Granted Patent
B2
US 12,558,350 · App. 17/815,256 · Granted Feb 24, 2026
Compositions and methods for treatment
Assignee:
Bausch + Lomb Ireland Limited
A61K31/4725A61B3/101A61B3/145A61K9/0014A61K9/0019A61K9/0043A61K9/0048A61K9/0051A61K9/0053A61K31/197A61K31/198A61K31/275A61K31/341A61K31/381A61K31/40A61K31/404A61K31/405A61K31/4162A61K31/4184A61K31/4192A61K31/44A61K31/4709A61K31/472A61K31/4745A61K31/495A61K31/496A61K31/517A61K31/5377A61K31/54A61K31/541A61K33/00A61K33/06A61K38/07A61K38/08A61K38/12A61K38/1703A61K45/06A61P27/02C07C279/28C07C317/50C07D207/06C07D217/00C07D217/02C07D217/06C07D217/20C07D217/26C07D307/52C07D333/38C07D401/06C07D405/06C07D405/14C07D409/14C07D413/14C07D471/04G01N33/5011G01N33/5032G01N33/5047G01N33/566G01N33/6872G01N2333/705G01N2333/70525G01N2333/70546G01N2500/02G01N2500/04G01N2500/10G01N2500/20G01N2800/16
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Abstract
The present invention provides compounds and methods for the treatment of LFA-1 mediated diseases. In particular, LFA-1 antagonists are described herein and these antagonists are used in the treatment of LFA-1 mediated diseases. One aspect of the invention provides for diagnosis of an LFA-1 mediated disease and administration of a LFA-1 antagonist, after the patient is diagnosed with a LFA-1 mediated disease. In some embodiments, the LFA-1 mediated diseases treated are dry eye disorders. Also provided herein are methods for identifying compounds which are LFA-1 antagonists.
Claims (7)
1 . A method of identifying LFA-1 antagonists, said compounds being competitive inhibitors of the LFA-1: ICAM interaction, comprising:
binding an antagonist candidate molecule at a known concentration to a ligand selected from group comprising ICAM-1, s-ICAM-1, and LFA-1 in a binding assay;
adding a set of concentrations of a labeled compound, wherein said compound is known to be an inhibitor of a LFA-1 and ICAM interaction on the I domain of the alpha chain of LFA-1;
obtaining a binding curve;
determining EC50 values for each set of binding competitions; and
determining the antagonistic properties of said candidate molecule based on said EC50 values.
2 . The method of claim 1 wherein said labeled compound comprises a compound of Formula VII:
Assignments (8)
INTELLECTUAL PROPERTY SECURITY AGREEMENT
Recorded Dec 23, 2025
From: BAUSCH + LOMB IRELAND LIMITED
To: CITIBANK, N.A., AS NOTES COLLATERAL AGENT
Reel/Frame 074050/0682 →
INTELLECTUAL PROPERTY SECURITY AGREEMENT
Recorded Dec 23, 2025
From: BAUSCH + LOMB IRELAND LIMITED
To: CITIBANK, N.A., AS NOTES COLLATERAL AGENT
Reel/Frame 074050/0709 →
INTELLECTUAL PROPERTY SECURITY AGREEMENT
Recorded Dec 23, 2025
From: BAUSCH + LOMB IRELAND LIMITED
To: JPMORGAN CHASE BANK, N.A., AS COLLATERAL AGENT
Reel/Frame 074050/0573 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 13, 2024
From: NOVARTIS AG
To: BAUSCH + LOMB IRELAND LIMITED
Reel/Frame 066455/0287 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 17, 2023
From: SARCODE BIOSCIENCE INC.
To: NOVARTIS AG
Reel/Frame 062391/0369 →
CHANGE OF NAME
Recorded Jan 17, 2023
From: SARCODE CORPORATION
To: SARCODE BIOSCIENCE INC.
Reel/Frame 062391/0249 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 17, 2023
From: NOVARTIS AG
To: NOVARTIS PHARMACEUTICALS CORPORATION
Reel/Frame 062391/0227 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 17, 2023
From: GADEK, THOMAS; BURNIER, JOHN
To: SARCODE CORPORATION
Reel/Frame 062390/0560 →
Continuity (12)
Continuation
17577575
· Jan 18, 2022
Provisional Application
60681723
· May 17, 2005
Provisional Application
60681722
· May 17, 2005
Provisional Application
60681684
· May 17, 2005
References Cited (301)
US 3773919A
· Boswell et al.
· 1973
[cited by applicant]
US 4668506A
· Bawa
· 1987
[cited by applicant]
US 4713244A
· Bawa et al.
· 1987
[cited by applicant]
US 4767628A
· Hutchinson
· 1988
[cited by applicant]
US 4931279A
· Bawa et al.
