Pegasus Laboratories v. US Compounding

8/13/2019 Pegasus Laboratories v. US Compounding

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FILEDU DISli{ICT COURTEASTERN DISTRICT ARKANSAS

IN THE UNITED STATES DISTRICT COURT FOR THEJAN O0 QEASTERN DISTRICT OF ARKANSAS 4WESTERN DIVISION JAMES W. McCORMACK, CLERK

PEGASUS LABORATORIES, INC., By =::liQ DEPCLERKPlaintiff, Case No. l.\ .\l\ c \1 \4 ::1 \Jo\

vs.US COMPOUNDING, INC., JURY TRIAL DEMANDED

Defendant. . ,-:·;a assigned to District Judge,: 111 ::( 1\ tagistrate Judge - - -----

COMPLAINT AND DEMAND FOR JURY TRIALPlaintiff Pegasus Laboratories, Inc., by its undersigned attorneys, for its Complaint

against Defendant US Compounding, Inc. alleges as follows:THE PARTIES

1 Plaintiff Pegasus Laboratories, Inc. (hereinafter, Pegasus or Plaintif f') is acorporation organized and existing under the laws of the State of Missouri, with its principaloffice located at 8809 Ely St., Pensacola, Florida 32514. Pegasus is a developer, manufacturer,and marketer of animal health products under the PRN Pharmacal brand name.

2 Pegasus is informed and believes, and on that basis alleges that Defendant USCompounding, Inc. (hereinafter, US Compounding or Defendant ), is a corporation organizedand existing under the laws of the State of Arkansas, with its principal office located at 1270Don s Lane, Conway, Arkansas 72032. US Compounding is a pharmacy that engages incompounding medications, including those sold in the animal pharmaceutical industry.

JURISDICTION AND VENUE3 This action arises under the patent laws of the United States and is an action for


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correct copy of the '308 Patent is attached hereto as Exhibit B and made a part hereof byreference as though fully set forth herein.

10. United States Patent Number 6,448,252 ( the '252 Patent ) entitledTREATMENT OF EQUINE PROTOZOAL MYELOENCEPHALITIS was duly, validly, and

legally issued by the United States Patent and Trademark Office on September 10, 2002. A trueand correct copy of the '252 Patent is attached hereto as Exhibit C and made a part hereof byreference as though fully set forth herein.

IDEXX Laboratories, Inc. s ownership o the Patents in Suit11. IDEXX Laboratories, Inc. ( IDEXX ), having a principal office at One IDEXX

Drive, Westbrook, Maine 04092, has been the sole assignee of each of the Patents in Suit since atleast September, 2004.

12. IDEXX owns the right, title, and interest to the Patents in Suit.IDEXX s grant o Exclusive License t Animal Health Pharmaceuticals

13. IDEXX, by an Exclusive License Agreement dated July 9 2010, granted toAnimal Health Pharmaceuticals, LLC ( AHP ) having a principal place of business at 1805 OakRidge Circle, Suite 101, P 0 Box 6292, Fairleigh Station, St. Joseph, Missouri 64506, anexclusive nationwide license to make, have made, use, sell, offer to sell, lease, import, export,and develop products covered by the Patents in Suit.

14. IDEXX also granted to AHP per this Exclusive License Agreement the sole right

to sublicense the Patents in Suit to alleged infringers.15. IDEXX further granted to AHP per this Exclusive License Agreement the right to

bring actions for patent infringement against third parties who infringe one or more of thePatents in Suit.

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AHP's transfer o rights in the Exclusive License Agreement and ReBalance®Antiprotozoal Oral Suspension Product ( ReBalance® Product ) t Pegasus16 AHP, by an Asset Transfer Agreement dated September 30, 2010, and with

IDEXX's consent, validly transferred its right, title, and interest in the Exclusive LicenseAgreement to Pegasus.

17 Thus, Pegasus has the legal right and authority to bring this action and stopinfringement of the Patents in Suit.

18 AHP, by this Asset Transfer Agreement, further transferred to Pegasus itsmarketing rights in the ReBalance® Product. The ReBalance® Product combines sulfadiazineand pyrimethamine and is used for treatment of horses with EPM caused by sarcocystic neurona.The ReBalance® Product is the subject of the Food and Drug Administration Center forVeterinary Medicine ( FDA-CVM ) approved New Animal Drug Application 141-240 ( NADA141-240 ), a Freedom of Information Summary of which is attached hereto as Exhibit D andmade a part hereof by reference as though fully set forth herein. Pegasus is the current sponsorofN D 141-240.

US Compounding's infringement o the Patents in Suit19 US Compounding markets and sells in this District and elsewhere, including via

US Compounding's website (www.uscompounding.com), compounded medication product fortreatment of horses with EPM caused by sarcocystic neurona. This compounded medicationproduct for treatment of EPM is compounded from bulk active sulfadiazine and pyrimethamineingredients. This compounded medication infringes at least one claim of each of the Patents inSuit.

20. Upon information and belief, US Compounding continues to compound, market,and sell its infringing product for treatment of EPM in the state of Arkansas and elsewhere.

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OUNT I(Infringement of the 476 Patent)

21. Pegasus incorporates by reference all previous allegations as if set forth herein.22. The 476 Patent is presumed to be valid.23. Pegasus has complied with any applicable marking requirements of 35 U.S.C. §

287 with respect to the 476 Patent.24. US Compounding has infringed and is infringing at least one claim of the 476

Patent in violation of 5 U.S.C. § 271(a) by compounding, manufacturing, marketing, and sellingthe infringing product. US Compounding is further infringing at least one claim of the 476Patent in violation of 5 U.S.C. § 271(b) by inducing infringement with its infringing product.

25. US Compounding has had actual notice of the Patents in Suit and of Pegasusrights in the 476 Patent since at least June 21, 2013. US Compounding s infringement of the476 Patent has been and continues to be willful and deliberate.

26. US Compounding s infringement of the 476 Patent has caused great damage toPegasus. The amount of these damages is not yet known, but Pegasus has lost profits androyalties as a result of the infringement and is entitled to damages adequate to compensate it forthe infringement in an amount that is in no event less than a reasonable royalty under 35 U.S.C. §284.

27. Pegasus may also be entitled to recover prejudgment interest, costs, and up totreble damages under 35 U.S.C. § 284.

28 Further, this is an exceptional case under 35 U.S.C. § 285 (e.g., due to the willfulnature of US Compounding s infringement) and Pegasus should be awarded its attorneys fees.

29. As a result of US Compounding s infringement of the 476 Patent, Pegasus hassuffered and continues to suffer irreparable harm and impairment ofthe value of its patent rights,

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and is suffering the violation of its patent rights, all of which will continue unless USCompounding is permanently enjoined by this Court from infringing the 476 Patent under 35U.S.C. 283. Pegasus has no adequate remedy at law.

COUNT II(Infringement o the 308 Patent)30 Pegasus incorporates by reference all previous allegations as if set forth herein.31. The 308 Patent is presumed to be valid.32. Pegasus has complied with any applicable marking requirements of 35 U.S.C.


Patent in violation of 5 U.S.C. 271(a) by compounding, manufacturing, marketing, and sellingthe infringing product. US Compounding is further infringing at least one claim of the 308Patent in violation of 5 U.S.C. 271(b) by inducing infringement with its infringing product.

34. US Compounding has had actual notice of the Patents in Suit and of Pegasus

rights in the 308 Patent since at least June 21, 2013. US Compounding s infringement of the308 Patent has been and continues to be willful and deliberate.

35. US Compounding s infringement of the 308 Patent has caused great damage toPegasus. The amount of these damages is not yet known, but Pegasus has lost profits androyalties as a result of the infringement and is entitled to damages adequate to compensate it forthe infringement in an amount that is in no event less than a reasonable royalty under 35 U.S.C. §284.

36. Pegasus may also be entitled to recover prejudgment interest, costs, and up totreble damages under 35 U.S.C. 284.

37 Further, this is an exceptional case under 35 U.S.C. 285 (e.g., due to the willful

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nature ofUS Compounding s infringement) and Pegasus should be awarded its attorneys fees.38. As a result of US Compounding s infringement of the 308 Patent, Pegasus has

suffered and continues to suffer irreparable harm and impairment of the value of its patent rights,and is suffering the violation of its patent rights, all of which will continue unless USCompounding is permanently enjoined by this Court from infringing the 308 Patent under 35U.S.C. § 283. Pegasus has no adequate remedy at law.

COUNT III(Infringement o the 252 Patent)

39. Pegasus incorporates by reference all previous allegations as if set forth herein.40. The 252 Patent is presumed to be valid.41. Pegasus has complied with any applicable marking requirements of 35 U.S.C. §


Patent in violation of35 U.S.C. § 271(a) by compounding, manufacturing, marketing, and selling

the infringing product. US Compounding is further infringing at least one claim of the 252Patent in violation of35 U.S.C. § 27l(b) by inducing infringement with its infringing product.

43. US Compounding has had actual notice of the Patents in Suit and of Pegasusrights in the 252 Patent since at least June 21, 2013. US Compounding s infringement of the252 Patent has been and continues to be willful and deliberate.

44. US Compounding s infringement of the 252 Patent has caused great damage toPegasus. The amount of these damages is not yet known, but Pegasus has lost profits androyalties as a result of the infringement and is entitled to damages adequate to compensate it forthe infringement in an amount that is in no event less than a reasonable royalty under 35 U.S.C §284.


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45 Pegasus may also be entitled to recover prejudgment interest, costs, and up totreble damages under 35 U.S.C. 284.

