`(10) Patent N0.:
`US 8,835,382 B2
`
`O’Connor et al.
`(45) Date of Patent:
`Sep. 16, 2014
`
`USOO8835382B2
`
`
`
`5,955,509 A
`6,194,383 B
`6,468,967 B
`6,696,412 B
`6,716,962 B2
`6,852,689 B2
`RE39,071 E
`7,138,487 B2
`
`7,279,597 E
`8,058,238 B2
`8,129,342 B2
`8,309,061 B2
`3,431,539 B2
`2002/0111311 A
`2002/0132762 A
`2003/0045484 A
`2003/0045678 A
`2004/0067878 A
`2004/0077601 A
`2004/0242467 A
`2005/0009747 A
`
`9/1999 Webber et a1.
`2/2001 Hammann et al.
`10/2002 Oleson et al.
`2/2004 Kelleher et a1.
`4/2004 Borders et al.
`2/2005 Oleson etal.
`4/2006 Baker ct a1.
`11/2006 Borders et al.
`
`100007 Leone'Bay 6t “L
`11/2011 Kelleheret a1.
`3/2012 Kelleher
`11/2012 Chau
`4/2013 Palepirzt 31.
`8/2002 Govardhan et a1.
`9/2002 Borders
`3/2003 Keith
`3/2003 Keith
`4/2004 Hill
`4/2004 Adams
`12/2004 Borders
`1/2005 Kelleher
`
`2005/0027113 A
`2005/0196418 A
`2006/0014674 A
`2006/0018933 A
`2006/0018934 A
`2006/0024365 A
`2006/0264513 A
`2006/0269485 A
`2007/0116729 A
`
`2/2005 Miao et a1.
`9/2005 Yu
`1/2006 Keith
`[/2006 Vaya
`1/2006 Vaya
`2/2006 Vaya
`11/2006 Leone-Bay et a1.
`11/2006 Friedman
`5/2007 Palepu
`(Continued)
`
`
`
`FOREIGN PATJN 1 DOCUMJNTS
`1592753 A
`3/2005
`1616083 A *
`/2005
`
`(54) LIPOPEPTIDE COIVIPOSITIONS AND
`RELATED lVlETHODS
`
`(75)
`
`Inventors: S‘andra 9’Connor, Hudson, NPI (US);
`50Phle bun, Lexmgton, MA (US);
`Gaauri Naik, Cambridge, MA (US)
`
`(73) Assignee: Cubist Pharmaceuticals, Inc.,
`L .
`I MA US
`cxmg on,
`1
`(
`)
`Subject to any disclaimer, the term ofthjs
`patent is extended or adjusted under 35
`U.S.C. 154(1)) by 0 days.
`
`( * ) Notice:
`
`(21) APP1~ N04
`_
`(22) PCT Filed:
`
`13/511346
`
`V0". 23, 2010
`
`(86) PCT N0.:
`§371 (c)(1),
`(2), (4) Date:
`i
`
`PC'l'lU82010/057910
`
`Ju]_10, 2012
`
`.
`(87) PCT PUb' N0" “102°11’06“”
`PCT Pub. Date: May 26 2011
`A
`’
`Prior Publication Data
`
`(65)
`
`US 2012/0270772 A1
`
`Oct. 25, 2012
`.
`.
`Relate‘i U'S' APPhcatmn Data
`
`CN
`CN
`
`A61K 38/12
`
`(60) Provisional application No. 61/263,784, filed on Nov.
`23, 2009.
`
`(Continued)
`OTI IER PUBLICATIONS
`
`(51)
`
`(2006.01)
`(2006 01)
`(200601)
`'
`$38238
`'
`
`Int. Cl.
