Granted Patent
B2
US 12,460,228 · App. 17/812,322 · Granted Nov 4, 2025
Gene therapy for treating Wilson's disease
Inventors:
James M. Wilson (Philadelphia, PA); Jenny Agnes Sidrane (Phoenixville, PA); Lakshmanan Govindasamy (Philadelphia, PA)
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Abstract
Compositions and regimens useful in treating Wilson's Disease are provided. The compositions include recombinant adeno-associated virus (rAAV) with a transthyretin enhancer and promoter driving expression of a human ATP7B.
Claims (32)
1 . A recombinant nucleic acid construct comprising a recombinant adeno-associated virus (AAV) vector genome, said vector genome comprising:
(a) an AAV 5′ inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a codon optimized coding sequence encoding a truncated human copper-transporting ATPase 2 (ATP7B) polypeptide comprising metal-binding domains (MBD) 4-6 and comprising a deletion of MBD 1-3; and
(d) an AAV 3′ ITR sequence.
2 . The recombinant nucleic acid construct of claim 1 , wherein the AAV 5′ ITR and/or the AAV 3′ ITR is from AAV2.
3 . The recombinant nucleic acid construct of claim 1 , wherein the promoter comprises a liver-specific promoter.
4 . The recombinant nucleic acid construct of claim 3 , wherein the liver-specific promoter is a transthyretin (TTR) promoter.
5 . The recombinant nucleic acid construct of claim 1 , wherein the codon optimized coding sequence comprises SEQ ID NO: 1 truncated to encode the ATP7B polypeptide comprising metal-binding domains (MBD) 4-6 and a deletion of MBD 1-3.
6 . The recombinant nucleic acid construct of claim 1 , wherein the vector genome further comprises an enhancer.
7 . The recombinant nucleic acid construct of claim 6 , wherein the enhancer is a TTR enhancer.
8 . The recombinant nucleic acid construct of claim 1 , wherein the vector genome further comprises a polyA signal.
9 . The recombinant nucleic acid construct of claim 8 , wherein the poly A signal is from SV40.
10 . The recombinant nucleic acid construct of claim 1 , wherein the vector genome further comprises an intron.
11 . The recombinant nucleic acid construct of claim 10 , wherein the intron is from SV40.
12 . The recombinant nucleic acid construct of claim 1 , wherein the recombinant nucleic acid construct is packaged in an AAV capsid.
13 . The recombinant nucleic acid construct of claim 12 , wherein the AAV capsid has tropism for liver.
14 . A host cell comprising a recombinant nucleic acid construct, said nucleic acid construct comprising a recombinant adeno-associated virus (AAV) vector genome, said vector genome comprising:
(a) an AAV 5′ inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a codon optimized coding sequence encoding a truncated human copper-transporting ATPase 2 (ATP7B) polypeptide comprising metal-binding domains (MBD) 4-6 and comprising a deletion of MBD 1-3; and
(d) an AAV 3′ ITR sequence.
15 . A method of treating a subject having Wilson's Disease, the method comprising administering to the subject a recombinant adeno-associated virus (AAV) useful as a liver-directed therapeutic for Wilson's Disease (WD), said recombinant AAV comprising an AAV capsid, and a vector genome packaged therein, said vector genome comprising:
(a) an AAV 5′ inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a codon optimized coding sequence encoding a human copper-transporting ATPase 2 (ATP7B) polypeptide comprising metal-binding domains (MBD) 4-6 and comprising a deletion of MBD 1-3; and
(d) an AAV 3′ ITR sequence.
16 . The method of claim 15 , comprising administering about 1×10 11 to about 1×10 14 genome copies (GC)/kg of the recombinant AAV to the subject.
17 . The method of claim 15 , comprising administering about 5×10 12 to about 2×10 13 genome copies (GC)/kg of the recombinant AAV to the subject.
18 . The method of claim 15 , wherein the recombinant AAV is administered to the subject intravenously.
19 . The method of claim 15 , wherein the recombinant AAV is administered in combination with one or more additional therapies for the treatment of Wilson's Disease.