46. Further, this is an exceptional case under 35 U.S.C. 285 (e.g., due to the willfulnature ofU Compounding s infringement) and Pegasus should be awarded its attorneys fees.

47. As a result of US Compounding s infringement of the 252 Patent, Pegasus hassuffered and continues to suffer irreparable harm and impairment of the value of its patent rights,and is suffering the violation of its patent rights, all of which will continue unless USCompounding is permanently enjoined by this Court from infringing the 252 Patent under 35U.S.C. 283. Pegasus has no adequate remedy at law.

PR YER FOR RELIEF S TO LL CL IMSWHEREFORE, PlaintiffPegasus Laboratories, Inc. respectfully prays for the entry of the

following orders and judgments against Defendant US Compounding:(a) Finding that US Compounding infringes, directly or indirectly, each of the Patents in

Suit;(b) Preliminary and permanent injunctions against US Compounding and its parents,

subsidiaries, divisions, agents, dealers, officers, employees, successors, and assigns,and all others acting in concert or participation with US Compounding from:

1. making, using, selling, offering to sell, or importing the inventionsclaimed in the Patents in Suit; and

u. inducing infringement of the Patents in Suit;(c) Finding infringement of the Patents in Suit to be willful;(d) Awarding Pegasus such damages, attorneys fees, costs, prejudgment interest, and

enhanced damages for patent infringement as may be shown by the evidence;

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(e) Finding this to be an exceptional patent infringement case and awarding Pegasus itsreasonable attorneys' fees under 35 U.S.C. § 285; and

(f) Awarding Plaintiff such other and further relief as the Court may deem just andproper.

DEM ND FOR JURY TRI LPursuant to Fed. R. Civ. P. 38, Pegasus demands a trial by jury on all issues so triable.

Dated: January 7 2014

21136383vl

LATHROP GAGE LLP

By:

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aurel E. Stevenson AR 2012094)LATHROP GAGE LLP910 East St. Louis Street, Suite 100Springfield, Missouri 65806417.877.5917 (Tel)417.886.9126 (Fax)[email protected]. Cameron GarrisonPro Hac Vice Application to befiled)LATHROP GAGE LLP2345 Grand Boulevard, Suite 2200Kansas City, Missouri 64108-2618

816.292.2000 (Tel)816.292.2001 (Fax)[email protected] for Plaintiff PegasusLaboratories, Inc


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United States atent [l9JRussell et al.[54] TREATMENT OF EQUINE PROTOZOALMYELOENCEPHALITIS[75] Inventors: Merl Charm Russell. Des Moines.

Iowa; Clan K. Fenger, Lexington. Ky.[73] Assignee: Mortar Pestle Veterinary

Pharmacy, Inc . Des Moines. Iowa[21] Appl. No.: 683,507[22] Filed: Jul. 17, 1996[51] Int. CL A61K 311505; C07D 239/48[52] U.S. CI.............. - ............................. 514/275; 5441325[58] Field r Search ..................................... 544 325. 297;5141275[56] Refenmces Cited

4.293,5474,340,6094,368,1934,599,4164,728,6414,795,6394,992,4445,273,9705,486,.5355 506 206

U.S. PATENT DOCUMENfS1011981 l.ewJS et al .............................42411807/1982 Cbou ....................................... 42413221/1983 Argoudelis et a ..................... 4241180711986 Kompis ................................... 54412963/1988 Tubaro et al ............................ 514/541/1989 Burchall et al ......................... 51412492/1991 Steveos et al .......................... 514127512/1993 McHaroy ................................ 51411571/1996 Marr et al............................... 51414504/1996 Kozarich et al .......................... 514/15arHER PUBUCATIONS

David S. Undsay et al .. "Evalutation of Anti-coccidialDrugs' Inhibtion of NeosporQ caninum Development in CellCultures." The Journal of Parasitology. Dec. 1989, pp.990-992.David S. Lindsay et al.. "Demonstration of SynergisticEffects of Sulfonamides and Dihydrofolate Reductase/lbymidylate Synthase Inhibitors Against Neospora caninumTachyzoltes in Cultured Cells, and Characterization ot·Mutants Resistant to Pyrimethamine." AJVR. voL 57, Jan.1996, pp. 68-72.J.P. Dubey et ai . "Anticoccidial Activity of 2-SulfamoyJ..-4.4-Diaminodiphenylsulfone, Sulfadiazine. Pyrimethamineand Clindamycin io Cats Infected with Toxop Dsmu G o n d i ~1be Canadian Veterinary Journal. vol. 18. No. J. Mar. 1977.pp. 51-57.Daniel Podzamczer et al.. 'Twice-weekly, Maintenancelberapy with Sulfadiazioe-Pyrirnethamine to PreventRecurrent Toxoplasmic Encephalitis in Patients with AIDS."Annals of Internal Medicine. vol. 123. No. 3, pp. 175-180.B.T. Nguyen et al . "Comparative Effects of Cotrim.oxazole(Trimethoprimsulpharoethoxazole). Pyrimetharoioe..;;ulphadlazine and Spiraroycin During Avirulent Infectionwith Toxcp/Qsmu gondii (Beverley Strain) in Mice." Br. J.Pharmac . vol. 79. 1983. pp. 923-928.Carol Harris et al . In Vitro Assessment of AntimlcroblalAgents Against Toxoplasmu gondii." The Journal of Infectious Diseases. vol 157, No. 1. Jan. 198S, pp. 14-22.Harley G. Sheffield et al • "Effect of Pyrimethamine andSulfadiazine on lhe Fine Structure IUid Multiplication ofToxop Dsma gondii in Cell Cultures." The JoLU'nal of Parasitology. vol. 61. No.4. Aug. 1975, pp. 704-712.

US005747476A[llJ Patent Number:{451 Date of Patent:

5,747,476MayS, 1998

I.G. Mayhew. "Large Animal Neuroloay: A Handbook forVeterinary Clinicians." Lee Febiger. Philadelphia. 1989.pp. 279-285.Bruce G. Gellin et al.. ''Coccidian Infections in AIDS:Toxoplasmosis, Cryptosporidiosis. and Isosporiasis." TheMedical Clinics of North America. vol. 76. No, I, Jan. 1992.pp. 206-234.Clara K. Fenger et al., "Identification of Opossums (Didelphis virginiaoo} as the Putative Definitive Host of Sarco-cystis Neurona," Journal of Parasitology. vol. 81. No.6. Dec.1995. pp. 916-919."Treatment of Equine Protozoal Myeloencephalitis" by Barbara Brewer Welsch. MA. DVM. et al. 1M CompendiumNorth American Edltion.Equine. 1 5 ~ 1 6 0 2 1991."Equine Protozoan Encephalomyelitis" by Till Beech.V.M.D. Veterinary Medicine/Small Animul Clinician, Dec.1974. 1562-1566."Comparative elfects of cotrimoxazole (trlmelhoprim-sulphamethoxazole), pyrimethamine-sulphadiazlne and spira-mycin during avirulent infection with Toxop/Qsmu goruJii(Bverely strain) in mice" by B.T. Nguyen et al . Br J,Pharmac. (1983). 79. 923-928.3615 Eriodicryon, The Merck IDdex, (1989} p. 530.7997 Pyrimethamine, The MC 'ck Index. (1989) p. 1270.8874 SulfadifJ7..ine, lbe Merck Index. (1989) p. 1404.15-Pharmacodynamics, vol. 69. 1968. p. 4749. Sec.50900p.Chemical Abstracts, vol. 85. 1976. pp. 46-47, Sec. 72303d.i-Pharmacodynamics, Vol. 78. 1973. p. 31. Sec. 52708s.1-Pharmacodynamics, vol. 77. 1972, p. 14. Sec. 109339h.l-Pharmacodynamics, vol. 92, 1980, p. 63. Sec. 92:15 58lp.Chemical Abstracts, vol. 87. 1977, p. 60. Sec. 87:95742b.ChemicQl Abstracts, vol. 101. 1984.p. 352. Sec. 101:873391.ChemicQl AbstrQcts, vol. 99. 1983. p. 20. Sec. 99:133330y.63-Phannaceutical.J, vol. 96. 1982, p. 373, Sec. 96:40845t.-Pharmacology. vol. 123. 1995.p. 37. Sec. 123:102131u.Chemical Abstracts, vol. 123. 1995 , p. 38. Sec. 123:74277a.Chemical Abstracts. vol. 122, 1995, p. 570. Sec.122;235089n.ChemicQ/ Abm'Qcts, vol. 122. 1995, p. 44. Sec, 122:45806w.1-Pharmacology. vol. 120. 1994, p. 33. Sec. 120:45263a.-Pharmacology. vol. 118, 1993. p. 29. Sec. ll8:182836n."Pharmacokinetics of intravenously and orally administeredpyrimethamine in horses" by Cyril R. Clarke, BVSc. Ph.D.et al . Am J Vet. Re.r. vol. 53. No. 12. Dec. 1992.

(List continued on next page.)Primary Exominer C. Warren IvyAssistant E.wminer-Charanjit S. AulakhAttorney. Agent, or Firm-Lowe. Price. LeBlanc Becker[57] ABSTRACTThe present invention relates to composltlons and methodsfor treating equines. such as hocses. afflicted with equineprotozoal myeloencephalitis or EPM. The therapeutic rompositions comprise a combination of pyrimethamine and asulfonamide. preferably. sulfadiazine, in the absence ofknown therapeutic amounts of trimethoprim.