· 1990
[cited by applicant]
US 4992445A
· Lawter et al.
· 1991
[cited by applicant]
US 5001139A
· Lawter et al.
· 1991
[cited by applicant]
US 5023252A
· Hseih
· 1991
[cited by applicant]
US 5134122A
· Orsolini
· 1992
[cited by applicant]
US 5149780A
· Plow et al.
· 1992
[cited by applicant]
US 5192741A
· Orsolini et al.
· 1993
[cited by applicant]
US 5236704A
· Fujioka et al.
· 1993
[cited by applicant]
US 5288854A
· Diamond et al.
· 1994
[cited by applicant]
US 5298492A
· Neustadt et al.
· 1994
[cited by applicant]
US 5340800A
· Liu et al.
· 1994
[cited by applicant]
US 5397791A
· Hartman et al.
· 1995
[cited by applicant]
US 5424289A
· Yang et al.
· 1995
[cited by applicant]
US 5424399A
· Arnaout
· 1995
[cited by applicant]
US 5445832A
· Orsolini et al.
· 1995
[cited by applicant]
US 5470953A
· Gallatin et al.
· 1995
[cited by applicant]
US 5585359A
· Breslin et al.
· 1996
[cited by applicant]
US 5597567A
· Whitcup et al.
· 1997
[cited by applicant]
US 5612052A
· Shalaby
· 1997
[cited by applicant]
US 5622700A
· Jardieu et al.
· 1997
[cited by applicant]
US 5672659A
· Shalaby et al.
· 1997
[cited by applicant]
US 5747035A
· Presta et al.
· 1998
[cited by applicant]
US 5840332A
· Lerner et al.
· 1998
[cited by applicant]
US 5849327A
· Berliner et al.
· 1998
[cited by applicant]
US 5877224A
· Brocchini et al.
· 1999
[cited by applicant]
US 5893985A
· Luo et al.
· 1999
[cited by applicant]
US 5922356A
· Koseki et al.
· 1999
[cited by applicant]
US 5936089A
· Carpino et al.
· 1999
[cited by applicant]
US 5968895A
· Gefter et al.
· 1999
[cited by applicant]
US 5973188A
· Alig et al.
· 1999
[cited by applicant]
US 5980945A
· Ruiz
· 1999
[cited by applicant]
US 6180608B1
· Gefter et al.
· 2001
[cited by applicant]
US 6204280B1
· Gante et al.
· 2001
[cited by applicant]
US 6294522B1
· Zablocki et al.
· 2001
[cited by applicant]
US 6331640B1
· Fotouhi et al.
· 2001
[cited by applicant]
US 6340679B1
· Peyman et al.
· 2002
[cited by applicant]
US 6358976B1
· Wityak et al.
· 2002
[cited by applicant]
US 6515124B2
· Fotouhi et al.
· 2003
[cited by applicant]
US 6524581B1
· Adamis
· 2003
[cited by applicant]
US 6605597B1
· Zablocki et al.
· 2003
[cited by applicant]
US 6620422B1
· Maquin et al.
· 2003
[cited by applicant]
US 6642225B2
· Albert et al.
· 2003
[cited by applicant]
US 6653478B2
· Urbanski et al.
· 2003
[cited by applicant]
US 6667060B1
· Vandecruys et al.
· 2003
[cited by applicant]
US 6667318B2
· Burdick et al.
· 2003
[cited by applicant]
US 6670321B1
· Adamis
· 2003
[cited by applicant]
US 6773916B1
· Thiel et al.
· 2004
[cited by applicant]
US 6803384B2
· Fotouhi et al.
· 2004
[cited by applicant]
US 6872382B1
· Gamache et al.
· 2005
[cited by applicant]
US 6872735B2
· Burdick et al.
· 2005
[cited by applicant]
US 7097851B1
· Takada
· 2006
[cited by applicant]
US 7211586B2
· Fenton et al.
· 2007
[cited by applicant]
US 7217728B2
· Fotouhi et al.
· 2007
[cited by applicant]
US 7314938B2
· Shen et al.
· 2008
[cited by applicant]
US 7745460B2
· Shen et al.
· 2010
[cited by applicant]
US 7785578B2
· Miller et al.
· 2010
[cited by applicant]
US 7790743B2
· Shen et al.
· 2010
[cited by applicant]
US 7928122B2
· Shen et al.
· 2011
[cited by applicant]
US 7989626B2
· Shen et al.
· 2011
[cited by applicant]
US 8071617B2
· Shen et al.
· 2011
[cited by applicant]
US 8080562B2
· Burnier et al.
· 2011
[cited by applicant]
US 8084047B2
· Shen et al.
