Allergan et. al. v. Medicis Aesthetics et. al

7/29/2019 Allergan et. al. v. Medicis Aesthetics et. al.

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F/Lt:O

1 Juanita R. Brooks (CA Bar No . 75934) ( b r o o k s @ f r . c ~ SEP 13 PM 3' 49FISH & RICHARDSON P.C. .2 12390.El Camino Real c a m ~ l J . ~ r .TRICT C" URSan Diego, CA 92130 11/ c. L "T . OF CiI' IF T3 Telephone: (858) 678-5070 / Fax: (858) 678-5099 o'\I 'T AM/, \ - .DY_4 Craig E. CountryIrlan (CA Bar No. 244601) ([email protected])FISH & RICHARDSON P.c.5 555 W. 5th Street, 31st FloorLos Angeles, California 900136 Telephone: (213) 533-4240 / Fax: (213) 996-8304

7 Jonathan E. Singer (CA Bar No. 187908) ([email protected])Michael 1. Kane(oro hac vice application forthcoming) ([email protected])8 FISH & RICHARDSON P.C.60 South Sixth Street, Suite 32009 Minneapolis, MN 55402Telephone: (612) 335-5070 / Fax: (612) 288-96961011 Elizabeth M. Flanagan (oro hac vice application forthcoming)Minnesota Bar No. 38919312 efianaganCalfr.comFISH & RYCHARDSON P.c.13 222 Delaware Avenue, 17th FloorWilmington, DE 1989914 Telephone: (302) 652-5070 / Fax: (302) 652-060715 Attorneys for Plaintiffs16 ALLERGAN USA, INC. and

ALLERGAN INDUSTRIE, SAS171819

UNITED STATES DISTRICT COURTCENTRAL DISTRICT OF CALIFORNIA

20 ALLERGAN USA, INg ,/,-,andALLERGAN INDUSTKJ.n, SAS,212223

Plaintiffs,Case No. SACV13-01436 AG (JPRx)COMPLAINT FOR PATENTINFRINGEMENT

v.MEDICIS A E S T H E T I C ~ C . ,24 MEDICIS PHARMACEu iiCAL CORP.,VALEANT PHARMACEUTICALS25 NORTH AMERICA LLCVALEANT PHARMACEtrrICALS26 INTERNATIONAL, andVALEANT PHARMACEUTICALS27 INTERNATIONAL, INC.

28

JURY TRIAL DEMANDED

COMPLAINTCase No.


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1 Plaintiffs Allergan USA, Inc. and Allergan Industrie, SAS (collectively,2 "Allergan" or "Plaintiffs") by their attorneys, Fish & Richardson P.C., for their3 complaint against Defendants Medicis Aesthetics, Inc., Medicis Pharmaceutical4 Corp. ("collectively Medicis"), and Valeant Pharmaceuticals North America LLC,5 Vale ant Pharmaceuticals International, and Vale ant Pharmaceuticals International,6 Inc. ("collectively Valeant") (Medicis and Valeant collectively, "Defendants"),7 alleges as follows:8 NATURE OF THE ACTION9 1. This is an action for infringement ofUnited States Patent

10 No. 8,450,475, which arises under the Patent Laws of the United States, including11 35 U.S.C. 271.12 PARTIES13 2. Allergan USA, Inc. is a corporation organized and existing under the14 laws of the State ofDelaware, with a principal place of business at 2525 Dupont15 Drive, Irvine, California 92612.16 3. Allergan Industrie, SAS is company incorporated in France, with a17 principal place of business at 254 ZA Pre Mairy, 74370 Pringy, France.18 4. On information and belief, Defendant Medicis Aesthetics, Inc. is a19 corporation organized and existing under the laws of the State ofDelaware with its20 principal place of business at 7720 N. Dobson Rd., Scottsdale, AZ 85456.21 5. On information and belief, Defendant Medicis Pharmaceutical Corp. is22 a corporation organized and existing under the laws of the State ofDelaware with its23 principal place of business at 7720 N. Dobson Rd., Scottsdale, AZ 85456.24 6. On information and belief, Valeant Pharmaceuticals North America25 LLC is a corporation organized and existing under the laws of the State ofDelaware26 with its principal place of business at 700 Route 202/206, Bridgewater, NJ 08807.2728 2 COMPLAINT

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1 7. On information and belief, Valeant Pharmaceuticals International is a2 corporation organized and existing under the laws of the State ofDelaware with its3 principal place ofbusiness at 7545 Irvine Center Dr. #100, Irvine, CA 92618.4 8. On information and belief, Valeant Pharmaceuticals International, Inc.,5 is a corporation organized and existing under the laws ofCanada with is principal6 place of business at 2150 St. Elzear Blvd. West, Laval, Quebec H7L4A8, Canada.7 9. On information and belief, Medicis Aesthetics, Inc. is a subsidiary of8 Medicis Pharmaceutical Corp., which is a wholly-owned subsidiary ofVale ant9 Pharmaceuticals International, Inc.

10 10. On information and belief, Vale ant Pharmaceuticals North America11 LLC is a subsidiary ofVale ant Pharmaceuticals International, which is a subsidiary12 ofVale ant Pharmaceuticals International, Inc.13 JURISDICTIONAND VENUE14 11. This Court has subject matter jurisdiction over the action under 2815 U.S.C. 1331 and 1338(a) because the action concerns a federal question arising16 under patent laws ofthe United States, including 35 U.S.C. 271.17 12. VenueisproperinthisCourtunder28U.S.C. 1391(b) and 1400(b),18 because, among other reasons, Defendants are both subject to personal jurisdiction19 in this judicial district and have committed acts of patent infringement in this20 judicial district.21 13. On information and belief, Defendants have placed infringing products22 into the stream of commerce by shipping those products into this judicial district23 and/or by knowing that such products would be shipped into this judicial district.24 14. On information and belief, Defendants have sold and/or offered to sell25 products that infringe the '475 patent in this district.262728 3 COMPLAINT

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1 The Patent-in-Suit2 15. The '475 patent, entitled "Hyaluronic Acid-Based Gels Including3 Lidocaine," issued to Pierre F. Lebreton on May 28, 2013. A copy ofthe '4754 patent is attached to this complaint as Exhibit A.5 16. Allergan Industrie, SAS, as assignee, owns the entire right, title, and6 interest in the '475 patent.7 17. Allergan USA, Inc. is the exclusive licensee of the '475 patent.8 Background9 18. Allergan is a leading developer, manufacturer, and distributor of dermal

10 filler products in the United States, including JUVEDERM Ultra XC and11 JUVEDERM Ultra Plus XC (together, "Allergan's JUVEDERM products").12 19. Dermal fillers are products that are injected into facial tissue to smooth13 wrinkles and folds, especially around the nose and mouth. The United States dermal14 filler market is currently valued at over $400 million annually.15 20. Allergan's JUVEDERM products are injectable hyaluronic acid gels16 that contain a small quantity oflocal anesthetic, lidocaine. Allergan's17 JUVEDERM products temporarily add volume to facial tissue and restore a18 smoother appearance to the face. The lidocaine included in the gel improves the19 comfort of he injection. The effects ofAllergan's JUVEDERM products last2021

, about 9 months to 1 year. Allergan's JUVEDERM products are the onlyhyaluronic acid dermal fillers approved by the Food and Drug Administration to last

22 up to one year from initial treatment.23 21. Allergan marks its JUVEDERM products with the '475 patent using24 its website at: http://www.allergan.com/products/patent_notices.htm.25 22. On information and belief, Defendants, on their own and/or through26 their subsidiaries, sell, offer to sell, and/or import into the United States Restylane-27 L, a dermal filler. On information and belief, Restylane-L is an injectable28 4 COMPLAINT

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1 hyaluronic acid gel that includes lidocaine, and is indicated for the correction of2 moderate to severe facial wrinkles and folds.3 23. On information and belief, Defendants, on their own and/or through4 their subsidiaries, sell, offer to sell, and/or import into the United States Perlane-L,5 a dermal filler. On information and belief, Perlane-L is an injectable hyaluronic6 acid gel that includes lidocaine, and is indicated for the correction ofmoderate to7 severe facial folds and wrinkles.8 24. As used hereinafter, the phrase "Accused Products" shall mean9 individually and collectively the Accused Restylane-L and Perlane-L dermal filler

10 products.11 25. On information and belief, Defendants offer for sale, sell, and/or12 distribute Accused Products in the United States, including within this district,13 and/or import the Accused Products into the United States.14 26. On information and belief, Q-Med AB, a company organized in15 Sweden, manufactures and the Accused Products in Sweden and sells the Accused16 Products to Defendants for ultimate distribution in the United States.17 27. On information and beliefQ-Med AB was acquired in 2011 by18 Galderma Pharma SA, a company organized in Switzerland.19 28. On information and belief, Defendants were aware ofAllergan's202122232425

JUVEDERMproducts that practice the '475 patent. On information and belief,, because Defendants were aware ofAllergan's JUVEDERM products, Defendants

were also aware ofthe '475 patent as a result ofpatent marking, including markingon the website.

COUNT I(Infringement of the '475 Patent Under 35 U.S.C. 271)

26 29. Paragraphs 1 to 28 are incorporated herein as set forth above.2728 5 COMPLAINT

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1 30. Defendants have been and are directly infringing the claims ofthe '4752 patent, literally and/or under the doctrine of equivalents, by offering to sell and/or3 selling within the United States, and/or importing into the United States, the4 Accused Products.5 31. On information and belief, Defendants have induced and continue to6 induce infringement of the '475 patent by actively encouraging customers to use the7 Accused Products in the United States with knowledge that such use would infringe8 the '475 patent. On information and belief, those customers in fact infringed the9 '475 patent by using the Accused Products in the United States.

10 32. As a result of Defendants' infringement of the '475 patent, Allergan11 has suffered and will continue to suffer damage. Allergan is entitled to recover from12 Defendants the damages adequate to compensate for such infringement, which have13 yet to be determined.14 33. Defendants' acts of infringement have caused and will continue to15 cause irreparable harm to Allergan unless and until enjoined by this Court.16 JURY TRIAL DEMAND17 Pursuant to Federal Rule of Civil Procedure 38(b), Allergan hereby demands18 a trial by jury on all issues so triable.19 PRAYER FOR RELIEF20 Allergan respectfully requests that this Court enter judgment and provide21 relief as follows:222324

a.b.c.