`A 61K 38/12
`A61K 58/10
`A61P 31/04
`it???gig/32
`(52) U'S' Cl'
`CPC ................. A61K38/12 (2013.01); A61K38/I0
`(2013-01); A61K 9/00 (2013-00; C07K I [/02
`(2013-01)
`514/24; 514/29; 514/31; 514/21.1;
`514/215
`
`USPC
`
`(58) Field of Classification Search
`CPC """""" A61K 38/10; A61K 38/12; A61K 9/00;
`CO7K 1 1/02
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,331,594 A
`4,439,425 A
`4,482,487 A
`4,537,717 A
`4,874,843 A
`.2/,o
`:«i‘géfii 2
`5,336,756 A
`5,387,670 A
`5,629,288 A
`5,912,226 A
`
`5/1982 Hamill et a1.
`3/1984 Tarcsay et a1.
`11/1984 Abbott et a1.
`8/1985 Abbott et al.
`10/1989 Baker et al.
`/
`rancoc a.
`3‘3: germ 6‘ 1:11
`8/1994 Schwartz et al.
`2/1995 Roy et al.
`5/1997 Lattrellet a1.
`6/1999 Baker et al.
`
`/
`_
`.
`_
`pH—water quallty, from http://extens1on.usu.edu/W:1terqua11ty/htm/
`Whats-in-your-Water/ph, pp. 1-2, accessed Jul. 23, 2013*
`Smales et al, Therapeutic proteins, methods and protocols, Humana
`press, 2005, pp. 287-292.*
`Wang, Lyophilization and development of solid protein pharmaceu—
`ticals, International Journal of Pharmaceutics, 2000, 203, pp. 1-60.*
`Machien translation ofCN 1616083 A, pp. 1—9, publication date May
`18, 2005*
`Miao eta1., “Daptomycin biosynthesis in Streptomyces roseosporus:
`cloning and analysis of the gene cluster and revision of peptide
`stereochemistry,” Microbiology 2005, vol. 151 (5), 1507—23.
`Debono, et al., “A21978C, A Complex of New Acidic Peptide Anti-
`biotics: Isolation, Chemistry, and Mass Spectral Strucmrc Elucida-
`tion,” The Journal ofAntibiotics 1987, vol. XL (6), p. 761-77.
`(Continued)
`
`Primary Examiner 7 Julie Ha
`Assistant Examiner 7 Li Ni Komatsu
`
`(74) Attorney, Agem, orFirm Lathrop & Gage LLP; Brian
`C. Trinque; Gang Wang
`
`(57)
`
`ABSTRACT
`,
`,
`,
`The present d1sc10sure prov1dcs novel powder daptomycm
`formulations which have improved chemical stability and
`-
`--
`-
`-
`faster reconstitution times when in the solid state. Some
`examples oi the comp051t1ons comprlse daptomycm and
`sucrose.
`
`18 Claims, 22 Drawing Sheets
`
`AMNEAL EX. 1009
`
`AMNEAL EX. 1009
`
`
`
`US 8,835,382 B2
`
`Page 2
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`2007/0128694 A1
`2007/0191280 A1
`2008/0220441 A1
`2009/0197799 A1
`2010/0041589 A2
`2011/0124551 A1
`2011/0172167 A1
`2011/0207658 A1
`2012/0149062 A1
`2012/0270772 A1
`
`6/2007 Baltz et a1.
`8/2007 Kelleher
`9/2008 Birnbaum
`8/2009 Keith
`2/2010 Keith et al.
`5/201 1 Palepu et al.
`7/2011 Palepu et a1.
`8/201 1 Kelleher
`6/2012 Kelleher et a1.
