(19) United States (12) Reissued Patent

(45) Date of Reissued Patent:

Emanuele et al. (54) POLYOXYPROPYLENE/

4,764,567 4,801,452 4,837,014 4,837,083 4,873,083 4,879,109 4,897,263 4,937,070 4,997,644 5,017,370 5,028,599 5,030,448 5,032,394 5,039,520 5,041,288


(75) Inventors: R. Martin Emanuele, Alpharetta, GA (US); Robert L. Hunter, Bellaire, TX

(US); Paula H. Culbreth, Loganville, GA (US)

(73) Assignee: CytRX Corporation, Los Angeles, CA

(Us) (21) Appl. No.: 09/460,298 (22) Filed:

Dec. 9, 1999




Dec. 9, 1997

Appl. No.:



Jun. 2, 1995

Division of application No. 08/087,136, ?led on Jul. 2, 1993, now Pat. No. 5,523,492, which is a continuation of appli cation No. 07/847,874, ?led on Mar. 13, 1992, now aban

doned, which is a continuation-in-part of application No. 07/673,289, ?led on Mar. 19, 1991, now abandoned.


Int. Cl? ....................... .. c07c 43/02; c07c 43/04;


US. Cl. ...................................... .. 568/623; 568/624


Field of Search ..

covc 43/11



4/1954 9/1958 4/1961 5/1962 5/1963

Lundsted Buckwalter et al. Lundsted Jackson Stone

3,140,232 A

7/1964 Noseworthy

3,228,834 A 3,391,196 A

1/1966 Gans 7/1968 Earing et al.

3,450,502 A 3,577,522 A 3,590,125 A

6/1969 Hymes 5/1971 Hymes 6/1971 Hymes

3,641,240 3,740,421 3,867,521 3,867,533 3,956,259 3,980,772 4,073,886 4,100,271 4,104,455 RE29,909 4,179,337 4,186,253 4,195,167


4,275,244 A

2/1972 6/1973 2/1975 2/1975 5/1976 9/1976 2/1978 7/1978 8/1978 2/1979 12/1979 1/1980 3/1980

Ott Hunter Hunter Hunter Hunter Hunter Hunter Hunter Hunte Hunter Hunter Hunter Hunter Hunter Hunter

et et et et

al. al. al. al.

et al.


0000704 0003399 0049422 0098110

33193/70 5094 206763/88 1183112 WO 87/06831 WO 87/06836 WO 88/06038 WO 90/07336

A1 A3 A3 A3

2/1979 9/1979 4/1982 1/1984

10/1970 1/1979 8/1988 10/1985 11/1987 11/1987 8/1988 7/1990


....... .. 568/623, 624

References Cited

2,674,619 2,854,378 2,979,528 3,036,118 3,089,818

8/1988 1/1989 6/1989 6/1989 10/1989 11/1989 1/1990 6/1990 3/1991 5/1991 7/1991 7/1991 7/1991 8/1991 8/1991


Reissue of:



Jul. 20, 2004

(List continued on neXt page.)

Related US. Patent Documents

(64) Patent No.:

US RE38,558 E

(10) Patent Number:

Hymes et al. Schmolka Miskel et al. Schmolka Garcia et al. Ginger et al. Kehm Krezanoski Nagasawa et al. KurtZ Davis et al. Yokoyama et al. Knopf et al.

6/ 1981 Helfert et al.

Schmolka, L., “A Review Of Block Polymer Surfactants”, Journal of theAmerican Oil Chemists Society, 54, No. 3, pp.

110—116 (1977). Block and Graft CopolymeriZation, vol. 2, (ed. by R]. Ceresa, John Wiley & Sons, 1976) “The Applications of Block Copolymer Polyol Surfactants”, L. G. Lundsted and I. R. Schmolka; pp. 174 through 205 and pp. 255—272

(references). Reindorf, C.A., et al., “Per?uorocarbon Compounds: Effects on the Rheological Properties of Sickle Erythrocytes in vitro”, American Journal of Hematology, vol. 19, pp.

229—236 (1985). (List continued on neXt page.)

Primary Examiner—Paul F. Shaver

(74) Attorney, Agent, or Firm—Andy Arismendi, Jr.



The present invention comprises novel preparations of

polyoXypropylene/polyoXyethylene copolymers which retain the therapeutic activity of the commercial preparations, but are substantially free from the undesirable effects which are inherent in the prior art preparations.