That Defendants have directly infringed the '475 patent;That Defendants have induced infringement of the '475 patent;That Defendants, and their respective officers, agents, servants,

25 employees, attorneys, and all persons in active concert or participation with any of26 them directly or indirectly, be permanently enjoined from infringing the'475 patent;2728 6 COMPLAINT

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1 d. That Defendants pay to Allergan damages in amounts sufficient to2 compensate it for Defendants' infringement ofthe'475 patent, together with3 prejudgment and post judgment interest and costs, pursuant to 35 U.S.C. 284;4 e. That Defendants be ordered to account for additional damages for any5 and all periods of infringement not included in the damages awarded by the Court or6 jury, including specifically any time periods between any order or verdict awarding7 damages and entry of final judgment;8 f. That this is an exceptional case under 35 U.S.C. 285, and Allergan be9 awarded reasonable attorneys' fees and costs incurred in this action;

10 g. That Allergan be awarded such other equitable or legal relief as the11 Court may deem just and proper.1213 Dated: September 13,2013141516171819202122232425262728

FISH & RICHARDSON P.C.

-"y: I /'CE iRCOU1itmanUAttorneys for Plaintiffs

ALLERGAN USA, INC. andALLERGAN INDUSTRIE, SAS

7 COMPLAINTCase No.


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Exhibit A


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(12) United States PatentLebreton(54) HYALURONIC ACID-BASED GELS

INCLUDING LIDOCAINE(75) Inventor: Pierre F. Lebreton, Annecy (FR)(73) Assignee: Allergan, Inc., Irvine, CA (US)( *) Notice: Subject to any disclaimer, the term of thispatent is extended or adjusted under 35

U.S.c. 154(b) by 656 days.(21) Appl. No.: 12/393,768(22) Filed: Feb. 26, 2009(65) Prior Publication Data

US 2010/0028437 Al Feb. 4, 2010

Related U.S. Application Data(60) Provisional application No. 611085,956, filed on Aug.4,2008, provisional application No. 611087,934, filed

on Aug. 11, 2008, provisional application No.611096,278, filed on Sep. 11,2008.(51) Int. Cl.

C07H 1/00 (2006.01)(52) U.S. Cl.USPC .............. 536/124; 514/54; 424/484; 424/488(58) Field of Classification SearchUSPC ...................... 5361124; 514/54; 424/484, 488See application file for complete search history.(56) References Cited

U.S. PATENT DOCUMENTS2,128,827 A 811938 Kill ian3,548,056 A 1211970 Eigen et al.3,763,009 A 1011973 Suzuki3,949,073 A 411976 Daniels et al.4,060,081 A 1111977 Yannas et al.4,140,537 A 211979 Luck et al.4,233,360 A 1111980 Luck et al.4,273,705 A 611981 Kato4,279,812 A 711981 Cioca4,424,208 A 111984 Wallace et al.4,501,306 A 211985 Chu et al.4,582,640 A 411986 Smestad et al.4,582,865 A 411986 Balazs et al.4,605,691 A 811986 Balazs et al.4,636,524 A 111987 Balazs4,642,117 A 211987 Nguy en et al.4,713,448 A 1211987 Balazs4,716,154 A 1211987 Malson et al.4,803,075 A 211989 Wallace et al.4,886,787 A 1211989 de Belder et al.4,896,787 A 111990 Delam our et al.5,009,013 A 411991 Wik lund5,087,446 A 211992 Suzuki et al.5,091,171 A 211992 Yu et al.5,143,724 A 911992 Leshchin er et al.5,246,698 A 911993 Leshchiner et al.5,314,874 A 511994 Miyata et al.5,328,955 A 711994 Rhee et al.5,356,883 A 1011994 Kuo et al.5,399,351 A 311995 Leshchiner et al.5,428,024 A 611995 Chu et al.5,531,716 A 711996 Luzio et al.5,565,519 A 1011996 Rhee et al.

111111 1111111111111111111111111111111111111111111111111111111111111

CAEP

US008450475B2

(10) Patent No.:(45) Date of Patent:

5,571,503 A 11119965,614,587 A 3/19975,616,568 A 4/19975,616,611 A 4/19975,616,689 A 4/19975,633,001 A 5/19975,643,464 A 7/19975,676,964 A 10/19975,823,671 A 10/19985,824,333 A 10/19985,827,529 A 10/19985,827,937 A 10/19985,843,907 A 12/19985,880,107 A 3/19995,886,042 A 3/19995,935,164 A 8/19995,980,930 A 11119996,013,679 A 1120006,066,325 A 5/20006,224,857 Bl 5/20016,335,035 Bl 1120026,372,494 Bl 4/20026,383,218 Bl 5/20026,383,219 Bl 5/20026,418,934 Bl 7/20026,544,503 Bl 4/20036,627,620 Bl 9120036,630,486 Bl 10120036,685,963 Bl 2120046,716,251 Bl 4/20046,734,298 Bl 5/20046,767,924 B2 7/20046,767,928 Bl 7/2004

US 8,450,475 B2May 28, 2013

MausnerRhee et al.Pouyani et al.YamamotoShenoyet al.AgerupRhee et al.della ValleMitchell et al.Scopelianos et al.Ono et al.AgerupSakaiBuenterYu et al.IversenFenton et al.Kuo et al.Wallace et al.Romeo et al.Drizen et al.Naughton et al.Sourdille et al.Telandro et al.ChinVanderhoff et al.NielsenRoyerTaupin et al.Asius et al.BarbucciYu et al.Murphy et al.

(Continued)FOREIGN PATENT DOCUMENTS

949965273823 6/19747/1988(Continued)

OTHER PUBLICATIONSLupo, "Hyaluronic Acid Fillers in Facial Rejuvenation", Oct. 18,2006, Seminars in Cutaneous Medic ine and Surgery, vol. 25 iss. 3, pp.122-126.*

(Continued)Primary Examiner - Ali Soroush(74) Attorney, Agent, or Firm - Linda Fox; StephenDonovan; Debra Condino

(57) ABSTRACTDisclosed herein are soft tissue fillers, for example, dermaland subdermal fillers, based on hyaluronic acids and pharmaceutically acceptable salts thereof. In one aspect, hyaluronicacid-based compositions described herein include a therapeutically effective amount of at least one anesthetic agent, forexample, lidocaine. The present hyaluronic acid-based compositions including lidocaine have an enhanced stability, relative to conventional compositions including lidocaine, forexample when subjected to sterilization techniques or whenstored for long periods of time. Methods and processes ofpreparing such hyaluronic acid-based compositions are alsoprovided.

37 Claims, 1 Drawing Sheet

Exhibit A, page 000008

(12) United States PatentLebreton(54) HYALURONIC ACID-BASED GELS

INCLUDING LIDOCAINE(75) Inventor: Pierre F. Lebreton, Annecy (FR)(73) Assignee: Allergan, Inc., Irvine, CA (US)( *) Notice: Subject to any disclaimer, the term of thispatent is extended or adjusted under 35

U.S.c. 154(b) by 656 days.(21) Appl. No.: 12/393,768(22) Filed: Feb. 26, 2009(65) Prior Publication Data

US 2010/0028437 Al Feb. 4, 2010

Related U.S. Application Data(60) Provisional application No. 611085,956, filed on Aug.4,2008, provisional application No. 611087,934, filed

on Aug. 11, 2008, provisional application No.611096,278, filed on Sep. 11,2008.(51) Int. Cl.

C07H 1/00 (2006.01)(52) U.S. Cl.USPC .............. 536/124; 514/54; 424/484; 424/488(58) Field of Classification SearchUSPC ...................... 5361124; 514/54; 424/484, 488See application file for complete search history.(56) References Cited

U.S. PATENT DOCUMENTS2,128,827 A 811938 Kill ian3,548,056 A 1211970 Eigen et al.3,763,009 A 1011973 Suzuki3,949,073 A 411976 Daniels et al.4,060,081 A 1111977 Yannas et al.4,140,537 A 211979 Luck et al.4,233,360 A 1111980 Luck et al.4,273,705 A 611981 Kato4,279,812 A 711981 Cioca4,424,208 A 111984 Wallace et al.4,501,306 A 211985 Chu et al.4,582,640 A 411986 Smestad et al.4,582,865 A 411986 Balazs et al.4,605,691 A 811986 Balazs et al.4,636,524 A 111987 Balazs4,642,117 A 211987 Nguyen et al.4,713,448 A 1211987 Balazs4,716,154 A 1211987 Malson et al.4,803,075 A 211989 Wallace et al.4,886,787 A 1211989 de Belder et al.4,896,787 A 111990 Delamo ur et al.5,009,013 A 411991 Wik lund5,087,446 A 211992 Suzuki et al.5,091,171 A 211992 Yu et al.5,143,724 A 911992 Leshchin er et al.5,246,698 A 911993 Leshchiner et al.5,314,874 A 511994 Miyata et al.5,328,955 A 711994 Rhee et al.5,356,883 A 1011994 Kuo et al.5,399,351 A 311995 Leshchiner et al.5,428,024 A 611995 Chu et al.5,531,716 A 711996 Luzio et al.5,565,519 A 1011996 Rhee et al.

111111 1111111111111111111111111111111111111111111111111111111111111

CAEP

US008450475B2

(10) Patent No.:(45) Date of Patent:

5,571,503 A 11119965,614,587 A 3/19975,616,568 A 4/19975,616,611 A 4/19975,616,689 A 4/19975,633,001 A 5/19975,643,464 A 7/19975,676,964 A 10/19975,823,671 A 10/19985,824,333 A 10/19985,827,529 A 10/19985,827,937 A 10/19985,843,907 A 12/19985,880,107 A 3/19995,886,042 A 3/19995,935,164 A 8/19995,980,930 A 11119996,013,679 A 1120006,066,325 A 5/20006,224,857 Bl 5/20016,335,035 Bl 1120026,372,494 Bl 4/20026,383,218 Bl 5/20026,383,219 Bl 5/20026,418,934 Bl 7/20026,544,503 Bl 4/20036,627,620 Bl 9120036,630,486 Bl 10120036,685,963 Bl 2120046,716,251 Bl 4/20046,734,298 Bl 5/20046,767,924 B2 7/20046,767,928 Bl 7/2004

US 8,450,475 B2May 28, 2013

MausnerRhee et al.Pouyani et al.YamamotoShenoyet al.AgerupRhee et al.della ValleMitchell et al.Scopelianos et al.Ono et al.AgerupSakaiBuenterYu et al.IversenFenton et al.Kuo et al.Wallace et al.Romeo et al.Drizen et al.Naughton et al.Sourdille et al.Telandro et al.ChinVanderhoff et al.NielsenRoyerTaupin et al.Asius et al.BarbucciYu et al.Murphy et al.