48 Claims, No Drawings


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·

5 747 476Page 2

GrH R PUBLICATIONS''PhiU'lllllcokilletics, penetration into cerebrospinal Ouid andhematologic eifects after multiple oral adminlstratioos orpyrlmethamlue to horses", by Cyril R. Clarke. BVSc. Pb.D.et al.. Am. J. Vet. Res. vol. 53. No. 12. Dec. 1992.In Vitro Effects of Sulfadiazine and Its Metabolites Aloneand in Combination with Pyrimethamine on Toxcplasrnogondlf by Esther Schoondermark-Van De Vco et al .. Anti-microbial Agents and Chemotherapy, Mar. 1995. vol. 39,No 3. pp. 763-765.

"New MJcromethod to Study the Btfect of A ltimicrobialAgents on Toxcplasma gondti: Comparison of Sulfadoxineand Sulfadiazine Jndjvldually and in Combination withPyrimethamine and Study of Clindamycio, Metronidazole.and Clyclosporio A" by D.O. Mack et al .. AntimicrobialAgents and Chematherapy. Jul. 1984. vol. 26. No. 1. pp.26-30.EPM Seminar. The liorse, Nov. 1995, pp. 14-23."Equine Protozoal Myelitis Workshop: Summary for theHorseman" Grayson Jockey Club Resecm:h FoundationEPM Seminar Mar. 8 1996.


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,

5,747,4761TREATMENT OF EQUINE PROTOZOALMYELOENCEPHALITIS

1. FIELD OF THE INVENTIONThe present invention relates to compositiollil and melh·

ods for treating equines, such as horses,llffi.lcted with equineprotozoal myeloencephalitis or EPM. £ PM ls a dehilitatingneurologic disease of equines which can aifect the brain. thebrain stem. spinal cord. or any combination of these threeareas of the equine's central ocrvous system. EPM is causedby infection by the pl'otozoan parasite Sarwcystit nrurcmu(recently referred to as Sa o e y s t i s falcaru/a . Tbete h novaccine or approved animal drug product available fccelfectively treating this disease in horses.2. BACKGROUND OF THE INVEN110N

2positive serum test Cllllnot be used to ma.ke a diagnosis: suchpositive se rwn test simply indicates exposure to the parashe.not necessarily presence of the disease. Cerebrospinal fluidtesting is now believed to be the most useful test to assist ins the diagnosis of this disease in a live horse.Cu.rrently available treatment of horses with EPM isexpensive and typically requires a duration of at least ninety(90) day$. In ClUe cases. lreatrnent lasts indefinitely, ThisCWTent treatment involves the adaptation of tablets intendedH'l for hullllln use. Thus. pyrimethamine tablets are administered along with tablets containing a triroethoprlmsulfonamide combination. Typically. the two types of tabletsare crushed and placed in suspension for oral administration.These meWcalions should be administered one hour prior tolS feeding hay and are accompa.n.ied with frequent. periodic.veterinary. neurologic examinations during the treatmentperiod.Although the symptoms and effects of RPM bavc been l>iscontl11uation of therapy is usually based on the admin-recognized since the 1970's. it was not Until 1991 Ulat Ole lstr.alion of medication Ulirty days beyond the plateau ofprotozoan parasite that causes EPM was cul Ured ftom a l1l clinical improvement or disappearance of antibody to thehorse and given the name Sarcocystis neurona. The borse is procozoa from the CSF. Suboptimal dosing or intennittent

an aberrant. dead-end host. as infectious forms of the tltetli 'Y has no proven efficacy.parasite are not passed from horse to horse or from intected . .horse to a definitive


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5,747.4763

U.S. Pat. No. 5.273.970, states that a protozoal disease.toxoplasmosis. 11111y be conlrolled to a certain extent usingpyrimethamine together with a sulfonamide. 'This patentasserts that bequiloprim can be used for the treatment and/orprophylaxis of protozoal infections in ani:mals, including shultlllns. Although the baquilopriro can be used the sole

4hampering their usefulness in other pathological conditions.like protozoan-mediated diseases. especially EPM. 'The factis that there is currently no approved drug or drug combination for the treatment of EPM.3. SUMMARY OF TilE INVENTION

active ingredient. it can be co-administered with a sulfona- Quite surprisingly. it has now been discovered that anmide. A long list of u i t b l e sulfonamides is provided. most eifec ive. convenient method of treating EPM is realized bypre I era bl Y s u f a di aJ.i n e · u f a me tho;u zo le • the administration to an equine suspected of being attlictedsulfadimethoxine. sulCadmune. sulfamoxole, or sulfadirni- IO with EPM of therapeutic amounts of pyrimethamine and adine. sulfonamide, preferably sulfadiazine. The relative weight

In U.S. Pat. No. 4.599.416. granted to Kompis. a process ratio of pyrimethamine to the sulfonamide m y range fromfor the preparation of aqueous compositions of sulfonamides about 1:10 to about 1:30. preferably. about 1:15 to aboutand sulfonamide potentiators for the treatment of bacterial 1:25. and most preferably about 1:20 in the case of ainfections in humans and ani.ma.ls is described. A long list of 1 :5 composition comprising pyrimetham.IDe and sulfadiazine.potential sulfonamides is provided. The ''J>otentiators" are It should be pointed out that the compositions of thedescribed as denoting compounds that increase the antibac- present invention do not contain signilicant amounts ofterlal activity of sulfonamides more than additlvely. An trimethoprim. certainly less than about two-thirds of theequally long "laundry" list of such polentiators is provided. weight amouat of sulfadiazine present. Preferably. the hera-which includes trimethoprim and pyrimethllllline. Other 20 peutic compositions used for the treatment of F.PM arepatents dealing with protozoan parasites Include: U.S. Pat. substan tially free of trlmethoprim. most preferably havingNo. 4.293,547. granted to Lewis et al. for the treaunent of no trimethoprim at all S.inilllll'ly. the methods of the presentmalaria; U.S. Pat No. 4.340.609. granted to Chou (various Invention do not rely on the p r e s e ~ ~ c e of slgnlllcant amount sprotozoal infestations); U.S. Pat. No. 4.368.193, granted to of trimethoprlm in effecting successful treatment of F.J>M.Argoudells et al. (malaria); U.S. Pat. No. 4.728.641. granted 15 LJslng substantially the pyrimethamine and a sulfonamide asto Tubaro et al. (protozoal infections generally); U.S. Pat. the principal active ingredients against the pathologic agent,No. 4,992.444. granted to Stevens et al. (trypanosomes and namely, the organism Sarcocystis neurona in EPM. Hence.malaria); and U.S. Pat. No. 5.486.535. granted to Marr et al. the methods of the present invention do not Include theTo.wpJaslnQ gOIIdii . co-administration of kllown therapeutlc amounts of trlme-Beech, in Veterinary Medlclne/SmaU Animal Clinic/Qn 30 thoprim.pp. 1562-1566 (December 1974) described a condition in In a preferred embodiment of the invention, the atmctedeight (8) horses with signs of neurological disorder. On the equine. e.g . a horse. is given a daily dose of pyrimethamine.assumption that toxoplasmosis was involved. the author which is equivalent to about 0.8-1.2 mg per kg of equine.suggested that pyrimethamine and sulfadiazine, used sue- 35 most preferably about 1.0 mg per kg. The subject is alsocessfuJly agllinst toxoplaslllll in man. might be useful in given. conCUITently for the greatest convenience, an amounthorses. per day of a sulfonamide. which is equivalent to about 15-30Welsch, B. 8 recommended the use ol pytimethamine mg per kg of equine, most preferably about 20 rug per kg.(0.5 mglkg). combilled with a 20 rug/kg two-part mbttlae of Once daily administration of the active illgredients, saysulfadia.Une (16.7 mgfkg) and lrimethoprim 33 mglkg). to 40 evc::ry morning on an empty stomach. for at least about 3treat horses suffering from EPM. See. Welsch. B. B • in The months, preferably about 9(}...180 days, is sufficient to treatCompendium North American EdiTion Equine. Morris. D. the infection. In some c a s e ~ however, the treatment regimenD. (Ed.) ( 1991) pp. 1599-16 02. can last indefinitely. sometimes for the remaining life of theTwo articles by CliU k et .. which appeared in American horse. For ease of administration, the therapeutic composi- oumot of Veterinary Research Volume 53. Number 12, 45 tion may be given orally (that is, by mouth).pages 2292 -2295 and 2296--2299 (December 1992). discuss It should be apparent that an object of the present inven-the phamlacokinetics of intravenously and orally adminis- lion is the treatmeot of equine protozoal myeloencephalitistcred pyrimethamine in horses. The first article. at page or EPM by providing a vetc:riniii)' composition comprising2292. states that clinical reports indicate the possible value pyrimethamine and a sulfonamide, provided that the com-of treatment of horses with protozoal encephalomyelitis with 30 position does not also include significant amounts of trime-pyrlmc:thamine ill combipation with trimethoprim and sui- thopriiiL By "not also include signilicant amounts of trlme-fomunides. On the other hand. the second article. at page thoprim" means that any trimethoprlm present in the2299. concludes that the oral administration of 1 mg veterinary composition should not reach any known thera-pyrlmethamine/kg once a day for 10 days apparently does peutic levels of trimcthoprirn. certainly not reaching annot present a serious toxicological problem to h o r ~ e s 5j amount by weight, which is equivalent to about two-thirdsHence, despite a great deal ol past and on-going effort, the weight of the active sulfonamide, preferably less thanthere remains an unfulfilled need for a treatment for EPM- about one-half and more preferably less than about one-thirdaftlicted equines. particuliU'ly horses. which is not only of the sulfonamide. Most preferably. the veterinary compo-dfective but is also convenient to administa- to maximize sltion of the present Invention (or the Instant method ofcompliance apd reduce the emergence of resistant strains In 60 treatment of EPM) is substantially free of trirnethoprim.particular, prior compositions for the treatment of EPM Convenient dosage formulations of the present inventioninvolve three- compone n 1 mixtures i c I u di g are also contemplated. including solid and liquid fortns, andpyrimethamine, sulfadiazine and trimetboprim. Moreover, unit dosage forms comprising about 0.3-0.7 gmwhere prior compositions contained pyrimethamine and pyrimethamine and about 6-14 gm sulfonamide, preferablysulfadlal.ine as the active ingredients, such compositions 6S about 0.5 gm pyrimethamine and about 10 gm sulfonamide.used very small ratios of pyrimethamine to sulfadiazine These and other objects of the invention will becomelimiting their effectiveness to treating malaria. only and apparent to those of ordinary skill in the art. especially after


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5.747,4765 6

consideration of the following detailed description of theprefared embodiments. sal azosulfadimidi oe. sulfa chi oropy r i dazine.sulfadimethoxine. su fadoxlne. sulfalene. sulfamerazine.sulfameter. sulfamethazine. sulfamethomidine.4, DliTAlLED DESCRIPI10N OF THE sulfamethoxypyridazioe. sulfaperine. sulfaphenazole. sul.

