May1,1997
`
`.
`
`Paul Leber, MD.
`Director, Division ofNeurophannacological
`Drug Products (HFD-IZO)
`Center for Drug Evaluation and Res
`Food and Drug Administration
`'
`WOOdmOIIt 11 Building
`1451 Rockville Pike
`Rockville, MD 20857
`
`
`
`BEST POSSIBLE COPY
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`
`a... .. fl DUP' lC
`
`Cephalon, Inc.
`
`-
`
`145 Brandywine Parkway
`West Chester, PA 193804245
`(6‘0) 3440200
`Fax (610) 344-0065
`
`NDA 20.717
`0319 -
`Provigil" (modafmil) Tablets MC m) -
`
`. Dear Dr. Leber:
`
`Reference is made to our New Drug Application (NDA) 20-717, Provigil‘” (modafinil) Tablets, for the
`improvement of wakefulness in patients with excessive daytime sleepiness associated with narcolepsy,
`which was dated December 27, 1996. Further reference is made to our request for exclusivity, which was
`submitted on April 9, 1997.
`In addition, please note that modafinil was granted orphan status for this
`indication on March 15, 1993.
`
`This submission provides a summary of patent and exclusivity information for Provigil. The following
`patents are included:
`
`US. Patent No. 4,927,855 claims an Optically pure levorotatory (“L-”) form of modafinil; modafinil is a
`racemic mixture, such that both the L— and D- fomts of modafinil can be considered “ingredients” of the
`active ingredient for which approval is being sought.
`In this sense, Cephalon believes, in good faith, that it
`is providing sufficient notice to the public ofthe potential patent infringement problems that might exist if a
`third party sought regulatory approval of a product comprised exclusively of the L-form of modafinil
`and/or a “weighted” ratio of modafinil; for example, a third party product comprised of greater than 50%
`of the L-form of modafinil, and less than 50% of the D-form of modafinil. This patent is currently set to
`expire on May 22, 2007.
`
`If you have any questions concerning this submission, please contact me at (610) 73 8-6373.
`
`Sincerely,
`
`mm
`
`Paul Nemeth, PhD.
`Senior Director
`
`Regulatory Affairs
`
`h:\reafi\cep1538\nda207l7\l970501,doc
`
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`

`Table of Contents
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`7,
`
`«
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`~-
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`PAGE
`
`Cover Letter............................................................................................................................ 001
`
`Form FDA 356k...................................................................................................................... 002
`
`Table ofContents .................................................................................................................... 004
`
`Patent and Exclusivity Infonhation .......................................................................................... 005
`
`ADDENDUM A
`U. 8. Patent No. 4,177,290 .......................................................................................... 006
`
`ADDENDUM B
`U.S. Patent No. 5,618,845 .......................................................................................... 014
`
`ADDENDUM C
`US. Patent No. 4,927,855 .......................................................................................... 029
`
`O O 4
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`

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`PATENT AND EXCLUSIVITY INFORMATION
`-
`PROVIGIL°(modafinil)Tab1eis‘ ‘
`
`l.
`
`ACTIVE INGREDIENT
`
`medafinil
`
`2.
`
`STRENGTH
`
`100 mg and 200 mg tablets
`
`3.
`
`TRADE NAME
`
`PROVIGIL"
`
`4.
`
`DOSAGE FORM/ROUTE OF ADMINISTRATION
`
`tablet/oral
`
`5.
`
`SPONSOR
`
`Cephalon, Inc.
`
`6.
`
`NDA NUMBER
`
`20-717
`
`7.
`
`APPROVAL DATE
`
`Pending
`
`8.
`
`EXCLUSIVII'Y
`
`Five years afier approval of the NDA
`Seven years after approval ofthe NDA (orphan indication)
`
`' W
`
`9.
`
`APPLICABLE PATENT NUMBERS AND EXPIRATION DATE OF EACH
`
`ADDENDUM A:
`ADDENDUM B:
`ADDENDUM C:
`
`US. Patent No. 4,177,290
`US. Patent No. 5,618,845
`US. Patent No. 4,927,855
`
`March 9, 1998
`October 6, 2014
`May 22, 2007
`
`h:\wafl\eep1538\nd3207l7\1970501.doc
`
`O 05
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`SUBMISSION 0F PATENT INFORMATION
`1N ACCORDANCE WITH 21 C.F.R. § 314.53
`(ADDENDUM A)
`
`In accordance with the requirements of21 C.F.R § 314.53(c)(1), applicant
`Cephalon, Inc. submits the following patent information:
`
`(1)
`
`(ii)
`
`(iii)
`
`Patent number and the Date on which the patent will expire:
`(a)
`Patent Number: 4,177,290 (copy attached)
`(b)(1) Expiration Date under the provisions of the Uruguay Round ofthe ,
`A
`V
`General Agreement on Tariffs and Trade (“GATT”):
`March 9, 1998
`(b)(2) Expiration Date under previous “17 year from issuance” term:
`December 4, 1996 (this expiration date is provided for convenience
`only; under the GATT, the term of US. Patent No. 4,177,290
`expires on March 9, 1998).
