Virus-like particle conjugates for diagnosis and treatment of tumors

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
  • Publication Date:
    September 07, 2021
  • Additional Information
    • Patent Number:
      11110,181
    • Appl. No:
      16/778361
    • Application Filed:
      January 31, 2020
    • Abstract:
      The present disclosure is directed to methods and compositions for the diagnosis and/or treatment of tumors, such as ocular tumors, using virus-like particles conjugated to photosensitive molecules.
    • Inventors:
      Aura Biosciences, Inc. (Cambridge, MA, US); The United States of America, as represented by the Secretary, Department of Health and Human Serv. (Bethesda, MD, US)
    • Assignees:
      Aura Biosciences, Inc. (Cambridge, MA, US), The United States of America, as represented by the Secretary, Department of Health and Human Services (Bethesda, MD, US)
    • Claim:
      1. A tumor-targeting virus-like particle comprising papilloma virus capsid proteins and 50 to 1000 photosensitive molecules conjugated to the capsid proteins, wherein the photosensitive molecules comprise (a) a photosensitive molecule that becomes toxic or produces a toxic molecule upon activation by light and (b) a photosensitive molecule that does not become toxic or produce a toxic molecule upon activation by light.
    • Claim:
      2. The virus-like particle of claim 1 , wherein the papilloma virus capsid proteins are non-human papilloma virus capsid proteins.
    • Claim:
      3. The virus-like particle of claim 2 , wherein the non-human papilloma virus capsid proteins comprise L1 capsid proteins.
    • Claim:
      4. The virus-like particle of claim 3 , wherein the non-human papilloma virus capsid proteins consist of L1 capsid proteins.
    • Claim:
      5. The virus-like particle of claim 1 , wherein the photosensitive molecules are covalently conjugated to the capsid proteins.
    • Claim:
      6. A method comprising delivering to a subject a tumor-tropic virus-like particle comprising papilloma virus capsid proteins and 50 to 1000 photosensitive molecules conjugated to the capsid proteins, wherein the photosensitive molecules comprise (a) a photosensitive molecule that becomes toxic or produces a toxic molecule upon activation by light and (b) a photosensitive molecule that does not become toxic or produce a toxic molecule upon activation by light.
    • Claim:
      7. The method of claim 6 , wherein the subject has a bladder tumor.
    • Claim:
      8. The method of claim 6 , wherein the papilloma virus capsid proteins are non-human papilloma virus capsid proteins.
    • Claim:
      9. The method of claim 8 , wherein the non-human papilloma virus capsid proteins comprise L1 capsid proteins.
    • Claim:
      10. The method of claim 9 , wherein the non-human papilloma virus capsid proteins consist of L1 capsid proteins.
    • Claim:
      11. The method of claim 6 , wherein the photosensitive molecules are covalently conjugated to the capsid proteins.
    • Claim:
      12. The method of claim 6 , further comprising activating the photosensitive molecule of (b) at a wavelength of light that permits visualization of the photosensitive molecule of (b).
    • Claim:
      13. The method of claim 6 , further comprising activating the photosensitive molecule of (a) at a wavelength of light that causes the photosensitive molecule of (a) to become toxic or produce a toxic molecule.
    • Claim:
      14. The method of claim 6 , wherein the virus-like particle is delivered by injection.
    • Patent References Cited:
      4625014 November 1986 Senter et al.
      4659839 April 1987 Nicolotti
      5126129 June 1992 Wiltrout et al.
      5290551 March 1994 Berd
      5334711 August 1994 Sproat
      5478556 December 1995 Elliott et al.
      5667764 September 1997 Kopia et al.
      5716824 February 1998 Beigelman
      6022522 February 2000 Sweet et al.
      6180389 January 2001 Douglas et al.
      6416945 July 2002 McCarthy et al.
      6599739 July 2003 Lowy et al.
      6719958 April 2004 Gozzini et al.
      6984386 January 2006 Douglas et al.
      6991795 January 2006 Lowe et al.
      7205126 April 2007 Qiao et al.
      7351533 April 2008 McCarthy et al.
      7951379 May 2011 Kuroda et al.
      8394411 March 2013 Roberts et al.
      9700639 July 2017 de los Pinos et al.
      9724404 August 2017 Coursaget et al.
      9855347 January 2018 de los Pinos et al.
      10117947 November 2018 de los Pinos et al.
      10179168 January 2019 Coursaget et al.
      10300150 May 2019 de los Pinos et al.
      10588984 March 2020 de los Pinos et al.
      10596275 March 2020 de los Pinos et al.
      10688172 June 2020 Coursaget et al.
      2003/0129583 July 2003 Martin
      2003/0206887 November 2003 Morrissey et al.
      2004/0005338 January 2004 Bachmann et al.
      2004/0028694 February 2004 Young et al.
      2004/0115132 June 2004 Young et al.
      2004/0121465 June 2004 Robinson
      2004/0146531 July 2004 Antonsson et al.
      2004/0152181 August 2004 McCarthy et al.
      2005/0112141 May 2005 Terman
      2005/0118191 June 2005 Robinson et al.
      2005/0181064 August 2005 Kuroda
      2006/0088536 April 2006 Kuroda
      2006/0141042 June 2006 Kuroda
      2006/0166913 July 2006 Suzuki
      2006/0204444 September 2006 Young et al.
      2006/0216238 September 2006 Manchester et al.
      2006/0269954 November 2006 Lowy et al.
      2007/0059245 March 2007 Young et al.
      2007/0059746 March 2007 Kuroda
      2007/0243157 October 2007 Tanaka et al.
      2007/0258889 November 2007 Douglas et al.
      2009/0012022 January 2009 Milner et al.
      2009/0041671 February 2009 Young et al.
      2010/0135902 June 2010 Roberts et al.
      2011/0052496 March 2011 Cid-Arregui
      2011/0065173 March 2011 Kingsman et al.
      2011/0104051 May 2011 Francis et al.
      2012/0015899 January 2012 Lomonossoff et al.
      2012/0171290 July 2012 Coursaget et al.
      2012/0207840 August 2012 de los Pinos
      2013/0071414 March 2013 Dotti et al.
      2013/0115247 May 2013 de los Pinos et al.
      2013/0116408 May 2013 de los Pinos
      2013/0136689 May 2013 Rohlff et al.
      2013/0202645 August 2013 Barner et al.
      2014/0377170 December 2014 de los Pinos et al.
      2015/0232880 August 2015 Hemminki et al.
      2016/0024469 January 2016 Wu
      2016/0228568 August 2016 de los Pinos et al.
      2017/0274099 September 2017 de los Pinos et al.
      2017/0368162 December 2017 Coursaget et al.
      2018/0110883 April 2018 de los Pinos et al.
      2018/0311269 November 2018 Lobb et al.
      2018/0311374 November 2018 Lobb et al.
      2019/0083647 March 2019 de los Pinos et al.
      2019/0142925 May 2019 Coursaget et al.
      2019/0275176 September 2019 de los Pinos et al.