Because the preparations of polyoXypropylene/

polyoXyethylene copolymers which comprise the present

4,305,922 A 4,378,347 A 4,395,393 A

12/1981 Rhodes 3/1983 Franco 7/1983 Schmolka

invention are a less polydisperse population of molecules

4,407,790 4,600,652 4,606,918 4,609,546

10/1983 Oakes et al. 7/1986 Solomon et al. 8/1986 Allison et al.

better de?ned and more predictable.


9/ 1986 Hiratani

than the prior art polyoXypropylene/polyoXyethylene

copolymers, the biological activity of the copolymers is 16 Claims, 20 Drawing Sheets

US RE38,558 E Page 2

5,047,236 5,057,540 5,064,643 5,071,649 5,078,995 5,080,894 5,089,260 5,114,708 5,183,687 5,198,211 5,250,294 5,294,365 5,340,916


Block, N.L., et al., “Acutely traumatized canine ureter,


Pluronic F—68”, Urology, vol. III, pp. 190—194 (1974). KniZe, D.M., et al., “Use of antisludging agents in experi mental cold injuries”, Surgery, Gynecology & Obstertrics, vol. 129, pp. 1019—1026 (1969).

9/1991 10/1991 11/1991 12/1991 1/1992 1/1992 2/1992 5/1992 2/1993 3/1993 10/1993 3/1994 8/1994

5,371,253 A

12/1994 Cooper

5,523,492 A 5,596,059 A

Hunter et al. Kensil et al. Hunter et al. Hunter Hunter et al. Hunter et al. Hunter et al. Hunter et al. Hunter et al. Hunter et al. Hunter et al. Welch et al. Henn et al.


Effects of loW molecular Weight dextran and surfactant

Organ Perfusion and Preservation, (ed. by Norman, J.C., Appleton—Century—Crofts, (1968)). Paton, B.C., et al., “The use of a nonionic detergent added to organ perfusates” pp. 105—120.

Smillie, J.A., et al., “Cryopreservation of Human Platelets With Polyvinylpyrrolidone”, Transfusion, vol. 21, pp.

552—556, (1981). Gaehtgens, P., et al., “Desaggregation of Human Red Blood

6/1996 Emanuele et al.

Cells by Various Surface—Active Agents as Related to

1/1997 Hager et al. .......... .. 568/623 X

Changes of Cell Shape and Hemolysis”, Act Heamat. vol. 33, pp. 82—89 (1975). Advances in Blood Substitute Research (ed. by Bolin, et al.,


Padilla, F., et al., “Effect of Fluorocarbon emulsions on the mechanical fragility of normal and sickle cells: in vitro studies” Federation Proceedings, vol. 34, pp. 1510—1512

(1975). Vercellotti, G.M., et al., “Activation of Plasma Complement by Per?uorocarbon Arti?cial Blood: Probable Mechanism of Adverse Pulmonary Reactions in Treated Patients and Ratio nale for Corticosteroid Prophylaxis”, Blood, vol. 59, pp.

1299—1304 (1982). Rodeheaver, G.T., “Pluronic® F—68: A Promising NeW Skin Wound Cleanser”, Ann Emerg Med, 9:11, pp. 572—576

(1980). J anoff, A.S., et al., “The Modi?cation of Human Erythrocyte Membrane Structure by Membrane Stabilizers: An Electron

Spin Resonance Study”, American Journal of Hematology, vol. 10, pp. 171—179 (1981). Moore, A.R., et al., “Reduction Of Splenic Vascular Resis tance During Profusion By Pluronic® F.—68”, Journal of Surgical Research, vol. 8, pp. 563—566 (1968). Benner, K.U., et al., “Cold—Induced Platelet Aggregation In Vivo And Its Inhibition By A Nonionic Surface Active

Substance”, Thrombosis Research, vol. 2, pp. 331—342

(1973). Hymes, A.C., et al., “The In?uence Of An Industrial Sur factant Pluronic® F—68, In The Treatment of Hemorrhagic

Shock”, Journal ofSurgical Research, vol. 11, pp. 191—197

Alan R. Liss, Inc. NeW York, (1983)) Sugi, et al., The use of Fluosol—DA (FDA) in emergency situations: a report of 67 clinical cases, Abstract/451.