20 . The method of claim 19 , wherein the one or more additional therapies comprise low copper diet, administration of D-penicillamine, trientine, sodium dimercaptosuccinate, dimercaptosuccinic acid, zinc, and/or tetrathiomolybdate.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 13, 2022
From: WILSON, JAMES M.; SIDRANE, JENNY AGNES; GOVINDASAMY, LAKSHMANAN
To: THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
Reel/Frame 060498/0402 →
Continuity (4)
Continuation
16474958
Provisional Application
62440659
· Dec 30, 2016
Provisional Application
62473656
· Mar 20, 2017
References Cited (125)
US 8999380B2
· Bancel et al.
· 2015
[cited by applicant]
US 20140032186A1
· Gustafsson et al.
· 2014
[cited by applicant]
US 20140196176A1
· Heintz et al.
· 2014
[cited by applicant]
US 20150111955A1
· High et al.
· 2015
[cited by applicant]
DE 10156121A1
· 2003
[cited by applicant]
WO WO2011126808
· 2011
[cited by applicant]
WO WO2013049493
· 2013
[cited by applicant]
WO WO2015012924
· 2015
[cited by applicant]
WO WO2016097218
· 2016
[cited by applicant]
WO WO2016097219
· 2016
[cited by applicant]
WO WO2016181123A1
· 2016
[cited by applicant]
WO WO2017100676
· 2017
[cited by applicant]
WO WO2018126116
· 2018
[cited by applicant]
WO WO2020102723A1
· 2020
[cited by applicant]
WO WO2020142653
· 2020
[cited by applicant]
Nguyen, et al. (2008) “Evaluation of Gene Promoters for Liver Expression by Hydrodynamic Gene Transfer”, Journal of Surgical Research, 148(1): 60-66. (Year: 2008).
[cited by examiner]
Brewer (2009) “Zinc and tetrathiomolybdate for the treatment of Wilson's disease and the potential efficacy of anticopper therapy in a wide variety of diseases”, Metallomics, 1: 199-206. (Year: 2009).
[cited by examiner]
Office Action issued in Chinese Patent Application No. 201780085376.9 on Sep. 28, 2022, with translation provided by local agent.
[cited by applicant]
Bartee et al., The loop connecting metal-binding domains 3 and 4 of ATP7B is a target of a kinase-mediated phosphorylation, Biochemistry. Jun. 23, 2009;48(24):5573-81.
[cited by applicant]
Bernard JM et al., Hepatic lesions in 90 captive nondomestic felids presented for autopsy, Vet Pathol. Mar. 2015;52(2):369-76. Epub May 1, 2014.
[cited by applicant]
Braiterman et al. Communication between the N and C termini is required for copper-stimulated Ser/Thr phosphorylation of Cu(I)-ATPase (ATP7B). J Biol Chem. Apr. 3, 2015;290(14):8803-19.
[cited by applicant]
Bronson RT et al., Acute cerebral neuronal necrosis in copper deficient offspring of female mice with the toxic milk mutation, Mouse Genome 1995;93:152-154.
[cited by applicant]
Buiakova OI et al., Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation, Hum Mol Genet. Sep. 1999;8(9):1665-71.
[cited by applicant]
Bull PC et al., The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene, Blood. Jul. 15, 2003;102(2):480-8. Epub Mar. 13, 2003.
[cited by applicant]
Calcedo et al., Worldwide Epidemiology of Neutralizing Antibodies to Adeno-Associated Viruses. J Infect Dis. Feb. 1, 2009;199(3):381-90.
[cited by applicant]
Cardone et al., Correction of Hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery. Hum Mol Genet. Apr. 1, 2006;15(7):1225-36.
[cited by applicant]
Chuah et al., Liver-specific transcriptional modules identified by genome-wide in silico analysis enable efficient gene therapy in mice and non-human primates. Mol Ther. Sep. 2014;22(9):1605-13.
[cited by applicant]
Coronado V et al., The Jackson toxic milk mouse as a model for copper loading, Mamm Genome. Oct. 2001;12(10):793-5.