PREFERRED EMBODIMENTS fapyrazine and sulfisomidioe.The instant invention Involves. in a preferred Still oth


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'•

5.747.4767boluses or capsules; olive oil or ethyl oleate for soft capsules; and water or vegetable oil for suspensions or emulsions; lubricating agents such as tak or magnesium stearate:gelling agents such as colloidal clays; thickening agentssuch as gum tragaciUith or sodium alginate; dedusting agentssuch as liquid paraffin. fixed oils and surfactaots and othertherapeutically acceptable accessmy ingredients, such ashumectants, preservatives. buffers. and anti-oxidants, whicharc useful as carriers in such formulations. When desired,other medicaments and/or nutrients. such as vitamins or the 10like. unless contraindicated. may also be included.

It is also to be understood that while the Xeferredformulation is administered once a day, it may be given twoor more times a day. dependi.Dg on the circumstances. Itshould be understood that while it is convenient to admin- ISseer the pyrimidine an d sulfonamide concurrendy. they canbe given separately With equal efficacy. However, the othc:roptimum conditions. such as the administration of the drugcombination on an empty. preferably at least about one hourbefore the horse is fed should be observed. 20

A further appreciation of the invention may be gleanedfrom the following ~ p e c i t i c examples, These specifice;r.amples are provided for illustration only and are not to beregarded as restricting the invention in any way.5. EXAMPLES

VeterinaJ)' compositions effective for the general treatment of EPM are provided. below, in the form of an oralsuspension. The amounts of each component are based on aliquid suspension having a total volume of about 1 Uter. As 30mentioned above. a useful dosage, e.g., for a 1,000 poundhorse infected with Sarcocystis neurrma (as evidenced bythe presence of the protozoan in a sample from the subject's~ - e r e b r o s p i n a l t l u i d is aboUt 30 m of the suspension. oncea day. given on an empty stomach in the morning. 35

I Sulfadia.W. B. . . \JSPz swt.dlal.iDo Sodium, USP3. Pyrimelbam.ille USP4 Sodium lleD:rorbat.e 80, NP

II. Pwified Wt101', USP

166.67166.67 116.67.2.22 a1.11.ll.U &2.78 a55.S6 mL5.56 mL6.67 wLq,o. to 1,000 mL

Preferably, the composition does n01 contain substantialamounts of natural sugars. Most preferably. the composition

45

83. Mix together the rnaterials prepared in steps 1 and 2 in

a large container and q.s. to one 1.000 liter with theremaining water.4. Beat the suspension on a micronizer for live minutes.being certain said suspension Is evenly mi;r.ed.5. P ~ t c k a g e the final product and refrigerate when nOI inuse. The suspension should be shaken well prior to use.As further illustrations of the composition of theinvention. the following descriptions of suitable alternative

formulations are provided

CompooonlI. Sulfodiazin


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9flonnulauon I'

CompooonI. Sul 'aumolo, liSP2. Pyrimelhamino, USP3. Sodium Benzoate, NP4. Xanlhan gum. NP

5 N U i r a i W o o ~ N F7. Carzncl Ooavorina, NP8. l'olyoorbatc NP9 Purified wafer, USP

formulation G

Per L1ter333.34 'n.34,

2.22'5 .015.0.10.56 mL6.67 mLq .. IO 1,000 mL

5.747.476 1012. The method of claJm l in which treatment is continuedfor at least about three months.13. The method of claim 1 which f\01her comprisesadmi.nistering folic acid.14. The method of claim 13 In whicn the folic acid isadministered daily at a dosage of about 40 mg per 1000-pound equlne.15. The method of claim 1 in which the pyrirnetha.millcand the sulfadiaz.ine are administered in a liquid fonn.

10 Hi. The method of cWrn 1 In which the pyrirnetha.milleand the sulfadiazine are administered in the fonn of a solid.17. A vcccrinary composition in unit dosage form foe tnetreatment of equine protozoal myeloencephalitis (BPM)comprising pyrimetnamine and a sulfonamide In a relativeS weight ratio of about 1:10 to about 1:30. respectively.provided that the composition does not also iuclude known

C o m p o ~ ~ e m Per L•ter tnerapeutic amounts of trirnetnoprim.18. 1be composition of claim 17 in which the sulfonamide1. Slllfodimoll Uxine. 1.1SP 500.10 a is sulfadiazine.2. """'-tbaminc, USP 16 673, ;;;;;;, BotwJOto, Nl' 2:22 : < O 19. The composition of claim 18 which in the fonn of4. X.:11han ' NP s o a an oral suspension.s N U i n l s W e e ~ NP 10.0 3 20. The composition of clllirn Ill which comprises about1 Caremelllavuriog, NP 5.56 wL 10--20 gm pyrimethamine and about 150-600 gm sulfona-8· Poly110rbatc NF 6.67 wL mlde per liter of composition.9 1'\lri&d water, USI' q.e. ro 1,000 mL .., Th ·u f aim 0 hi h ri '--·25 1. e compos1 on o c ... w c comp ses avvvt10--20 gm pyrimethamine and about 200-400 gm sulfona-Only the preferred embodiments of tne invention and but mlde per liter of composition.

a few examples of Its versatility are shown and described In n. The composition of claim 19 which does not includethe present disclosure. n s to be understood tnat the inven- substantial amounts of natural sugars.lion is capable of use in various oilier combinations and 30 ZJ. The composition of claim 17 in which theenvironments and is capable of changes and modifications pyrimethamine and the sulfonamJde are present 1n 8 relativewithin tne scope of the inventive concept as expressed weight ratio of about 1:15 to about 1:25. respectively.herein. Foe example. ttle active Ingredients of the contem- :w. The composition of claim 17 in which theplated veterinary composition can simply be mixed l.o aoaqueous medium to provide a mixture that can be adminis- pyrimethamine and the sulfonamide are present In a relativetered to tne affec.:ted equine, usually by mouth. 5 weight ratio of ab


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EXHI IT


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(12) United States atentRussell et al.(54) TREATMENT OF F:QUINE PROTOZOAL

MYELOENCEPHALITIS(75) Inventors: Mt>ri Chnrm Russell, Des M o i n e ~ . lA(US); Clnra K. h·nger, Lexington, KY(US)(73) A - , s i g n ~ e : Blue Ridge Pharmuceutlcals, Inc.,GrccnsboJO, NC (US)( • Notice: Subject to 11ny di-;claimer, the terr:J of thispat.:nt is .:xtcnd711 . 2't'i'l.l Mdla>dy .............. ..... ..... ~ i ' 1 i l ~ 7

~ . 4 2 4 , 3 1 1 h/1(/{J ... lukami cl al. . . . . . . . . . . . . . . . . . 514/24'-').'16 n t ~ ot' t r i m ~ h o p n n

29 (' aim,, 'I/o Drawing"


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•

us 6,255,308 1311

TnEATMENT OF I•:QlJINE I'RO'IOZOALMYELOENCEPHALITlS

CROSS ltEFERENC'ED TO RELATEDAP 'UC'A'I10NThis app i,:ation i;. 1ica.ion ScrNo. 08/683,507 flied Jul 17, 1996 and will i s ~ u ~ into USPat. No. 5,747,476 on May 5 1998.

f1El.D OF THE INVENTIONThe present invention relates to compositions and meth

o d ~ for treating equines, such as horses, afllicted with equineprotozoal myeloencephalitis or EPM. EPM is n debilitatingneurologk disease of equines which can affect the bra1n, thebrain stem, spinal cord, or any combinatiou of these threeareas of the equine's centrai nervous system. EPM is caused·by infection by the protozoan parasite Sarcocyslis neurona(recently referred to as SarcocysrL1· Jillcatula . There is novaccine or approved animal drug product available foreffectively treating this disease in horses.BA< KGIWUND OF THE l N V N T l O ~Alihough the ~ y m p t o m ~ and dTccl" of :PM have hcen

r ~ C O ) , I l l / . c d ~ . n e e the I 7 0 ' ~ . rt WI'.' nut until lt'i was based on the presence of antibodie> to Sar~ o < . : y s l i ' neurona ir. ' J ~ I < I I l t. , t r a i n ~ of/ fii/c·rjJ nunrbcr ol arll dcs dc.,crrbing th truatrnlr pyrrmclhamme md ~ u l f u d i n ~ m c ,hut at .1 r t ~ I P l lh.t1 u ~ · - ; .1 Vt.:''Y l i r g ~ c moun I o ' , u ; t ' H d J a t . t n c . ~rdat.vc ll> pynrnc>h.ln·inc S


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US 6,255,308 Bl3

(1995). Chem1caJ ; \ b ~ t r a c t s , Volume 123: 10213Ju (1995)de..-;crihes tht: daily administration of 25 mg p y r i r n e t h a m l f l ~and .1 total ni' 2 g 'ulfadiaLrnc to prevent loxoplasmk~ n . : c p h a l i t i ' r d ~ p c in ;\JI)S pal :cnls.