(Continued)FOREIGN PATENT DOCUMENTS

949965273823 6/19747/1988(Continued)

OTHER PUBLICATIONSLupo, "Hyaluronic Acid Fillers in Facial Rejuvenation", Oct. 18,2006, Seminars in Cutaneous Medic ine and Surgery, vol. 25 iss. 3, pp.122-126.*

(Continued)Primary Examiner - Ali Soroush(74) Attorney, Agent, or Firm - Linda Fox; StephenDonovan; Debra Condino

(57) ABSTRACTDisclosed herein are soft tissue fillers, for example, dermaland subdermal fillers, based on hyaluronic acids and pharmaceutically acceptable salts thereof. In one aspect, hyaluronicacid-based compositions described herein include a therapeutically effective amount of at least one anesthetic agent, forexample, lidocaine. The present hyaluronic acid-based compositions including lidocaine have an enhanced stability, relative to conventional compositions including lidocaine, forexample when subjected to sterilization techniques or whenstored for long periods of time. Methods and processes ofpreparing such hyaluronic acid-based compositions are alsoprovided.

37 Claims, 1 Drawing Sheet


10/22

US 8,450,475 B2Page 2

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3/20066/20062120076/20077/2007111200711120073/20086/20086/20087/20088/200812/20082120092120093/20093/20096/20092120103/2010512010OTHER PUBLICATIONS

Sannino, et aI., "Crosslinking of Cellulose Derivatives andHyaluronic Acid With Water-Soluble Carbodiimide," Polymer 46(2005) 11206-11212 pp.Kulicke, et aI., "Visco-Elastic Proeprties of Sodium HyaluronateSolutions," American Institute of Physics (2008).Tezel, "The Science of Hyaluronic Acid Dermal Fillers," Journal ofCosmetic and Laser Therapy (2008) 10: 35-42 pp.Hassan, HG., et aI., Effects ofAdjuvants to local anaesthetics on theirduration. III. Experimental studies of hyaluronic acid. Abstract PubMed [Acta Anesthesiol Scand. May 1985;29(4):384-8].Desai, et aI., J Pharm Sci Feb. 1995; 84 (2): 212-5, abstract only.Lamar, et aI., "Antifibrosis Effect of Novel Gels in Anterior CiliarySierotomy (ACS)," ARVO 2002 abstract.F.H. Silver, et aI., "Physical Properties of Hyaluronic Acid andHydroxypropylmethylcellulose in Solution: Evaluation of CoatingAbility," Journal of Applied Biomaterials, vol. 5, 89-98 (1994).GinShiCei MH Hydroxy Propyl methyl Cellulose, Web Page http://www.ginshicel.cn/MHPC.html. Nov. 12, 2008.Adams; "An Analysis of Clinical Studies of the Uses of CrosslinkedHyaluronan, Hylan, in the Treatment ofOsteoarthritis"; J. RheumatolSuppl. ; vol. 39; pp. 16-18; Aug. 1993.Allemann et al.; "Hyaluronic acid gel (JUVADERM) preparations inthe treatment offacial wrinkles and folds"; Clinical Interventions inAging; vol. 3, No.4; pp. 629-634; 2008.Bluel et al.; "Evaluation of Reconstituted Collagen Tape as a Modelfor Chemically Modified Soft Tissues", Biomat. Med. Dev. Art. Org.;vol. 9(1); pp. 37-46; 1981.Capozzi et aI., "Distant Migration of Silicone Gel From a RupturedBreast Implant", Plastic and Reconstructive Surgery; vol. 62; pp.302-303; 1978.Champion et aI., "Role ofTarget Geometry in Phagocytosis"; S. Proc.Nat. Acad. Sci.; vol. 103; No. 13; pp. 4930-4934; Mar. 28, 2006.Chvapil, "Collagen Sponge: Theory and Practice of Medical Applications", J. Biomed Mater. Res., vol. II, pp. 721-741; 1977.Clark et aI., "The Influence of Triamcinolone Acetonide on JointStiffness in the Rat", J Bone Joint Surg; vol. 53-A; pp. 1409-1414;Oct. 1971.Cohen et aI., "Organization and Adhesive Properties of theHyaluronan Pericellular Coat of Chrondrocytes and EpithelialCells", Biophys J.; vol. 85; pp. 1996-2005; Sep. 2003.Deland, "Intrathecal Toxicity Studies with Benzyl Alcohol", ToxicolAppl Pharmacol; vol. 25; pp. 153-156; 1973.Eyre et al., Top Curro Chern., vol. 247, pp. 207-229; 2005.Grecomoro et aI., "Intra-Articular Treatment with SodiumHyaluronate in Gonarthosis: A Controlled Clinical Trial Versus Placebo", Pharmatherapeutica, vol. 5(2); pp. 137-141; 1987.Grillo et al., "Thermal Reconstitution of Collagen from Solution andthe Response to Its Heterologous Implantation", JSR; vol. II, No.1,pp. 69-82; Jan. 1962.

Hayashibara, "AA2G"; Sep. 23, 2007, http://web.archive.orglweb/200792307201 O/http://www.hayashibara-intl.comlcosmetics/aa2g.html.Helliwell, "Use of an Objective Measure of Articular Stiffness toRecord Changes in Finger Joints After Intra-Articular Injection ofCorticosteroid", An Theum Dis; vol. 56; pp. 71-73; 1997.Hertzberger-Ten Cate et aI., "Intra-Articular Steroids inPauciarticular Juvenile Chronic Arthritis", Type I, Eur J Pediatr; vol.150; pp. 170-172; 1991.Hetherington, "Potential for Patient Harm From Intrathecal Administration of Preserved Solutions", Abstract only Med J; vol. 173(3); p.141; Aug. 2000.Hurst, "Adhesive Arachnoiditis and Vascular Blockage Caused byDetergents and Other Chemical Irritants: an Experimental Study", JPath Bact, vol. LXX, No. 70; pp. 167-177; 1955.Jones et aI., "Intra-Articular Hyaluronic Acid Compared to IntraArticular Triamcinolone Hexacetonide in Inflammatory KneeOsteoarthritis", Osteoarthritis Cartilage, vol. 3; pp. 269-273; 1995.Klein, "Skin Filling Collagen and Other Injectables of the Skin",Dermatologic Clinics; vol. 19, No.3, pp. 491-588; Jul. 2001.Kopp et al., "The Short-Term Effect ofIntra-Articular Injections ofSodium Hyaluronate and Corticosteroid on TemporomandibularJoint Pain and Dysfunction", J. Oral Maxillofac Surg.; V. 43; pp.429-435; 1985.Laeschke, "Biocompatibility of Microparticles into Soft Tissue Fillers", Semin. Cutan. Med. Surg., vol. 23; pp. 214-217; 2004.Mancinelli et aI., "Intramuscular High-Dose TriamcinoloneAcetonide in the Treatment of Severe Chronic Asthma", West J. Med;vol. 167(5); pp. 322-329; Nov. 1997.McCarty et aI., "Inflammatory Reaction After Intrasynovial Injectionof Microcrystalline Adrenocorticosteroid Esters", Arthritis andRheuymatism; vol. 7(4); pp. 359-367; 1964.Remington's Pharmaceutical Science Mac Publishing Company,Easton, PA 16th Edition 1980; I-page.Rosenblatt et aI., "T he Effect of Collagen Fiber Size Distribution onthe Release Rate of Proteins from Collagen Matrices by Diffusion",J. Controlled ReI., vol. 9; pp. 195-203; 1989.Rosenblatt et aI., "Chain Rigidity and Diffusional Release inBiopolymer Gels", Proceed. Inter. Symp. Control. ReI. Bioact.Mater.; vol. 20; pp. 264-265; Controlled Release Society, Inc.Selvi et ai, "Arthritis Induced by Corticosteroid Crystals", J.Rheumatology; vol. 34:3; 1 page; 2004.Zulian et aI., "Triamcinolone Acetonide and Hexacetonide IntraArticular Treatment of Symmetrical Joints in Juvenile IdiopathicArthritis: a Double-Blind Trial", Rheumatology; vol. 43; No. 10; pp.1288-1291; 2004.Powell; "Stability of Lidocaine in Aqueous Solution: Effect of Temperature, pH, Buffer, and Metal Ions on Amide Hydrolysis"; Pharmaceutical Research; vol. 4, No.1, 1987.Cui et al; "The Comparison of Physicochemical Properties of FourCross-Linked Sodium Hyaluronate Gels with Different Cross-Linking Agents"; Advanced Material Research; vols. 396-398; pp. 1506-1512; 2012.Lindvall et al.; "Influcence of Various Compounds on the Degradation of Hyaluronic Acid by a Myeloperoxidase System"; ChemcioBiological Interactions; vol. 90; pp. 1-12; 1994.Weidmann; "Ne w Hyaluronic Acid Filler for Subdermal and LongLasting Volume Restoration of the Face"; European Dermatology;pp. 65-68; 2009.Skardal etal "Bioprinting Vessel-Like Constructs Using HyaluronanHydrogels Crosslinkedwith Tetrahedral Polyethylene GlyolTetracyclates"; BioMaterials. Elsevier Science Publishers BV; vol.31; No. 24; pp. 6173-6181; Aug. 1,2010.Aesthetic Buyers Guide, "Juvaderm Raises Standards" Jan./Feb.2007 (5pp.), www.miinews.com.Albano, Emanuele, et aI., "Hyroxyethyl Radicals in EthanolHepatotoxicity," Frontiers in Bioscience 4:533-540 (1999).Antunes, Alberto A., et al., "Efficacy ofIntrar ectal Lidocaine Hydrochloride Gel for Pain control in Patients Undergoing TransrectalProstate Biopsy", International Braz J Urol, vol. 30(5): 380-383,Sep.-Oct., 2004.


