IP Library Granted Patent US 12,465,642
Granted Patent B2
US 12,465,642 · App. 18/187,878 · Granted Nov 11, 2025

Targeting microbubbles

Inventors: Robert H. Grubbs (South Pasadena, CA); Marshall L. Stoller (San Francisco, CA); Hoyong Chung (Pasadena, CA); Alissa M. Fitzgerald (San Francisco, CA); Thomas W. Kenny (San Francisco, CA); Renee M. Thomas (Gainesville, FL)
Assignees: California Institute of Technology; The Regents of the University of California
A61K41/0028A61B17/22004A61B17/2202A61B17/22022A61K9/0009A61K9/0019A61K9/08A61K9/1075A61K31/663A61K41/0033A61K47/24A61K47/6911A61N7/00A61B2017/22007A61B2017/22008A61K2121/00A61N2007/0039
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,465,642
App. No.
18/187,878
Granted
Nov 11, 2025
Kind
B2
Abstract

This invention related to manufactured microbubbles, as well as methods of using manufactured microbubbles, for example, in medicinal applications. The invention pertains to the physical structure and materials of the microbubbles, as well as to methods for manufacturing microbubbles, methods for targeting microbubbles for specific medicinal applications, and methods for delivering microbubbles in medical treatment.

Claims (26)

1 . A method of fragmenting a target within a patient comprising:

(a) administering microbubbles to the patient, the microbubbles comprising (i) gas, and (ii) a targeting moiety, wherein the targeting moiety comprises a bisphosphonate;

(b) concentrating the microbubbles on or near the target; and

(c) fragmenting the target by applying ultrasound or electromagnetic energy to the microbubbles within the patient, wherein the target is a urinary stone, a biliary stone, a kidney stone, a blood clot, a fibroid, or atheromatous plaque.

2 . The method of claim 1 , wherein the administering is via injection, inhalation, or implantation.

3 . The method of claim 1 , wherein the target is a urinary stone.

4 . The method of claim 1 , wherein the targeting moiety is chemically attached to an anchoring moiety.

5 . The method of claim 4 , wherein the anchoring moiety comprises a bio-lipid, synthetic polymer, protein, or surfactant, or combination thereof.

6 . The method of claim 4 , wherein the chemical attachment is via a linking polymeric moiety.

7 . The method of claim 1 , wherein the microbubbles within the patient are attached to the target.

8 . The method of claim 1 , wherein the microbubbles within the patient are in proximity to the target, but are not attached to the target.

9 . The method of claim 1 , wherein the target is fragmented by applying ultrasound.

10 . The method of claim 1 , wherein the target is fragmented by applying electromagnetic energy.

11 . A method of treating a patient, the method comprising:

(a) delivering a solution comprising microbubbles to a site within the patient, the microbubbles comprising a targeting moiety with a specific affinity to a target selected from a urinary stone, a biliary stone, a kidney stone, a blood clot, a fibroid, and atheromatous plaque;

(b) concentrating the microbubbles on or near the target; and

(c) fragmenting the target by applying ultrasound or electromagnetic energy to the microbubbles within the patient.

12 . The method of claim 11 , wherein the solution is delivered directly to the site via implantation or via a catheter.

13 . The method of claim 11 , wherein the solution is delivered to the patient via injection or inhalation.

14 . The method of claim 11 , wherein the microbubbles further comprise a bio-lipid, synthetic polymer, protein, or surfactant.

15 . The method of claim 11 , wherein the microbubbles within the patient are attached to the target.

16 . The method of claim 11 , wherein the microbubbles within the patient are in proximity to the target, but are not attached to the target.

17 . The method of claim 11 , wherein the targeting moiety is chemically attached to an anchoring moiety.

18 . The method of claim 17 , wherein the anchoring moiety comprises a bio-lipid, synthetic polymer, protein, or surfactant, or combination thereof.

19 . The method of claim 17 , wherein the chemical attachment is via a linking polymeric moiety.