[cited by applicant]
Davidoff Am et al., Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway, Blood 2003; 102:480-488.
[cited by applicant]
Dong et al., Quantitative analysis of the packaging capacity of recombinant adeno-associated virus, Hum Gene Ther. Nov. 10, 1996;7(17):2101-12.
[cited by applicant]
European Association for Study of Liver, EASL Clinical Practice Guidelines: Wilson's disease, J Hepatol. Mar. 2012;56(3):671-85. doi: 10.1016/j.jhep.2011.11.007.
[cited by applicant]
Gao et al., Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc Natl Acad Sci U S A. May 13, 2003;100(10):6081-6. Epub Apr. 25, 2003.
[cited by applicant]
Gao G et al., Biology of AAV serotype vectors in liver-directed gene transfer to nonhuman primates, Mol Ther. Jan. 2006;13(1):77-87. Epub Oct. 10, 2005.
[cited by applicant]
Gourdon et al., Structural models of the human copper P-type ATPases ATP7A and ATP7B, Biol Chem. Apr. 2012;393(4):205-16. doi: 10.1515/hsz-2011-0249.
[cited by applicant]
Gray LW et al., Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load, PLoS One. 2012;7(6):e38327. doi: 10.1371/journal.pone.0038327. Epub …
[cited by applicant]
Greig et al., A Gene Therapy Approach to Improve Copper Metabolism and Prevent Liver Damage in a Mouse Model of Wilson Disease, Hum Gene Ther Clin Dev. Mar. 2019;30(1):29-39.
[cited by applicant]
Greig Ja et al., Characterization of Adeno-Associated Viral Vector-Mediated Human Factor VIII Gene Therapy in Hemophilia A Mice, May 2017;28(5):392-402. doi: 10.1089/hum.2016.128. Epub Jan. 5, 2017.
[cited by applicant]
Grimm et al., Titration of AAV-2 particles via a novel capsid ELISA: packaging of genomes can limit production of recombinant AAV-2, Gene Ther. Jul. 1999;6(7):1322-30.
[cited by applicant]
Hasan et al., Molecular events initiating exit of a copper-transporting ATPase ATP7B from the trans-Golgi network, J Biol Chem. Oct. 19, 2012;287(43):36041-50.
[cited by applicant]
Huster D and Lutsenko S, The distinct roles of the N-terminal copper-binding sites in regulation of catalytic activity of the Wilson's disease protein, J Biol Chem. Aug. 22, 2003;278(34):32212-8. Epub Jun. 6, 2003.
[cited by applicant]
Huster D et al., Consequences of copper accumulation in the livers of the Atp7b−/− (Wilson disease gene) knockout mice, Am J Pathol. Feb. 2006;168(2):423-34.
[cited by applicant]
Irani An et al., Correction of liver disease following transplantation of normal rat hepatocytes into Long-Evans Cinnamon rats modeling Wilson's disease. Mol Ther. Mar. 2001;3(3):302-9.
[cited by applicant]
Lock et al., Absolute determination of single-stranded and self-complementary adeno-associated viral vector genome titers by droplet digital PCR. Hum Gene Ther Methods. Apr. 2014;25(2):115-25. Epub Feb. 14, 2014.
[cited by applicant]
Lock M et al., Rapid, simple, and versatile manufacturing of recombinant adeno-associated viral vectors at scale, Hum Gene Ther. Oct. 2010;21(10):1259-71. doi: 10.1089/hum.2010.055.
[cited by applicant]
Loeb et al., Enhanced expression of transgenes from adeno-associated virus vectors with the woodchuck hepatitis virus posttranscriptional regulatory element: implications for gene therapy, Hum Gene Ther. Sep. 20, 1999;1…
[cited by applicant]
Lutsenko S et al., Function and regulation of human copper-transporting ATPases, Physiol Rev. Jul. 2007;87(3):1011-46.
[cited by applicant]
McFarland et al., Evaluation of a novel short polyadenylation signal as an alternative to the SV40 polyadenylation signal, Plasmid. Jul. 2006;56(1):62-7.