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WO 2006/023645WO 2006/067608WO 2007/018124WO 2007/070617WO 2007/0773992007136738WO 2007/128923WO 2008/034176WO 2008/068297WO 2008/072230WO 2008/077172WO 2008/098019WO 2008/157608WO 20091024719WO 20091026158WO 20091028764WO 20091034559WO 20091073437WO 20101015900WO 2010/028025WO 2010/053918

3/20066/20062120076/20077/2007111200711120073/20086/20086/20087/20088/200812/20082120092120093/20093/20096/20092120103/2010512010OTHER PUBLICATIONS

Sannino, et aI., "Crosslinking of Cellulose Derivatives andHyaluronic Acid With Water-Soluble Carbodiimide," Polymer 46(2005) 11206-11212 pp.Kulicke, et aI., "Visco-Elastic Proeprties of Sodium HyaluronateSolutions," American Institute of Physics (2008).Tezel, "The Science of Hyaluronic Acid Dermal Fillers," Journal ofCosmetic and Laser Therapy (2008) 10: 35-42 pp.Hassan, HG., et aI., Effects ofAdjuvants to local anaesthetics on theirduration. III. Experimental studies of hyaluronic acid. Abstract PubMed [Acta Anesthesiol Scand. May 1985;29(4):384-8].Desai, et aI., J Pharm Sci Feb. 1995; 84 (2): 212-5, abstract only.Lamar, et aI., "Antifibrosis Effect of Novel Gels in Anterior CiliarySierotomy (ACS)," ARVO 2002 abstract.F.H. Silver, et aI., "Physical Properties of Hyaluronic Acid andHydroxypropylmethylcellulose in Solution: Evaluation of CoatingAbility," Journal of Applied Biomaterials, vol. 5, 89-98 (1994).GinShiCei MH Hydroxy Propyl methyl Cellulose, Web Page http://www.ginshicel.cn/MHPC.html. Nov. 12, 2008.Adams; "An Analysis of Clinical Studies of the Uses of CrosslinkedHyaluronan, Hylan, in the Treatment ofOsteoarthritis"; J. RheumatolSuppl. ; vol. 39; pp. 16-18; Aug. 1993.Allemann et al.; "Hyaluronic acid gel (JUVADERM) preparations inthe treatment offacial wrinkles and folds"; Clinical Interventions inAging; vol. 3, No.4; pp. 629-634; 2008.Bluel et al.; "Evaluation of Reconstituted Collagen Tape as a Modelfor Chemically Modified Soft Tissues", Biomat. Med. Dev. Art. Org.;vol. 9(1); pp. 37-46; 1981.Capozzi et aI., "Distant Migration of Silicone Gel From a RupturedBreast Implant", Plastic and Reconstructive Surgery; vol. 62; pp.302-303; 1978.Champion et aI., "Role ofTarget Geometry in Phagocytosis"; S. Proc.Nat. Acad. Sci.; vol. 103; No. 13; pp. 4930-4934; Mar. 28, 2006.Chvapil, "Collagen Sponge: Theory and Practice of Medical Applications", J. Biomed Mater. Res., vol. II, pp. 721-741; 1977.Clark et aI., "The Influence of Triamcinolone Acetonide on JointStiffness in the Rat", J Bone Joint Surg; vol. 53-A; pp. 1409-1414;Oct. 1971.Cohen et aI., "Organization and Adhesive Properties of theHyaluronan Pericellular Coat of Chrondrocytes and EpithelialCells", Biophys J.; vol. 85; pp. 1996-2005; Sep. 2003.Deland, "Intrathecal Toxicity Studies with Benzyl Alcohol", ToxicolAppl Pharmacol; vol. 25; pp. 153-156; 1973.Eyre et al., Top Curro Chern., vol. 247, pp. 207-229; 2005.Grecomoro et aI., "Intra-Articular Treatment with SodiumHyaluronate in Gonarthosis: A Controlled Clinical Trial Versus Placebo", Pharmatherapeutica, vol. 5(2); pp. 137-141; 1987.Grillo et al., "Thermal Reconstitution of Collagen from Solution andthe Response to Its Heterologous Implantation", JSR; vol. II, No.1,pp. 69-82; Jan. 1962.

Hayashibara, "AA2G"; Sep. 23, 2007, http://web.archive.orglweb/200792307201 O/http://www.hayashibara-intl.comlcosmetics/aa2g.html.Helliwell, "Use of an Objective Measure of Articular Stiffness toRecord Changes in Finger Joints After Intra-Articular Injection ofCorticosteroid", An Theum Dis; vol. 56; pp. 71-73; 1997.Hertzberger-Ten Cate et aI., "Intra-Articular Steroids inPauciarticular Juvenile Chronic Arthritis", Type I, Eur J Pediatr; vol.150; pp. 170-172; 1991.Hetherington, "Potential for Patient Harm From Intrathecal Administration of Preserved Solutions", Abstract only Med J; vol. 173(3); p.141; Aug. 2000.Hurst, "Adhesive Arachnoiditis and Vascular Blockage Caused byDetergents and Other Chemical Irritants: an Experimental Study", JPath Bact, vol. LXX, No. 70; pp. 167-177; 1955.Jones et aI., "Intra-Articular Hyaluronic Acid Compared to IntraArticular Triamcinolone Hexacetonide in Inflammatory KneeOsteoarthritis", Osteoarthritis Cartilage, vol. 3; pp. 269-273; 1995.Klein, "Skin Filling Collagen and Other Injectables of the Skin",Dermatologic Clinics; vol. 19, No.3, pp. 491-588; Jul. 2001.Kopp et al., "The Short-Term Effect ofIntra-Articular Injections ofSodium Hyaluronate and Corticosteroid on TemporomandibularJoint Pain and Dysfunction", J. Oral Maxillofac Surg.; V. 43; pp.429-435; 1985.Laeschke, "Biocompatibility of Microparticles into Soft Tissue Fillers", Semin. Cutan. Med. Surg., vol. 23; pp. 214-217; 2004.Mancinelli et aI., "Intramuscular High-Dose TriamcinoloneAcetonide in the Treatment of Severe Chronic Asthma", West J. Med;vol. 167(5); pp. 322-329; Nov. 1997.McCarty et aI., "Inflammatory Reaction After Intrasynovial Injectionof Microcrystalline Adrenocorticosteroid Esters", Arthritis andRheuymatism; vol. 7(4); pp. 359-367; 1964.Remington's Pharmaceutical Science Mac Publishing Company,Easton, PA 16th Edition 1980; I-page.Rosenblatt et aI., "T he Effect of Collagen Fiber Size Distribution onthe Release Rate of Proteins from Collagen Matrices by Diffusion",J. Controlled ReI., vol. 9; pp. 195-203; 1989.Rosenblatt et aI., "Chain Rigidity and Diffusional Release inBiopolymer Gels", Proceed. Inter. Symp. Control. ReI. Bioact.Mater.; vol. 20; pp. 264-265; Controlled Release Society, Inc.Selvi et ai, "Arthritis Induced by Corticosteroid Crystals", J.Rheumatology; vol. 34:3; 1 page; 2004.Zulian et aI., "Triamcinolone Acetonide and Hexacetonide IntraArticular Treatment of Symmetrical Joints in Juvenile IdiopathicArthritis: a Double-Blind Trial", Rheumatology; vol. 43; No. 10; pp.1288-1291; 2004.Powell; "Stability of Lidocaine in Aqueous Solution: Effect of Temperature, pH, Buffer, and Metal Ions on Amide Hydrolysis"; Pharmaceutical Research; vol. 4, No.1, 1987.Cui et al; "The Comparison of Physicochemical Properties of FourCross-Linked Sodium Hyaluronate Gels with Different Cross-Linking Agents"; Advanced Material Research; vols. 396-398; pp. 1506-1512; 2012.Lindvall et al.; "Influcence of Various Compounds on the Degradation of Hyaluronic Acid by a Myeloperoxidase System"; ChemcioBiological Interactions; vol. 90; pp. 1-12; 1994.Weidmann; "New Hyaluronic Acid Filler for Subdermal and LongLasting Volume Restoration of the Face"; European Dermatology;pp. 65-68; 2009.Skardal etal "Bioprinting Vessel-Like Constructs Using HyaluronanHydrogels Crosslinkedwith Tetrahedral Polyethylene GlyolTetracyclates"; BioMaterials. Elsevier Science Publishers BV; vol.31; No. 24; pp. 6173-6181; Aug. 1,2010.Aesthetic Buyers Guide, "Juvaderm Raises Standards" Jan./Feb.2007 (5pp.), www.miinews.com.Albano, Emanuele, et aI., "Hyroxyethyl Radicals in EthanolHepatotoxicity," Frontiers in Bioscience 4:533-540 (1999).Antunes, Alberto A., et al., "Efficacy ofIntrare ctal Lidocaine Hydrochloride Gel for Pain control in Patients Undergoing TransrectalProstate Biopsy", International Braz J Urol, vol. 30(5): 380-383,Sep.-Oct., 2004.