4

The patent lJicraturc r n c l ; ~ d ~ ' many tk\Criplif ucating p r o t u t o a n - m ~ d i < ~ t c d diwa.,c'llci nnint,Jl'> j c ~ < . . r i h c d . / \ Jonp, l i ~ l or:H>Ienliilf -;ul 'onH•nrdc' i > f'tovidcd. lltc "putcnti:rlur'>" ;m:tk:,.cribcd ,1.., d c n o t : n ~ compounds t ldl irtL'n..::l"\1. 1hc a o 1 t h a ~ :erial activlly A ~ u t r o n i l : n i c l c ' > more thns generally); U.S. Pat.No. 4,992,444, granted to Stevens et al. (trypanosomes andm:.Jaria), anc l;.S Pat. No. 5,486,535, granted to Mnrr c.:t al.( J Jxoplavna gondi1).

lkcge., : 2 2 1 1 2 - 2 ~ ' ~ . nd 22%-2:'99 (lkn·mbcr 1W2 , d i ' n ~ ' "

he p h , t r H ; t t · ~ ~ k i n l ' l 11:.., n mlr;l'_.ennu .. ly . ~ n d orn:ly H d 0 1 J n i ~ lcred p,Y Iff'elh.rn1ifW in hor'c' ' ill' llr'l n lic·lc, al p a g ~~ : t J 2 ; - , 1 , 1 1 ~ . . , 1h:1: cluw :d H.porh u ~ d k a l c the p o ~ ' - l i h k valuLoltrealm cnt of borscs wi:h p n • l o ~ < > a l c n c e ; > H r l o n i y d i l i s Willepyrimethamine in C I H • n ~ for tb l EPM

_,, 1 I :2.1, .1nd mosl prckrably about 1:20 n the c ; r ~ c orc o r n p n ~ i t i n n L ' n m p r i ~ i n g pyrirncth;ornine and -.ulLHit.rlincIt ~ h o u l d he pointed out thai the n' (.J thepresent iuYCIIIIL>fl do IIlli \.0.1'.'111 'lgniJk:ant amour: ,'> oflTIcntinvention do not rely on the presen(..-e of significant amounts30 of trimethoprim in effecting successful treatment of EPM,using s u b ~ t a n t i a l l y the pyrimethamine and a sulfonamide asthe principal active ingredients against the pathologic agent,namely, the organism Sarcm.:ystis ;Jeuruua in EPM. Hence,the methods of the present invention do not include the_,5 c.:o-admimstration or known t h ~ r a p c u l i c amounts of trimethoprirn.

In u preferred embodiment ,,f the mwntion, hu al'fli•:lcdcyuinc,


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US 6,255,308 Bl5

unit dosage forms comprising about 0.3-0.7 gmpyrimethamine and about 6-14 gm l>llifooamide, preferablyaoout 0.5 grn pyrirncthaminc wd >C ~ u l f o n a r n t d c ' h ~ . v i n g a d nllrogen MO·malic ri11g ar1. C o f ' < . : C i < ~ l l y u'dul , 'u a c ~ t y lh ~ » e and other o b j e c t ~ or the lriVCIItion will \ w c o m ~apparcnt to t h o ~ c ol ortl,nary skill in the .ut, c;,pcciallv •i'icrcon-.Kkration ol' the followmg detailed dcM.:np:iou o theprd'crrcd cmbodtmout I .\0. pn.d-.,rly -dxntl I : 0.Typi uti:t/.in) .

or.c or more suJonarnid o l l . ~ .p a ~ l c . ,., 111 '-"l''>l.lc, t·r K h c · ~ 1 1 It"· dry '\Hie w 10 a

n o o - ~ 1 4 l l " - ' l ' l l ' - . ~ p c u ~ h ' l . , tH I . . . , u . . , . p v n ~ i t , 1 HI w.1tcr ~ l r' ) ' fUj1 \ V , l ~ f l ' < . l ~ ' > • r < ~ h : ~ or f l C L C ~ ~ a r y , JHCS


24/48

us 6,255,308 ill7

gelatin or polyvmylpyrrolidonc; i l u b r k a t i r : ~ a ~ c n ' ' ·such ao; m a ~ n c ~ i u m stl. aratc or ~ h : a n c dl' OOther l:OrHFl11111f L'.ll''ulus, ol1vc tHI or cll:yl nk111e lor '"II c:op-;uJcs; dOd Wd\cr or vc·gctahk oil ror ' i J ~ p c 1 1 ' > i o n ' i or emulsions; h1brka1ing agtmls "ud1 asIa:..: or magne,ltlm >leilf.llc,gelling ngmts su"h a> colloidal c l a y ~ . tbi,·kening agentssuch as gum tragacanth or wdium algma1e; dedusting agents 10such as hquid paratlin, fi:...:d oils and surfnctanls and othertherapeutically acceptable accessory ingrcdtLrHs, sm:h ashumcctanl,, p r c ~ c r v a t i v c s , buffers, and anti-oxidants, whicharc useful as carriers in such formulations. When des1red,other medicaments and/or nutrients, s ~ c h as vitamir1 or tt:c ' 5like, unless contraindicated, may also be included

II is a l ~ > 10 1>.: umkr,tootl that wnik t h ~ prclc'l cdlormul,>lion I'> mlnHill'lcrcd ,,,_._a d.>y, il r·,w he ~ > W I >v.or more l111es .t day, d q h ; n ~ h f l g 011 1 h ~ l'•rCulll..,ldiH.:L'· ll 'L

~ > h n u k l he umlcr,lood llio l v.hlic 11 ' ' Lonvc"'"'ll lo .>dmin''ler the pymniclinc nnd sullonam>cie c o n c o u r r ~ n ' l y , they feel should be observe-dA further appreciation of the invention may be gleaned[rom the following specific examples. T h c s ~ specificexamples arc provicletl fm illustration only anc are nol to beregarded dS re:;trictiug the inveotwn 111 any w • y. .ion is 1:vcnly mixed5. Pl d,age lbt: f w t ~ l prodult dOd rdngertt: whn not inu,e, The su,pensi,>n ~ h o u l d be shaken well pritll to uSt.A' l'urthcr i l u ~ t r : l l i o n s of the composition ,,r the

urvcnliun, the J(,l owing dc,l'rip tinuh D hUilal>le a lcmahvci'IITII idlltllh i l i L pn>v:ded.

h mnu ntion BCompo11ent.

l. Sutfadiarine Sod.Jum, U .2. l)yrimdham·ne, USP3. Sodium lletu;oate, NF4, ~ n t h a n gum, Nl•'5 N1ttm'Oweet, 1\ 1 ·7, l e t f f l m c l tlavoling1 'Nl•3 r ~ l y i > o r O J l C so. NF9, Pl,nht..d W;lll:r, USP

('omj)onenl1 Std(amelhoxazole, lJSP2 Pynmelh.amine, USP3. Sod tum Bel:l.i..Cate, \. E4 Xnnthon gum,5 NlltJnr,weet, NF

Caromcl f\.wm tng '\ll·~ P o l y > N h ~ t l L ~ 0 . Nl• , Put1f1ed w.llel, liSP

~ t . l \ , \ J i < V I H \;•..,._, l : ~ ~ >1 Pvr ·1t1h l1l1ll• l , l l : - . ~ ){, SO.JlUIP /hrvwttc ,4, t 'Wlid ')WC:L(, '\J•

Lacto\t::, r-.:r•

:::hilt.nJv:>.J \{,. B ~ , . , e l ' i l '-· P\ tdl .eLhcnuH l'S '

.:),'d ': n he J t , a \ ~ · , '\;["t'-.'1, . t \ w ~ e t . :-..1

-., : ,,._1 . ,. '\ll·

Per LLter333.34 g

3.L\4 g2.22 g5.0 glO.U g5.56 mLb.(i7 mL

ll ._ ltl 1 , 0 \ ~ U ntl

Per L i l ~ l313.}4 &33 3•1 g

2.'27 gI l l SD.Cg'i.5ri mLL6 ntl

(j b ttl ,01.;1:; l"'ll

.. q J( {> '

J (..Jt) ')

t . ' ~ b ll g

].00.05 glt; 67 g2 2 ~ ~j)( l -

:)7 ~ ~ .