· 2011
[cited by applicant]
US 8168655B2
· Gadek et al.
· 2012
[cited by applicant]
US 8367701B2
· Burnier et al.
· 2013
[cited by applicant]
US 8592450B2
· Gadek et al.
· 2013
[cited by applicant]
US 8771715B2
· Oslob et al.
· 2014
[cited by applicant]
US 8927574B2
· Burnier et al.
· 2015
[cited by applicant]
US 9045457B2
· Gadek et al.
· 2015
[cited by applicant]
US 9085553B2
· Zeller et al.
· 2015
[cited by applicant]
US 9248126B2
· Shen et al.
· 2016
[cited by applicant]
US 9353088B2
· Burnier et al.
· 2016
[cited by applicant]
US 9447077B2
· Burnier et al.
· 2016
[cited by applicant]
US 9890141B2
· Burnier et al.
· 2018
[cited by applicant]
US 20010031260A1
· Lee et al.
· 2001
[cited by applicant]
US 20020115692A1
· Archibald et al.
· 2002
[cited by applicant]
US 20020119994A1
· Burdick et al.
· 2002
[cited by applicant]
US 20020132807A1
· Wang et al.
· 2002
[cited by applicant]
US 20020176841A1
· Barker et al.
· 2002
[cited by applicant]
US 20020177591A1
· O'Donnell et al.
· 2002
[cited by applicant]
US 20030044406A1
· Dingivan
· 2003
[cited by applicant]
US 20030064105A1
· Kim et al.
· 2003
[cited by applicant]
US 20030068320A1
· Dingivan
· 2003
[cited by applicant]
US 20030166630A1
· Auvin et al.
· 2003
[cited by applicant]
US 20030171296A1
· Gefter et al.
· 2003
[cited by applicant]
US 20040006236A1
· Fotouhi et al.
· 2004
[cited by applicant]
US 20040028648A1
· Adamis
· 2004
[cited by applicant]
US 20040038973A1
· Nahra et al.
· 2004
[cited by applicant]
US 20040120960A1
· Jardieu et al.
· 2004
[cited by applicant]
US 20050148588A1
· Burdick et al.
· 2005
[cited by applicant]
US 20070025990A1
· Dingivan
· 2007
[cited by applicant]
US 20080019977A1
· Adamis
· 2008
[cited by applicant]
US 20090155176A1
· Burnier et al.
· 2009
[cited by applicant]
US 20090258069A1
· Burnier et al.
· 2009
[cited by applicant]
US 20090258070A1
· Burnier et al.
· 2009
[cited by applicant]
US 20100092541A1
· Burnier et al.
· 2010
[cited by applicant]
EP 0314863A2
· 1989
[cited by applicant]
EP 0326151A2
· 1989
[cited by applicant]
EP 0362526A2
· 1990
[cited by applicant]
EP 0362531A1
· 1990
[cited by applicant]
EP 0656789A2
· 1992
[cited by applicant]
EP 0656789A1
· 1995
[cited by applicant]
EP 1392306A1
· 2004
[cited by applicant]
JP H07500107A
· 1995
[cited by applicant]
JP 2002520355A
· 2002
[cited by applicant]
JP 2003512439A
· 2003
[cited by applicant]
JP 4193895B2
· 2008
[cited by applicant]
WO 9003400A1
· 1990
[cited by applicant]
WO 9010652A1
· 1990
[cited by applicant]
WO 9013316A1
· 1990
[cited by applicant]
WO 9119511A1
· 1991
[cited by applicant]
WO 9203473A1
· 1992
[cited by applicant]
WO 9316702A1
· 1993
[cited by applicant]
WO 9324150A1
· 1993
[cited by applicant]
WO 9403481A1
· 1994
[cited by applicant]
WO 9411400A1
· 1994
[cited by applicant]
WO 9415587A2
· 1994
[cited by applicant]
WO 9504531A1
· 1995
[cited by applicant]
WO 9528170A1
· 1995
[cited by applicant]
WO 9609836A1
· 1996
[cited by applicant]
WO 9704744A1
· 1997
[cited by applicant]
WO 9726015A1
· 1997
[cited by applicant]
WO 9740085A2
· 1997
[cited by applicant]
WO 9813029A1
· 1998
[cited by applicant]
WO 9825642A2
· 1998
[cited by applicant]
WO 9846599A1
· 1998
[cited by applicant]
WO 9949856A2
· 1999
[cited by applicant]
WO 0021920A1
· 2000
[cited by applicant]
WO 0038714A1
· 2000
[cited by applicant]
WO 0044731A1
· 2000
[cited by applicant]
WO 0101964A2
· 2001
[cited by applicant]
WO 0112233A2
· 2001
[cited by applicant]
WO 200112233A2
· 2001
[cited by applicant]
WO 0127102A1
· 2001
[cited by applicant]
WO 0149249A2
· 2001
[cited by applicant]
WO 200149249A2
· 2001
[cited by applicant]
WO 200149311A1
· 2001
[cited by applicant]
WO 200158853A1
· 2001
[cited by applicant]
WO 200187840A1
· 2001
[cited by applicant]
WO 200230398A2
· 2002