      1904012 January 2007
      102481378 May 2012
      102573910 July 2012
      1491210 December 2004
      2005-527493 September 2005
      2007-65646 March 2007
      2009-532564 September 2009
      2012-523455 October 2012
      WO 91/03162 March 1991
      WO 92/07065 April 1992
      WO 93/15187 August 1993
      WO 97/26270 July 1997
      WO 99/15630 April 1999
      WO 00/09673 February 2000
      WO 01/55393 August 2001
      WO 03/008573 January 2003
      WO 03/061696 July 2003
      WO 2005/051431 June 2005
      WO 2005/086667 September 2005
      WO 2006/125997 November 2006
      WO 2008/048288 April 2008
      WO 2008/054184 May 2008
      WO 2008/103920 August 2008
      WO 2008/140961 November 2008
      WO 2010/027827 March 2010
      WO 2010/120266 October 2010
      WO 2011/039646 April 2011
      WO 2013/009717 January 2013
      WO 2017/031367 February 2013
      WO 2013/080187 June 2013
      WO 2013/119877 August 2013
      WO 2014/039523 March 2014
      WO 2015/042325 March 2015
      WO 2015/075468 May 2015
      WO 2015/120363 August 2015
      WO 2015/142675 September 2015
      WO 2016/139362 September 2016


































































































    • Other References:
      Extended European Search Report for Application No. EP 1915654.5 dated Jun. 27, 2019. cited by applicant
      International Search Report and Written Opinion dated Aug. 18, 2011 for Application No. PCT/IB2010/002654. cited by applicant
      International Search Report and Written Opinion dated Dec. 29, 2014 for Application No. PCT/US2014/056412. cited by applicant
      International Preliminary Report on Patentability dated Mar. 31, 2016 for Application No. PCT/US2014/056412. cited by applicant
      Supplementary European Search Report dated Apr. 4, 2017 for Application No. EP 14845738.5. cited by applicant
      [No Author Listed] Bac-to-Bac Baculovirus Expression System. An efficient site-specific transposition system to generate baculovirus for high-level expression of recombinant proteins. Sep. 4, 2010. Retrieved from the Internet on Sep. 23, 2013. 80 pages. cited by applicant
      [No Author Listed] GenBank Accession No. P03101, Major Capsid Protein L1, Jan. 11, 2011. cited by applicant
      Alvarez, Insertion de sequences peptidiques dans la proteine majeure de capside du papillomavirus de type 16: application au ciblage pulmonaire de vecteurs derives et a la production d'un vaccine chimerique. Thesis. Universite Francois Rabelais. Jun. 20, 2006. 203 pages. cited by applicant
      Bergsdorf et al., Highly efficient transport of carboxyfluorescein diacetate succinimidyl ester into COS7 cells using human papillomavirus-like particles. FEBS Lett. Feb. 11, 2003;536(1-3):120-4. cited by applicant
      Bousarghin et al., Inhibition of cervical cancer cell growth by human papillomavirus virus-like particles packaged with human papillomavirus oncoprotein short hairpin RNAs. Mol Cancer Ther. Feb. 2009;8(2):357-65. Epub Jan. 27, 2009. cited by applicant
      Brasch et al., Encapsulation of phthalocyanine supramolecular stacks into virus-like particles. J Am Chem Soc. May 11, 2011;133(18):6878-81. doi: 10.1021/ja110752u. Epub Apr. 20, 2011. cited by applicant
      Brumfield et al., Heterologous expression of the modified coat protein of Cowpea chlorotic mottle bromovirus results in the assembly of protein cages with altered architectures and function. J Gen Virol. Apr. 2004;85(Pt 4):1049-53. cited by applicant
      Buck et al., Efficient intracellular assembly of papillomaviral vectors. J Virol. Jan. 2004;78(2):751-7. cited by applicant
      Buck et al., Production of papillomavirus-based gene transfer vectors. Current Protocols in Cell Biology. 26.1.1-26.1.19, Dec. 2007. cited by applicant