[cited by applicant]
McIntosh et al., Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant, Blood. Apr. 25, 2013;121(17):3335-44. doi: 10.1182/blood-2012-10-…
[cited by applicant]
McMillin et al., Direct measurement of free copper in serum or plasma ultrafiltrate, Am J Clin Pathol. Feb. 2009;131(2):160-5.
[cited by applicant]
Michalczyk A et al., ATP7B expression in human breast epithelial cells is mediated by lactational hormones, J Histochem Cytochem. Apr. 2008;56(4):389-99. doi: 10.1369/jhc.7A7300.2008. Epub Jan. 7, 2008.
[cited by applicant]
Miyatake et al., Transcriptional targeting of herpes simplex virus for cell-specific replication. J Virol. Jul. 1997;71(7):5124-32.
[cited by applicant]
Mizukami et al., A Protocol for AAV vector production and purification. Diss. Division of Genetic Therapeutics, Center for Molecular Medicine, 1998.
[cited by applicant]
Murillo et al., Long-term metabolic correction of Wilson's disease in a murine model by gene therapy, J Hepatol. Feb. 2016;64(2):419-426. doi: 10.1016/j.jhep.2015.09.014. Epub Sep. 25, 2015.
[cited by applicant]
NCBI Reference Sequence: NP_000044.2, copper-transporting ATPase 2 isoform a [
[cited by applicant]
NCBI Reference Sequence: NP_001005918.1, copper-transporting ATPase 2 isoform b [
[cited by applicant]
NCBI Reference Sequence: NP_001230111.1, copper-transporting ATPase 2 isoform c [
[cited by applicant]
NCBI Reference Sequence: NP_001317507.1, copper-transporting ATPase 2 isoform d [
[cited by applicant]
NCBI Reference Sequence: NP_001317508.1, copper-transporting ATPase 2 isoform e [
[cited by applicant]
NCBI Reference Sequence: XM_005266430.4, Predicted:
[cited by applicant]
Petrukhin K et al., Mapping, cloning and genetic characterization of the region containing the Wilson disease gene, Nat Genet. Dec. 1993;5(4):338-43.
[cited by applicant]
Roberts EA and Schilsky ML, American Association for Study of Liver D. Diagnosis and treatment of Wilson disease: an update, Hepatology. Jun. 2008;47(6):2089-111. doi: 10.1002/hep.22261.
[cited by applicant]
Roybal et al., Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease, Gene Ther. Nov. 2012;19(11):1085-94. doi: 10.1038/gt.2011.186. Epub De…
[cited by applicant]
Safaei R et al., The role of metal binding and phosphorylation domains in the regulation of cisplatin-induced trafficking of ATP7B, Metallomics. Aug. 2013;5(8):964-72. doi: 10.1039/c3mt00131h.
[cited by applicant]
Samadani et al., Identification of a transthyretin enhancer site that selectively binds the hepatocyte nuclear factor-3 beta isoform, Gene Expr. 1996;6(1):23-33.
[cited by applicant]
Sandig et al., HBV-derived promoters direct liver-specific expression of an adenovirally transduced LDL receptor gene, Gene Ther. Nov. 1996;3(11):1002-9.
[cited by applicant]
Sasaki N et al., The gene responsible for LEC hepatitis, located on rat chromosome 16, is the homolog to the human Wilson disease gene, Biochem Biophys Res Commun. Jul. 15, 1994;202(1):512-8.
[cited by applicant]
Schosinsky et al., Measurement of ceruloplasmin from its oxidase activity in serum by use of o-dianisidine dihydrochloride, Clin Chem. Dec. 1974;20(12):1556-63.
[cited by applicant]
Shanmugavel et al., Probing functional roles of Wilson disease protein (ATP7B) copper-binding domains in yeast, Metallomics. Jul. 19, 2017;9(7):981-988.
[cited by applicant]
Smedley R et al., Copper-associated hepatitis in Labrador Retrievers, Vet Pathol. May 2009;46(3):484-90. doi: 10.1354/vp.08-VP-0197-S-FL. Epub Jan. 27, 2009.