`10/2012 O’Connor
`
`FOREIGN PATENT DOCUMENTS
`
`CN
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`JP
`JP
`JP
`JP
`“’0
`VVO
`WO
`W0
`“’0
`“’0
`“’0
`\VO
`“’0
`VVO
`WO
`WO
`“’0
`“’0
`“’0
`“’0
`“’0
`“’0
`WO
`WO
`W0
`“’0
`“’0
`“’0
`“’0
`“’0
`VVO
`WO
`W0
`“’0
`“’0
`“’0
`
`101330905 A
`0178152
`0294990
`0386951 A2
`0511866
`0521408
`0629636
`1252179
`64047388
`04224197
`05239090
`05271284
`WO9321207
`WO9927954
`WO 9927957
`W0 9940113
`WO9943700
`WO 0018419
`W001/44274 A1
`“/0 01/53330
`W001/53330 A2
`W00153330
`WOW/055537 AI
`WOW/056829 A2
`VVOOZ/059145 A1
`VV002059145
`VVOOZ/096936 A2
`W002096936
`VVOZOO4/004658 A2
`VVO2006/084174 A2
`WOZOO6/084174 A3
`“702007061529 AI
`W02007/099396 A2
`VVOZOO7/099396 A3
`VVOZOOS/127291 A2
`VVOZOOS/127291 A3
`W'02009144739 A1
`VVO2011/019839 A2
`VVOZOlI/035108 AI
`WOZOII/062676 AI
`W02011/063419 A2
`VV()2012/061360 A2
`VVOZOlZ/088441 A1
`VVOZOlZ/112319 A1
`
`12/2008
`4/1986
`12/1988
`3/1989
`11/1992
`1/1993
`12/1994
`10/2002
`2/1989
`8/1992
`9/1993
`10/1993
`10/1993
`6/1999
`6/1999
`8/1999
`9/ 1 999
`4/2000
`6/2001
`7/2001
`7/2001
`7/2001
`7/2002
`7/2002
`8/2002
`8/2002
`12/2002
`12/2002
`1/2004
`8/2006
`8/2006
`5/2007
`9/2007
`9/2007
`10/2008
`10/2008
`12/2009
`2/2011
`3/2011
`5/2011
`5/2011
`5/2012
`6/2012
`8/2012
`
`
`OTHER PUBLICATIONS
`Lodish et al., Molecular Cell Biology (ed. By J. Darnell, II. I odish,
`and D. Baltimore, Scientific American Books, Inc , NeWYork: 1986),
`Chapter 3, p. 53.
`Woodworth et al., “Single-Dose Pharmacokinetics and Antibacterial
`Activity of Daptomycin, a New Lipopeptide Antibiotic, in Healthy
`Volunteers.” Antimicrobial Agent and Chemotherapy 1992. vol. 36.
`[1. 318-25.
`McKindley et al., “Drug Use in the Critically III Patient With Renal
`Dysfunction-Application ofthe DREM System,” Infectious Diseases
`in Critical Care Medicine Biotechnology of Antibiotics (ed. B.A.
`Cunha. NewYork: Marcel Dekker. Inc.. 1998) Chapter 41. pp. 781-
`801 .
`Tally et al., Daptomycin: anovel agent for Gram-p0 sitive infections;
`Expert Opinion. On Investigational Drugs; 1999, vol. 8, pp. 1223-
`123 8.
`
`Janson et al., Protein Purification: Principles, High Resolution Meth-
`ods. and Applications; Ch. 1: Introduction to Protein Purification;
`John Wiley & Sons, Inc., 1998; pp. 3-48, p. 80, and pp. 125-126.
`Lin et
`al.,
`“Recovery and Purification of
`the Lipopeptide
`Biosurfactant of Bacillus subtilis by Ultrafiltration,” Biotechnology
`Techniques, 1997. vol. 11, p. 413-16.
`Shaw. D.J.. “Liquid-Gas and Liquid—Liquid Interfaces,” Introduction
`to Colloid and Surface Chemistiy, Butteiworth-Heinemaim Ltd.,
`1989, pp. 49-90.
`Kirsch, et al., “Kinetics of the Aspaityl Transpeptidation of
`Daptomycin, a Novel Lipopeptide Antibiotic,” Pharmaceutical
`Research: 1989. vol. 6. p. 387-93.
`Remington: The Science and Practice of Pharmacy, (:19th edition,
`Mack Publishing Company, 1985), pp. 539-551, 1529-1530, 1549-
`1550, and 1558.