      Butz et al., siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells. Oncogene. Sep. 4, 2003;22(38):5938-45. cited by applicant
      Canti et al., Photodynamic therapy with photoactivated aluminum disulfonated phthalocyanine and cellular immune response. Proc. SPIE 3254, Laser-Tissue Interaction IX (May 13, 1998); doi: 10.1117/12.308158. Event: BIOS '98 International Biomedical Optics Symposium, 1998, San Jose, CA, United States. Retrieved from the Internet: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on Jul. 19, 2019. 8 pages. cited by applicant
      Carpentier et al. Mutations on the FG surface loop of human papillomavirus type 16 major capsid protein affect recognition by both type-specific neutralizing antibodies and cross-reactive antibodies. J Med Viral. Dec. 2005;77(4):558-65. Abstract only. cited by applicant
      Carpentier et al., Cell targeting for CF gene therapy: Identification of a new specific cell ligand and selection of infectious papillomavirus mutants. J Cystic Fibro. Jun. 1, 2009;8:S31. cited by applicant
      Carpentier, Retargeting human papillomavirus-mediated gene transfer to human airway epithelial cells. J Cystic Fibro. Jun. 1, 2010;9:517. cited by applicant
      Carter et al., Identification of a human papillomavirus type 16-specific epitope on the C-terminal arm of the major capsid protein L1. J Virol. Nov. 2003;77(21):11625-32. cited by applicant
      Carter et al., Identification of human papillomavirus type 16 L1 surface loops required for neutralization by human sera. J Virol. May 2006;80(10):4664-72. cited by applicant
      Christensen et al. Surface conformational and linear epitopes on HPV-16 and HPV-18 L1 virus-like particles as defined by monoclonal antibodies. Virology. Sep. 1, 1996;223(1):174-84. cited by applicant
      Cohen et al., Targeted in vitro photodynamic therapy via aptamer-labeled, porphyrin-loaded virus capsids. J Photochem Photobiol B. Apr. 5, 2013;121:67-74. doi: 10.1016/j.jphotobiol.2013.02.013. Epub Feb. 28, 2013. cited by applicant
      Combita et al., Gene transfer using human papillomavirus pseudovirions varies according to virus genotype and requires cell surface heparan sulfate. FEMS Microbiol Lett. Oct. 16, 2001;204(1):183-8. cited by applicant
      Cook et al., Purification of virus-like particles of recombinant human papillomavirus type 11 major capsid protein L1 from Saccharomyces cerevisiae. Protein Expr Purif. Dec. 1999;17(3):477-84. cited by applicant
      Culp et al., Papillomavirus particles assembled in 293TT cells are infectious in vivo. J Virol. Nov. 2006;80(22):11381-4. Epub Aug. 30, 2006. cited by applicant
      Douglas et al., Protein engineering of a viral cage for constrained nanomaterials synthesis. Adv Mater. Mar. 12, 2002;14(6):415-8. cited by applicant
      Elbashir et al., Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods. Feb. 2002;26(2):199-213. cited by applicant
      Ewers et al., GM1 structure determines SV40-induced membrane invagination and infection. Nat Cell Biol. Jan. 2010;12(1):11-20; sup pp. 1-12. doi: 10.1038/ncb1999. Epub Dec. 20, 2009. cited by applicant
      Feltkamp et al., Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur J Immunol. Sep. 1993;23(9):2242-9. cited by applicant
      Finnen et al., Interactions between papillomavirus L1 and L2 capsid proteins. J Viral. Apr. 2003;77(8):4818-26. cited by applicant
      Fleury et al., Identification of neutralizing conformational epitopes on the human papillomavirus type 31 major capsid protein and functional implications. Protein Sci. Jul. 2009;18(7):1425-38. cited by applicant
      Gaden et al., Gene transduction and cell entry pathway of fiber-modified adenovirus type 5 vectors carrying novel endocytic peptide ligands selected on human tracheal glandular cells. J Virol. Jul. 2004;78(13):7227-47. cited by applicant
