420 dated May 25, 2018. [cited by applicant]
Extended European Search Report for corresponding European Application No. 15807069.8 dated Mar. 19, 2018. [cited by applicant]
Extended European Search Report for corresponding European Application No. 16744125.2 dated Dec. 21, 2018. [cited by applicant]
Extended European Search Report for corresponding European Application No. 18788604.9 dated Apr. 15, 2021. [cited by applicant]
Extended European Search Report for corresponding European Application No. 19194070.9 dated Mar. 2, 2020. [cited by applicant]
Extended European Search Report for corresponding European Application No. 20157916.6 entitled “Modulators of Complement Activity” dated May 13, 2020. [cited by applicant]
First Examination Report dated May 22, 2017 in New Zealand Application No. 727420 entitled “Modulation of Complement Activity”. [cited by applicant]
First Examination Report for corresponding India Application No. 201617040921 entitled “Modulation of Complement Activity” dated Dec. 9, 2019. [cited by applicant]
Forster, A.C. et al. (2003) Programming peptidomimetic syntheses by translating genetic codes designed de novo, Proc. Natl. Acad. Sci. USA 100: 6353-6357. [cited by applicant]
Fourth Examination Report for corresponding Australian Application No. 2015274482 dated Sep. 13, 2018. [cited by applicant]
Frankel, A. et al., (2003) Encodamers: unnatural peptide oligomers encoded in RNA, Chem. Biol. 10:1043-1050. [cited by applicant]
Fredslund, F. et al. (2008). Structure of and influence of a tick complement inhibitor on human complement component 6, Nature. 9:753-760. [cited by applicant]
Freskgard, Per-Ola et al. “Antibody therapies in CNS diseases”, Neuropharmacology, Pergamon Press, Oxford, GB, vol. 120, Mar. 10, 2016. [cited by applicant]
Garbuzova-Davis and Sanberg “Blood-CNS Barrier Impairment in ALS patients versus an animal model” Frontiers in Cellular Neuroscience, vol. 8, Jan. 1, 2014. [cited by applicant]
Garland Donita L. et al: “Abstract”, Scientific Reports, vol. 11, No. 1, Jan. 1, 2021, Retrieved from the Internet: URL:https://www.nature.com/articles/s41598-021-89978-8.pdf. [cited by applicant]
Genbank Accession No. EKQ53330.1, hypothetical protein B655 1297 [ [cited by applicant]
Goto, Y. et al. (2008) Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides, ACS Chem. Biol. 3:120-129. [cited by applicant]
Hadders, M.A. et al. (2012). Assembly and regulation of the membrane attack complex based on structures of C5b6 and sC5b9, Cell Reports. 1:200-207. [cited by applicant]
Haeger M., et al., (1992) Complement, neutrophil, and macrophage activation in women with severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelet count in Obstetrics & Gynecology, 79(… [cited by applicant]
Hajishengallis G. (2010) Complement and periodontitis. Biochem Pharmacol. 15; 80(12): 1. [cited by applicant]
Hammer, R.P., “Harnessing mRNS-display for the Discovery of Macrocyclic Peptide Drugs” BPS Peptide Showcase East, Mar. 14, 2016. [cited by applicant]
Hartman et al., (2006) Enzymatic aminoacylation of tRNA with unnatural amino acids, Proc. Natl. Acad. Sci. USA 103:4356-4361. [cited by applicant]
Hartman, M.C.T. et al. (2007) An expanded set of amino acid analogs for the ribosomal translation of unnatural peptides, PLoS ONE 2:e972. [cited by applicant]
He, M and Taussig, M (2002). Briefs in Functional Genomics and Proteomics. 1(2): 204-212. [cited by applicant]
Heinis, C. et al., (2009) Phage-encoded combinatorial chemical libraries based on bicyclic peptides. Nat Chem Biol. 5(7):502-7. [cited by applicant]
Hill et al., (2006) The incidence and prevalence of paroxysmal nocturnal hemoglobinuria (PNH) and survival of patients in Yorkshire. Blood 2006;108:Abstract 985. [cited by applicant]