Lane, T.A., et al., “Reduction in the Toxicity of a component of an arti?cial blood substitute by supercritical ?uid frac

tionation”, Transfusion, vol. 28, pp. 375—378 (1987). Lane, T.A., et al., Paralysis of phagocyte migration due to an arti?cial blood substitute, Blood, vol. 64, pp. 400—405

(1984). Spiess, B.D., et al., “Protection from cerebral air emboli

With per?uorocarbons in rabbits”, Stroke, vol. 17, pp. 1146—1149 (1986). Kanter, K.R., et al., “Superiority of per?uorocarbon car dioplegia over blood or crystalloid cardioplegia”, Circula

tion, vol. 64, pp. II—75—II—80 (1981). Harjula, A., et al., “Per?uorocarbon solution as a myocardial

preservative”, J. Applied Cardiology, vol. 2, pp. 121—136

(1987). Tokioka, M.D., et al., “Effects of intracoronary infusion of arterial blood or Fluosol—DA 20% on regional myocardial

metabolism and function during brief coronary artery occlu

sions”, Laboratory Investigation, vol. 75, pp. 473—481

(1987). Forman, M.B., et al., “Reduction of infarct siZe With intra coronary per?uorochemical in a canine preparation of rep

erfusion”, Circulation, vol. 71, pp. 1060—1068 (1985). Forman, M.B., et al., “Bene?cial long—term effect of intra


coronary per?uorochemical on infarct siZe and ventricular

Hoie, J ., et al., “Effects of Pluronic® F—68, Poloralkol, On

function in a canine reperfusion model”, J. Am. Col. of

Vascular Resistance In Vivo”, Journal of Surgical Research, vol. 11, pp. 515—517, (1971). Grover, F.L., et al., “A Nonionic Surfactant And Blood

Viscosity”, Arch. Surg., vol. 106, pp. 307—310 (1973). Grover, F.L., et al., “The Effect of Pluronic® F—68 On

Circulatory Dynamics And Renal And Carotid Artery FloW

Cardiol., pp. 1082—1090 (May, 1987). Goodman, R.L., et al., “Per?uorocarbon emulsions in cancer

therapy: preliminary observations on presently available formulations”, Int. J. Radiation Oncology Biol. Phys., vol. 10, pp. 1421—1424 (1984). Grover et al., “A Nonionic Surfactant and Blood Viscosity—

During Hemorrhagic Shock”, Journal of Surgical Research,

Experimental Observations,” Arch. Surg., vol. 106, pp.

vol. 17, pp. 30—35 (1974). Ketchum, L.D., et al., “Experimental Use Of Pluronic®

307—310 (Mar. 1973).

F—68 In Microvascular Surgery”, Plastic and Reconstructive

Connaghan et al., “Speci?c Identi?cation of Fibrin Poly mers, Fibrinogen Degradation Products, and Crosslinked

Surgery, vol. 53, pp. 288—292 (1974). Ketchum, L.D., “Pharmacological alterations in the clotting

Fibrin Degradation Products in Plasma and Serum With a

NeW Sensitive Technique,” Blood, vol. 65, No. 3, pp.

mechanism: Use in microvascular surgery”, Journal of Hand Surgery, vol. 3, pp. 407—415 (1978).

Atkinson et al., “Iontransport mediated by copolymers com

Vasko, K. A., et al., “Poloxalkol® (Pluronic F—68): A priming solution for cardiopulmonary bypass”, Trans. Am. Soc. Artif. Int. Organs, 18, pp. 526—531 (1972).

posed of polyoxyethylene and polyoxypropylene.” The American Physiological Society, 0363—6143/88, pp. C20—C26 (1988).

589—597 (Mar. 1985).

US RE38,558 E Page 3

Wiman et al., “Determination of Soluble Fibrin in Plasma by

Hunter et al., Increased Whole Blood Viscosity during

a Rapid and Quantitative Spectrophotometric Assay,” Thrombosis and Haemostasis, F.K. Schattauer Verlag GmbH

Coronary Bypass Surgery, Thromb. Haemost., vol. 63, No. 1, pp. 6—12 (Feb. 19, 1990).

(Stuttgart) 55 (2), pp. 18—193 (1986).

Hymes, A.C., et al., “In?uence of an Industrial Surfactant

Hunter et al., “The Adjuvant Activity of Nonionic Block Polymer Surfactants,” Scand. J. Immunol., No. 23, pp.

(Pluronic F—68) on Human Amniotic Fluid Embolism”, American Journal Obstertrics and Gynecology, vol. 107(8),

287—300 (1986).

pp. 1217—1222 (Aug. 15, 1970).