`
`,
`
`Type of Patent:
`—
`US. Patent No. 4,177,290 contains claims for both a drug
`substance and a drug product.
`
`Name of Patent Owner:
`-
`Laboratoire L. Lafon
`Maisons Alfort
`FRANCE
`
`(iv)
`
`Not Applicable
`(Applicant resides and has a place of business in the United States)
`
`APPEARS THIS WAY 0N ORIGINAL
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`In accordance with the requirements of21 C.F.R. § 314.53(c)(2), the following
`original declaration is submitted; in accordance with 21 ORR. § 314.53(c)(4), the original
`declaration has been signed by the applicant’s patent attorney.
`
`“The undersigned declares that Patent Number 4,177,290 covers the formulation,
`composition, and/or method ofuse ofthe acetamide derivative referred to as
`‘modafinil.’ This product is the subject ofthe application for which approval is
`being sought.”
`
`
`
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`..«A-.q:l~_-_..
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`
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`
`
`
`
`
`
`
`
`
`-
`
`Louis won. Pan's. France
`Inventor:
`[75]
`[73] Assignee: Labor-tone L L-fon. Maison:
`‘
`Alfort. France
`'
`
`[2:] Appl. No.: 885.009
`
`[22] Filed:
`
`Mn. 9. ms
`
`foreign Appllatton' Priority Data
`(.101
`
`Mn. 31. 1917 [on] United Kingdom
`
`tam/71
`
`[5!]
`
`Int. CL! .................. AGIK 31/165; C07C 103/22;
`.
`007C 103/82; CO7C i03/76
`[52] U.S. Ci. .............
`424/324; 260/239 BF;
`260/326.42; 260/3405 R; 260/558 S: 260/559
`T; 260/558 A:'424/250;'424/267; 424/244;
`424/274; 424/282; 544/l 59; 544/i 68: 544/393;
`544/396; 546/234; 546/235; 424/248.5;
`'
`424/248.“
`
`United States Patent {19]
`Lafon
`Dec. 4, 1979
`[45]
`\N“
`[54] ACETMDE namwmvm
`
`[I l]
`
`4,177,290
`
`[58]
`
`field ofScnrch L....... 260/558 s. 559 12340.5 R;
`424/324
`
`[56]
`
`References Gted
`
`3.993.683
`4.061.973
`
`>
`U.S. PATENT DOCUMENTS
`
`ii/l976 Nicki ct ui. .
`... 260/55! 8 X
`
`i2/i977 Nicki ct CL
`260/558 S X
`OTHER PUBLICATIONS
`
`Dahlbom et 11.. CA 43:50i8i (i949).
`l’n'mmy Examiner—Woman A. Waitz'
`.Xuarney. Agent. or Firm—Ducal! & 1110mm
`ABSTRACI‘
`' [571'
`
`..
`
`Novel Icetamide derivative: hive been discovered to
`have useful pharmaceutical activity on the central ner-
`vous system. They may be prepared» by reacting the
`corresponding ester 'or3cid hniide with the appropri-
`ately substituted umine.
`‘
`
`6 Gums, No Drawings
`
`
`
`
`
`
`
`
`
`
`
`
`
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`APPEARS THIS WAY ON ORIGINAL
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`a
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`V
`4,177,290
`,
`2
`'
`‘
`.
`v
`Certain illustrative compounds offormula l in which
`
`
`ACETAMIDE DERIVATIVES ‘
`rings (a) and (b) are. unsubstituted are given in the fol-
`lowing Table:
`
`
`Code No.
`CR L 40416
`
`2
`
`\
`
`TABLE
`A '
`ll
`
`Melting point
`lu-Mti‘ C.
`
`
`
` /
`
`,
`
`ll
`
`0" c.
`
`\ /
`
`Wimhyl {me hate: llb-llT‘C.
`-
`_
`HCl salt: txo-ttt'c.
`\
`cat. toss:
`/Nr-CO*-~
`
`10
`By. addition salts there are understood here the acid
`
`addition salts of aetds obtained
`
`by reacting the free base
`'atives;theirpreparation and their therapeuticcomposi- wig: gnggaozfiwggfifil may be prepared by
`
`
`
`
`conventional methods. The preferred method ofprepa-
`“0'.” and "“5- “ plarucular '5 ingredients thh are
`
`
`
`
`active on the centra nervous system.
`'
`_
`g
`25 ration wmpfim reacti
`
`
`
`c new compounds according to the Invention are
`
`acetamide derivatives of the general formula I:
`
`The present inv'entio
`
`it relates to new acetamide deriv-
`
`.