I ' l l ~ p co.:ed.ng lwt. t n r m ; ~ L • . i o n ' < jllOV.dt puwdcf'> w l ~ : c h\.dr i)t' ~ , ' ( ' f ' V L l l l • il\ly d.\ Hied 111:0 ,ml ivH \Ud ' ~ ~ ~ I C k L ' l < . , . , Ltii.:h(,nn d fltng l l l l (,f t i · ~ _ l n v ~ n l l V L ' u)mpo:-.itiu:-L


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US 6,255,308 Bl

J ~ u J f a n \ l i ~ < J k v.;r2 Py •trelhl T'JOI.... I ..;p

SodilHH Berv ol te, Nr-1. Xa•nhan g u n ~ , Ni"5. ~ u t 1 a s w e e t , Nf7 C:1ra-:nel J'\nvonng, NF

P o t y s o 1 b a ~ e 80, NF.. PtH ~ i . e d wa:er. USP

9

F01 m1.1latlon Gi. Sulf3d m ~ of v c r ~ a t i l i t y are :,howo and dc:-.cribed 10the pn:scnt d ,dosure. It is to he u n d c r . ~ t o o d that tht: invention is capable of use in various other combina\lons andenvironments and is capable of ch,mges and modificationswithin the scope of the inventiw concept as expressedherein_ For example, the active ingrcdtcnts of the contemplated veterinary composition .::an simply be mixed in anaqueous m ~ ; d i u n t to l''ovicly weight oJ' the HfTlL>llfll or l h ~ 'ulf,I-J_, diat.inc prcrnpo,i:ionot' t kr


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EXHIBIT C


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',

(12) United States PatentRussell et al.(54) TREATMENT OF EQUINE PROTOZOAL

:\-1YELOENCEPHALITIS(75) Inventors: Mer Chnrm Russell, Des Moines, A

(US); Clara K. Fenger, Lexington, KY(US)

(7'>) Assignee: IDEXX Plmnnaceutlcals, Im:.,U r c w ~ b o r o , NC (U.S)

( • Notice· Subject to ~ n y disclaimer, the term or thisp•tcn extended or a d j u ~ t c d under :ISUS( 154(h) hy 0 dnys.Th1s p•te nt is subject to a terminal discla mcr.

(21) Appl. No.: 09/685,943~ 2 2 ) Filed. Oct. tO, 2000

Related U.S. Applicutlon llata( 63) Conhnuation of upplicution No. 09/0&'1,956, ileu on Ap1.30, 1998, now Pat. Nc. 6 , 2 ~ ~ . 3 0 8 , whtch is a contuJuationof npplicn Jon No. ORI6R3.507. filed on Jul. 17, J'Jl¥) A 7/I'Jil2 Chou . . . . . . . . . . . . . . . . . ..... 4.24.'.122·l . i>ll,1''-' A l / l ~ H 3 A t g . o : ~ d e l b et al. ......... 424:180

4 , 4 ' 1 l , ' > 4 ~ i\ 9il'IH4 I'Jcnkrl C .tl . . . . . . . . . . . . . 424iH8~ . : > 4 9 A l f ) A 7tt 7 , 7 £ ; ( ) A X:1 1Jt H H o c ~ k x cl al. ... , . , _ > ¥ · · ~ :d4;242'.79':•"1 1\ l i i%\1 lllllehall cl a 'i14.?4'J-l.-h·'.'7ll t\ • Sii•NO Bon·kx ~ t a l . .............. ) 4,'242;,-N.'.4+1 A 7/l'l'lt Str•cns ct al. ......... ) 1 1 ; 2 7 ~5,:17 ,\ • SiJ'In Lindnet et nl. ........... ::>1·1 242.

~ , 2 1 4 , l l 4 3 A • 'i l 'N3 Lindner et al. . . . . . 'il4/242'i,27J,'J70 A • 12 1\:93 Me Hardy ............. 514/157.424,3 W \ • b/IWS I uk•mi el al. ......... 5H.'J425.464,H37 ,\ • 11/1 A 5/I•;c in allorse"; Equine Veterinary Science, vol. 8, No. 4, pp302-304 (Apr. 1988). •Kobluk, cl al., (cds.) The Horse Diseases & ClicJcal Management, W.B. Saunders Company, pp. 459-462 aud pp729-TJO (1995).Schoondcrm3rk, ct al., "In vitro etl'ects of sulfadinine andits m


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U 6 448 252 BlPage

OTHEH PUBLICATIONSMoore, Bonnie R l t ~ b ...Informal Survey of Equine ProtozoalMycloenccphalitis," Kansas Slllle Univers1ty, Mar., 19%.Bertone, Joseph J, ·'Update on Equine Proto:wal Myeloencephalitis," fDA Vet., vol. XI, No. III, May/Juu. (May/JlJtL1996).Fenger, et al., ·'Epizootic ol' Equine Protozoal Mye oen

< : ~ p h a l i t ' on a r·arm", Journal of the A r n c r i c < ~ n VctcnmtryMedical A ~ ' ' " . : i a t i o n , vol 210, No. 7, pp. 923-927 (Apr.997)..Tn;atmcnt of I.:.quine Protozoul Myelocncephttlitb" by B.trbarn Brewer Welsch, MA. DVM. ct a . The Compendiwn,North Americ-an Edition, Equine, 1599-1602 (1991).''Equine Protozoan Encephhlomyelitis" by Jill Beech,V.M.D., Veterinary Medicine/Small Animal Clinician, Dec.1'.174, 1562-1566...Comparative cm: and Chemolli< mpy, M,lr. I nJduo c,and C l y l ' l o ~ l l l H i n n" by D.G Mnck t;;t a ., Anlilli/t:rohiair \ ~ : e n 1 1 and Ch< , Nov. 11')5, pp. 1 4 - - 2 · ~" l : J L I O ~ l'roto/.u,J Myd1t1'> \Vork.'>hop. Sunlllldf)' r' theIlorscrnau" (/ra_nrm ockev Clul> Re.search i"oundaltonl ~ - P M Seminar, Mur. I d Cells, and C h a r a c t e m ~ a t i o n ofMutants Re;,istant In P y r i m e t h ~ m i n c , AJVR, vol. 57, Jan.19910, pp .. (Jil--72 .J P J)uh..:y eta , · Antkocc:idiu f:trnnyl 4,4-DiaminodiphcnyhuJf,mc. Sulladu.inc, l'ynrncthammcand Clindarnycin in Cats lllfe,·ted Wtlh J >:rc>pla\11111 Klll l?a) .,.., 1 e Pu:atiw Udinitivc I-lo'>l of .\arco-' pti., fl< urom,," Jour71al of Par,tsitnlogy, vol. HI. No 6, Dec.1995, pp I) 1 J-'J I')• cted by examiner


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US 6/\48,252 B 15

Couvcnicnl dosage formulations of the present inventionare also cor.templated, includmg solid and liquid forms, andumt dosage forms comprising about 0.3-0.7 gmpyrimclhaminc and about 6-14 gm sulfonamide, preferablyabout 0.5 gm p y r i r n d b ~ r n i u e and about 10 grn sulfonamide.

These .md other o h j ~ t ' l s ol the invention will bcmmeappawnl to hose or ordinary >Kill in the arl, especially afterconstderation of the following dctmlcd dcscnption of lhepreferred embodmlents.4. [)J..rli\JLED DESCRWJ'JON Of' TilEPREI'I::RRED EMBODIMENTS

The instant invention iuvolvcs, in a prefe:redo;;mbooimenl, the administration or tin oral ~ u - ; p e n s 1 o n , cuntaining p y r i r n ~ : t h a r r u u c ami a sulfonamide, ~ u < . : l ;~ u l f < ~ d l u . i u e , designned, pyrimethamine may he gJVcn in apreferred dose of about 1 mg/kg equine with a sulfonamidein a dose of about 15 to 30 mg kg equine, preferably 20mg./kg.

6b a .'>irmbr manner, nuf lerm;s sulfonamide1. mav besuitably utilized in the presilion" ol' the p t c ~ c n t tnvcniJn arc rnatcril1b nKom-prc, been lound to 'uccc;..,:ullyinhibit lhc growlh of thtn Srm:oq• fi. n umrw i11

c y ~ i m . : > , ~ u c : h u;. mule;., fl The >;arne ipplie' for .wy addedthe effectiveness of the present


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US 6,44R,252 U 17

binding a g e n t ~ , such "larch in the form of ;nUt'ildgc, ~ l a r c hderivatives, such as methykellulose, calcium stearate, talc,gelatin or polyvinylpyrrolidone; a n d / o ~ lubricating a g c u t ~ ,SUI.'h as magnesium stearate or steanc acid.

Other c o m p o u n d ~ which may be.. included ~ r c forexJrnple, rnedk:llly inert i:lgrcdieots, e.g solid and liyu1d

d i l u e n t ~ . such as stMch or ca.tium phosphate for tablet>,h o l u ' c ~ or capsules; olive ml or ethyl olea "' ,

1 . tlh > ,, l l , ({f \I·j•, 11 , d t' , , -.,p

l'crl.it uu1 c:onJ,Itn -;uh,t,lnltdl '"'nmouni:, ofnrtlllf,d 'ugar' Mr"l prdcrahl_v, the '"''TII"''JIHHJss -;ubstanlially free of n a t u r ~ l sugeparate conta iner mix all thc liquid; and add halfthe volume of wMer : - ~ e e d e d for one liter

3 Mix l < > g c h ~ r t h ~ malcri,tls prepared in steps I and 2 in,t urge mnlaJJlcr and q.'>. to nne ],000 liter with .ber c m : - ~ i n i n g w ~ 1 l e r .