`Sexton D. et al., “The Use ofDaptomycin, a Lipopeptide Antibiotic,
`in the Treatment of Gram Positive Infections in Man,” Interscience
`Conference on Antimicrobial Agents and Chemotherapy 1988,
`Abstract No. 932.
`Selwyn, et al.; Infections (Excluding AIDS) of Inj ection Drug L sers;
`Harrison’s Principles ofInternal Medicine; Fauci, et al. eds., 14th ed.,
`McGraw—Hill. 1998. pp. 831—832. and 847.
`Lee et al., Program and Abstracts of the ICAAC 1991, Abstract No.
`865.
`Rotschafer et al., “Therapeutic Update on Clycopeptide and
`Lipopeptide Antibiotics,” Pharmacotherapy 1988, vol. 8, 211-19.
`Mutschler et al., Drug Actions: Basic Principles and Therapeutic
`Aspects; Ch. 2: Pharmacokinetics; Medpharm Scientific Publishers,
`Stuttgart, Germany (1995); p. 5, 47 pages.
`Freeman et al., Once-daily Dosing ofAminoglycosides: Review and
`Recommendations for Clinical Practice; J. Antimicr. Chemother.
`1997, vol. 39, p. 677-86.
`Ebeit et al., Pharmacodynamics Propelties of Antibiotics: Applica-
`tion to Drug Monitoring and Dosage Regimen Design; Infection
`Control and Hospital Epidemiology; 1990, 11(6), pp. 319-326.
`Barclay et al., What is the Evidence for Once-Daily Aminoglycoside
`Therapy; Clin. Pharmacokinetics. 1994, 27(i), pp. 32-48.
`Baltz,
`“Lipopeptide Antibiotics Produced
`by Streptomyces
`roseosporus and Streptomycesfifiadiae," Biotechnology of Antibiot—
`ics 1997, 2d ed.; pp. 415-435.
`of
`dosing
`multiple-daily
`Craig,
`“Once-daily
`versus
`aminoglycosides,” J Chemother; 1995, vol. 7 (Suppl 2), pp. 47-52.
`Sclmellmann et al.; Cassarett and Douls Toxicology: The Basic Sci-
`ence of Poisons; Chapter 14: Toxic Responses of the Kidney; (5th
`ed.) (1996), pp. 491-514.
`Benoit et al. “Destruction and regeneration of skeleml muscle after
`treatment with a local anesthetic, bupivacaine (Marcaine®)," J Anat.
`1970, vol, 107, pp. 547-556.
`Cubist Pharmaceuticals. Press Release, Feb. 5, 2008. Lexington, MA.
`US. Appl. No. 07/060,148, filed Jun. 10, 1987;P'i1e History; Aban-
`doned.
`In Vitro Activities of Daptomycin, Arbekacin,
`Akins et al.,
`Vancomycin, and Gentamicin Alone and/or in Combination against
`Glycopeptide Intermediate—Resistant Staphylococcus aureus in an
`Infection Model; Antimicrobial Agents and Chemotherapy; 2000,
`vol. 44, pp. 1925-1929.
`Akins et al.; Bactericidal Activities of Two Daptomycin Regimens
`against Clinical Strains Glycopeptide
`Intermediate-Resistant
`Staphylococcus aureus, Vancomycin—Resistant Enterococcus facr
`cium, and Methicillin-Resistant Staphylococcus aureus Isolates in an
`In Vitro Pharmacodynamic Model with Simulated Endocardial Veg-
`etations; Antimicrobial Agents and Chemotherapy; 2001 , v01. 4 5, pp.
`454-459.
`Arbeit et al., The Safety and Efficacy of Daptomycin for the Treat—
`ment of Complicated Skin and Skin-Structure Infections; Clinical
`Infectious Diseases; 2004, vol. 38, pp. 1673-1681.