[cited by applicant]
Sommer JM et al., Quantification of adeno-associated virus particles and empty capsids by optical density measurement, Mol Ther. Jan. 2003;7(1):122-8.
[cited by applicant]
Stromeyer FW and Ishak KG, Histology of the liver in Wilson's disease: a study of 34 cases, Am J Clin Pathol. Jan. 1980;73(1):12-24.
[cited by applicant]
Tanzi RE et al., The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. Dec. 1993;5(4):344-50.
[cited by applicant]
Terada K and Sugiyama T, The Long-Evans Cinnamon rat: an animal model for Wilson's disease, Pediatr Int. Aug. 1999;41(4):414-8.
[cited by applicant]
Theophilos MB et al., The toxic milk mouse is a murine model of Wilson disease, Hum Mol Genet 1996;5:1619-1624.
[cited by applicant]
Thompson et al., A comprehensive comparison of multiple sequence alignments, Nucleic Acids Res. Jul. 1, 1999;27(13):2682-90.
[cited by applicant]
Thornburg LP et al., Hereditary copper toxicosis in West Highland white terriers, Vet Pathol. Mar. 1986;23(2):148-54.
[cited by applicant]
Toole JJ et al., A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity, Proc Natl Acad Sci U S A. Aug. 1986;83(16):5939-42.
[cited by applicant]
Valencia et al., Splicing promotes rapid and efficient mRNA export in mammalian cells, Proc Natl Acad Sci U S A. Mar. 4, 2008;105(9):3386-91.
[cited by applicant]
Ward NJ et al., Codon optimization of human factor VIII cDNAs leads to high-level expression, Blood. Jan. 20, 2011;117(3):798-807. doi: 10.1182/blood-2010-05-282707. Epub Nov. 1, 2010.
[cited by applicant]
Wobus et al., Monoclonal antibodies against the adeno-associated virus type 2 (AAV-2) capsid: epitope mapping and identification of capsid domains involved in AAV-2-cell interaction and neutralization of AAV-2 infection…
[cited by applicant]
Wu et al., Effect of genome size on AAV vector packaging, Mol Ther. Jan. 2010;18(1):80-6. Epub Nov. 10, 2009.
[cited by applicant]
Wu et al., Optimization of self-complementary AAV vectors for liver-directed expression results in sustained correction of hemophilia B at low vector dose, Mol Ther. Feb. 2008;16(2):280-9. Epub Dec. 4, 2007.
[cited by applicant]
Wu J et al., The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene, Nat Genet. Aug. 1994;7(4):541-5.
[cited by applicant]
Yan et al. Human thyroxine binding globulin (TBG) promoter directs efficient and sustaining transgene expression in liver-specific pattern. Gene. Sep. 15, 2012;506(2):289-94.
[cited by applicant]
International Search Report and Written Opinion in International Patent Application No. PCT/US2017/068919, dated May 11, 2018.
[cited by applicant]
Supplementary Search Report in European Patent Application No. EP 17888104, issued Jul. 6, 2020.
[cited by applicant]
International Search Report and Written Opinion in International Patent Application No. PCT/US2020/012131, mailed Mar. 30, 2020.
[cited by applicant]
Office Action issued in Japanese Patent Application No. 2019-535891 on Oct. 27, 2021, with translation provided by local agent.
[cited by applicant]
Restriction Requirement in U.S. Appl. No. 16/474,958, mailed Dec. 8, 2021.
[cited by applicant]
Applicant's Response and Amendment in U.S. Appl. No. 16/474,958, filed Jan. 26, 2022.
[cited by applicant]
Non-Final Office Action in in U.S. Appl. No. 16/474,958, mailed Mar. 15, 2022.
[cited by applicant]
Applicant's Response and Amendment in U.S. Appl. No. 16/474,958, filed Jun. 10, 2022.
[cited by applicant]
Notice of Allowance in U.S. Appl. No. 16/474,958, mailed Jun. 28, 2022.