`
`ng an acid halide of formula ll:
`
`O
`
`-
`
`Z-CHr-CO-Nih-A
`
`(I)
`
`’°
`
`f")
`
`Z—Cilr-CO~X
`
`40 with an amine of formula lll:
`":Nék
`
`
`
`
`
`
` F. Cl. Br or I. the preferred halogen being chlorine,
`in which
`_
`each of rings a and b may optionally be substituted by
`
`
`one or more of the grbups. F.'Cl. Br. CF}. N02. NHZ,
`(lll)
`'CHalkyl. Cualkoxy and methylenedioxy;
`z is >CHSO¢— or >NCO—; and
`45 in which A is a defined above.
`
`
`A is hydrogen. Ctmkyl. Clshydroxyalltyl or a
`The sulphtnyl compounds (2:.- >Cl-lSO—) are pref-
`hod or by a variation
`
`hich comprises reacting a sulpho dc-
`he same of different and
`rivative of formula Ila:
` ing, optionally. a second heteroatom such as N or O.
`and which, may be substituted; and the addition salts of
`the compounds wherein A is a basic group.
`
`
`Among the gran
`
`
`
`
`
`
`
`in which Hal is F. Cl. Br or l. preferably Cl. with an
`phur amide which is oxidimd with
`'
`amine of formula lll to obtain the corresponding sul-
`
`
`'
`dcsircd sulphinyl derivative.
`
`
`mentioned in particular: dimethyl-
`amino. dicthylamino. pyrroljdino. pipen'dino. 4~methyl~
`#phenylpipefidino.
`4o(p-ehlor0phenyl)-
`piperidino.
`piperidino.
`morpholino.
`piperazino.
`4-methyl-
`pipcrazino. 4-(B~hydroxyethyl)piperazino. 4-phenyl- 60
`ptpcrazino. 4-(p~chlorophenyl)piperazino and perhya
`droazepino.
`A is preferably hydrogen. B-hydroxymethyl or B-
`‘
`morpholinoethyl.
`
`Particularly preferred co
`.
`.
`
`
`
`ctt—s—cu—co-mu
`
`
`
`
`
`
`
`

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`”-01.70 16:01
`
`3
`
`"4. 177,290
`
`4
`out heat are carried out. in this way. the benzhydrylsul-
`phinylacetic acid is obtained.
`(c) Methyl benzhydrylsulphinylacetate
`The above acid is placed in a 20~liter reactiOn Vessel
`
`dimethyl sulphate are added. After one hour. crystalli-
`sation is induced. Filtration. drying without heat and
`Washing are carried out. Methyl benzhydrylsulplliny.
`'0 lacetate is obtained.
`(d) CRL 40476.
`
`“
`
`‘
`
`’
`
`for l hour. and then left invcontact for 4 hours. Filtra-
`tion. drying withoutheat and washing with water are
`then carried out.in recrystallisation from a mixture of " ‘
`Water and methanol (4:1 v/v) and then from a mixture
`of water and methanol (9:! v/v) and drying under re—
`duced preasure.‘CRL 40476 is obtained in the form of a
`white crystalline powder.
`Mpg”, (K6t'ier): l64'-l66' C.
`-
`-
`Total yield (calculated from the benzhydrol): 4l%.
`EXAMPLE 2
`
`N.N~diphcnylmalonamide
`(CsHs)z-—N—Co—-CH2~CONH2
`Code No: CRL 40542
`
`.
`EXAMPLE l
`Benzhydrylsulphinylacetamide
`(2.! l5)1CH~SO—CHz-CONH2
`Code No: CRL 40476
`(i) Benzhydrylthioacetyl chloride
`l9.5 g (0.076 mol) ofbenzhydrylthiqacetic acid in l 14
`ml of benzene are placed in a three-necked flask pro-
`vided with a condenser and a dropping funnel. The
`mixture is heated and I9 ml of thionyl chloride are
`added drop by drop. Once the addition is complete. the
`reflux is continued for about I hour. cooling and filter-
`ing are carried out and the benzene and the excess thie-
`nyl chloride and then evaporated. In this way. a clear .5
`orange oil is obtained.
`(2)“ Benzhydrylthioacetamide
`.15 ml oi‘ ammonia in 40 ml of water are introduced
`into a three-necked flask provided with a condenser and
`a dropping funnel and the benzhydrylthioacetyl chlo- to
`ride dissolved in about too ml of methylene chloride is
`added drop by drop. Once the addition is complete. the
`organic phase is washed with a dilute solution of soda
`and dried over NazSOa. the solvent is evaporated and
`the residue isjtalten up in diisopropyl ether; in this way. 25
`the benzh;drylthioac‘etamide is crystallised.
`l6.8 g of
`product (yield =86%) are obtained.
`'M.p.m,=ll0' C.
`(3) CR1. 40476
`
`placed in a balloon flask and 60 ml ofacetic acid and 5.6
`ml oil-1102 (about 1 l0 volumes) are added. The mixture
`is left in contact for one night at 40' C. and about 200 ml
`ofwater are then added; the CRL 40476 crystallisa. By
`recrystallisation rrotn methanol. ll.2 g ol‘benzhydryl- 35
`sulphinylacetamide are obtained.