`Auwera et al., Ex-vivo study of serum bactericidal titers and kiilling
`rates of daptomycin (LY146032) combined or not combined with
`amikacin compared with those ofvancomycin; Antimicrobial Agents
`and Chemotherapy; 1989, vol. 33, pp. 1783-1790.
`Barry et al., In vitro activities of daptomycin against 2,789 clinical
`isolates from 11 North American Medical Centers; Antimicrobial
`Agents and Chemotherapy; 2001, vol. 45, pp 1919-1922.
`
`AMNEAL EX. 1009
`
`AMNEAL EX. 1009
`
`
`
`US 8,835,382 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Benvenuto et al., Pharmacokinetics and Tolerability of Daptomycin
`at Doses up to 12 Milligrams per Kilogram of Body Weight Once
`Daily in Healthy Volunteers; Antimicrobial Agents and Chemo-
`therapy; 2006, vol. 50, pp. 3245 -3249
`Dvorchik et al., Daptomycin Pharmacokinetics and Safety following
`Administration of Escalating Doses Once Daily to Healthy Subjects;
`Antimicrobial Agents and Chemotherapy; 2003, vol. 47, pp. 1318-
`1323.
`Bingen et al., Bactericidal activity of Fancomycin, Daptomycin,
`Ampicillin and Aminoglycosides against Vancomycin-resistant
`Enterecoccus; J of Antimicrobial Chemotherapy; 1990, vol. 26, pp.
`619-626.
`Bryant et al., Effect of Abscess Milieu on Bactericidal Activity of
`IXl46032 against Staphylococci; Eur J. Clin. Microbiol; 1987, vol.
`6, pp. 186-188.
`CaballeroiGranado et al .; Case-control Study ofR isk Factors for the
`Development of Enterococcal bacteremia; Eur. J. Clin. Microbiol.
`Infect. Dis. 2001, vol. 20, p. 83-90.
`Caron et al.; Daptomycin or teicoplanin in combination with
`gentamicin for treatment ofexperiemental endocarditis due to highly
`glycopeptide-resistant isolate of Enterococcuvfaecium; Anti micro-
`bial Agents and Chemotherapy; 1992, vol. 36, pp. 2611-2616.
`Carter et al., Protein Crystallization Using Incomplete Factorial
`Experiments; J. Biol. Chem., 1979, vol. 254, pp 12219-12223.
`Chaftari et al.; Efficacy and safety of daptomycin in the treatment of
`Gram-positive catheter-related bloodstream infections in cancer
`patients; International Journal of Antimicrobial Agents; 2010, vol.
`36, pp. 182-186.
`Chayen et al.; Recent advances in methodology for the crystallization
`of biological macromolecules; Journal of Crystal Growth; 1999, pp.
`649-655.
`Crompton et a1., Outocmes with daptomycin in the treatment of
`Staphylococcus aureus infections with a range ofvancomycin Mics;
`Jotu‘nal of Antimicrobial Chemotherapy; 2010, vol. 65, pp 1784-
`1791.
`Cubicin label, \Iov. 2011; 34 pages.
`Cui et a1., Correlation between Reduced Daptomycin Susceptibility
`and Vancomycin
`Resistance
`in Vancomycin-Intermediate
`Staphylococcus aureas; Antimicrobial Agents and Chemotherapy;
`2006. vol. 50. pp. 1079-1082.
`Cunha et al ., Daptomycin resistance and treatment failure following
`vancomycin
`for methicillin-resistant Staphylococcus
`aureus
`(MRSA) mitral valve acute bacterial endocarditis (ABE); Eur. J. Clin.
`Microbiol. Infect. Dis.; 2009, vol. 28, pp. 831-833
`Davis et a1., Daptomycin versus Vancomycin for Complicated Skin
`and Skin Structure Infections: Clinical and Economic Outcomes,
`Pharmacotherapy, 2007, vol. 27, pp. 1611-1618.