[cited by applicant]
WO 200238129A2
· 2002
[cited by applicant]
WO 200250080A1
· 2002
[cited by applicant]
WO 2002058672A2
· 2002
[cited by applicant]
WO 2002059114A1
· 2002
[cited by applicant]
WO 2002074247A2
· 2002
[cited by applicant]
WO 2002098426A1
· 2002
[cited by applicant]
WO 2003053401A2
· 2003
[cited by applicant]
WO 2003075887A1
· 2003
[cited by applicant]
WO 2004026406A1
· 2004
[cited by applicant]
WO 2005014532A1
· 2005
[cited by applicant]
WO 2005014533A2
· 2005
[cited by applicant]
WO 2005042710A1
· 2005
[cited by applicant]
WO 2005044817A1
· 2005
[cited by applicant]
WO 2005123706A1
· 2005
[cited by applicant]
WO 2006125119A1
· 2006
[cited by applicant]
WO 2009139817A2
· 2006
[cited by applicant]
National Eye Institute, Types and Causes of Retinal Detachment, printed from https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/retinal-detachment/types-and-causes-retinal-detachment, Jul. 9, 201…
[cited by applicant]
www.WebMD.com, Retinal Detachment—Treatment Overview, Aug. 26, 2009, printed from http://www.webmed.com/eye-health/tc/retrain-detachment-treatment-overview, 2 pages.
[cited by applicant]
UC San Diego Health, Acute Glaucoma Discovered to be an Inflammatory Disease, Jul. 11, 2014, printed from https://health.ucsd.edu/news/releases/Pages/2014-07-14-acute-close-angle-glaucoma.aspx, 3 pages.
[cited by applicant]
Woodward et al., “The inflow and outflow of anti-glaucoma drugs,” Trends Pharmacol. 25(5):238-41 (2004).
[cited by applicant]
Medical News Today, Cataracts: Causes, Symptoms, and Treatment, Jul. 1, 2017, printed from https://web.archive.org/web/2017071123318/http://medicalnewstoday.com/articles/157510.php, 8 pages.
[cited by applicant]
Rivera et al., Retinopathy of prematurity: inflammation, chorodial degeneration, and novel promising therapeutic strategies, J Neuroinflammation. 2107; 14:165, printed from https://pubmed.ncbi.nih.gov/28830469/, Abstrac…
[cited by applicant]
National Eye Institute, Facts about Retinopathy of Prematurity (ROP), Oct. 2009, printed from http://ww.nei.nih.gov/health/rop/rop.asp#2, 6 pages.
[cited by applicant]
Connell et al., Vision Rehabilitation in Progressive Supranuclear Palsy: a Case Report, 2012, American Academy of Optometry, printed from http://www.aaopt.org/vision-rehabilitation-progressive-supranuclear-balsy-case-re…
[cited by applicant]
Higuera, www.healthline.com, Sarcoidosis, May 29, 2017, printed on Jun. 11, 2017 from http://www.healthline.com/health/sarcoidosis#/overview1, 18 pages.
[cited by applicant]
Mack, A Closer Look at Ocular Allergy, Contact Lens Spectrum, Apr. 1, 1999, printed from http://clspectrum.com/issues/1999/april-1999/a-closer-look-at-ocular-allergy, 6 pages.
[cited by applicant]
McFarland et al., CD11b (Mac-1): A Marker for CD8+ Cytotoxic T Cell Activation and Memory in Virus Infection, J Immunol 149 (4), 1326-1333. Aug. 15, 1992.
[cited by applicant]
Melis et al., Increased expression of leukocyte function associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) by alveolar macrophages of patients with pulmonary sarcoidosis, Chest. Oct. 1991;100(4…
[cited by applicant]
Pathway Medicine, T-cell-mediated Cytotoxicity, http://www.pathwaymedicine.org, 2015, printed from http://www.pathwaymedicine.org/t-cell-mediated-cytotoxicity, 1 page.
[cited by applicant]
Rasanen et al., Immediate and delayed hypersensitivity reactions to birch pollen in patients with atopic dermatitis, Acta Derm Venereol. 1992;72(3):193-6, printed from http://www.ncbi.nlm.nih.gov/pubmed/1357857, abstrac…
[cited by applicant]
Sadhu et al., CD11c/CD18: novel ligands and a role in delayed-type hypersensitivity, J Leukoc Biol. Jun. 2007;81(6):1395-403. Epub Mar. 27, 2007, printed from http://www.ncbi.nlm.nih.gov/pubmed/17389580, Abstract only.