Technical bulletin entitled “Performance Chemicals”, 1971. Technical bulletin entitled “Pluronic® Block copolymer

Justice, C., et al., “Prevention of Thrombosis With Agents

surfactants”, 1972. Uno, T., et al., “Determination of Surface—Active Agents, VIII, Infrared Determination of the Proporation of the Eth ylene Oxide and Propylene Oxide in Pluronic”, Chem. Pharm. Bull., vol. 15(1), pp. 77—82 (1967). Williams, J .H. et al., “Modulation of Rat Granulocyte Traffic by a Surface Active Agent in Vitro and Bleomycin Injury,”

Proceedings of the Society of Experimental Biology and Medicine, vol. 188, pp. 461—470 (1988). Database WPI, DerWent Publications Ltd., London, GB; AN 82—14781E(08) & JP—A—57 008 223 (mitsui Petrochem.)

Which Reduce Platelets Adhesiveness”, The American Sur

geon, vol. 40, pp. 186—189 (Mar. 1974). Kondo et al., “Prolonged Suspended Animation in Puppies.” Cryobiology, vol. 11, No. 5, pp. 446—451 (1974). Maugh, T.H., “Per?uorochemical Emulsions: Promising Blood Substitutes”, Science, vol. 179, pp. 669—672 (Feb.

1973). MeZroW et al., “Poloxamer 188 improves neurologic out come after hypothermic circulatory arrest,” J. Thorac. Car

diovas. Surg., vol. 103, No. 6, pp. 1143—1146 (Jun., 1992). Nagata et al., “Clinical Evaluation on the Effect of Polox amer 188 on the Hemolysis during Cardiopulmonary

Bypass,” J. Aichi, Med. Univ. assoc., vol. 11, No. 1, pp.

Jan. 16, 1982. *abstract only*. Schick, M.J., Non—ionic Surfactants, Marcel Dekker Inc., NeW York, pp. 893—920 (1967). Per?urochemical Blood Substitute, Technical Information Ser. No. 5, Jun. 30, 1978, Revised, Jul. 1, 1981, Manufac

48—54 (1983).

turer: The Green Cross Corporation. Benner, K.U., et al., “Uber die Wirkung von Pluronic®

Richard, M.N., et al., Effect of Lysine and Wettig Agents on Activiated Plasinogen Solutions:, Canadaian Journal of Bio


chemistry & Physiology, vol. 41, pp. 211—217 (1963).



en—Kondensat, auf die ADP—induZierte Thrombocytenag gregation in vitro”, Plugers Arch., vol. 315, pp. 45—52

(1970). Byars, N.E., et al. “Adjuvant formulation for use in vaccines to elicit both cell—mediated and humoral immunity,” Vac

cine, vol. 5, pp. 223—228 (Sep. 1987). Danielson, G., et al., “Use of Pluronic F—68 to Dimish Fat

Emboli and Hemolysis During Cardiopulmonary Bypass”, The Journal of Thoracic and Cardiovascular surgery, vol.

59(2)., pp. 178—184 (Feb. 1970). Grover, F.L., et al., “Bene?cial Effect of Pluronic F—68 on

the Microcirculation in Experimental Hemmorrhagic Schock”, Surgical Forum, vol. 21, pp. 30—32 (1970). Heron, M. W., et al., “A Method for measuring a Nonionic

surface—Active Agent (Pluronic F—68) in Biological Fluids”, Analytical Biochemistry, vol. 214, pp. 491—495 (1968). Hunter et al, “The Adjuvant Activity of Nonionic block Polymer Surfactants I. The Role of Hydrophile—Lipophile Balance,” I J. of Immunology, vol. 127, No. 3, pp.

1244—1250, (1981). Hunter, R.L., “The Adjuvant Activity of Nonionic block Polymer Surfactants II AntibodyFormulation and Infamma

Papadea et al, “Effect of RheothRx (TM) Copolymer on Blood viscosity related to Fibrin(ogen) concentration,” Faseb J., vol. 2, No. 4, p. A384A, abstract 512 (Mar. 15,


Rodeheaver et al, “Mechanical Cleansing of Contaminated Wounds With Surfactant,” Am. J. surg., vol. 129, No. 3, pp.