`Yield: 73%.
`M.p.;,.,,=l64'—l66‘ C.
`
`40
`
`45
`
`a mixture ofconccntrated H2804(120'ml) and H20 (15
`rnl). The rtsultlng solution is poured. with agitation.
`
`obtain CR1. 40542.
`Yield 44%.
`Mp: l36' c.
`
`EXAMPLE 3
`N.N-diphenyl-N'-B-morpholinoethylrnalonarnide
`hydrochloride
`
`EXAMPLE la
`Example In relat: to the same procedure for the
`manufacture of benzhydrylsulphinylacetamide (CR1.
`40476). as Example I, but on an industrial scale.
`(a) Benzhydrylthioacetic acid
`LOO] ltg of thiourea is dissolved in 5.72 liters of 48%
`hydrobromic acid and 0.880 liter of water in a 20-liter
`reaction Vessel. The mixture is heated to 60' C. and
`2.024 kg of benzhydrol are introduced. The tempera-
`ture is increased to 95‘ C. and the contents of the vessel
`areallOWed to cool to room temperature (l5'—25' C1).
`The crystals are filtered off and washed with water.
`They are made into a paste again in 5.5 liters of water
`and this is introduced into a 20-liter reaction vessel with
`3.5 litersol'soda lye (d: LBJ). The mixture is heated to
`70‘ C. and ”44 g of chloroacetic acid dissolved in 2.2
`liters of water are passed in slowly. The reflux is main-
`tained for 30 minuts after the chloroacetic acid has
`been passed in. The contents of the vessel are allowed to
`cool to room temperature (in this way. the benzhydryl-
`thioacetic acid is obtained. but is not isolated).
`(b) Benzhydrylsulphinylacetic acid
`L430 liters of hydrogen peroxide at l30 volumes are
`passed in over 3 hours at-about 30‘ C. into the above
`reaction mixture. 22 liters of water arcgthen passed in.
`the insoluble material is filtered off and acidification is
`carried out with hydrochloric acid (d = l. l 8). Filtration.
`
`55
`
`65
`
`N-CO-C‘il1*C‘O‘NlI~Cll3Cliy~N
`
`(LIICI
`
`Code No.: CRL 40543
`(I) N.N-diphcnylcarbamoylacctic acid
`22.6 g (0.08 mol) of ethyl N.N-diphenylcarbamoy~
`lacetate (tn.p.=75‘e76’ C.) are added to a solution of
`5.6 g(0.l mol) of KOH in a mixture or50 ml of water
`and 25 ml of ethanol. The mixture is heated to 40' C.
`with agitation until dissolution is complete (that is. for
`about I hour) and agitation is continued for two hours.
`Acidification is then carried out with 3 N HCL followed
`by drying without heat. washing with Witter and
`
`
`
`

`

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`
`4,177.290
`5
`drying.20.2 g (yield: 98%) of N.N-diphenylcarbamoyla-
`cetic acid (m.p.= l26'-I27' C.) are obtained.
`_
`(2) N.N-diphenyl-N’-fl-morpholinoethylmalonamide
`A solution of 13 g (0.05 mol) of N.N4diphenylcar-
`bamoylacetic acid and 7.1 g (0.055 mol) ofN-(Z-aminoe-
`thyl)morpholine in 120 ml of methylene chloride is
`refluxed with agitation. A solution of
`ll g (0.055 mol) of
`dicyclohexylcarbodiimide in 30 ml of CHzClz is slowly
`added and the mixture is maintained under reflux for 3
`hours.'
`,
`the dicyclohexylurea
`precipitate is filtered off. the filtrate is extraded with
`
`5
`
`l0
`
`stereotypy.
`IVe—lNTERACTION WITH RESERI’INE
`Batches of 6 mice received an mtrapcntoncal injec-
`
`mg/ltg. CRL 40476 partially counteracted the body
`temperature lowering effects of the reserpine. but the
`reserpine ptosis was hot changed by CRL 40476.
`V—INTERAC‘ITION WITH OXOTREMORINE
`Oxotremorine (0.5 mg/ltg) Was
`
`strongly alkaline with concentrated NaOH. Drying
`‘without heat.»washing with water and drying are car-
`ried out: by recrystallisation from ethyl acetate. l6 3 of
`the title haw.- are obtained.
`..
`.
`t.
`.
`-
`
`IS
`
`he trembling caused by the oxotremorine; and CRL
`40476 did not altersghe Iacrymal and salivary hyperse-
`eretion and the defecation following upon the adminis-
`tration of oxotremorine.
`.
`,
`Vlh-ACTION ON THE FOUR-PLAQUE TEST.
`TRACTION AND ELECTRIC SHOCK
`The test was performed on batches of IO mice 30
`minuts after the administration of CRL 40476. It was
`40476 led to an increase in the number
`of punished passages (probably in connection with an
`exciting effect). that it did not cause any major motor
`' deficit. and that.