Hillmen et al., (2013) Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013;162:62-73. [cited by applicant]
Hillmen, P. et al. (2006) “The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria” The New England Journal of Medicine, 355(12):1233-1243. [cited by applicant]
Hollinger, P. et al., “Diabodies”:Small bivalent and bispecific antibody fragments. PNAS. 1993. 90:6444-8. [cited by applicant]
Howard et al: “Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Pla… [cited by applicant]
Howard, James F. et al: “Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (Regain): a phase 3, randomised, double-blind, placebo-controlled, mul… [cited by applicant]
Huber-Lang, et al., (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nature Med. 12(6):682-687. [cited by applicant]
International Search Report and Written Opinion dated Apr. 22, 2016 in application No. PCT/US2016/015412, entitled: Modulators of Complement Activity. [cited by applicant]
International Search Report and Written Opinion dated Apr. 24, 2018 in application No. PCT/US2017/065005, entitled: Modulators of Complement Activity. [cited by applicant]
International Search Report and Written Opinion dated Dec. 4, 2015 in Application No. PCT/US2015/035473, entitled: Modulation of Complement Activity. [cited by applicant]
International Search Report and Written Opinion dated Mar. 1, 2019 in application No. PCT/US2018/063719 entitled “Modulators of Complement Activity”. [cited by applicant]
International Search Report and Written Opinion dated Mar. 17, 2017 in Application No. PCT/US2016/065228, entitled: Modulators of Complement Activity. [cited by applicant]
International Search Report and Written Opinion dated Nov. 15, 2018 in applicaiton No. PCT/US2018/050317 entitled: Formulations for Compound Delivery. [cited by applicant]
International Search Report and Written Opinion dated Sep. 3, 2020 in PCT Application No. PCT/US2020/021330 entitled “Modulators of Complement Activity”. [cited by applicant]
International Search Report and Written Opinion in application No. PCT/US2019/057316 entitled “Neurological Disease Treatment With Complement Inhibitors” dated Apr. 2, 2020. [cited by applicant]
Israel Office Action for corresponding Israel application No. 259762 entitled “Modulators of Complement Activity” dated Jun. 30, 2019. [cited by applicant]
Jackson, R.J., et al., (2001) Development of a tRNA-dependent in vitro translation system, RNA 7:765-773. [cited by applicant]
Janke et al. The arginine mimicking [beta]-amino acid [beta]3hPhe(3-H2N—CH) as S1 ligand in cyclotheonamide-based [beta]-tryptase inhibitors. Bioorg Med Chem. 2011, 19(23):7236-43;p. 7237, col. 1, Scheme 2. [cited by applicant]
Japanese Office Action for corresponding Japanese Application No. 2017-517219 dated Jun. 5, 2018. [cited by applicant]
Japanese Office Action for corresponding Japanese Application No. 2017-517219, dated Nov. 21, 2017. [cited by applicant]
Jennette et al., (2013) Complement in ANCA-associated vasculitis., Semin Nephrol. 33(6): 557-64. [cited by applicant]
Jha P., et al., (2007) The role of complement system in ocular diseases including uveitis and macular degeneration., Mol Immunol. 44(16): 3901-3908. [cited by applicant]
Jiang et al: “Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV”, Emerging Microbes & Infections, vol. 7, No. 1, Apr. 24, 2018. [cited by applicant]
Johnston, J. “A Phase 1 Multiple-Dose Clinical Study of RA101495, a Subcutaneously Admin1stered Synthetic Macrocyclic Peptide Inhibitor of Complement C5 for Treatment of Paroxysmal Nocturnal Hemoglobinuria” Library of t… [cited by applicant]
Johnston, Jeffrey et al. “A Phase 1 Single-Ascending-Dose Clinical Study of RA101495, a Subcutaneously Administered Synthetic Macrocyclic Peptide Inhibitor of Complement C5 for Treatment of Paroxysmal Nocturnal Hemoglob… [cited by applicant]