·I llc 1 < ~ l ) .'1. l'unlkd waltr, I Sr

Per L1lct,;,i u.L

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1. A method of treating equine protozoal myclocnccpha·litis (EPM) comprising administering to an equine suspected JSof sufferi:Jg from EPM therapeutically e Iective amounts ofpyrimethamine and a sulfonamide, wherein the relativeweight r.1tio of pyrimethamine to the sulfona:nide is fromabout 1: lO to about 1 30; and

12. The method of datm 2 in which the pyrimcthamin is6dministcrcd in a daily dosage of about 15 to about 30 mg,/kgof equine.13. The method of claim 2 further comprising the administration of folic acid.14. The method of claim 13 in which the folic acid isadministered daily at a dosage of about 40 mg per 1000-pound equine.

whertir., when the ~ u l f o n n m i c l c is sulfadi tl.lnc, the l'orn- 4n; m ~ i t i o r . d o c ~ not conloinlnmct:Jopr rn in an amount in~ n : H i t . : r lhan a,)out \ A - O - t h i r n ~ L)i he W(.:ight c m ~ \ l l H l l o

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15. ' be method of ciaim 2 in which the pynmethamincand the sulf6diazine are administered m the form of a solid.


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EXHI ITD


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.•

Date of Approval: November 5, 2004

FREEDOM OF INFORM TION SUMM RY

N D 141-240

REBALANCEAntiprotozoal Oral Suspension(sulfadiazine and pyrimethamine)

for the treatment of horses with equine protozoal myeloencephalitis (EPM)caused by Sarcocystis neurona.

Sponsored by:Animal Health Pharmaceuticals, LLC


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Freedom of Information SummaryNADA 141-240 Page

T BLE OF CONTENTS

1 GENERAL INFORMATION2 EFFECTIVENESS . .. .. .. . .. .. .. . .. . . . . . .. . . . . . . . .. . . .. . . . . .. . . . .. .. . . .. .. . .. 2

a Dosage Characterization . . . . . . . . .. . . . . . .. . . .. . . . . .. . .. . . . .. . . . . . . . . . . 2b Substantial Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . .. .. . .. . . . .. . . . ..... 2

3 TARGET ANIMAL SAFETY 94 HUMAN SAFETY 115 AGENCY CONCLUSIONS . . . . ... . .. . .. .. .. . . .. .. . .. .. .. . .. . . .. . .. ... 116 ATTACHMENTS 12


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2 EFFECTIVENESS:a Dosage Characterization:

Freedom of Information SummaryNADA 141-240 Page 2

Sulfadiazine (20 mg/kg) and pyrimethamine 1 mglkg) once per day for a minimumof 90 days is the empirical regimen of therap currently recommended in thescientific literature for the treatment of EPM . Sulfadiazine and pyrimethamine aretwo different antimicrobial agents which inhibit folic acid synthesis at two differentsites in the same synthetic pathway. The combination of sulfadiazine andpyrimethamine is synergistic, with the drug combination having an antiprotozoaleffect. Because of the greater frequency and severity of bone marrow suppression atthe 2X dose level, REBALANCE Antiprotozoal Oral Suspension should beadministered at the labeled lX dose level, sulfadiazine (20 mg/kg) andpyrimethamine 1 mg/kg) once per day for a minimum of90 days.

b Substantial Evidence:(1) Historical Control:

EPM is usually a progressive neurological disease. t has been estimated that upto 55 to 65 2 of horses respond favorably to treatment. However, it is furtherestimated that a small percentage (no more than 10 ) of treated horses recovercompletely. One of the most important points to consider is that EPM produces ahighly variable clinical disease. Historical controls were used in the field studiesbecause, without treatment, EPM is usually a progressive disease. At the timethese studies were conducted, there was no FDA approved treatment for EPM.The use of historical controls in the evaluation of compounds for effectivenessis described in 21 CFR 514.117(b)(4)(iv).

(2) Field Study: Clinical Field Effectiveness and Safety ofDaily Pyrimethamineand Sulfadiazine Oral Suspension in Horses Affected with EPM(a) Type of Study:

This study was conducted as a multi-site, randomized field effectivenessevaluation oftwo dose levels of REBALANCE Antiprotozoal OralSuspension. The two dose levels IX) 20 mg/kg sulfadiazine and 1 mg/kgpyrimethamine and (2X) 40 mg/kg sulfadiazine and 2 mg/kg pyrimetraminewere administered daily for a minimum of 90 days.(b) Investigators:

MacKay RJ, Granstrom DE, Saville WJ, Reed SM. Equine Protozoal Myeloencephalit is: Veterinary Clinicso North America/Equine Practice 2000:16:405-425.2 Granstrom DE. Understanding Equine Protozoal Myeloencephalitis: Your Guide to Horse Health Care andManagement. Lexington: The Blood-Horse Inc., 1997:10.


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Dr Laurie A. BeardOhio State UniversityVeterinary Teaching HospitalColumbus, OHDr. Deme M. EricksonRochester Equine ClinicRochester, NH

Dr. Philip J JohnsonUniversity o MissouriCollege ofVeterinary MedicineColumbia, MODr. John M. LeonardFox Run Equine CenterApollo, PA

c) Study Design:

Freedom o Information SummaryNADA 141-240 Page 3

Dr. Stephen M. ReedOhio State UniversityVeterinary Teaching HospitalColumbus, OHDr. Bonnie RushKansas State UniversityVeterinary Teaching HospitalManhattan, KSDr. Harold C. SchottMichigan State UniversityCollege o Veterinary MedicineEast Lansing, MIDr. Corinne R. SweeneyUniversity o PennsylvaniaSchool ofVeterinary MedicineNew Bolton CenterKennett Square, P A

Purpose: This study was designed to evaluate the clinicaleffectiveness and safety o sulfadiazine and pyrimethamine for thetreatment o horses with EPM at a dosage o 20 mg/kg sulfadiazineand 1 mg/kg pyrimethamine or 40 mg/kg sulfadiazine and 2 mg/kgpyrimethamine administered in a daily oral dosage for a minimum o90 days .

f Test Animals: There were 97 horses enrolled in this study, consistingo 34 females, 13 males and 50 geldings ranging from nine months to32 years o age. Seventy-two percent o the horses wereThoroughbreds, Standardbreds and Quarter Horses, with theremainder represented by Tennessee Walker Horses, Appaloosas,Arabians and mixed breeds.Enrollment Criteria: Initial selection o the animals into the fieldeffectiveness study was based upon a qualifying physicalexamination and on a clinical neurological examination. Blood andcerebrospinal fluid CSF) samples were collected for determination oserum and CSF serological status for EPM Western Blot Test),


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Freedom of Information SummaryNADA 141-240 Page 5was predetermined by a randomized treatment schedule. Forty-eight(48) horses were assigned to the lX treatment group (20 mg/kgsulfadiazine and l mg/kg pyrimethamine); forty-nine horses wereassigned to the 2X treatment group (40 mg/kg sulfadiazine and 2mg/kg pyrimethamine). The scheduled dosage regimen was for dailyoral administration for a duration of9 to 180 days. In 4 horses, theduration of administration exceeded 180 days, with the duration ofadministration ranging from 195 to 270 days.

§ Dosage Form: The oral suspension formulation used during this studywas identical to the product intended for marketing. REBALANCEAntiprotozoal Oral Suspension contains 250 mg/mL sulfadiazine (asthe sodium salt) and 12.5 mg/mL pyrimethamine.Route ofAdministration: REBALANCE Antiprotozoal OralSuspension was administered by the oral route via syringe.Dose, Frequency and Duration: The horses were dosed with either IX(20 mg/kg sulfadiazine and I mg/kg pyrimethamine) or 2X (40 mg/kgsulfadiazine and 2 mg/kg pyrimethamine) daily for a duration of9 to270 days. Horses were dosed at least one hour prior to feeding hay orgrain

2 Treatment Success: The primary effectiveness variables for thedetermination of response to test article treatment were the CSFWestern Blot Test results and the overall assessment of neurologicaldysfunction (OND score). A horse was considered a success if anyof the following criteria applied at the time the horse was evaluated:• Negative CSF Western Blot Test and clinical neurologicalimprovement (one or more grade improvement in OND score)• Negative CSF Western Blot Test and no clinical neurologicalimprovement (zero or less improvement in OND score)• Positive CSF Western Blot Test and marked clinical neurologicalimprovement (two or more grades improvement in OND score)All neurological examinations were videotaped. In order tocorroborate the investigators OND scores, independent experts wereasked to view the videotapes and confirm that the horses that weredeemed to be clinical successes by the investigators appeared toimprove on videotape. If the independent experts agreed that the horseshowed improvement, the horse was considered a corroboratedsuccess.

(d) Results:


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Forty-eight horses were assigned to the 20 mg sulfadiazine/kg and 1 mgpyrimethamine/kg dose of REBALANCE Antiprotozoal Oral Suspension1 X treatment group). The final database consisted of 26 horses treated

at the 1X dose, the other 22 horses in the IX group failing to complete thestudy. Day 0 was the day the horse was first administered testarticle. Evaluations were made every 30 days. All horses were treatedwith drug at least 90 days.

Table 1 Summary of Effectiveness Outcomes for 26 horses treated at the lX dose.Day of 30 60 90 120 150 180 >210 TotalsEvaluationCSF Successes - 2 1 2 - . 5

OND Successes 1 1 2 3 2 1 lUncorroborated - - - 1 l 2OND SuccessesFailures - - 2 1 3 4 10OND Successes 1 1 4 4 4 1 1 16

&CSFSuccessesCorroborated 1 1 4 4 4 0 0 14OND Successes

&CSFSuccessesBased on the clinical investigator's evaluations and the results ofthe CSF WesternBlot Analysis, 16/26 (61.5 ) of horses treated at the IX dose were successes. Basedon the corroborated clinical investigator's evaluation and the results of the CSFWestern Blot Analysis, 14/26 (53.8 ) of horses treated at the lX dose weresuccesses. The 95 Blyth-Still-Casella confidence interval for the cumulativepercent of corroborated successes is (33.4 , 71.8 ).