`Debbia et al., In Vitro Activity of LY146032 Alone and in Combina-
`tion with Other Antibiotics against Gram-Po sitive Bacteria, Antimi-
`crobial Agents and Chemotherapy. 1988. vol. 32. pp. 279—281.
`El-Vlady et al., The Bactericidal Activity ofAmpicillin, Daptomycin,
`and Vancomycin Against Ampicillin-Resistant Enteroccusflzecium,
`Diagn. Micro. Inf. Dis., 1991, vol. 14, pp. 141-145.
`Evdokimov et al., Overproduction, purification, crysmllization and
`preliminary X-ray diffraction analysis of YopM. an essential viru-
`lence factor extruded by the plague bacterium Yeltsinia pestis, Acta
`Crystallographica, 2000, vol. 56, pp. 1676-1679.
`DuCruix, et al., Crystallization of Nucleic acids and Proteins, A
`Practical Approach, 2d ed., 1999, pp. 92-95, 4 pages.
`Forward et a1., Comparative activity of daptomycin and teicoplanin
`against enterococci isolated from blood and urine, Can. J. Infect. Di s.,
`1992, vol. 3, pp. 173-178.
`Fowler et al., Daptomycin versus Stande Therapy for Bacteremia
`and Endocarditis Caused by Staphylococcus aureus, The New
`England Journal of Medicine. 2006, vol. 355. pp. 653-665.
`Cubicin label.
`Amorij: Development of Stable Influenza Vaccine Powder Formula-
`tions: challenges and possibilities, Pharmaceutical Research, 2008,
`25:1256-1273.
`
`Hawofih et al.; Staphylococcus aureus ventriculitis treated with
`single-do se
`intraventricular
`vancomycin
`or
`daptomycin
`(lYl46032): bacterial and antibiotic kinetics in hydrocephalic rab-
`bits; Antimicrobial Agents and Chemotherapy 1990, vol. 34, pp.
`245-251.
`Jancarik et al., Sparse matrix sampling: a screening method for crys-
`tallization ofproteins. J Appl. Cryst. 1991. vol. 24. pp. 409-411.
`Johnson et al., ICAA 1987, poster 161, 1 page.
`Katz et al., A pilot study ofhigh-dose short duration daptomycin for
`the treatment of patients with complicated skin and skin structure
`infections caused by gIaJn-positive bacteria, International Journal of
`Clinical Practice. 2008. pp. 1-10.
`LeClercq et
`al , Effects of Combinations of Beta-Lactams,
`Daptomycin, Gentamicin and Glycopeptides against Glycopeptide-
`Resistant Enterococci; Antimicrobial Agents and Chemotherapy,
`1991, vol. 35, pp. 92-98.
`Louie et a1., Comparison of in vitro inhibitory and Bactericial Activi—
`ties of Daptomycin (LY 146032) and Four Reference Antibiotics,
`Singly and in Combination, against Genmmicin-Susceptible and
`High-Level-(jentamicin-Resistant Enterococci; Chemotherapy;
`1993, vol. 39, pp. 302-310.
`Luu et al.. Treatment of Chronic Experimental Staphylococcus
`aureus Osteomyelitis with LY 146032 and Vancomycin; Eur. J Clin.
`Microbiol. Infect. Dis. 1989, vol. 8. pp. 562-563.
`Mader et al., Comparative Evalulation of Daptomycin (LY146032)
`and comycin in the Treatment of Experimental Methicillin-Resistant
`Staphylococcus aureus Osteomyelitis in Rabbits; Comparative
`Evaluation of DaptomycinAntimicrobia1 Agents and Chemotherapy,
`1989, vol. 33, pp. 689-692.
`Mariani
`et
`al., Development of decreased susceptibility to
`daptomycin and vancomycin in a Staphylococcus aureus strain dur-
`ing prolonged therapy; Journal of Antimicrobial Chemotherapy
`2013, p. 481-83.
`Mathews et al., IDSA poster. 2001.