Josephson, K. et al., (2005) Ribosomal synthesis of unnatural peptides, J. Am. Chem. Soc. 127: 11727-11735. [cited by applicant]
Josephson, K. et al., (2013) “mRNA display: from basic principles to macrocycle drug discovery” Drug Discovery Today, vol. 00, No. 00. [cited by applicant]
Kairemo E et al., (2010) A nationwide survey of paroxysmal nocturnal haemoglobinuria in Finland. Haematologica 2010;95[suppl.2]:303:Abstract 0727. [cited by applicant]
Kay, B.K. et al. (2001) Screening phage-displayed combinatorial peptide libraries, Methods. 24:240-246. [cited by applicant]
Keefe, A.D. and Szostak, J.W. (2001) Functional proteins from a random-sequence library, Nature 15:715-718. [cited by applicant]
Keshari et al 2014 (Dec. 2014 ASH abstract) A Novel C5 Complement Inhibitor Protects Against Sepsis-Induced Activation of Complement, Coagulation and Inflammation and Provides Survival Benefit in [cited by applicant]
Keshari et al 2015 (ASH abstract—Blood 2015 126(765)) Complement C5 Inhibition Blocks the Cytokine Storm and Consumptive Coagulopathy by Decreasing Lipopolysaccharide (LPS) Release in [cited by applicant]
Korean Office Action for corresponding Korean Application No. 10-2016-7034788 dated Jun. 5, 2018. [cited by applicant]
Korean Office Action for corresponding Korean Application No. 10-2019-7014115 dated Aug. 14, 2020. [cited by applicant]
Kourtzelis I., et al., (2010) Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis., Blood, 116(4):631-639. [cited by applicant]
Krisinger, et al., (2014) Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Blood. 120(8):1717-1725. [cited by applicant]
Langenheim, J.F. et al., (2009) Improving the pharmacokinetics/pharmacodynamics of prolactin, GH, and their antagonists by fusion to a synthetic albumin-binding peptide. J Endocrinol. 203(3):375-87. [cited by applicant]
Law, S.K., et al. (1997). The internal thioester and the covalent binding properties of the complement proteins C3 and C4. Protein Science. 6:263-274. [cited by applicant]
Lea, W.A. et al., (2011) Fluorescence polarization assays in small molecule screening. Expert Opin Drug Discov. Jan;6(1)17-32. [cited by applicant]
Lee et al. “Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis” British Journal of Pharmacology, vol. 174, N… [cited by applicant]
Legendre, C.M. et al. (2013) “Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome” The New England Journal of Medicine, 368(23):2169-2181. [cited by applicant]
Levengood, M.R. and Van der Donk, W.A., (2008) Use of lantibiotic synthetases for the preparation of bioactive constrained peptides, Bioorg. and Med. Chem. Lett. 18:3025-3028. [cited by applicant]
Levi, M. et al., (2013) Sepsis and thrombosis. Seminars in thrombosis and hemostasis 39, 559-66. [cited by applicant]
Liu, R. et al. (2000). Optimized synthesis of RNA-protein fusions for in vitro protein selection, Methods Enzymol. 318:268-293. [cited by applicant]
Mackworth-Young, (2004) Antiphospholipid syndrome: multiple mechanisms., Clin Exp Immunol 136:393-401. [cited by applicant]
Markiewski, et al., (2007) The role of complement in inflammatory diseases from behind the scenes into the spotlight . Am J Pathol. 171: 715-27. [cited by applicant]
Meri S., (2013) Complement activation in diseases presenting with thrombotic microangiopathy., European Journal of Internal Medicine, 24: 496-502. [cited by applicant]
Mexican Office Action for corresponding Mexican Application No. Mx/a/2016/016449 dated Jul. 20, 2020. [cited by applicant]
Milletti, F., 2012 Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov Today. Aug;17(15-16):850-60. [cited by applicant]
Millward, S.W. et al., (2005) A general route for post-translational cyclization of mRNA display libraries, J. Am. Chem. Soc. 127:14142-14143. [cited by applicant]