`in strong doses (from 64 to 256 mg/kg).
`it counteracted the eonvulsing elTect of electric shock.
`VII—ACTION ON SPONTANEOUS MOTILITY
`Mice (12 per dose. 24 controls) received CRL‘40176
`
`Intraperitoneally. CRL 40476 leads to an increase in
`motility which is perceptible from 16 mg/kg. This ef~
`feet begins rapidly (less than I5 minutes) and reaches its
`
`Yield: 78%
`M.p.=180‘~l81' C.
`The results of the
`compounds according to the in-
`'
`vention and in particular the products of Examples I to
`3 are summarised below.
`>
`g
`In the following.’in the absence of precise details to
`the contrary. each product was administered intraperi-
`toncally in suspension in a gummy solution (gum ara-
`bic). in a volume of 20 ml/Itg to mice and 5 ml/ltg to 35 .
`rats.
`TESTS WITH CRL 40476
`I—TOXICI'IY
`
`30
`
`animal was found dead after 24 hours. At a dose of 5I2
`mg’lltg. the symptoms were identical. but the animal
`survived. At 256 mg/ltg hypermotility was noted above
`all. accompanied by milling. perhaps stereotyped. the
`gait was abnormal and the animal showed dyspnoea. At
`128 and 64 mg/ltg. the hypermotility and the stereo-
`typed sniffing were still present for more than 3 hours.
`The maximum non-fatal dose per os was higher than 5 I2
`
`>45
`
`(2) By the gastric route, at a.dose of 64 mg/ltg and
`above. CRL 40476 leads to considerable hypermotility
`immediately after the ‘
`‘
`
`-
`em. but lasts Ies long.
`(3) To determine the effect of repeated administra-
`tions. mice (l2 per dose. 24 controls) received a daily
`intrapen'toneal administration ofdistilled water or CRL
`40476. On the fifth day. the animals were placed in the
`actimeters 30 minutes after the last administration and
`their motility was recorded for 30 minutes. CRL 40476
`was found to retain its activity on the motility of the
`
`
`
`Batches of 6 rats each received a subcutaneous injec-
`tion of 0.5 mg/ltg of apomorphine 30 minutes after the
`administration of CRL 40476. It was found that. with a
`strong dose. CRL 40476 seemed moderately to potenti-
`ate the stereotypy of apomorphine.
`.
`(2) Mice
`Bathces of 6 mice received CRL 40476 30 minutes
`before the subcutaneous injection of l mg/ltg of apo-
`morphine. It was observed that CRL 40476 did not
`counteract the hypothermia. stereotypy and verticalisa-
`tion behaviour induced in the mice by the apornorphinc.
`Ill—INTERACTION WITH AMPHETAMINE
`IX—INTERACTION WITH HYPNOTICS
`Amphetamine-(2 nag/kg) was injected intraperitonc-
`(l) Batches of IO mice received CRL 40476 30 min«
`ally into batches of 6 rats 30 minutes after the adminis-
`utes before the administrution of: ltypnogenic dose of
`tration of CRL 40476. It was found lllnl CRL 40476
`chloral (400 mg/kg, injected intraperitoneally).
`
`
`
`55
`
`65
`
`After a stay of3 weeks in each of the halves ofa box
`separated by an opaque partition. groups ofthree mice
`received CRL 40476 Half an hour later.
`they were,
`brought together by withdrawing the partition and the
`number of lights that occurred in the course
`‘
`
`
`
`
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`“HIM (007 JR [2040* .‘hlfl
`
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`W;I!
`
`"-01.70 In”) 71147.0 (“INN Ill:
`
`At a low dose (l6 and 32 mg/kg). CRL 40476 re-
`duced significantly the length of the sleep induced by
`the chloral. By increasing the doses. this effect disnp~
`peared. but the number 'of mice put to sleep decreased.
`(2) Metsqualone (125 mg/kg) was injected intraperi-
`toncally into batches of 10 mice 30 minutes after the
`administration of CR1. 40476.
`,
`At a low dose. CR1. 40476 did not alter the length of
`the sleep induced by the metaqualone. but by increasing
`the doses the number of mice put to sleep decreased.
`whereas the length of the sleep increased significantly.
`30 With mice used for recording motility after repeated
`administrations of CRL 40476. pentobarbital
`(50
`mg/ltg. administered intraperitoneally) was injected
`into the mice as soon as the recording of spontaneous
`motility was completed. that is 60 minutis after the final
`administration of CRL 40476.
`»
`CRL 40476 did not alter the length ofthe barbiturate-
`induced sleep. With repeated administrations. it led to a
`reduction of the length of the sleep with respect tothe 20
`effects of a single administration:
`.
`,
`X—lNTERACTmN WITH YOHIMBINE
`~ CR1. 40476 was administered to mice grouped in
`lives one hour before the injection ofa subtoxic dose of
`yohimbine hydrochloride (40 mg/lcg. administered sub-
`cutaneousiy). The dath rate was taken 24 hours later. it
`was found that CRL 40476_potentiated the toxicity of
`the yohimbine.