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Atanassoff, Peter G., et aI., "The Effect of Intradermal Administration of Lidocaine and Morphine on the Response to Thermal Stimulation", AnesthAnalg 1997; 84:1340-3.Baumann et al. "JUV EDERM vs. ZYPLAST Nasolabial Fold StudyGroup, Comparison of smooth-gel hyaluronic acid dermal fillers withcross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study." Dermatol. Surg. 33(SuppI2): S128-S135 (2007).Beasley et al. :Hyaluronic acid fillers: a comprehensive review. FacialPlast. Surg. 25(2): 86-94 (2009).Beer "Dermal fillers and combinations of fillers for facial rejuvenation." Dermatol. Clin. 27(4): 427-432 (2009).Beida, Jose I., et aI., "Hyaluronic acid combined with mannitol toimprove protection against free-radical endothelial damage: Experimental Model," J. Cataract Refract Surg 2005; 31:1213-1218.Bircher, Andreas J., et aI., "Delayed-type hypersensitivity to subcutaneous lidocaine with tolerance to articaine: confirmation by in vivoand in vitro tests", Contact Dermatitis 1996, 34, 387-389.Carlin, G., et aI., "Effect of anti-inflammatory drugs on xanthineoxidase and xanthine oxidase induced depolymerization ofhyaluronic acid," Agents and Actions. 16 (5):377-384 (1985).Carruthers et al. "The science and art of dermal fillers for soft-tissueaugmentation." J. Drugs Dermatol. 8(4): 335-350 (2009).Chin, Thomas M., et aI., "Allergic Hypersensitivity to LidocaineHydrochloride", International journal of Dermatology, vol. 19, Apr.1980, pp. 147-148.Falcone et al. "Crosslinked hyaluronic acid dermal fillers: a comparison of heological properties." J Biomed Mater ResA. 87(1): 264-271(2008).Falcone et al. "Temporary polysaccharide dermal fillers: a model forpersistence based on physical properties." Dermatol Surg. 35(8):1238-1243 (2009).Farley, Jon S., et aI., "Diluting Lidocaine and Mepivacaine in Balanced Salt Solution Reduces the Pain of Intradermal Injection",Regional Anesthesia 19(1):48-51,1994.Frati, Elena, et al., "Degradation of hyaluronic acid byphotosensitized riboflavin in vitro. Modulation of the effect by transition metals, radical quenchers, and metal chelators," Free RadicalBiology Medicine 22 (7): 1139-1144 (1997).Fujinaga, Masahiko, et aI., "Reproductive and Teratogenic Effects ofLidocaine in Sprague-Dawley Rats", Anesthesiology 65:626-632,1986.Gammaitoni, Arnold R., et al., "Pharmacokinetics and safety of continuously applied lidocaine patches 5%", Am J Health Syst Pharm,vol. 59, Nov. 15,2002, pp. 2215-2220.Gold MH, "Use of Hyaluronic acid fillers for the treatment of theaging face." Clin. Interventions Aging 2(3): 369-376 (2007).Goldberg "Breakthroughs in US dermal fillers for facial soft-tissueaugmenta tion." J Cosmet Laser Ther. 11(4): 240-247 (2009).Graefe, Hendrik, et aI., "Sensitive and specific photometric determination of mannitol in human serum," Clin Chern Lab Med. 41(8):1049-1055 (2003).Intramed Mannitol 20% mlv Infusion, package insert, pp. 1-2 (2010),http://homme.intekom.comlpharmlintramedlmanitI20.html.Kablik et al. "Comparative physical properties of hyaluronic aciddermal fillers." Dermatol. Surg. Suppl. 35(Suppl. 1): 302-312 (2009).Levy, Jaime et aI., "Lidocaine hypersensitivity after subconjunctivalinjection", Can J Ophthalmol 2006; 41 :204-6.Mackley, et al., "Delayed-Type Hypersensitivity to Lidocaine", ArchDermatol, vol. 139, Mar. 2003, pp. 343-346.Matsumoto, Alan H, et aI., "Reducing the Discomfort of LidocaineAdministration through pH Buffering," Journal of Vascular andInterventional Radiology, Jan.-Feb. 1994, pp. 171-175.McCleland, Plastic Reconstructive Surg., 100(6), Nov. 1997, pp.1466-1474.McPherson, John M., "Development and Biochemical Characterization of Injectable Collagen," J. Dermatol Surg Oncoo, 14 (Suppll):Jul. 7, 1988, pp. 13-20.Orvisky, E., et aI., "High-molecular-weight hyaluronan-a valuabletool in testing the anti oxidative activity of amphiphilic drugs

stobadine and vinpocetine," Pharm.Biomed.Anal. 16:419-424(1997).Osimitrol (generic name Mannitol), Official FDA Information, sideeffects and uses, pp. 1-10 (2010), http://www.drugs.comlpro/osmitrol.html.Prestwich, Glenn D., "Evaluating drug efficacy and toxicology inthree dimensions: using synthetic extracellular matrices in drug discovery," Accounts of Chemical Research 41 (1): 139-148 (2008).Rehakova, Milena, et aI., "Properties of collagen and hyaluronic acidcomposite materials and their modifications by chemical crosslinking," Journal of Biomedical Research, vol. 30, 1996, pp. 369-372XP002590342.SCULPTRA Aesthetic (injectable poly-L-Iactic acid) Directionsfor Use, Dermik Laboratories product insert (Jul. 2009), sanofiaventis U. LLC.Segura et al. "Crosslinked hyaluronic acid hydrogels: a strategy tofunctionalize and pattern." Biomaterials 26(4): 359-371 (2005).Serban et al. "Modular Extracellular Matrices: Solutions for thePuzzle." Methods 45(1): 93-98 (2008).Shu et al. "Synthesis a nd evaluation of injectable, i n situ crosslinkable synthetic extracellular matrices for tissue engineering." J.Biomed. Mater. Res. A. 79(4): 902-912 (2006).Smith, Kevin c., et aI., "Five Percent Lidocaine Cream AppliedSimultaneously to Skin and Mucosa of the Lips Creates ExcellentAnesthesia for Filler Injections", Dermatol Surg 2005; 31:1635-1637.Visiol, Visoelstic gel for use in ocular surgery, (2010) p. 1, http://

w w w . t r b c h e m e d i c a . c o m l i n d e x . p h p / o p t i o n ~ c o m . c o n t e n t & t a s .Waraszkiewicz, Sigmund M., et aI., "Stability-Indicating High-Performance Liquid Chromatographic Analysis of Lidocaine Hydrochloride and Lidocaine Hydrochloride with Epinephrine InjectableSolutions", Journal of Pharmaceutical Sciences, vol. 70, No. 11, Nov.1981, pp. 1215-1218.Xia, Yun et al., "Comparis on of Effects of Lidocaine Hydrochloride,Buffered Lidocaine, Diphenydramine, and Normal Saline AfterIntradermal Injection", Journal of Clinical Anesthesia, 14:339-343,2002.Yeom et al. "Effect of Cross-Linking Reagents for Hyaluronic AcidHydrogel Dermal Fillers on Tissue Augmentation and Regeneration."Bioconjugate Chern., 21(2): 240-247 (2010).Yui, Nobuhiko, et aI., "Inflammation responsive degradation ofcrosslinked hyaluronic acid gels," Journal of Controlled release, 22(1992) pp. 105-116.Yui, Nobuhiko, et aI., "Photo-responsive degradation of heterogeneous hydro gels comprising crosslinked hyaluronic aci d and lipidmicro spheres for temporal drug delivery," Journal of ControlledRelease, 26 (1993) pp. 141-145.Yun, YH et aI., "Hyaluronan Microspheres for Sustained Gene Delivery and Site-Specific Targeting.", Biomaterials, vol. 25, 2004, pp.147-157.Zheng et al. "In situ crosslinkable hyaluronan hydro gels for tissueengineering." Biomaterials 25(7-8): 1339-1348 (2004).Millay et al.; "Vasoconstrictors in Facial Plastic Surgery"; Archivesof Otolaryngology-Head & Neck Surgery; vol. 117; pp. 160-163;Feb. 1991.Wahl, " European Evaluation of a New Hyaluronic Acid Filler Incorporating Lidocaine", Journal of Cosmetic Dermatology; vol. 7; pp.298-303; 2008.Bucket al, "Injectable Fillers for our Facial Rejuvenation: a Review",Journal of Plastic, Reconstructive and Aesthetic Surgery, (2009),62:11-18, XP002668828.Park et aI., "Biological Characterization of EDC-crosslinked Collagen-Hyaluronic Acid Matrix in Dermal Tissue Restoration",Biomaterials 24 (2003) 1631-1641.Park et aI., "Characterization of Porous Collagen/HyaluronicAcid Scaffold Modified by l-ethyl-3-(3-dimethylaminopropyl)carbodiimide cross-linking", Biomaterials 23(2002): 1205-1212.* cited by examiner