      Gillitzer et al., Controlled ligand display on a symmetrical protein-cage architecture through mixed assembly. Small. Aug. 2006;2(8-9):962-6. cited by applicant
      Hagensee et al. Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins. Journal of virology. Jan. 1, 1993;67(1):315-22. cited by applicant
      Jiang et al., Gel-based application of siRNA to human epithelial cancer cells induces RNAi-dependent apoptosis. Oligonucleotides. 2004 Winter;14(4):239-48. cited by applicant
      Jiang et al., Selective silencing of viral gene E6 and E7 expression in HPV-positive human cervical carcinoma cells using small interfering RNAs. Methods Mol Biol. 2005;292:401-20. cited by applicant
      Jiang et al., Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference. Oncogene. Sep. 5, 2002;21(39):6041-8. cited by applicant
      Jost et al., A novel peptide, THALWHT, for the targeting of human airway epithelia. FEBS Lett. Feb. 2, 2001;489(2-3):263-9. cited by applicant
      Kawana et al., In vitro construction of pseudovirions of human papillomavirus type 16: incorporation of plasmid DNA into reassembled L1/L2 capsids. J Virol. Dec. 1998;72(12):10298-300. cited by applicant
      Kines et al., An Infrared Dye-Conjugated Virus-like Particle for the Treatment of Primary Uveal Melanoma. Mol Cancer Ther. Feb. 2018;17(2):565-574. doi: 10.1158/1535-7163.MCT-17-0953. Epub Dec. 14, 2017. cited by applicant
      Kines et al., Human papillomavirus capsids preferentially bind and infect tumor cells. Int J Cancer. Feb. 15, 2016;138(4):901-11. doi: 10.1002/ijc.29823. Epub Oct. 27, 2015. cited by applicant
      Kirnbauer et al. Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into virus-like particles. Journal of virology. Dec. 1, 1993;67(12):6929-36. cited by applicant
      Kirnbauer et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proceedings of the National Academy of Sciences. Dec. 15, 1992;89(24):12180-4. cited by applicant
      Lavelle et al., The disassembly, reassembly and stability of CCMV protein capsids. J Virol Methods. Dec. 2007;146(1-2):311-6. Epub Sep. 4, 2007. cited by applicant
      Lee et al., Adaptations of nanoscale viruses and other protein cages for medical applications. Nanomedicine. Sep. 2006;2(3):137-49. cited by applicant
      Leong et al., Intravital imaging of embryonic and tumor neovasculature using viral nanoparticles. Nat Protoc. Aug. 2010;5(8):1406-17. doi: 10.1038/nprot.2010.103. Epub Jul. 8, 2010. cited by applicant
      Li et al, Expression of the human papillomavirus type 11 L1 capsid protein in Escherichia coli: characterization of protein domains involved in DNA binding and capsid assembly. J Viral. Apr. 1997;71(4):2988-95. cited by applicant
      Li et al, Trackable and Targeted Phage as Positron Emission Tomography (PET) Agent for Cancer Imaging. Theranostics. 2011;1:371-80. Epub Nov. 18, 2011. cited by applicant
      Lin et al., Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res. Jan. 1, 1996;56(1):21-6. cited by applicant
      Melero et al., Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. Aug. 2015;15(8):457-72. doi: 10.1038/nrc3973. cited by applicant
      Mitsunaga et al., In vivo longitudinal imaging of experimental human papillomavirus infection in mice with a multicolor fluorescence mini-endoscopy system. Cancer Prev Res (Phila). May 2011;4(5):767-73. doi: 10.1158/1940-6207.CAPR-10-0334. Epub Mar. 23, 2011. cited by applicant
      Oh et al., Enhanced mucosal and systemic immunogenicity of human papillomavirus-like particles encapsidating interleukin-2 gene adjuvant. Virology. Oct. 25, 2004;328(2):266-73. cited by applicant
      Pedersen et al. Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. Journal of Adolescent Health. Jun. 30, 2007;40(6):564-71. cited by applicant