Mollnes, T. E. et al., (2002) Essential role of the C5a receptor in [cited by applicant]
Morgan, Paul et al. “Complement, a target for therapy in inflammatory and degenerative diseases” Nature Reviews Drug Discovery 14:857-877. (Year: 2015). [cited by applicant]
Murakami, H. et al. (2006) A highly flexible tRNA acylation method for non-natural polypeptide synthesis, Nat. Methods 3:357-359. [cited by applicant]
Nakayama H et al., (2016) Eculizumab dosing intervals longer than 17 days may be associated with greater risk of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria. Biol Pharm Bull. [cited by applicant]
Nemoto, H. et al., (1997) In vitro virus: bonding of mRNA bearing puromycin at the 3′-terminal end to the C-terminal end of its encoded protein on the ribosome in vitro, FEBS Lett. 414:405-408. [cited by applicant]
Nguyen A. et al., (2006) The pharmacokinetics of an albumin-binding Fab (AB.Fab) can be modulated as a function of affinity for albumin. Protein Eng Des Sel. 19:291-7. [cited by applicant]
Nishimura et al. (2012) A rare genetic polymorphism in C5 confers poor response to the anti-C5 monoclonal antibody eculizumab by nine Japanese patients with PNH Blood (ASH Annual Meeting Abstracts) 120: Abstract 3197. [cited by applicant]
Nishimura J-I et al., (2004) Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine 2004;83:193-207. [cited by applicant]
Nishimura, J. et al., (2014) Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 370: 632-9. [cited by applicant]
Oliva, B. et al., (1997) An automated classification of the structure of protein loops, J Mol Biol. Mar. 7;266(4):814-30. [cited by applicant]
Park, Brian “Zilucoplan for Myasthenia Gravis Gets Orphan Drug Designation” Neurology Advisor, Sep. 9, 2019. [cited by applicant]
Parker, C. et al., (2005) Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 106: 3699-709. [cited by applicant]
Parker, C.J., (2007) the pathophysiology of paroxysmal nocturnal hemoglobinuria. Exp Hematol. 35: 523-33. [cited by applicant]
Parker, C.J., (2012) Paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol. 19: 141-8. [cited by applicant]
Parker, G.J. et al., (2000) Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase/phosphatase assays. J Biomol Screen. Apr. 2000;5(2):77-88. [cited by applicant]
Prystay, L. et al., (2001) Determination of equilibrium dissociation constants in fluorescence polarization. J Biomol Screen. Jun;6(3):141-50. [cited by applicant]
Pu, J.J. et al., (2011) Paroxysmal nocturnal hemoglobinuria from bench to bedside. Clin Transl Sci. Jun;4(3):219-24. [cited by applicant]
Quigg RJ., (2003) Complement and the kidney., J Immunol 171:3319-24. [cited by applicant]
RA Pharmaceuticals, Inc., Protocol, RA101495-01.201: A Phase 2 Multicenter, Open-Label, Uncontrolled Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of RA101495 in Subjects W… [cited by applicant]
RA Pharmaceuticals, Inc., Statistical Analysis Plan, RA101495-01.201: A Phase 2 Multicenter, Open-Label, Uncontrolled Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of RA101… [cited by applicant]
RAPharma: “Zilucoplan in Generalized Myasthenia Gravis”, dated Dec. 10, 2018 URL:https://rapharma.com/wp-content/upload s/2018/12/Zilucoplan-in-Generalized-Myasthenia-Gravis-1.pdf. [cited by applicant]
Ricardo A. et al. 939 Preclinical evaluation of RA101495, a potent cyclic peptide inhibitor of C5 for the treatment of paroxysmal nocturnal hemoglobinuria. 57th Annual Meeting and Exposition. Orlando, FL. Dec. 5-8, 2015. [cited by applicant]
Ricardo et al 2014 (Dec. 2014 ASH abstract) Development of RA101348, a Potent Cyclic Peptide Inhibitor of C5 for Complement-Mediated Diseases. [cited by applicant]
Ricardo et al 2015 (Dec. 2015 ASH abstract) Preclinical Evaluation of RA101495, a Potent Cyclic Peptide Inhibitor of C5 for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. [cited by applicant]