[cited by applicant]
Office Action dated Feb. 20, 2023 issued in corresponding Korean Patent Application No. 10-2019-7021756, with English translation provided by local agent.
[cited by applicant]
Daniel E, et al. ATGme: Open-source web application for rare codon identification and custom DNA sequence optimization. BMC Bioinformatics Sep. 21, 2015;16(1):303 (6 pages).
[cited by applicant]
Daya S and Berns KI. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev. Oct. 2008;21(4):583-93.
[cited by applicant]
Fumoto et al., Chapter 1: Targeted Gene Delivery: Importance of Administration Routes, INTECH, Nova Gene Therapy Approaches, pp. 3-31; editors Wei and Good, publisher Books on Demand, Feb. 2013.
[cited by applicant]
Greenberg B. Gene therapy for heart failure. J Cardiol, Sep. 2015;66(3):195-200.
[cited by applicant]
Grote A et al. JCat: a novel tool to adapt codon usage of a target gene to its potential expression host. Nucleic Acids Res, Ju. 1, 2005;33(Web Server issue):W526-31.
[cited by applicant]
Harding TC et al. Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B. Gene Ther. Jan. 2004;11(2):204-13.
[cited by applicant]
Kattenhorn LM, Tipper CH, Stoica L, Geraghty DS, Wright TL, Clark KR, Wadsworth SC. Adeno-Associated Virus Gene Therapy for Liver Disease. Hum Gene Ther. Dec. 2016;27(12):947-961.
[cited by applicant]
Leng Y et al. Long-Term Correction of Copper Metabolism in Wilson's Disease Mice with AAV8 Vector Delivering Truncated ATP7B. Hum Gene Ther. Dec. 2019;30(12):1494-1504.
[cited by applicant]
Maguire CA and Corey DP. Viral vectors for gene delivery to the inner ear. Hear Res. Sep. 1, 2020;394:107927 (13 pages).
[cited by applicant]
Mingozzi F and High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. Jul. 4, 2013;122(1):23-36.
[cited by applicant]
Murillo O) et al., [Abstract] 164. Improvement of Gene Therapy for Wilson Disease. Molecular Therapy. vol. 24, Supplement 1, S64, May 2016 (1 page).
[cited by applicant]
NCBI GenBank Accession No. U03464.1, Human P-type ATPase ATP7B mRNA, complete cds, Apr. 23, 1997 (3 pages).
[cited by applicant]
Perrin S. Preclinical research: Make mouse studies work. Nature. Mar. 27, 2014;507(7493):423-5.
[cited by applicant]
Tian LC et al. Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma. Arch Med Res. Aug. 2019;50(6):384-392.
[cited by applicant]
Tobias E et al. Let's not get overexcited about any mouse study used in research, Multiple Sclerosis News Today, https://multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study…
[cited by applicant]
Applicant's Response to the Written Opinion in European Patent Application No. 17888104.1, filed Jan. 23, 2021.
[cited by applicant]
Examination Report in European Patent Application No. 17888104.1, issued Apr. 30, 2021.
[cited by applicant]
Applicant's Response to Examination Report in European Patent Application No. 17888104.1, filed Aug. 30, 2021.
[cited by applicant]
Examination Report in European Patent Application No. 17888104.1, issued Nov. 5, 2021.
[cited by applicant]
Applicant's Response to Examination Report in European Patent Application No. 17888104.1, filed Mar. 3, 2022.
[cited by applicant]
Communication pursuant to Rule 114(2) EPC (Third Party Observation) in European Patent Application No. 17888104.1, issued Mar. 13, 2024.
[cited by applicant]
Examination Report in European Patent Application No. 17888104.1, issued Mar. 19, 2024.
[cited by applicant]
Applicant's Response to Examination Report in European Patent Application No. 17888104.1, filed Jul. 2, 2024.
[cited by applicant]
Extended European Search Report in European Patent Application No. 24161028.6, issued Jun. 28, 2024.
[cited by applicant]
Applicant's Response in European Patent Application No. 24161028.6, filed Jan. 29, 2025.
[cited by applicant]