`.
`.Xi—lNTERACI‘lONr WITH 5-HYDROXYTRYP-
`TOPHAN and 1.M.A.O.
`-
`.
`‘Batches of lo mice received a gastric administration
`of Nialamidc (20 mg/kg) l8 hours before an intraperito-
`heal injection of DL-S-HTP. in doses of 32. 64 and. 128
`mg/kg. CRL 40476 did not lead to potentiation of the
`
`25
`
`30
`
`to
`
`B
`
`8
`(4) Prolonged avoidance conditioning
`Rats placed in a shuttle
`avoid an electric shock (5 s) by changing compartments.
`signal appearing every 20 seconds. When the animals
`Were perfectly conditioned. they remained subjected to
`the signal and possibly to the shock until apparent disap-
`pearance of conditioning. which generally occurred
`after 24 hours.
`'
`‘
`.
`CRL 40476 was then administered intraperitoneally
`and the possible resumption ofavoidance was reckoned
`until disappearance of the effect; at a dose of 128
`tug/kg. CRL 40476 caused very distinct resumption of
`avoidance in the animals whose conditioning had appar-
`ently disappeared following a prolongation of the ses
`sion. With a lOwer dose (64 mg/kg). this effect was
`practically non-existant.
`‘
`XIII—CONCLUSIONS
`CRL 40476 presents a neuropsychophannacological
`spectrum characterised by the presence of excitation
`with hyperactivity and of hypermotility; and by the
`absence of stereotypy (except in strong doses) and of
`potentialisation of the effects of apomorphine and am-
`» phetamine.
`Moreover. in some respects. CRL 40476 could ap«
`proximate to the itnipramine antidepressants (antago~
`nism to reserpine hypothermia. potentation of the toxic-
`ity of yohimbine). but the absence of potentiation of
`5-HT? and of antagonism to the hypothermia induced
`by apomorphine would make it a very special case in
`this pharmacological elm.
`Finally. in mice whose motility has been reduced by
`habituation of their enclosure. the presence of a motor
`35'
`
`
`
`>
`
`death rate (30%) appeared.
`XIIé—ACTION '
`BEHAVIOURAL
`WRBED BY VARIOUS AGENTS
`.
`(l) Motility reduced by habituation
`After 'a sojourn of 18 hours. mice received CRL
`40476. Immediately afterwards they returned to their
`respective enclosures and half an hour later the record-
`ing of motility began and was continued for 30 minuts.
`it was foundthat CRL 40476 caused, starting from a
`dese of 2 mg/kg, an appreciable mumption at a dose of
`2 or 4 mg/kg. This effect was very marked at 8 and l6
`mg/kg.
`(2) Motility reduced by hypoxic aggression
`'
`30 minutes after receiving CR1. 40476.
`subjected to hypobaric anoxia (depressionrof 600 mm
`Hg in 90 5. expansion of45 s). and they were then placed
`in an actimeter where their motility was recorded for ID
`minutes. It was observed that. for doses higher than l6
`mg/kg. CR1. 40476 led to an improvement in motor
`recovery in mice whose motility has been lowered by
`hypoxic aggrssion.
`(3) Asphyxic anoxia
`Mice (10 per dose. 20 controls) received an intraperi-
`toneal injection of gallamine triethiodide at a dose of 32
`mg/kg 30 minutes after the administration of CRL
`40476 and the time taken for the appearance of convul~
`sions and death was noted. It was found that. in doses of
`
`45
`
`50
`
`55
`
`65
`
`chism than of activity.
`TESTS WITH CLR 40542 and CRL 40543
`The following tests are numbered parallel to those for
`CR1. 40476:
`
`mg/kg. and greater than‘5l2 mg/kg for CRL 40543. At
`doses of 256 and
`g
`-
`for both products.
`ll. in rats, CRL 40542 potentiates the stereotypy of
`apomorphine but CRL 40543 does not affect the stereo-
`typed behaviour induced by apomorphine. in mice, the
`
`. "
`
`phine at doses of l and l6 mg/kg.
`lll. At a dose of 256 mg/kg. CRL 40542 potentiates.
`but CRL 40543 does not modify. the amphetamine ste-_
`reotypy.
`W. The hypothermia induced by reserpine is antago-
`nised by CR1. 40542 at a dose of 128 mg/kg and aggra-
`vated at a dose of 512 mg/kg. CR1. 40543 doesnot
`modify reserpine-induced hypothermia. Neither pr
`.
`not has any action with respect to reserpine ptosis.
`V. The hypothermia induced by oxotremorine is
`antagonised by CRL 40542 at doses of 32 and I28
`mg/‘kg and by CRL 40543 at a dose of 256 mg/kg.
`Neither product is active on the trembling or peripheral
`cholinergic symptoms provoked by oxotremorine.