[cited by applicant]
Santos et al., Hashimoto's thyroiditis and Sjogren syndrome. Association or autoimmune multiple syndrome?]., An Med Interna. Feb. 2001;18(2):86-7, printed from https://www.ncbi.nlm.nih.gov/pubmed/11322005, 1 page, Abstr…
[cited by applicant]
Semba et al., A phase 2 randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye, Am J Ophthalmol. Jun. 2012;153(6):1050-60.e1. doi: 10.1016/j.ajo.2011.1…
[cited by applicant]
Tjiang et al., Eye and eyelid abnormalities are common in patients with Hashimoto's thyroiditis, Thyroid. Mar. 2010;20(3):287-90, printed from https://www.ncbi.nlm.nih.gov/pubmed/20146657, 2 pages, Abstract only.
[cited by applicant]
Venet et al, Enhanced alveolar macrophage-mediated antigen-induced T-lymphocyte proliferation in sarcoidosis, J Clin Invest. Jan. 1985;75(1): 293-301, printed from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC423439/, 4…
[cited by applicant]
Weetman et al., Thyroid Autoantigen-Induced Lymphocyte Proliferation in Graves' Disease and Hashimoto's Thyroiditis, J Clin Lab Immunol 17 (1), 1-6. 5 1985.
[cited by applicant]
Blackford et al., A monoclonal antibody, 3/22. to rabbit CD11c which induces homotypic T cell aggregation: evidence that ICAM-1 is a ligand for CD11c/CD18, Eur J Immunol Mar. 1996; 26(3):525-31 printed from https://www.…
[cited by applicant]
www.webmd.com, Hashimoto's Thyroiditis, Sep. 25, 2014, printed from http://www.webmd.com/women/hashimotos-thyrioditis-symptoms-causes-treatments?page=2&print=true on May 8, 2016, 4 pages.
[cited by applicant]
Akiyama et al., Expression of Intercellular adhesion molecule (ICAM)-1 by a subset of astrocytes in Alzheimer disease and some other degenerative neurological disorders, Acta Neuropathol. 1993;85(6):628-34, printed from…
[cited by applicant]
Mayo Clinic, Amyotrophic lateral sclerosis, Apr. 9, 2014, printed from http://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/basics/treatement/con-20024397 on May 9, 2016, 4 pages.
[cited by applicant]
U.S. National Library of Medicine, Pick Disease, Feb. 24, 2014, printed from https://www.nlm.nih.gov/medlineplus/ency/article/000744.htm on May 8, 2016, 6 pages.
[cited by applicant]
National Institute fof Neurological Disorders and Stroke, Progressive Supranuclear Palsy Face Sheet, Nov. 5, 2015, printed from http://www.ninds.nih.gov/disorders/psp/detail_psp.htm on May 8, 2016, 7 pages.
[cited by applicant]
Danilenko et al., “A novel canine leukointegrin, alpha d beta 2, is expressed by specific macrophage subpopulations in tissue and a minor CD8+ lymphocyte subpopulation in peripheral blood,” J Immol. Jul. 1, 1995;155(1):…
[cited by applicant]
Office action dated Jan. 11, 2016 for U.S. Appl. No. 14/610,043.
[cited by applicant]
Office action dated Jan. 11, 2016 for U.S. Appl. No. 14/610,346.
[cited by applicant]
Office action dated Jan. 12, 2016 for U.S. Appl. No. 14/610,465.
[cited by applicant]
Office action dated Feb. 1, 2016 for U.S. Appl. No. 13/962,440.
[cited by applicant]
Office action dated Feb. 8, 2016 for U.S. Appl. No. 13/962,369.
[cited by applicant]
Office action dated May 12, 2016 for U.S. Appl. No. 14/610,414.
[cited by applicant]
Stern, et al. “Evaluation of Ocular Surface Inflammation in the Presence of Dry Eye and Allergic Conjuctival Disease.” Supplement. (Oct. 2003); vol. 3(4), pp. 161-164. (Cited but not considered due to copy not submitted…
[cited by applicant]
Winfield, “Pharmaceutical Practice, Inhaled Route”, Churchill Livingstone, (2004), pp. 235-246.
[cited by applicant]
Office action dated Jun. 7, 2011 for U.S. Appl. No. 11/436,906.
[cited by applicant]
Musza et la., “Potent new cell adhesion inhibitory compounds from the root of Trichilia rubra,” Tetrahedron. 1994; 50(39):11369-78.