US 8,450,475 B2Page 4

Atanassoff, Peter G., et aI., "The Effect of Intradermal Administration of Lidocaine and Morphine on the Response to Thermal Stimulation", AnesthAnalg 1997; 84:1340-3.Baumann et al. "JUV EDERM vs. ZYPLAST Nasolabial Fold StudyGroup, Comparison of smooth-gel hyaluronic acid dermal fillers withcross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study." Dermatol. Surg. 33(SuppI2 ): S128-S135 (2007).Beasley et al. :Hyaluronic acid fillers: a comprehensive review. FacialPlast. Surg. 25(2): 86-94 (2009).Beer "Dermal fillers and combinations of fillers for facial rejuvenation." Dermatol. Clin. 27(4): 427-432 (2009).Beida, Jose I., et aI., "Hyaluronic acid combined with mannitol toimprove protection against free-radical endothelial damage: Experimental Model," J. Cataract Refract Surg 2005; 31:1213-1218.Bircher, Andreas J., et aI., "Delayed-type hypersensitivity to subcutaneous lidocaine with tolerance to articaine: confirmation by in vivoand in vitro tests", Contact Dermatitis 1996, 34, 387-389.Carlin, G., et aI., "Effect of anti-inflammatory drugs on xanthineoxidase and xanthine oxidase induced depolymerization ofhyaluronic acid," Agents and Actions. 16 (5):377-384 (1985).Carruthers et al. "The science and art of dermal fillers for soft-tissueaugmentation." J. Drugs Dermatol. 8(4): 335-350 (2009).Chin, Thomas M., et aI., "Allergic Hypersensitivity to LidocaineHydrochloride", International journal of Dermatology, vol. 19, Apr.1980, pp. 147-148.Falcone et al. "Crosslinked hyaluronic acid dermal fillers: a comparison of heological properties." J Biomed Mater ResA. 87(1): 264-271(2008).Falcone et al. "Temporary polysaccharide dermal fillers: a model forpersistence based on physical properties." Dermatol Surg. 35(8):1238-1243 (2009).Farley, Jon S., et aI., "Diluting Lidocaine and Mepivacaine in Balanced Salt Solution Reduces the Pain of Intradermal Injection",Regional Anesthesia 19(1):48-51,1994.Frati, Elena, et al., "Degradation of hyaluronic acid byphotosensitized riboflavin in vitro. Modulation of the effect by transition metals, radical quenchers, and metal chelators," Free RadicalBiology Medicine 22 (7): 1139-1144 (1997).Fujinaga, Masahiko, et aI., "Reproductive and Teratogenic Effects ofLidocaine in Sprague-Dawley Rats", Anesthesiology 65:626-632,1986.Gammaitoni, Arnold R., et al., "Pharmacokinetics and safety of continuously applied lidocaine patches 5%", Am J Health Syst Pharm,vol. 59, Nov. 15,2002, pp. 2215-2220.Gold MH, "Use of Hyaluronic acid fillers for the treatment of theaging face." Clin. Interventions Aging 2(3): 369-376 (2007).Goldberg "Breakthroughs in US dermal fillers for facial soft-tissueaugmentation." J Cosmet Laser Ther. 11(4): 240-247 (2009).Graefe, Hendrik, et aI., "Sensitive and specific photometric determination of mannitol in human serum," Clin Chern Lab Med. 41(8):1049-1055 (2003).Intramed Mannitol 20% mlv Infusion, package insert, pp. 1-2 (2010),http://homme.intekom.comlpharmlintramedlmanitI20.html.Kablik et al. "Comparative physical properties of hyaluronic aciddermal fillers." Dermatol. Surg. Suppl. 35(Suppl. 1): 302-312 (2009).Levy, Jaime et aI., "Lidocaine hypersensitivity after subconjunctivalinjection", Can J Ophthalmol 2006; 41 :204-6.Mackley, et al., "Delayed-Type Hypersensitivity to Lidocaine", ArchDermatol, vol. 139, Mar. 2003, pp. 343-346.Matsumoto, Alan H, et aI., "Reduc ing the Discomfort of LidocaineAdministration through pH Buffering," Journal of Vascular andInterventional Radiology, Jan.-Feb. 1994, pp. 171-175.McCleland, Plastic Reconstructive Surg., 100(6), Nov. 1997, pp.1466-1474.McPherson, John M., "Development and Biochemical Characterization of Injectable Collagen," J. Dermatol Surg Oncoo, 14 (Suppll):Jul. 7, 1988, pp. 13-20.Orvisky, E., et aI., "High-molecular-weight hyaluronan-a valuabletool in testing the anti oxidative activity of amphiphilic drugs

stobadine and vinpocetine," Pharm.Biomed.Anal. 16:419-424(1997).Osimitrol (generic name Mannitol), Official FDA Information, sideeffects and uses, pp. 1-10 (2010), http://www.drugs.comlpro/osmitrol.html.Prestwich, Glenn D., "Evaluating drug efficacy and toxicology inthree dimensions: using synthetic extracellular matrices in drug discovery," Accounts of Chemical Research 41 (1): 139-148 (2008).Rehakova, Milena, et aI., "Properties of collagen and hyaluronic acidcomposite materials and their modifications by chemical crosslinking," Journal of Biomedical Research, vol. 30, 1996, pp. 369-372XP002590342.SCULPTRA Aesthetic (injectable poly-L-Iactic acid) Directionsfor Use, Dermik Laboratories product insert (Jul. 2009), sanofiaventis U. LLC.Segura et al. "Crosslinked hyaluronic acid hydrogels: a strategy tofunctionalize and pattern." Biomaterials 26(4): 359-371 (2005).Serban et al. "Modular Extracellular Matrices: Solutions for thePuzzle." Methods 45(1): 93-98 (2008).Shu et al. "Synthesis a nd evaluation of injectable, i n situ crosslinkable synthetic extracellular matrices for tissue engineering." J.Biomed. Mater. Res. A. 79(4): 902-912 (2006).Smith, Kevin c., et aI., "Five Percent Lidocaine Cream AppliedSimultaneously to Skin and Mucosa of the Lips Creates ExcellentAnesthesia for Filler Injections", Dermatol Surg 2005; 31:1635-1637.Visiol, Visoelstic gel for use in ocular surgery, (2010) p. 1, http://

w w w . t r b c h e m e d i c a . c o m l i n d e x . p h p / o p t i o n ~ c o m . c o n t e n t & t a s .Waraszkiewicz, Sigmund M., et aI., "Stability-Indicating High-Performance Liquid Chromatographic Analysis of Lidocaine Hydrochloride and Lidocaine Hydrochloride with Epinephrine InjectableSolutions", Journal of Pharmaceutical Sciences, vol. 70, No. 11, Nov.1981, pp. 1215-1218.Xia, Yun et al., "Comparis on of Effects of Lidocaine Hydrochloride,Buffered Lidocaine, Diphenydramine, and Normal Saline AfterIntradermal Injection", Journal of Clinical Anesthesia, 14:339-343,2002.Yeom et al. "Effect of Cross-Linking Reagents for Hyaluronic AcidHydrogel Dermal Fillers on Tissue Augmentation and Regeneration."Bioconjugate Chern., 21(2): 240-247 (2010).Yui, Nobuhiko, et aI., "Inflammation responsive degradation ofcrosslinked hyaluronic acid gels," Journal of Controlled release, 22(1992) pp. 105-116.Yui, Nobuhiko, et aI., "Photo-responsive degradation of heterogeneous hydro gels comprising crosslinked hyaluronic aci d and lipidmicro spheres for temporal drug delivery," Journal of ControlledRelease, 26 (1993) pp. 141-145.Yun, YH et aI., "Hyaluronan Microspheres for Sustained Gene Delivery and Site-Specific Targeting.", Biomaterials, vol. 25, 2004, pp.147-157.Zheng et al. "In situ crosslinkable hyaluronan hydro gels for tissueengineering." Biomaterials 25(7-8): 1339-1348 (2004).Millay et al.; "Vasoconstrictors in Facial Plastic Surgery"; Archivesof Otolaryngology-Head & Neck Surgery; vol. 117; pp. 160-163;Feb. 1991.Wahl, "European Evaluation of a New Hyaluronic Acid Filler Incorporating Lidocaine", Journal of Cosmetic Dermatology; vol. 7; pp.298-303; 2008.Bucket al, "Injectable Fillers for our Facial Rejuvenation: a Review",Journal of Plastic, Reconstructive and Aesthetic Surgery, (2009),62:11-18, XP002668828.Park et aI., "Biological Characterization of EDC-crosslinked Collagen-Hyaluronic Acid Matrix in Dermal Tissue Restoration",Biomaterials 24 (2003) 1631-1641.Park et aI., "Characterization of Porous Collagen/HyaluronicAcid Scaffold Modified by l-ethyl-3-(3-dimethylaminopropyl)carbodiimide cross-linking", Biomaterials 23(2002): 1205-1212.* cited by examiner


13/22

u.s. Patent

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May 28,2013 US 8,450,475 B2

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theoretical result if idocaine isretained in the gel/theoretical result if idocaineis freely released/

60 80Time (hrs)

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14/22

US 8,450,475 B21

HYALURONIC ACID-BASED GELSINCLUDING LIDOCAINE

CROSS REFERENCE TO RELATEDAPPLICATIONS

2can, which is a major component of the extra-cellular matrixand is widely distributed in animal tissues. HA has excellentbiocompatibility and does not cause allergic reactions whenimplanted into a patient. In addition, HA has the ability tobind to large amounts of water, making it an excellent volumizer of soft tissues.The development ofHA-ba sed fillers which exhibit ideal invivo properties as well as ideal surgical usability has provendifficult. For example, HA-based fillers that exhibit desirable

This application claims the benefit of U.S. provisionalpatent application No. 611085,956, filed Aug. 4, 2008, U.S.provisional patent application No. 611087,934 filed on Aug.11,2008, and U.S. provisional patent application No. 611096,278 filed Sep. 11,2008 , the entire disclosures all ofwhich areincorporated herein by reference.10 stability properties in vivo, can be so highly viscous thatinjection through fine gauge needles is difficult. Conversely,HA-based fillers that are relatively easily injected throughfine gauge needles often have relatively inferior stabilityFIELD OF THE INVENTION

The present invention generally relates to injectable softtissue fillers and more specifically relates to hyaluronic acidbased dermal and subdermal fillers including an anestheticagent.BACKGROUND

15

20

properties in vivo.One method to overcome this problem is to use crosslinkedHA-based fillers. Crosslinked HA is formed by reacting freeHA with a crosslinking agent under suitable reaction conditions. Methods of preparing HA based soft tissue fillersincluding both crosslinked and free HA are well known.

It has been proposed to incorporate certain therapeuticagents, for example, anesthetic agents such as lidocaine, intoinjectable HA-based compositions. Unfortunately, HA-basedinjectable compositions which incorporate lidocaine duringthe manufacturing process are prone to partial or almost com-It is generally accepted that as a person ages, the facebegins to show effects of gravity, sun-exposure, and years offacial muscle movement, such as smiling, frowning, chewingand squinting. The underlying tissues that keep the skinappearing youthful begin to break down, often resulting inlaugh lines, smile lines, "crow' s feet" and facial creases oftenreferred to as the "effects of aging."

25 plete degradation prior to injection, particularly during hightemperature sterilization steps and/or whe n placed in storagefor any significant length of time.

In an effort to treat or correct the effects of aging, soft tissuefillers have been developed to help fill in facial lines anddepressions and for restoring fat loss-related tissue volumeloss. The soft tissue fillers thereby temporarily restore asmoother, more youthful appearance.

It is an objective of the HA-based soft filler compositionsand methods ofmaking and using them as described herein to30 provide soft tissue fillers that do not cause allergic reactions inpatients, are biocompatible and are stable and usable in vivoand include one or more local anesthetic agents.