Ricardo et al. “Preclinical Evaluation of RA101495, a Potent Cyclic Peptide Inhibitor of C5 for the Treatment of Paroxysmal Nocturnal Hemoglobinuria”, ASH Meeting 2015, Abstract #939. Dec. 5, 2015. [cited by applicant]
Ricardo et al., “Development of RA101348, a Potent Cyclic Peptide Inhibitor of C5 for Complement-Mediated Diseases”, Dec. 17, 2014 56th ASH Annual Meeting and Exposition, (last updated Dec. 17, 2014) Abstract retrieved … [cited by applicant]
Ricklin, Daniel et al. “Complement in Immune and Inflammatory Disorders: Pathophysiological Mechanisms” J. Immunol. 190: 3831-3838. (Year: 2013). [cited by applicant]
Ripka, A.S. et al., (1998) Synthesis of novel cyclic protease inhibitors using grubbs olefin metathesis. Bioorg Med Chem Lett. 8(4):357-60. [cited by applicant]
Risitano et al., (2012) The complement receptor 2/factor H fusion protein TT30 protects paroxysmal nocturnal hemoglobinuria erythrocytes from complement-mediated hemolysis and C3 fragment. Blood 119(6): 6307-16. [cited by applicant]
Risseeuw, M.D.P., (2009) Alkylated and bicyclic sugar amino acids: synthesis and applications. Doctoral Thesis, Leiden University. Chapter 1, p. 9-26. [cited by applicant]
Rittirsch D., et al., (2008) Harmful molecular mechanisms in sepsis. Nature Reviews Immunology 8, 776-87. [cited by applicant]
Rittirsch, et al., (2012) Role of complement in multiorgan failure. Clin Dev Immunol, 2012:962927. [cited by applicant]
Roberts, R.W., and Szostak, J.W. (1997) RNA-peptide fusions for the in vitro selection of peptides and proteins, Proc. Natl. Acad. Sci. USA 94, 12297-12302. [cited by applicant]
Rock, et al., (2010) The sterile inflammatory response. Annu Rev Immunol. 28:321-342. [cited by applicant]
Roth et al., (2009) Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease.,Blood, 113:3885-86. [cited by applicant]
Rothe, A. et al. (2006) In vitro display technologies reveal novel biopharmaceutics, The FASEB Journal. 20(10)1599-1610. [cited by applicant]
Rubartelli, et al., (2013) Mechanisms of sterile inflammation. Frontiers in Immunology 4:398-99. [cited by applicant]
Russian Office Action for corresponding Russian Application No. 2016147080 dated May 30, 2018. [cited by applicant]
Russian Office Action for corresponding Russian Application No. 2016147080, dated Dec. 20, 2017. [cited by applicant]
Russian Office Action for corresponding Russian Application No. 2018121615 entitled “Modulators of Complement Activity” dated Mar. 16, 2020. [cited by applicant]
Salmon, et al., (2002) Complement activation as a mediator of antiphospholipid antibody induced pregnancy loss and thrombosis. Ann Rheum Dis 2002;61 (Suppl II):ii46-ii50. [cited by applicant]
Sando, S. et al., (2007) Unexpected preference of the [cited by applicant]
Schafmeister and Verdine (2000) An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides, J. Am. Chem. Soc., 122 (24), 5891-5892. [cited by applicant]
Schlippe, et al. (2012) In vitro selection of highly modified cyclic peptides that act as tight binding inhibitors. J Am Chem. 134:10469-77. [cited by applicant]
Schrezenmeier, H. et al., (2014) Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica. 99: 922-9. [cited by applicant]
Scott et al. (1999) Production of cyclic peptides and proteins in vivo, PNAS. vol. 96 No. 24 p. 13638-13643. [cited by applicant]
Second Examination Report for corresponding Australian Application No. 2015274482 dated May 10, 2018. [cited by applicant]
Seebeck, F.P. and Szostak, J.W. (2006) Ribosomal synthesis of dehydroalanine-containing peptides J. Am. Chem. Soc. Jun. 7;128(22):7150-1. [cited by applicant]
Sergeeva, A. et al. (2006). Display technologies: application for the discovery of drug and gene delivery agents, Adv. Drug Deliv. Rev. 58:1622-1654. [cited by applicant]