(e) Adverse Reactions:Adverse reactions pertaining to bone marrow suppression were two or more timesmore frequent in the 2X treatment group than the IX treatment group. Adversereactions were categorized under the following categories: bone marrow, appetite,gastrointestinal, integument, treatment crisis and unusual daily observations.Although 97 horses were enrolled in the study (48 in the 1X treatment group, 49in the 2X treatment group), only 75 horses were administered the drug in thetwo treatment groups for a duration of at least 90 days, thus a total of 75 horseswere evaluated for adverse reactions. Adverse reactions were evaluated in 37horses treated with the IX dosage, which included 5,910 daily observations, and38 horses treated with the 2X dosage, which included 6,210 daily observations.


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Freedom of Information SummaryNADA 141-240 Page 7Bone Marrow: Bone marrow suppression due to test article administrationcaused overall anemia (classification of anemia based on RBC, Hgb,PCV/HCT variables) in 12 of the scheduled observations n the lX groupand 21 of the scheduled observations in the 2X group. In the 37 clinicalcases that were treated with lX dose of test article 90 or more days, anemiawas noted in 22 , leukopenia in 19 , neutropenia in 5 and thrombocytopenia in 3 of the cases. Similarly, in the 38 clinical cases n the 2Xtreatment group, anemia was noted in 58 , leukopenia in 55 , neutropenian 29 and thrombocytopenia in 5 ofthe cases. The incidence of bonemarrow suppression n the 2X treatment group was two or more times thatofthe lX treatment group and the degree of suppression was more serious(mild to severe vs. mild to moderate). Because of these blood dyscrasias,test article was interrupted over four times more often in horses treated atthe 2X dosage than those treated at IX, although both groups were offtreatment for about the same amount of time ( ~ 2 0 of the treatmentperiod). In some instances of bone marrow suppression, diet wassupplemented with folinic acid to aid in recovery of the bone marrow.Interruption of test article administration with or without folinic acidsupplementation proved adequate in preventing any detrimental effects tothe overall health and well being of the test animals. Blood counts were notlow enough for a long enough period of time to allow development ofclinical signs.Appetite: Anorexia was reported in 0.24 of the daily observations for thiscategory in the lX. treatment group (two out of37 horses) and in 0.03 ofthe daily observations for the 2X treatment group (one out of38 horses).The one horse in the 2X treatment group exhibiting anorexia had aconcurrent fever associated with liver disease/cholestasis and/orenterotoxemia (hepatocellular disease). Decreased appetite (off feed) wasreported in 0.10 of the daily observations for the 1X treatment group (oneout of 37 horses) and in 0.05 of the daily observations for the 2Xtreatment group (one out of 38 horses).

l Gastrointestinal: Loose stools were observed in three out of37 horses n the1X treatment group and five out of 38 horses in the 2X treatment group.Twenty-four of the 26 loose stool observations n both treatment groupsoccurred between Day 0 and Day 30. Fifteen loose stool observationsoccurred in one horse in the lX treatment group between Day 0 and Day30. Diarrhea was observed in one out of 38 cases in the 2X treatment group(one observation on Day 4).: Integument: Urticaria was observed in one out of37 horses n the lXtreatment group and in two out of 38 horses n the 2X treatment group.One of the horses received conservative topical treatment and two horsesreceived no treatment. The urticaria resolved without sequelae.


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Freedom of Information SummaryNADA 141-240 Page 82 Treatment Crisis (marked worsening of the neurological condition duringtreatment believed to be due to n inflammatory reaction in the CNS to thedead/dying protozoan organisms): One horse in the IX treatment group

became progressively more neurologic and recumbent after 99 days oftreatment. The worsening of the neurologic signs was assumed to be due toinflammation in the central nervous system associated with dead or dyingprotozoa. The horse was euthanized on test day 1142 Unusual Daily Observations: The following daily observations were alsonoted. Lethargy/mild depression was observed in five horses; seizureoccurred in one horse; mild colic was observed once in three individualhorses; elevated liver enzymes associated with acute onset of hepatocellulardisease was observed in one horse; increased urination/defecation wasobserved in one horse; fever was observed in four cases (two with upperrespiratory infection, one with hepatocellular disease and one of unknown

etiology); neutrophilia associated with inflammation, infection, and/orstress was observed in five horses; leukocytosis associated with upperrespiratory infection or hepatocellular disease was observed in two horses;and itchiness/delayed shedding was observed in one horse.Serum Chemistry: There was no test article affect on any of the clinicalchemistry variables.

(f) Conclusions:Based on the clinical investigator's evaluations and the results ofthe CSFWestern Blot Analysis, 16/26 (61.5 ) of horses treated at the X dose weresuccesses. Based on the corroborated clinical investigator's evaluation and theresults of the CSF Western Blot Analysis, 14/26 (53.8 ) of horses treated atthe 1X dose were successes. The total number of horses that became CSFWestern Blot negative was five out of 26 or 19.2 .REBALANCE Antiprotozoal Oral Suspension is effective for the treatment ofhorses with equine protozoal myeloencephalitis (EPM) caused by Sarcocystisneurona


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3. TARGET NIM L SAFETYa) Type of Study: Toxicityb) Investigator and Trial Location:

Dr. Steven G. Kamerling


Department f Physiology, Pharmacology and ToxicologySchool ofVeterinary MedicineLouisiana State UniversityBaton Rouge, LAc) Study Design

1 Compliance: This study was conducted in compliance with the FDA GoodLaboratory Practice Standards, 21 CFR 58 .

f Purpose: The purpose of the study was to evaluate the safety of REBALANCEAntiprotozoal Oral Suspension in horsesl Test Animals: Fourteen healthy Thoroughbred and Quarter Horse test animalsseven males and seven females), ranging in age from three to 16 years

.1. Dosage Form: The test article was an oral suspension2_ Route of Administration: The test article was administered orally.§ Dosage, Frequency and Duration of Treatment: Ten horses five males and fivefemales) were administered REBALANCE Antiprotozoal Oral Suspension ata dosage of 8 mL/50 kg 11 0 lbs) a day 2X the labeled dose) for 92 days.Treatments were given at least one hour prior to feeding of hay and grain.

Controls: Four horses two males and two females) were not treated.Evaluation ofVariables: The health of each animal was evaluated daily. Acomplete physical examination was conducted and blood was. drawn for CBCand serum chemistry analyses three times prior to treatment on test days minus14 and minus 7 for study eligibility and on Day 0 immediately prior to start oftreatment). The average of the two baseline measurements on test days minus14 and minus 7 were used as the covariate for each response variable. Thephysical examinations and blood analyses were repeated at 14-day intervalsduring treatment and 14 and 29 days following the end of treatment total ofeight physical examination/blood sample observations/analyses per animalduring/following treatment).


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Freedom o Information SummaryNADA 141-240 Page 10,2 Statistical Methods: CBC and clinical chemistry variables were analyzed usinganalysis o covariance. Treatment and treatment by time interactions wereconsidered significant if their p-values were less than or equal to 0.10.

d) Results:Physical Examinations: The observations from biweekly physical examinationswere not associated with any clinically significant condition in either group.Complete Blood Count CBC): CBC variables were analyzed using repeatedmeasures analysis o covariance. Both the treated and control groupsexperienced a decline in RBC starting on Day 70; however, the treated groupwas statistically significantly lower p,S 0.1 0) than the control group on Days105 and 120. Hgb also decreased in both groups; however, it was statisticallysignificantly lower p.S 0.10) in the treated group on Days 28 and 120. PCVand HCT decreased along with the RBC; however, there were no statisticallysignificant differences between treated and control groups. MCV valuesremained within normal limits for both groups; however, MCV values wereslightly elevated in the treated group on Days 70, 84, 105 and 120. Despite thefindings o the CBC, there were no clinical signs o anemia observed in eithergroup. Twenty-nine days after cessation o treatment, all values returned to orabove baseline levels in both groups. There were no clinically significantchanges in white blood cells.Clinical Chemistry: Most serum chemistry variables remained within normallimits throughout the study in both treated and untreated groups. There wasconsiderable variation between groups and from baseline values in both groups,e.g., creatinine, alkaline phosphatase ALP), gamma glutamyl transferaseGGT), total protein, globulin and albumin. Elevated ALP values wereobserved in three o the ten treated horses. These values were slightly abovethe upper end o the normal range on study days 84 and 105 .

± Daily Observations: Daily animal care observations indicated that the testarticle was well tolerated for the duration o the treatment period. The mostsignificant observation was the transient appearance o loose stools in both thetreated and untreated groups, although the frequency o occurrence was greaterin the treated group. Diarrhea was infrequently observed in the treated groupand not observed in the untreated group. At no time during the study was theoccurrence o loose stools or diarrhea worthy o medical intervention and allcases resolved without sequelae.2 Appetite: Depressed appetite occurred infrequently in all but one o the treatedhorses during the study period affected horses had a depressed appetite for oneor two days during the 92-day treatment period). Depressed appetite was notobserved in the untreated group. In one o the treated horses, depressed


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Freedom o Information SummaryNADA 141-240 Page 12

REBALANCE Antiprotozoal Oral Suspension is protected under the followingU.S. patent numbers:J.S. Patent Number5,747.4766,255,3086,448,252

6. ATTACHMENTS

Date o ExpirationJuly 17 2016July 17,2016July 17,2016

Facsimile labeling is attached as indicated below:a. Bottle Labelb. Package Onsert

Pegasus Laboratories v. US Compounding

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