`Vl. CR1. 40542 (at 32 and 128 mg/kg doses) and
`
`
`
`
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`
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`
`INN-7C 2‘!!!
`
`"OI-7’ nuts: "I410 01mm ".0
`
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`
`
`4,177,290
`
`10
`I. An acetamide derivative selected from the com—
`pounds of formula I
`
`[0
`
`[5
`
`2°
`
`(l)
`
`z-ucny-oo—Nu—A
`
`. \
`
`0
`
`wherein ring a and ring b are each substituted zero. one
`or more times by substituents selected from the group
`consisting of fluoro. chloro. bromo. trilluoromethyl.
`nitro. amino. alkyl of l to 4 carbon atoms. inclusive.
`alkoxy of l to 4 carbon atoms, inclusive. and methylene-
`dioxy: wherein Z is the radical >CHSO—f: and wherein
`A is selected from the group consisting of hydrogen.
`alkyl of l to 4 carbon atoms. inclusive. hydroxyalkyl of
`l to 4 carbon atoms. inclusive. and a group of formula
`R1R2N~Y~wherein Y is a divalent linear or branched
`chain hydrocarbon radical having I to 4 carbon atoms.
`inclusive. in the chain. and R: and R1. being the same or
`different. are selected from the group consisting of hy-
`drogen and alkyl of l to 4 carbon atoms. inclusive; and
`addition salts of the compounds wherein A is a basic
`group.
`'
`
`9
`(at l28 and 256 mg/kg doses) did not modify the con-
`vulsions.
`_
`VII. CRL 4054:! does not appear to modify spontane-
`ous motor activity. In mice. CRL 40543 leads to an
`increase in motor activity. at a dose of 256 mg/kg.
`VIII. CRI. 40542 does not provoke any noticeable
`change in intergroup aggression CRL 40543. at a dose
`of 16 to 256 mg/kg.'leads to a reduction in the number
`of fights.
`'
`‘
`.
`XII. CRL 40542 (at a 8 mg/ltg dose) and CRL 40543
`(at
`l6 and 64 mg/kg doses) lead to a resumption of
`motdr activity in mice whose motility has been reduced
`by staying in the same enclosure.
`CRL 40542 (at 32. 64 and 128 rug/kg doss) and CRL
`40543 (at a 256 rag/kg dose) lead to an ameloriation of
`motor recovery in mice whose motility has been re
`duced by hypoxic aggression.
`;
`,
`' With regard to asphyaic anoxia. CRI. 40542 and
`CRL 40543 lead. with strong doses. to a shortening of
`the delay in the appearance of convulsions and death
`caused by gallamine triethiodate. a curan‘zing agent.
`XI". The neuropsychopharmaeological study of
`CRL 40542 reveals _a number of cacitator behavioural
`effects; excitation with hyperactivity in mice and rats;
`the presence of stereotypy and the potentiation of the ‘25
`stereotyped effects owing to apomorphine and amphet-
`amine; an increase in motility in animals whose activity
`has been reduced by habituation or hypoxia aggmion;
`“anti-fatigue“ activity in an avoidance conditioning test
`over a prolonged period; the prsence of convulsions at
`high dose: and the moderate antagonism of hypother-
`mia induced by oxotretnorine or merpine.
`.
`CRL‘ 40543 shows a certain number of excitatory
`propertis (excitation. hyperactivity and hypennotility)
`rwhich can be accounted for in the results observed in
`the four plaque tat. Further. the compound possesses
`convulsive activity which lads to heightening of cori~
`vulsions induced by .asphyxic anoxia. Finally. it exerts
`an anti-aggressive effect at all doses.
`'
`The compounds according to the invention are useful
`as therapeutic agents in the treatment of neurophysical
`disorders. being agents active on the central nervous
`
`35
`
`.Inman.CRL40476canbeusedin
`the form of cap-
`suls or compressed tablets at a dose of 200 mg. three
`times daily. Very favourable results are obtained in the
`treatment of aged asthenics. Further. without antagoni-
`sation ' of antipsychotic effects.
`the compound has
`proved to be useful in the treatment of slow dyskinesia
`in neuroleptit:
`I claim:
`
`45
`
`50
`
`SS
`
`65
`
`2. A compound of claim I wherein A is
`R|R1N-—Y-wherein Y is a divalent linear or branched
`chain hydrocarbon radical having I to 4 carbon atoms.
`inclusive. in the chain. and R1 and R2. together with the
`N atom to which they are attached, form a group se-
`lected from the group consisting of dimethylamine and
`diethylamine.
`.
`‘
`3. A compound of claim 1 wherein rings a and b are
`both unsubstituted and A is hydrogen. and pharmaco~
`logically acceptable acid addition salu thereof.
`' 4. A compound of claim 1 which is benzhydrylsul~
`phinylacetamide.
`-
`5. A pharamaceutical composition having activity on
`the central nervous system and consisting of. as an es—
`sential active ingredient. an active amount of a com-
`pound of claim 1.