      Peng et al., Construction and production of fluorescent papillomavirus-like particles. J Tongji Med Univ. 1999;19(3):170-4, 180. cited by applicant
      Pinto et al. Cellular immune responses to human papillomavirus (HPV)-16 L1 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles. Journal of Infectious Diseases. Jul. 15, 2003;188(2):327-38. cited by applicant
      Pyeon et al., Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation. Proc Natl Acad Sci U S A. Jun. 28, 2005;102(26):9311-6. Epub Jun. 15, 2005. cited by applicant
      Raja et al., Hybrid virus-polymer materials. 1. Synthesis and properties of PEG-decorated cowpea mosaic virus. Biomacromolecules. May-Jun. 2003;4(3):472-6. cited by applicant
      Rhee et al., Glycan-targeted virus-like nanoparticles for photodynamic therapy. Biomacromolecules. Aug 13, 2012;13(8):2333-8. doi: 10.1021/bm300578p. Epub Jul. 24, 2012. Author manuscript. cited by applicant
      Rose et al. Expression of human papillomavirus type 11 L1 protein in insect cells: in vivo and in vitro assembly of viruslike particles. Journal of Virology. Apr. 1, 1993;67(4):1936-44. cited by applicant
      Rudolf et al., Human dendritic cells are activated by chimeric human papillomavirus type-16 virus-like particles and induce epitope-specific human T cell responses in vitro. J Immunol. May 15, 2001;166(10):5917-24. cited by applicant
      Ruehlmann et al., MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma. Cancer Res. Dec. 1, 2001;61(23):8498-503. cited by applicant
      Ryding et al., Deletion of a major neutralizing epitope of human papillomavirus type 16 virus-like particles. J Gen Virol. Mar. 2007;88(Pt 3):792-802. cited by applicant
      Sadeyen et al., Insertion of a foreign sequence on capsid surface loops of human papillomavirus type 16 virus-like particles reduces their capacity to induce neutralizing antibodies and delineates a conformational neutralizing epitope. Virology. Apr. 25, 2003;309(1):32-40. cited by applicant
      Schädlich et al., Refining HPV 16 L1 purification from E. coli: reducing endotoxin contaminations and their impact on immunogenicity. Vaccine. Mar. 4, 2009;27(10):1511-22. Epub Jan. 25, 2009. cited by applicant
      Singh, Tumor targeting using canine parvovirus nanoparticles. Curr Top Microbiol Immunol. 2009;327:123-41. cited by applicant
      Speir et al., Structures of the native and swollen forms of cowpea chlorotic mottle virus determined by X-ray crystallography and cryo-electron microscopy. Structure. Jan. 15, 1995;3(1):63-78. cited by applicant
      Stephanopoulos et al., Dual-surface modified virus capsids for targeted delivery of photodynamic agents to cancer cells. ACS Nano. Oct. 26, 2010;4(10):6014-20. doi: 10.1021/nn1014769. cited by applicant
      Touze et al., In vitro gene transfer using human papillomavirus-like particles. Nucleic Acids Res. Mar. 1, 1998;26(5):1317-23. cited by applicant
      Touze et al., The L1 major capsid protein of human papillomavirus type 16 variants affects yield of virus-like particles produced in an insect cell expression system. J Clin Microbiol. Jul. 1998;36(7):2046-51. cited by applicant
      Touzé et al., The nine C-terminal amino acids of the major capsid protein of the human papillomavirus type 16 are essential for DNA binding and gene transfer capacity. FEMS Microbiol Lett. Aug. 1, 2000;189(1):121-7. cited by applicant
      Uchida et al., Biological Containers: Protein Cages as Multifunctional Nanoplatforms. Adv Mater. 2007;19:1025-42. cited by applicant
      Varsani et al., Chimeric human papillomavirus type 16 (HPV-16) L1 particles presenting the common neutralizing epitope for the L2 minor capsid protein of HPV-6 and HPV-16. J Virol. Aug. 2003;77(15):8386-93. cited by applicant