Shimizu, Y. et al. (2001) Cell-free translation reconstituted with purified components, Nat. Biotech. 19:751-755. [cited by applicant]
Singapore Written Opinion for corresponding Singapore Application No. 11201610222U, dated Dec. 28, 2017. [cited by applicant]
Sjoberg A.T., et al., (2009) Complement activation and inhibition: a delicate balance. Trends in Immunology. 30(2):83-90. [cited by applicant]
Smith, A. B. 3rd, et al. (1994) De Novo Design, Synthesis, and X-ray Crystal Structures of Pyrrolinone-Based .beta.-Strand Peptidomimetics, J. Am. Chem. Soc. 116:9947-9962. [cited by applicant]
Smith, G.P. and Petrenko, V.A., (1997) Phage Display, Chem. Rev. 97:391-410. [cited by applicant]
Socie' G et al., (1996) Paroxysmal nocturnal haemoglobinura: long-term follow-up and prognostic factors. Lancet 1996;348:573-577. [cited by applicant]
Sorbera et al: “Taking aim at a fast-moving target: targets to watch for SARS-CoV-2 and COVID-19”, Drugs of the Future, vol. 45, No. 4, Jan. 1, 2020. [cited by applicant]
Soto, Y. et al. (2008) Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides, ACS Chem. Biol. 3:120-129. [cited by applicant]
Stahel et al., (1998) The role of the complement system in traumatic brain injury.Brain Research Reviews, 27: 243-56. [cited by applicant]
Subtelny et al., (2008) Ribosomal synthesis of N-methyl peptides, J. Am. Chem. Soc. 130: 6131-6136. [cited by applicant]
Sun et al: Treatment With Anti -C5a Antibody Improves the Outcome of H7N9 Virus Infection in African Green Monkeys11 , Clinical Infectious Diseases, vol. 60, No. 4, Nov. 27, 2014. [cited by applicant]
Takashashi, T.T et al. (2003) mRNA display: ligand discovery, interaction analysis and beyond, Trends in Biochem. Sci. 28(3):159-165. [cited by applicant]
Third Examination Report for corresponding Australian Application No. 2015274482 dated Aug. 28, 2018. [cited by applicant]
Thomas et al., (1996) Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Molecular Immunology. 33(17-18):1389-401. [cited by applicant]
Tian, W. et al., (2012) Development of novel fluorescence polarization-based assay for studying the β-catenin/Tcf4 Interaction. J Biomol Screen. Apr;17(4):530-4. [cited by applicant]
Timmerman, P. et al., (2005) Rapid and quantitative cyclization of multiple peptide loops onto synthetic scaffolds for structural mimicry of protein surfaces, ChemBioChem 6:821-824. [cited by applicant]
US National Library of Medicine: “Phase 2 Safety and Efficacy Study of RA101495 to Treat PNH Patients”, Mar. 8, 2017 (Mar. 8, 2017), XP055661467. [cited by applicant]
Van De Goot F., et al., (2009) Acute inflammation is persistent locally in burn wounds: a pivotal role for complement and C-reactive protein . J Burn Care Res 2009, 30:274-280. [cited by applicant]
Van De Walle Inge et al: “ARGX-117, a therapeutic complement inhibiting antibody targeting C2”, Journal of Allergy and Clinical Immunology, Elsevier, Amsterdam, NL, vol. 147, No. 4, Sep. 11, 2020, p. 1420. [cited by applicant]
Van Den Elsen, J.M.H., (2002) X-ray crystal structure of the C4d fragment of human complement component C4, J. Mol. Biol. 322:1103-1115. [cited by applicant]
Vogt, (1999) Cleavage of the fifth component of complement and generation of a functionally active C5b6-like complex by human leukocyte elastase. Immunobiology. 201:470-477. [cited by applicant]
Yamagishi, Y. et al., (2011) Natural product-like macrocyclic N-methyl peptide inhibitors against a ubiquitin ligase uncovered from a ribosome-expressed de novo library. Chemistry & Biology 18:1562-70. [cited by applicant]
Girrbach, M. et al., “A fluorescence polarization assay for the experimental validation of an in silica model of the chemokine CXCL8 binding to receptor-derived peptides,” Phys. Chem. Chem. Phys., vol. 16, Mar. 2014, pp… [cited by applicant]