20 . The method of claim 11 , wherein the target is a urinary stone or kidney stone.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2023
From: STOLLER, MARSHALL L.
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 063972/0943 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2023
From: GRUBBS, ROBERT H.; CHUNG, HOYONG; FITZGERALD, ALISSA M.; THOMAS, RENEE M.; KENNY, THOMAS W.
To: CALIFORNIA INSTITUTE OF TECHNOLOGY
Reel/Frame 063973/0056 →
Continuity (7)
Continuation 17544630 · Dec 7, 2021
Continuation 16431605 · Jun 4, 2019
Continuation 16154677 · Oct 8, 2018
Division 15199710 · Jun 30, 2016
Division 13593747 · Aug 24, 2012
Provisional Application 61527031 · Aug 24, 2011
Related Publication 20230285561A1 · Sep 14, 2023
References Cited (67)
US 5463092A · Hostetler et al. · 1995 [cited by applicant]
US 5860972A · Hoang · 1999 [cited by applicant]
US 6245318B1 · Klibanov et al. · 2001 [cited by applicant]
US 6261537B1 · Klaveness et al. · 2001 [cited by applicant]
US 10149906B2 · Grubbs et al. · 2018 [cited by applicant]
US 10357565B2 · Grubbs et al. · 2019 [cited by applicant]
US 10953023B1 · Laser et al. · 2021 [cited by applicant]
US 20070110674A1 · Xu et al. · 2007 [cited by applicant]
US 20070207194A1 · Grayburn et al. · 2007 [cited by applicant]
US 20070258908A1 · Lanza et al. · 2007 [cited by applicant]
US 20080009561A1 · Unger et al. · 2008 [cited by applicant]
US 20080045865A1 · Kislev · 2008 [cited by applicant]
US 20080269668A1 · Keenan et al. · 2008 [cited by applicant]
US 20080319375A1 · Hardy · 2008 [cited by applicant]
US 20090136594A1 · McLeroy et al. · 2009 [cited by applicant]
US 20090215729A1 · Johnson et al. · 2009 [cited by applicant]
US 20100285112A1 · Novobrantseva et al. · 2010 [cited by applicant]
US 20120201900A1 · Borden et al. · 2012 [cited by applicant]
US 20130123781A1 · Grubbs et al. · 2013 [cited by applicant]
US 20140010848A1 · Kheir et al. · 2014 [cited by applicant]
US 20190200659A1 · Smutzer et al. · 2019 [cited by applicant]
US 20190282695A1 · Grubbs et al. · 2019 [cited by applicant]
CN 101679463A · 2010 [cited by applicant]
CN 103917637A · 2014 [cited by applicant]
EP 2468760A1 · 2012 [cited by applicant]
JP 2009280500A · 2009 [cited by applicant]
WO WO1997029782A1 · 1997 [cited by applicant]
WO WO200109146A1 · 2001 [cited by applicant]
WO WO2008131217A1 · 2008 [cited by applicant]
WO WO2009055014A2 · 2009 [cited by applicant]
WO WO2009141823A2 · 2009 [cited by applicant]
WO WO2012094541A2 · 2012 [cited by applicant]
WO WO2012143739A1 · 2012 [cited by applicant]
WO WO2015134671A1 · 2015 [cited by applicant]
WO WO2016205820A1 · 2016 [cited by applicant]
WO WO2017197726A1 · 2017 [cited by applicant]
Bhadane, S., “High Intensity Focused Ultrasound and Microbubble Induced Tissue Ablation: Effect of Treatment Parameters on Thermal Lesion Volume and Temperature,” Thesis, Ryerson University, 2009, 104 pages. [cited by applicant]
Bhushan, K. R., et al., “Synthesis of Conjugatable Bisphosphonates for Molecular Imaging of Large Animals,” Angewandte Chemie International Edition, 2007, pp. 7679-7971, vol. 46. [cited by applicant]
Chen et al., “Bone Targeted Delivery of SDF-1 via Alendronate Functionalized Nanoparticles in Guiding Stem Cell Migration,” ACS Applied Materials & Interfaces (2018), vol. 10, Issue 28, p. 23700-23710. [cited by applicant]
Deelman, L. E., et al., “Targeted renal therapies through microbubbles and ultrasound,” [cited by applicant]
Geers, B., et al., “Adeno-associated virus loaded microbubbles as a tool for targeted gene Delivery,” [cited by applicant]
Hernot, S., et al., “Microbubbles in Ultrasound-triggered drug and gene delivery,” [cited by applicant]
Hu, Y., et al., “Mesenchymal stem cells: A promising targeted-delivery vehicle in cancer gene Therapy,” [cited by applicant]