[cited by applicant]
Office Action dated Jun. 8, 2011 for U.S. Appl. No. 12/508,367.
[cited by applicant]
Office action dated Jun. 25, 2012 for U.S. Appl. No. 12/909,241.
[cited by applicant]
Office action dated Sep. 15, 2011 for U.S. Appl. No. 13/011,760.
[cited by applicant]
Office Action dated Sep. 28, 2010 for U.S. Appl. No. 12/508,311.
[cited by applicant]
Office Action dated Sep. 28, 2010 for U.S. Appl. No. 12/508,367.
[cited by applicant]
Office action dated Oct. 5, 2011 for U.S. Appl. No. 13/011,775.
[cited by applicant]
Office Action dated Dec. 21, 201 O for U.S. Appl. No. 11/436,906.
[cited by applicant]
Park, et al. Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metab Rev. 1994;26(3):605-43.
[cited by applicant]
Park, et al. Metabolism of fluorine-containing drugs. Annu Rev Pharmacol Toxicol. 2001 ;41 :443-70.
[cited by applicant]
Paschides et al., Evaluation of tear break-up time, Schirmer's-I test and rose bengal staining as confirmatory tests for keratoconjunctivitis sicca, Clin Exp Rheumatol. Mar.-Apr. 1989;7(2), printed from http://www.ncbi.…
[cited by applicant]
Patani, et al. Bioisosterism: A rational approach in drug design. Chem. Rev. 1996; 96:3147-3176.
[cited by applicant]
Plobeck, et al. New diarylmethylpiperazines as potent and selective nonpeptidic .delta. opioid receptor agonists with increased in vitro metabolic stability. J Med Chem. 2000; 43: 3878-94.
[cited by applicant]
Rothlein, et al. 1. Leukocyte adhesion in inflammation: From discovery to the clinic. Adhesion Molecules. Wegner, C.D., Ed.; 1994: 1-8.
[cited by applicant]
Kaiser, et al. Hydrolysis-induced racemization of amino acids. Limnol. Oceanogr. Methods. 2005; 3:318-325.
[cited by applicant]
Kavanaugh et al. Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum. 1994; 37(7): 992-1004.
[cited by applicant]
Keating, et al. Competition between intercellular adhesion molecule-1 and a small-molecule antagonist for a common binding site on the alphal subunit of lymphocyte function-associated antigen-1. Protein Sci. 2006; 15(2)…
[cited by applicant]
Keating, et al. Putting the pieces together: Contribution of fluorescence polarization assays to small molecule lead optimization. Proc. SPIE. 2000; vol. 3913, p. 128-137. (Online Publication Date: Jul. 2, 2003).
[cited by applicant]
Kishimoto, et al. Integrins, ICAMs, and selectins: Role and regulation of adhesion molecules in neutrophil recruitment to inflammatory sites. Adv Pharmacol. 1994; 25: 117-69.
[cited by applicant]
Klausner, et al. Novel gastroretentive dosage forms: evaluation of gastroretentivity and its effect on levodopa absorption in humans. Pharm Res. 2003; 20(9): 1466-73.
[cited by applicant]
Kunert et al. Analysis of Topical Cyclosporine Treatment of Patients with Dry Eye Syndrome. Arch Ophthalmol, vol. 118, Nov. 2000, 1489-1496.
[cited by applicant]
Kunert, et al. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol. Mar. 2002;120(3):330-7.
[cited by applicant]
Lang, Ocular drug delivery conventional ocular formulations, Advanced Drug Delivery Reviews, 16(1995) 39-43.
[cited by applicant]
Le Mau ff, et al. Effect of anti-LFA 1 (CD11 a) monoclonal antibodies in acute rejection of human kidney transplantation. Transplantation. 1991; 52(2): 291-5.
[cited by applicant]
Legarreta Eye Center, Dry Eye, Jan. 2002, printed fromhttp://www.legarretaeyecenter.com/dry-eye.html with Google date entry, 3 pages.
[cited by applicant]
Ley, et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. Sep. 2007;7(9):678-689.
[cited by applicant]
Liebeskind, D. S. Paraneoplastic encephalopyelitis. eMedicine. Updated Jun. 11, 2009. Available at http://emedicine.medscape.com/article/1157060. Accessed Dec. 29, 2009.
[cited by applicant]
Liu, G. Inhibitors of LFA-1/ICAM-1 interaction: from monoclonal antibodies to small molecules. Drugs of the Future. 2001; 26: 767-78.
[cited by applicant]
Liu, G. Small molecule antagonists of the LFA-1/ICAM-1 interaction as potential therapeutic agents. Expert Opin Ther Patents. 2001; 11: 1383-93.