241—245 (1975). Sakauchi, “Prevention of Excess Hemolysis During Car diopulmonary bypass by the use of Ploronic F—68,” Kita kanto Med. J., vol. 23, No. 3, pp. 231—238 (1973). Schmolka, I.R. et al., “Arti?cial skin I. Preparation and Properties of Pluronic F—127 Gels for Treatment of Burns,” J. Biomed. Mater. Res., vol. 6, pp. 571—582 (1972). Snippe, H. et al., “Adjuvant Effect of Nonionic Block Polymer Surfactants in Humoral and Cellular Immunity,” Int. Archs Allergy appl. Immun., vol. 65, pp. 390—398

(1981). Takayama, K. et al., “Adjuvant activity of non—ionic block copolymers, v. Modulation of antibody isotype by lipopolysaccharides, lipid A and precursors,” Vaccine, vol.

9, pp. 257—265 (Apr. 1991). National Institute of Health, Final Report: Supercritical

Fluid Fractionation of Pluronic 68, (May 12, 1986). P. K. Bentley et al., Purification of Pluronic F—68 for Per?uorochemical Emulsi?cation, J. Pharm. Pharmacol. 41, 661—63 (1989).

tion related to the Structure of Triblock and Octablock

Herbert G. Nadeau and Paul H. WasZeciak, Separational

Copolymers,” J. Immun., vol. 133, No. 6, pp. 3167—3175

Methods, NONIONIC SURFACTANTS, 893—920 (1967). P. J. Flory et al., High Polymers.'A Series of Monographs on

(1984). Hunter R.L. et al., “Adjuvant activity of non—ionic block copolymers. IV. Effect of molecular Weight and formulation on titre and isotype of antibody,” Vaccine, vol. 9, pp.

the Chemistry, Physics, and Technology of High Polymeric Substances, (Interscience Publishers 19##), 1967.

250—256 (Apr. 1991).

Surface—Active Polyoxyethylene Ethers in Mice, NATURE, vol. 168, 150—53 (Jul. 28, 1951).

Hunter, R.L. et al., “Nonionic Block Copolymer surfactants as Immunological Adjuvants; Mechanisms of Action and

Novel Formulations,” Immunological Adjuvants and Vac cines, ed. By Gregoriadis, g. et al., Plenum Publishing corp., pp. 133—144 (1989).

J. W Comforth et al., Antituberculous E?rect of Certain Thomas A. Lane and G. E. Lamkin, Increased Infection Mortality and Decreased Neutrophil Migration Due to a

Component of an Arti?cial Blood Substitute, BLOOD, vol.

68, No. 2, 351—54 (Aug. 1986).

US RE38,558 E Page 4

Alfred J. CroWle, Studies ofAntitubercolosis Chemotherapy

The Patent Coorperation Trreaty International Search Report

With an In Wtro Model ofHuman Tuberculosis. SEMINARS

for PCT Patent Application No. PCT/US87/01067.

IN RESPIRATORY INFECTIONS, vol. 1, No. 4, 262—64

(Dec. 1986). H. Ohyanagi et. al., Clinical Studies of Per?uorochemical Whole Blood Substitutes: Safety of Fluosoi—DA (20%) in Normal Human Volunteers, CLINICAL THERAPEUTICS, vol. 2, No. 4, 306—12 (1979). F. H. Armstrong and K. C. Lowe, E?rects of Emisi?ed

Patent Coorperation Treaty International Search Report for the PCT Patent Application No. PCT/US86/01747.

Ketchum, L.D., Experimental Use of Pluronic F—68 in Microvascular Surgery, Plastic Reconstructive Surgery, vol.

Per?uorochemicals on Liver Cytochromes R—450 in Rats, COMP. BIOCHEM. PHYSTOL., vol. 94C, No. 1, 345—49

54, p. 478 (Oct. 1974).

(1989). “Nissan Plonon Tokushu Kobunshi Kaimen Kassei Zai

Hunter R.L. et al., “The Adjuvant Activity of Nonionic Block Polymer Surfactants. III. Characterization of Selected Biologically Active Surfaces,” Scand. J. Immunol., vol. 23, pp. 287—300 (1986).*

(phonetically)”, Nippon Oil & Fats Co.’s catalog issued Apr., 1980.

* cited by examiner

Brooks, et al, “Rheology of blood cells,” Dept. of Pathology and Chemistry, University of British Columbia, Vancouver, BC, Canada, pp. 73—96, 1985.

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Polyoxypropylene/polyoxyethylene copolymers with improved ...

Dec 9, 1999 - 307—310 (1973). Grover, F.L., et al., “The Effect of Pluronic® F—68 On ..... National Institute of Health, Final Report: Supercritical. Fluid Fractionation of ... the Chemistry, Physics, and Technology of High Polymeric. Substances ...

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