      Vaysse et al., Improved transfection using epithelial cell line-selected ligands and fusogenic peptides. Biochim Biophys Acta. Jul. 26, 2000;1475(3):369-76. cited by applicant
      Wang et al., Insertion of a targeting peptide on capsid surface loops of human papillomavirus type-16 virus-like particles mediate elimination of anti-dsDNA Abs-producing B cells with high efficiency. J Immunother. Jan. 2009;32(1):36-41. cited by applicant
      Wang et al., Expression of Human Papillomavirus Type 6 L1 and L2 Isolated in China and Self Assembly of Virus-like Particles by the Products. Acta Biochimica et Biophysica Sinica. 2003;35(1):27-34. 10 pages. cited by applicant
      Wang et al., Human papillomavirus type 6 virus-like particles present overlapping yet distinct conformational epitopes. J Gen Virol. Jun. 2003;84(Pt 6):1493-7. cited by applicant
      White et al., Genetic modification of adeno-associated viral vector type 2 capsid enhances gene transfer efficiency in polarized human airway epithelial cells. Hum Gene Ther. Dec. 2008;19(12):1407-14. cited by applicant
      Willits et al., Effects of the cowpea chlorotic mottle bromovirus beta-hexamer structure on virion assembly. Virology. Feb. 15, 2003;306(2):280-8. cited by applicant
      Xu et al., Papillomavirus virus-like particles as vehicles for the delivery of epitopes or genes. Arch Virol. Nov. 2006;151(11):2133-48. Epub Jun. 22, 2006. cited by applicant
      Yoshinouchi et al., In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA. Mol Ther. Nov. 2003;8(5):762-8. cited by applicant
      Zhang et al. Expression of Human Papillomavirus Type 16 L1 Protein in Escherichia coli: Denaturation, Renaturation, and Self-Assembly of Virus-like Particlesin Vitro. Virology. Apr. 10, 1998;243(2):423-31. cited by applicant
      Zhou et al. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology. Nov. 1, 1991;185(1):251-7. cited by applicant
      U.S. Appl. No. 13/264,213, filed Mar. 2, 2012, Granted, U.S. Pat. No. 9,724,404. cited by applicant
      U.S. Appl. No. 15/636,112, filed Jun. 28, 2017, Granted, U.S. Pat. No. 10,179,168. cited by applicant
      U.S. Appl. No. 16/204,019, filed Nov. 29, 2018, Granted, U.S. Pat. No. 10,688,172. cited by applicant
      U.S. Appl. No. 15/930,116, filed May 12, 2020, Pending. cited by applicant
      U.S. Appl. No. 14/376,408, filed Aug. 1, 2014, Granted, U.S. Pat. No. 9,700,639. cited by applicant
      U.S. Appl. No. 15/615,485, filed Jun. 6, 2017, Granted, U.S. Pat. No. 9,855,347. cited by applicant
      U.S. Appl. No. 15/824,685, filed Nov. 28, 2017, Granted, U.S. Pat. No. 10,300,150. cited by applicant
      U.S. Appl. No. 16/376,435, filed Apr. 5, 2019, Granted, U.S. Pat. No. 10,596,275. cited by applicant
      U.S. Appl. No. 16/778,410, filed Jan. 31, 2020, Pending. cited by applicant
      U.S. Appl. No. 15/023,169, filed Mar. 18, 2016, Granted, U.S. Pat. No. 10,117,947. cited by applicant
      U.S. Appl. No. 16/143,147, filed Sep. 26, 2018, Granted, U.S. Pat. No. 10,588,984. cited by applicant
      U.S. Appl. No. 15/772,134, filed Apr. 30, 2018, Published, 2018-0311269. cited by applicant
      U.S. Appl. No. 16/604,790, filed Oct. 11, 2019, Pending. cited by applicant
      Blackhall et al., Heparan sulfate proteoglycans and cancer. Br J Cancer. Oct. 19, 2001;85(8):1094-8. doi: 10.1054/bjoc.2001.2054. cited by applicant
      Davies et al., Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer. Clin Cancer Res. Aug. 1, 2004;10(15):5178-86. doi: 10.1158/1078-0432.CCR-03-0103. cited by applicant
      Sanderson, Heparan sulfate proteoglycans in invasion and metastasis. Semin Cell Dev Biol. Apr. 2001;12(2):89-98. doi: 10.1006/scdb.2000.0241. cited by applicant
    • Primary Examiner:
      Russel, Jeffrey E.
    • Attorney, Agent or Firm:
      Wolf, Greenfield & Sacks, P.C.
    • Accession Number:
      edspgr.11110181