[cited by applicant]
Lu, et al. The binding sites for competitive antagonistic, allosteric antagonistic, and agonistic antibodies to the I domain of the integrin LFA-1. J Immunol. 2004; 173: 3972-8.
[cited by applicant]
Lupus erythematosus (online), retrieved on Dec. 28, 2006. Retrieved from the internet URL; http://en.wikipedia.org/wiki/Lupus.sub.-erythematosus.
[cited by applicant]
Murphy, et al. The Pharmacologic Assessment of a Novel Lymphocyte Function-Associated Antigen-1 Antagonist (SAR 1118) for the Treatment of Keratoconjunctivitis Sicca in Dogs. Invest Ophthalmol Vis Sci. May 16, 2011 ;52(…
[cited by applicant]
Salas, et al. Rolling adhesion through an extended conformation of integrin .alpha.LB2 and relation to .alpha. I and BI-like domain interaction. Immunity. 2004; 20(4): 393-406.
[cited by applicant]
Sapirstein et al. Volumes of Distribution and Clearances of Intravenously Injected Creatinine in the Dog. American Journal of Physiology. 1955; 181 :330-336.
[cited by applicant]
Sanfilippo et al., Novel thiazole based hereocycles as inhibitors of LFA/ICAM-1 mediated cell adhesion. J Med Chem. 1995; 38:1057-9.
[cited by applicant]
Shimaoka, et al. Small molecule integrin antagonists that bind to the B2 subunit llike domain and activate signals in one direction and block them in the other. Immunity. 2003; 19(3): 391-402.
[cited by applicant]
Shimoaka et al., Reversibly locking a protein fold in an active conformation with a disulfide bond: Integrin alpha L I domains with high affinity and antagonist activity in vivo. PNDAS. 2001; 98(11):6009-14.
[cited by applicant]
Shimaoka, et al. Structures of the .alpha.L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell. 2003; 112(1): 99-111.
[cited by applicant]
Shimaoka, et al. Therapeutic antagonists and the conformational regulation of the B2 integrins. Curr Topics Med Chem. 2004; 4: 1485-95.
[cited by applicant]
Shulman, et al. Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin. Immunity. Mar. 20, 2009;30(3):384-396.
[cited by applicant]
Solomans. Fundamentals of Organic Chemistry. 5th ed. 1982; 630.
[cited by applicant]
Springer, T. Adhesion receptors of the immune system. Nature. 1990; 346: 425-34.
[cited by applicant]
Stern, et al. Conjunctiva! T-cell subpopulations in Sjogren's and non-Sjogren's patients with dry eye. Invest Ophthalmol Vis Sci. Aug. 2002;43(8):2609-14.
[cited by applicant]
Streubel, et al. Gastroretentive drug delivery systems. Expert Opin Drug Deliv. 2006; 3(2): 217-33.
[cited by applicant]
The Eye Digest, Eye Exam for Dry Eyes, Mar. 2003, printed from http://www.agingeye.net/dryeyes/dryeeyeseyeexam.php and google date entry, 4 pages.
[cited by applicant]
Ward, S. Millipede-like lymphocyte crawling: feeling the way with filopodia. Immunity. Mar. 20, 2009;30(3):315-317.
[cited by applicant]
Welzenbach, et al. Small molecule inhibitors induce conformational changes in the I domain and the I-like domain of lymphocyte function-associated antigen-1. J Biological Chemistry. 2002; 277(12): 10590-8.
[cited by applicant]
Wermuth. The practice of medicinal chemistry-molecular variations based on isosteric replacements. Academic Press Limited. 1996; 226-228.
[cited by applicant]
Zhong, et al. Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye. ACS Med. Chem. Lett. DOI: 10.1021/ml2002482. Publication Date (Web): Jan. 31, 2012.
[cited by applicant]
Stern, et al. Evaluation of Ocular Surface Inflammation in the Presence of Dry Eye and Allergic Conjuctival Disease. Supplement. Oct. 2003;3(4):161-164.
[cited by applicant]
Boschelli, et al. 3-Alkoxybenzo[b]thiophene-2-carboxamides as inhibitors of neutrophil-endothelial cell adhesion. J Med Chem. 1994; 37(6): 717-8.
[cited by applicant]
Boschelli, et al. Inhibition of E-Selectin-, ICAM-1-, and VCAM-1-mediated cell adhesion by benzo[b]thiophene-, penzufuran-, indole-, and naphthalene-2-carboxamides: Identification of PD 144795 as an antiinflammatory age…
[cited by applicant]
Burdick, et al. N-Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: Structure-activity relationship of the benzoyl moiety. Bioorganic & Medicinal Chemistry Letters. 2004; 14(9): 2055-9.