`Mchenney et al., Molecular Cloning and Physical Mapping of the
`Daptomycin Gene Cluster from Streptomyces roseosporus; Journal
`ofBacteriology, 1998. vol. 180, pp. 143-151.
`Mobarakai et al., Bactericidal Activities of Peptide Antibiotics
`against Multidrug-Resistant Enterococcus faecium; Antimicrobial
`Agents and Chemotherapy; 1994, vol. 38, pp. 385-387.
`Moise et al., Susceptibility relationship between vancomycin and
`daptomycin in Staphylococcus aureus: facts and assumptions; Lancet
`Infect. Dis. 2009, vol. 9, pp. 617-624.
`Patel et al., An Association bettween Reduced Susceptibility to
`Daptomycin and Reduced Susceptibility to Vancomycin in
`Staphylococcus aureus; Clinical Infectious Diseases: C orrespon-
`dence to the Editor; Jun. 1, 2006. vol. 42, pp. 1652-1653.
`Sader et al., Nine-Hospital Study Comparing Broth Microdilution
`and Etest method Results for Vaqncomycin and Daptomycin against
`Methicillin-Resistant Staphylococcus aureus; Antimicrobial Agents
`and Chemotherapy, 2009. vol. 53, pp. 3162-3165.
`Sader et al., Update on the In Vitro Activity of Daptomycin Tested
`against 17,193 Grain-positive Bacteria Isolated from European
`Medical Centers (2005-2007); Journal of Chemotherapy 2009, vol.
`21, pp. 500-506.
`Sakoulas et al., Clinical Outcomes ofPatients Receiving Daptomycin
`for the Treatment of Staphylococcus aureus Infections and Assess—
`ment of Clinical Factors for Daptomycin Failure: A Retrospective
`Cohort Study Tuilizing the Cubicin Outcomes Registry and Experi—
`ence; Clinical Therapeutics, 2009, vol. 31, pp. 1936-1945.
`Sapico et al., 146032, Alone nad in Combination with Genmnicin,
`for the Treatment of Enterococcalpyelonephritis in the Rat Model;
`Antimicrobial Agents and Chemotherapy 1988, vol. 32, pp. 81-83.
`Silva et al., In Vitro Activity of LY146032 Against Gram-Positive
`Bacteria; Diagn. Microbiol. Infect. Dis., 1988. vol. 9, pp. 79-85.
`Silverman et a1., Inhibition of Daptomycin by Pulmonary Surfactant:
`In Vitro Modeling and Clinical Impact; The Journal of Infectious
`Disease; 2005, vol. 191, pp. 2149-2152.
`Silverman et a1., Resistance Studies with Daptomycin; Antimicrobial
`Agents and Chemotherapy; 2001, vol. 45, pp. 1799-1802.
`Snydman et al., Comparative In Virro Activities of Daptomycin and
`Vancomycin against Resistant Gram-Positive Pathogens; Antimicro—
`bial Agents and Chemotherapy; 2000, vol 44, pp. 3447-3450.
`
`AMNEAL EX. 1009
`
`AMNEAL EX. 1009
`
`
`
`US 8,835,382 B2
`Page 4
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`
`
`Steenbergen et a1., Daptomycin: a lipopeptide antibiotic for the treat-
`ment of serious Gram-positive infections; Journal of Antimicrobial
`Chemotherapy, 2005, VD . 55, pp. 283-288.
`Stratton et al, Bactericidal Activity of Deptomycin (LY146032)
`Compared with Those ofCiprofioxacin,Vancomycin. and Ampicillin
`against Enterococci as Determined by Kill-Kinetic Studies; Antimi-
`crobial Agents and Chemotherapy 1987, vol. 31, pp. 1014-1016.
`US. Appl. No. 10/024,405 (Abandoned).
`Tenover et a1., Characterisation of a Staphylococcus aureus strain
`with progressive
`loss of
`susceptibility to vancomycin and
`daptomycin during therapy; International Journal of Antimicrobial
`Agents; 2009, p. 564-68.