Ideally, soft tissue fillers are long-lasting, soft, smooth and 35natural appearing when implanted in the skin or beneath theskin. Further, soft tissue fillers are easy to implant into apatient using a fine gauge needle and require low extrusionforce for injection. Ideal fillers would also cause no adverseside effects, and would be injectable with minimal or no 40discomfort to the patient.Collagen based soft tissue fillers were developed over 20years ago, and for some time, bovine collagen-based fillerswere the only U.S. Food and Drug Administration (FDA)approved dermal fillers. Because these dermal fillers are 45bovine based, one of the main disadvantages has been thepotential for allergic reaction in patients. It is believed thatapproximately 3-5% ofhuman subjects show serious allergicreactions to bovine collagen, thus requiring careful testingbefore using these fillers in any particular person. In addition 50to allergic reactions, collagen based fillers degrade rapidlyupon injection and require frequent treatments to sustain asmoother, more youthful appearance.In February 2003, human-derived collagen filler compositions received FDA approval. These collagens provide the 55advantage of a significantly reduced risk of allergic reactions.However, despite the reduced incidence of allergic reactions,the human derived collagen fillers still suffered from the rapiddegradation of the injected product.

SUMMARYThe present description relates to soft tissue fillers, forexample, dermal and subdermal fillers, based on hyaluronic

acid (HA) and pharmaceutically acceptable salts of HA, forexample, sodium hyaluronate (NaHA). HA-based compositions described herein include a therapeutically effectiveamount of at least one anesthetic agent. In one embodiment,for example, the anesthetic agent is lidocaine. The presentHA-based compositions including at least one anestheticagent have an enhanced stability, relative to conventionalHA-based compositions including, for example, lidocaine,when subjected to sterilization techniques such as autoclav-ing, and/or when stored for long periods at ambient temperature. Methods for preparing such HA-based compositions arealso provided as well as products made by such methods.Described herein are soft tissue filler compositions, saidcompositions generally comprise: a hyaluronic acid (HA)component crosslinked with a crosslinking agent selectedfrom the group consisting of 1,4-butanediol diglycidyl ether(BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane, and 1,4-butanedioldiglycidyl ether; and at least one an anesthetic agent combined with the crosslinked HA component.In yet another embodiment, the at least one anestheticagent is lidocaine. In a further embodiment, the amount of heanesthetic agent is present at a concentration between about

0.1 % and about 5.0% by weight of the composition. In stillanother embodiment, the anesthetic agent is present at a concentration between about 0.2% and about 1.0% by weight of

The search for fillers that do not provoke allergic reactions 60and sustain a smoother, more youthful appearance hasbrought about the development of hyaluronic acid (HA)based products. In December 2003, the first HA-based fillerwas approved by the FDA. This was rapidly followed by thedevelopment of other HA-based fillers. 65 the composition. In one embodiment, the anesthetic agent islidocaine and is present at a concentration of about 0.3% byweight of the composition.HA, also known as hyaluronan, is a naturally occurring,water soluble polysaccharide, specifically a glycosaminogly-


US 8,450,475 B21

HYALURONIC ACID-BASED GELSINCLUDING LIDOCAINE

CROSS REFERENCE TO RELATEDAPPLICATIONS

2can, which is a major component of the extra-cellular matrixand is widely distributed in animal tissues. HA has excellentbiocompatibility and does not cause allergic reactions whenimplanted into a patient. In addition, HA has the ability tobind to large amounts of water, making it an excellent volumizer of soft tissues.The development ofHA-ba sed fillers which exhibit ideal invivo properties as well as ideal surgical usability has provendifficult. For example, HA-based fillers that exhibit desirable

This application claims the benefit of U.S. provisionalpatent application No. 611085,956, filed Aug. 4, 2008, U.S.provisional patent application No. 611087,934 filed on Aug.11,2008, and U.S. provisional patent application No. 611096,278 filed Sep. 11,2008 , the entire disclosures all ofwhich areincorporated herein by reference.10 stability properties in vivo, can be so highly viscous thatinjection through fine gauge needles is difficult. Conversely,HA-based fillers that are relatively easily injected throughfine gauge needles often have relatively inferior stabilityFIELD OF THE INVENTION

The present invention generally relates to injectable softtissue fillers and more specifically relates to hyaluronic acidbased dermal and subdermal fillers including an anestheticagent.BACKGROUND

15

20

properties in vivo.One method to overcome this problem is to use crosslinkedHA-based fillers. Crosslinked HA is formed by reacting freeHA with a crosslinking agent under suitable reaction conditions. Methods of preparing HA based soft tissue fillersincluding both crosslinked and free HA are well known.

It has been proposed to incorporate certain therapeuticagents, for example, anesthetic agents such as lidocaine, intoinjectable HA-based compositions. Unfortunately, HA-basedinjectable compositions which incorporate lidocaine duringthe manufacturing process are prone to partial or almost com-It is generally accepted that as a person ages, the facebegins to show effects of gravity, sun-exposure, and years offacial muscle movement, such as smiling, frowning, chewingand squinting. The underlying tissues that keep the skinappearing youthful begin to break down, often resulting inlaugh lines, smile lines, "crow' s feet" and facial creases oftenreferred to as the "effects of aging."

25 plete degradation prior to injection, particularly during hightemperature sterilization steps and/or whe n placed in storagefor any significant length of time.

In an effort to treat or correct the effects of aging, soft tissuefillers have been developed to help fill in facial lines anddepressions and for restoring fat loss-related tissue volumeloss. The soft tissue fillers thereby temporarily restore asmoother, more youthful appearance.

It is an objective of the HA-based soft filler compositionsand methods ofmaking and using them as described herein to30 provide soft tissue fillers that do not cause allergic reactions inpatients, are biocompatible and are stable and usable in vivoand include one or more local anesthetic agents.

Ideally, soft tissue fillers are long-lasting, soft, smooth and 35natural appearing when implanted in the skin or beneath theskin. Further, soft tissue fillers are easy to implant into apatient using a fine gauge needle and require low extrusionforce for injection. Ideal fillers would also cause no adverseside effects, and would be injectable with minimal or no 40discomfort to the patient.Collagen based soft tissue fillers were developed over 20years ago, and for some time, bovine collagen-based fillerswere the only U.S. Food and Drug Administration (FDA)approved dermal fillers. Because these dermal fillers are 45bovine based, one of the main disadvantages has been thepotential for allergic reaction in patients. It is believed thatapproximately 3-5% ofhuman subjects show serious allergicreactions to bovine collagen, thus requiring careful testingbefore using these fillers in any particular person. In addition 50to allergic reactions, collagen based fillers degrade rapidlyupon injection and require frequent treatments to sustain asmoother, more youthful appearance.In February 2003, human-derived collagen filler compositions received FDA approval. These collagens provide the 55advantage of a significantly reduced risk of allergic reactions.However, despite the reduced incidence of allergic reactions,the human derived collagen fillers still suffered from the rapiddegradation of the injected product.

SUMMARYThe present description relates to soft tissue fillers, forexample, dermal and subdermal fillers, based on hyaluronic

acid (HA) and pharmaceutically acceptable salts of HA, forexample, sodium hyaluronate (NaHA). HA-based compositions described herein include a therapeutically effectiveamount of at least one anesthetic agent. In one embodiment,for example, the anesthetic agent is lidocaine. The presentHA-based compositions including at least one anestheticagent have an enhanced stability, relative to conventionalHA-based compositions including, for example, lidocaine,when subjected to sterilization techniques such as autoclav-ing, and/or when stored for long periods at ambient temperature. Methods for preparing such HA-based compositions arealso provided as well as products made by such methods.Described herein are soft tissue filler compositions, saidcompositions generally comprise: a hyaluronic acid (HA)component crosslinked with a crosslinking agent selectedfrom the group consisting of 1,4-butanediol diglycidyl ether(BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane, and 1,4-butanedioldiglycidyl ether; and at least one an anesthetic agent combined with the crosslinked HA component.In yet another embodiment, the at least one anestheticagent is lidocaine. In a further embodiment, the amount of heanesthetic agent is present at a concentration between about

0.1 % and about 5.0% by weight of the composition. In stillanother embodiment, the anesthetic agent is present at a concentration between about 0.2% and about 1.0% by weight of

The search for fillers that do not provoke allergic reactions 60and sustain a smoother, more youthful appearance hasbrought about the development of hyaluronic acid (HA)based products. In December 2003, the first HA-based fillerwas approved by the FDA. This was rapidly followed by thedevelopment of other HA-based fillers. 65 the composition. In one embodiment, the anesthetic agent islidocaine and is present at a concentration of about 0.3% byweight of the composition.HA, also known as hyaluronan, is a naturally occurring,water soluble polysaccharide, specifically a glycosaminogly-


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US 8,450,475 B23

In still another embodiment, the soft tissue filler composition has an extrusion force ofbetween about 10 N and about13 N, for example, at a rate of about 12.5 mmlminute. In yetanother embodiment, the composition has a viscosity ofbetween about 5 Pa*s and about 450 Pa*s, for example, whenmeasured at about 5 Hz.In one embodiment, the HA component is a gel, forexample, a cohesive, hydrated gel. In one embodiment, theHA component is a crosslinkedHA gel having no greater thanabout 1% to about 10% free HA. For purposes of this disclosure, free HA includes truly uncrosslinked HA as well aslightly crosslinked HA chains and fragments, all in solubleform in water.In yet other embodiments, the HA component comprisesgreater than about 10%, for example, greater than about 15%,for example, up to or greater than about 20% free HA.In yet another embodiment, the HA component is a gelcomprising particles ofcrosslinked HA in a relatively fluidicmedium of free HA. In some embodiments, the HA component has an average particle size of greater than about 200 flm,for example, greater than about 250 flm.Further described herein is a soft tissue filler compositioncomprising: a HA component crosslinked with 1,4-butanediol diglycidyl ether (BDDE), said HA component having adegree of crosslinking of less than about 5%, for example,about 2%, and an anesthetic component having a concentration between about 0.1 % and about 5.0% by weight of he softtissue filler composition, wherein the anesthetic is lidocaine.

4some embodiments, the average size of such particles is atleast about 200 fllll, and in other embodiments the averagesize of such particles is at least about 250 fllll.