[cited by applicant]
Burdick, et al. N-Benzoyl amino acids as LFA-1/ICAM inhibitors 1: amino acid structure-activity relationship. Bioorganic & Medicinal Chemistry Letters. 2004; 13(6): 1015-8.
[cited by applicant]
Chang, et al. Effects of pharmacologic agents on the reversed passive Arthus reaction in the rat. Eur J Pharmacol. 1981; 69(2): 155-64.
[cited by applicant]
Chavanpatil, et al. Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin. Int J Pharm. 2006; 316(1-2): 86-92.
[cited by applicant]
Coleman, et al. Chemoselective Cleavage of Benzyl Ethers, Esters, and Carbamates in the Presence of Other Easily Reducible Groups. Synthesis. 1999;1399-1400.
[cited by applicant]
Cosimi, et al. In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts. J Immunol. 1990; 144(12): 4604-12.
[cited by applicant]
Crocker, et al. The role of fluorine substitution in the structure-activity relationships (SAR) of classical cannabinoids. Bioorg med chem lett. 2007; 17(6):1504-1507.
[cited by applicant]
Davies et al. Physiological Parameters in Laboratory Animals and Humans. Pharmaceutical Research. 1993; 10: 1093-1095.
[cited by applicant]
Diamond, et al. The dynamic regulation of integrin adhesiveness. Current Biology. 1994; 4(6): 506-32.
[cited by applicant]
Earle et al. A Simplified Clinical Procedure for Measurement of Glomerular Filtration Rate and Renal Plasma Flow. Proc Soc Exp Biol Med. 1946;62:262-9.
[cited by applicant]
European office action dated Mar. 28, 2012 for Application No. 11181066.9.
[cited by applicant]
European Office Action dated Nov. 9, 2010 for Application No. 6770607.7.
[cited by applicant]
European office action dated Nov. 24, 2011 for Application No. 06770607.7.
[cited by applicant]
European search report dated May 20, 2009 for Application No. 06770607.7.
[cited by applicant]
Fischer, et al. Prevention of graft failure by an anti-HLFA-1 monoclonal antibody in HLA-mismatched bone-marrow transplantation. The Lancet. 1986; 2: 1058-60.
[cited by applicant]
Fox. Systemic diseases associated with dry eye. Int Ophthalmol Clin, 1994 Winter, 34(1):71-87.
[cited by applicant]
Frishberg et al. Cyclosporine A regulates T cell-epithelial cell adhesion by altering LFA-1 and ICAM-1 expression. Kidney Int Jul. 1996-;50(1):45-53.
[cited by applicant]
Gadek, et al. Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science. 2002; 295: 1086-9.
[cited by applicant]
Gao et al., ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjogrens syndrome-like MRL/Ipr mice. Exp Eye Res. Apr. 2004;78(4):823-35.
[cited by applicant]
Gennaro et al., Remington: The Science and Practice of Pharmacy, 1995, 19th Edition, Mack Publishing Company, pp. xiv-xvi, 1496-1503, 1562-1567, 1588-1589, 1598-1599, 1672-1677.
[cited by applicant]
Goodman et al., Amino acid active esters. III. Base-catalyzed racemization of peptide active ester. Journal of Organic Chemistry. 1962; 27:3409-3416.
[cited by applicant]
Gorski, A. The role of cell adhesion molecules in immunopathology. Immunology Today. 1994; 15: 251-5.
[cited by applicant]
Hecht, et al. Effects of methyl and fluorine substitution on the metabolic activation and tumorigenicity of polycyclic aromatic hydrocarbons. ACS Symposium series. 1985; 283(5):85-105. Abstract only.
[cited by applicant]
Hildreth, et al. Monoclonal antibodies against porcine LFA-1: Species cross-reactivity and functional effects of .beta.-subunit-specific antibodies. Molecular Immunology. 1989; 26(9): 883-95.
[cited by applicant]
Hoffman, et al. Pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms. Int J Pharm. 2004; 277(1-2): 141-53.
[cited by applicant]
Huang, et al. A binding interface of the I domain of lymphocyte function-associated antigen-1 (LFA-1) required for specific interaction with intercellular adhesion molecule 1 (ICAM-1 ). J Biological Chemistry. 1995; 270…
[cited by applicant]
International search report and written opinion dated Dec. 22, 2010 for PCT Application No. US10/53571.
[cited by applicant]
International search report and written opinion dated Sep. 24, 2009 for PCT Application No. US2009/02391.
[cited by applicant]
International search report dated Sep. 19, 2006 for PCT Application No. PCT/US2006/19327.
[cited by applicant]
International Search Report dated Mar. 30, 2005, issued in International Application No. PCT/US2004/036942.
[cited by applicant]