`Thibault et a1., Attenuation 1W Daptomycin of Gentamicin-Induced
`Experimental Nephrotoxicity; Antimicrobial Agents and Chemo-
`therapy; 1994, vol. 38, pp. 1027-1035.
`Woodworth et a1.. Tobramycin and daptomycin disposition when
`co-adnini stered to healthy volunteers; Journal ofAntimicrobial Che-
`motherapy, 1994, vol. 33 pp. 655-659.
`US. Appl. No. 61/243.402. filed Sep. 17. 2009 (Priority Document
`forWO2011035108).
`U.S. Appl. No. 61/263,695, filed Nov. 23. 2009 (Priority Document
`for W02011035108 and W02011062676).
`US. Appl No 61/371,802, filedAug. 9, 2010 (Priority Document for
`WO2011062676).
`l: 12cv367 (D.
`Cubist Pharmaceutical, Inc. v. Hospira, Inc, No.
`Mass. Filed Mar. 21. 2012) ('Def. Hospira, Inc. Preliminary Invalidity
`Contentions).
`International Search Report andVVritten Opinion dated Aug. 22, 201 1
`in international application No. PCT/US2010/057910, 15 pgs.
`
`Notification of Transmittal of International Preliminaiy Repofi on
`Patentability in International Application No. PCT/U520 1 0/0 57910.
`mailed May 24. 2012, 7 pages.
`Sun et a1. , “Development of an Improved Daptomycin Drug Product:
`Immediate Reconstitution, Room Temperature Product Stability and
`Reconstitution Smbility", AAPS 201 1, Abstract for Poster No. T3328
`Published
`Abstract:
`http: //abstracts. aaps.org/SecureVi ew/
`AAPSJournal/vmqutdm9e4880v6bh0dypdf.
`Horowitz et al.. Isolation and Characterization of a Surfactant Pro—
`duced by Bacillus lichen/formis 86; Journal of Industrial Microbiol-
`ogy 1990, vol. 6, pp. 243-248.
`Fostel, et a1., “Emerging Novel AntifungalAgents.” DDT; v01. 5; No.
`1; Jan. 2000; pp. 25-32.
`Caballero Granado et al.; Case-control Study of Risk Factors for the
`Development of Enlerococcal bacteremia; Eur. J. Clin. Microbiol.
`Infect. Dis. 2001. vol. 20. p. 83-90.
`Desaj et a1., Microbial Production of Surfacmnts and Their Commer-
`cial Potential; Microbiology and Molecular Biology Reviews l997,
`vol. 61, pp. 47-64.
`Debmin. Michael F , Efficacy and safety of daptomycin for the treat-
`ment of bacteremia and serious infections due to gram-positive bac—
`teria; 4th Decennial International Conference on Nosocomial and
`Healthcare-Associated Infections; Poster #594 P-S2-37 (Mar. 5-9,
`2000), 14 pages.
`Supplementary European Search Report PCT/ISSZO 100 57910 Dated
`Feb. 28, 2014. 8 Pages.
`Debono: Enzymatic and Chemical Modifications of Lipopeptide
`Antibiotic A21978C: The Synthesis and Evaluation of Daptomycin,
`The Journal ofAntibiotics, 1988. 41(8):1093-1105.
`
`* cited by examiner
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`AMNEAL EX. 1009
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`US. Patent
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`Sep. 16, 2014
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`Sheet 1 of 22
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`US 8,835,382 B2
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`Daptomycin
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`US. Patent
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`Sep. 16, 2014
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`Sheet 2 of 22
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`US 8,835,382 B2
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`Sep. 16, 2014
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`Sheet 3 of 22
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`US 8,835,382 B2
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`Sep. 16, 2014
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`Sheet 4 of 22
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`US 8,835,382 B2
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`US. Patent
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`Sep. 16, 2014
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`US 8,835,382 B2
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`Sheet 10 0f 22
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