Further described herein is a soft tissue filler compositioncomprising: a hyaluronic acid (HA) component crosslinkedwith 1 4-butanediol diglycidyl ether (BDDE), said HA component having a degree of crosslinking ofless than about 5%,and an anesthetic component having a concentration betweenabout 0.1 % and about 5.0% by weight of the soft tissue filler

10 composition, wherein the anesthetic is lidocaine.In a specific embodiment of the invention, a method ofpreparing a soft tissue filler composition is further described,the method comprising the steps of: providing dry free NaHAmaterial and hydrating the dry free NaHA material in an

15 alkaline solution to obtain an alkaline, free NaHA gel;crosslinking the free NaHA gel with BDDE to form acrosslinked alkaline HA composition with a degree ofcrosslinking less than about 5% and a pH above about 7.2;adding a solution containing 0.3% lidocaine HCl to the HA20 component having the adjusted pH to obtain said HA-basedfiller composition; homogenizing the HA-based filler composition thereby forming a homogenized HA-based filler

composition; and sterilizing the homogenized HA-basedfiller composition thereby forming a sterilized HA-based25 filler composition, wherein the soft tissue filler compositionhas a particle size of greater than about 200 flm, for example,a particle size of greater than about 250 fllll.

Further described herein are methods of preparing softtissue filler compositions, the methods comprising the steps 30of: providing a HA component crosslinked with at least onecrosslinking agent selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-ep-

BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1 graphically illustrates the lidocaine concentrationover time, in a gel tested in accordance with Example 4.

DEFINITIONSoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3- 35epoxycyclohexane, and 1,4-butanediol diglycidyl ether orcombinations thereof; adjusting the pH of said HA component to an adjusted pH above about 7.2; and adding a solutioncontaining at least one anesthetic agent to the HA componenthaving the adjusted pH to obtain a HA-based filler composi- 40tion.

Certain terms as used in the specification are intended torefer to the following definitions, as detailed below. Wherethe definition of terms departs from the commonly usedmeaning of the term, applicant intends to utilize the definitions provided below, unless specifically indicated.Autoclave stable or stable to autoclaving as used hereindescribes a product or composition that is resistant to degradation such that the product or composition maintains at leastone, and preferably all, of he following aspects after effective

In another embodiment, the composition is sterilized, forexample, by autoclaving, to form a sterilized composit ion andwherein the sterilized composition is stable at ambient temperature for at least about 6 months, for example, at least 9months, at least about 12 months or more. 45 autoclave sterilization: transparent appearance, pH, extrusionforce and/or rheological characteristics, hyaluronic acid(HA) concentration, sterility, osmolarity, and lidocaine concentration.In still another embodiment, the adjusted pH is above about7.5. In another embodiment, the method further comprises thestep of homogenizing the HA component during or after thestep of adding the solution containing the at least one anes- 50thetic agent. In a further embodiment, the step ofhomogeni zing comprises subjecting the composition to mixing wi th acontrolled shear.In another embodiment, the step of providing a HA component comprises providing dry free NaHA material andhydrating the dry free NaHA material in an alkaline solutionto obtain an alkaline, free NaHA gel. In yet another embodiment, the alkaline, free NaHA gel has a pH greater than about8.0. In still another embodiment the pH is greater than about10.In a further embodiment, the HA component comprisesgreater than about 20% free HA and the crosslinked portion ofthe HA component has a degree of cro s slinking of less thanabout 6% or less than about 5%.In still a further embodiment, the soft tissue filler composition has a particulate nature in that it comprises particles ofcrosslinked HA dispersed in a fluid soluble HA medium. In

High molecular weight HA as used herein describes a HAmaterial having a molecular weight of at least about 1.0million Daltons ( m w ~ 1 0 6 Da or 1 MDa) to about 4.0 MDa.For example, the high molecular weight HA in the presentcompositions may have a molecular weight of about 2.0MDa. In another example, the high molecular weight HA may55 have a molecular weight of about 2.8 MDa.Low molecular weight HA as used herein describes a HAmaterial having a molecular weight of less than about 1.0MDa. Low molecular weight HA can have a molecularweight of between about 200,000 Da (0.2 MDa) to less than60 about 1.0 MDa, for example, between about 300,000 Da (0.3MDa) to about 750,000 Da. (0.75 MDa).Degree of Crosslinking as used herein refers to the intermolecular junctions joining the individual HA polymer molecules, or monomer chains, into a permanent structure, or as65 disclosed herein the soft tissue filler composition. Moreover,degree of cro s slinking for purposes of the present disclosureis further defined as the percent weight ratio of he crosslink-


US 8,450,475 B23

In still another embodiment, the soft tissue filler composition has an extrusion force ofbetween about 10 N and about13 N, for example, at a rate of about 12.5 mmlminute. In yetanother embodiment, the composition has a viscosity ofbetween about 5 Pa*s and about 450 Pa*s, for example, whenmeasured at about 5 Hz.In one embodiment, the HA component is a gel, forexample, a cohesive, hydrated gel. In one embodiment, theHA component is a crosslinkedHA gel having no greater thanabout 1% to about 10% free HA. For purposes of this disclosure, free HA includes truly uncrosslinked HA as well aslightly crosslinked HA chains and fragments, all in solubleform in water.In yet other embodiments, the HA component comprisesgreater than about 10%, for example, greater than about 15%,for example, up to or greater than about 20% free HA.In yet another embodiment, the HA component is a gelcomprising particles ofcrosslinked HA in a relatively fluidicmedium of free HA. In some embodiments, the HA component has an average particle size of greater than about 200 flm,for example, greater than about 250 flm.Further described herein is a soft tissue filler compositioncomprising: a HA component crosslinked with 1,4-butanediol diglycidyl ether (BDDE), said HA component having adegree of crosslinking of less than about 5%, for example,about 2%, and an anesthetic component having a concentration between about 0.1 % and about 5.0% by weight of he softtissue filler composition, wherein the anesthetic is lidocaine.

4some embodiments, the average size of such particles is atleast about 200 fllll, and in other embodiments the averagesize of such particles is at least about 250 fllll.

Further described herein is a soft tissue filler compositioncomprising: a hyaluronic acid (HA) component crosslinkedwith 1 4-butanediol diglycidyl ether (BDDE), said HA component having a degree of crosslinking ofless than about 5%,and an anesthetic component having a concentration betweenabout 0.1 % and about 5.0% by weight of the soft tissue filler

10 composition, wherein the anesthetic is lidocaine.In a specific embodiment of the invention, a method ofpreparing a soft tissue filler composition is further described,the method comprising the steps of: providing dry free NaHAmaterial and hydrating the dry free NaHA material in an

15 alkaline solution to obtain an alkaline, free NaHA gel;crosslinking the free NaHA gel with BDDE to form acrosslinked alkaline HA composition with a degree ofcrosslinking less than about 5% and a pH above about 7.2;adding a solution containing 0.3% lidocaine HCl to the HA20 component having the adjusted pH to obtain said HA-basedfiller composition; homogenizing the HA-based filler composition thereby forming a homogenized HA-based filler

composition; and sterilizing the homogenized HA-basedfiller composition thereby forming a sterilized HA-based25 filler composition, wherein the soft tissue filler compositionhas a particle size of greater than about 200 flm, for example,a particle size of greater than about 250 fllll.

Further described herein are methods of preparing softtissue filler compositions, the methods comprising the steps 30of: providing a HA component crosslinked with at least onecrosslinking agent selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-ep-

BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1 graphically illustrates the lidocaine concentrationover time, in a gel tested in accordance with Example 4.

DEFINITIONSoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3- 35epoxycyclohexane, and 1,4-butanediol diglycidyl ether orcombinations thereof; adjusting the pH of said HA component to an adjusted pH above about 7.2; and adding a solutioncontaining at least one anesthetic agent to the HA componenthaving the adjusted pH to obtain a HA-based filler composi- 40tion.

Certain terms as used in the specification are intended torefer to the following definitions, as detailed below. Wherethe definition of terms departs from the commonly usedmeaning of the term, applicant intends to utilize the definitions provided below, unless specifically indicated.Autoclave stable or stable to autoclaving as used hereindescribes a product or composition that is resistant to degradation such that the product or composition maintains at leastone, and preferably all, of he following aspects after effective

In another embodiment, the composition is sterilized, forexample, by autoclaving, to form a sterilized composit ion andwherein the sterilized composition is stable at ambient temperature for at least about 6 months, for example, at least 9months, at least about 12 months or more. 45 autoclave sterilization: transparent appearance, pH, extrusionforce and/or rheological characteristics, hyaluronic acid(HA) concentration, sterility, osmolarity, and lidocaine concentration.In still another embodiment, the adjusted pH is above about7.5. In another embodiment, the method further comprises thestep of homogenizing the HA component during or after thestep of adding the solution containing the at least one anes- 50thetic agent. In a further embodiment, the step ofhomogeni zing comprises subjecting the composition to mixing wi th acontrolled shear.In another embodiment, the step of providing a HA component comprises providing dry free NaHA material andhydrating the dry free NaHA material in an alkaline solutionto obtain an alkaline, free NaHA gel. In yet another embodiment, the alkaline, free NaHA gel has a pH greater than about8.0. In still another embodiment the pH is greater than about10.In a further embodiment, the HA component comprisesgreater than about 20% free HA and the crosslinked portion ofthe HA component has a degree of cro s slinking of less thanabout 6% or less than about 5%.In still a further embodiment, the soft tissue filler composition has a particulate nature in that it comprises particles ofcrosslinked HA dispersed in a fluid soluble HA medium. In

High molecular weight HA as used herein describes a HAmaterial having a molecular weight of at least about 1.0million Daltons ( m w ~ 1 0 6 Da or 1 MDa) to about 4.0 MDa.For example, the high molecular weight HA in the presentcompositions may have a molecular weight of about 2.0MDa. In another example, the high molecular weight HA may55 have a molecular weight of about 2.8 MDa.Low molecular weight HA as used herein describes a HAmaterial having a molecular weight of less than about 1.0MDa. Low molecular weight HA can have a molecularweight of between about 200,000 Da (0.2 MDa) to less than60 about 1.0 MDa, for example, between about 300,000 Da (0.3MDa) to about 750,000 Da. (0.75 MDa).Degree of Crosslinking as used herein refers to the intermolecular junctions joining the individual HA polymer molecules, or monomer chains, into a permanent structure, or as65 disclosed herein the soft tissue filler composition. Moreover,degree of cro s slinking for purposes of the present disclosureis further defined as the percent weight ratio of he crosslink-


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US 8,450,475 B25

ing agent to HA-monomeric units with in the crosslinked po

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Allergan et. al. v. Medicis Aesthetics et. al