International Search Report and Written Opinion, Patent Cooperation Treaty Application No. PCT/US2012/052187, dated Jan. 28, 2013, 11 Pages. [cited by applicant]
International Search Report and Written Opinion, Patent Cooperation Treaty Application No. PCT/US2016/038428, dated Oct. 27, 2016, 16 Pages. [cited by applicant]
International Search Report and Written Opinion, Patent Cooperation Treaty Application No. PCT/US2020/015493, Apr. 14, 2020, 13 pages. [cited by applicant]
Khelfallah, S. K., et al., “Synthesis of novel polymerizable molecules bearing bisphosphonate,” [cited by applicant]
Liu, Y., et al., “Encapsulated ultrasound microbubbles: Therapeutic application in drug/gene Delivery,” [cited by applicant]
Matheson Tri-Gas, Inc., “Material Safety Data Sheet, Substance: Perfluoropropane,” 1989, [online] [Retrieved on Sep. 22, 2016] Retrieved from the Internet <URL: https://www.mathesongas.com/pdfs/msds/MAT18290.pdf>. [cited by applicant]
Mayer, C. R., et al., “Ultrasonic gene and drug delivery to the cardiovascular system,” [cited by applicant]
Mcdonald, C. J., et al., “Hollow latex particles: synthesis and applications,” [cited by applicant]
Mellema, M. et al., “PD22-11 Absence of Ureteral/Renal Injury Following Low Intensity Extracorporeal Acoustic Energy Lithotripsy With Stone-Targeting Microbubbles in an in Vivo Swine Model,” [cited by applicant]
Pishchalnikov, Y. et al., “Experimental observations and numerical modeling of lipid-shell microbubbles with calcium-adhering moieties for minimally-invasive treatment of urinary stones,” [cited by applicant]
Ramaswamy, K. et al., “Targeted Microbubbles: A Novel Application for the Treatment of Kidney Stones,” BJU International, 2015, John Wiley & Sons Ltd., pp. 9-16, vol. 116. [cited by applicant]
Rapoport, N. et al., “Multifunctional Nanoparticles for Combining Ultrasonic Tumor Imaging and Targeted Chemotherapy,” Journal Natl. Cancer. Inst., Jul. 18, 2007, vol. 99, Issue 14, pp. 1095-1106. [cited by applicant]
Shi, Y., et al., “Multistep Targeted Nano Drug Delivery System Aiming at Leukemic Stem Cells and Minimal Residual Disease,” Mol. Pharmaceutics, 2013, pp. 2479-2489, vol. 10. [cited by applicant]
Sirsi, S. et al., “Microbubble Compositions, Properties and Biomedical Applications,” Bubble Sci. Eng. Technol., Nov. 2009, pp. 3-17, vol. 1, No. 1-2. [cited by applicant]
Tinkov, S., et al., “New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: Part I—Formulation development and in-vitro characterization,” Journal of Controlled Release, 2010, pp. 143-150, vol. 143. [cited by applicant]
Unger, E. C. et al., “Therapeutic applications of microbubbles,” European Journal of Radiology, vol. 42, Iss. 2, May 2002, pp. 160-168. [cited by applicant]
Unger, E. C., et al., “Therapeutic applications of lipid-coated microbubbles,” Advanced Drug Delivery Reviews, 2004, pp. 1291-1314, vol. 56. [cited by applicant]
Vachal, P. et al., “Synthesis and Study of Alendronate Derivatives as Potential Prodrugs of Alendronate Sodium for the Treatment of Low Bone Density and Osteoporosis,” [cited by applicant]
Wu, T.Y. et al., “Advances in Ultrasound Technology for Environmental Remediation,” SpringerBriefs in Green Chemistry for Sustainability, 2013, pp. 5-12. [cited by applicant]
Yoshizawa, S. et al., “High Intensity Focused Ultrasound Lithotripsy with Cavitating Microbubbles,” Med. Biol. Eng. Comput., 2009, pp. 851-860, vol. 47. [cited by applicant]
Pishchalnikov, Y., et al., “High-speed video microscopy and numerical modeling of bubble dynamics near a surface of urinary stone,” [cited by applicant]
United States Office Action, U.S. Appl. No. 17/879,267, filed Apr. 11, 2023, 15 pages. [cited by applicant]
United States Office Action, U.S. Appl. No. 17/879,285, filed Apr. 13, 2023, 15 pages. [cited by applicant]
United States Office Action, U.S. Appl. No. 17/879,267, filed Jul. 18, 2023, 12 pages. [cited by applicant]