`6. The compound of claim 1. wherein Z is --CHSO—
`and A is hydrogen. alkyl of l
`to 4 carbon atoms or
`0
`hydroxyalkyl of I to 4 carbon atoms.
`O
`O
`C
`O
`
`013
`
`
`
`

`

`1
`
`.
`
`,
`
`BESTPBSSIBLECOPY
`BEST POSSIBLE COPY
`
`SUBMISSION OF PATENT INFORMATION
`IN ACCORDANCE wrrn 21 C.F.R. § 314.53
`(ADDENDUM B)
`
`In accordance with the requirements of21 CPR § 3 14.53(c)(1), applicant
`Cephalon, Inc. submits the following patent information on US. Patent No. 5,618,845
`which issued on April 8, 1997:
`
`(i)
`
`,
`
`Patent number and the Date on which the patent will expire:
`, (a)
`Patent Number: 5,618,845 (copy attached),
`"
`(b)(1) Expiration Date under the provisions of the Uruguay Round of the
`General Agreement on Tariffs and Trade (“GATT”):
`October 6, 2014
`(b)(2) Expiration Date under previous “17 year fiom issuance” term:
`April 8, 2014 (this expiration date is provided for convenience
`only; under the GATT, the term of US. Patent No. 5,618,845
`expires on October 6, 2014).
`
`(ii)
`
`Type of Patent:
`—
`US. Patent No. 5,618,848 contains claims for a drug product
`(pharmaceutical composition) and use of a drug product
`(pharmaceutical composition).
`
`(iii)
`
`Name of Patent Owner:
`
`-
`
`Cephalon, Inc.
`145 Brandywine Parkway
`West Chester, PA 19380
`UNITED STATES
`
`(iv)
`
`Not Applicable
`(Applicant resides and has a place of business in the United States)
`
`APPEARS THIS WAY ON ORIGINAL
`
`
`
`

`

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`
`In accordance with the requirements of21 CPR. § 314.53(c)(2), the following
`original declaration is submitted; in accordance with 21 C.F.R. § 314.53(c)(4), the original
`declaration has been signed by the applicant’s patent attorney.
`
`“The undersigned declares that Patent Number 5,618,845 covers the formulation,
`composition, and/or method ofuse ofthe acetamide derivative referred to as
`‘modafinil.’ This product is the subject ofthe application for which approval is
`being sought.”
`
`
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`015
`
`

`

`.
`
`-
`
`-
`
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`111111 1111111111111111111111111111111111111151151111111111 511121 51111 15591
`0800561884.511
`
`A
`
`-
`
`.
`
`71131162?”! Sis-lites Patent . 1191
`Grebow at al.
`
`H“_‘H__“
`[54] ACETAMIDE DERIVATIVE HAVING
`DEFINED PARTICLE SIZE
`
`[75]
`
`inventors: PeterE. Grebow, Penllyn. Pa: Vincent
`Corvari. Hockessin. Del.; David Stong.
`Coatsville. Pa.
`
`[73] Assignee: Cephnlon, Inc” West Chester. Pa.
`
`[21] Appl. No.: 319,124
`
`[22) Filed:
`
`Oct. 6, 1994
`
`-8-
`
`Int. Cl.“ .............................. AGIK 9/14; A61K 31/16
`[51]
`[52] US. Cl. '........................._.....~~~~~ 514/618; 424/489
`‘ .(581' Field of Search .............................. 424/489; 514/618
`
`[56]
`
`Referenets Cited
`
`U.S. PATENT DOCUMENTS
`
`.......................... 424/37
`1/1977 Cordelia et a1.
`4.002.718
`
`10/1973 Huber ........................ 424/21
`4.122.157
`12/1979 Lafon ............................
`.. 514/618
`4.177.290
`4/1980 Besins ................................ 424/37
`4.196.188
`6/1982 Bemini .............
`260/2395?
`4.332.721
`
`..... 424/455
`4.713.246 12/1987 Begum et :11.
`
`..... 424/465
`4.880.623
`11/1989 Piergiorgio eta].
`1/1990 Cunet et a1. ................ 424/456
`4.895.726
`
`5/1990 Lafon ..............
`..... 514/618
`4.927.855
`
`............ 424/436
`5.021.242
`6/1991 Romeretnl.
`..
`
`1/1993 Litton ..................... 514/618
`5.180.745
`
`.
`..... 424/489
`5.202.129
`4/1993 Samejima et a1.
`5.391.576
`2/1995 Lal’on ................................. 514/618
`
`FOREIGN PATENT DOCUMENTS
`
`European Pal. 00'. .
`8/1987
`233106
`8/1987 Eutopean Fat. 00‘. .
`02.33106
`462004 1fl1991
`European Pat. OH.
`.
`547952
`6/1993 European Fat. 011'.
`.
`594507
`4/1994 European Pat. om.
`94/21371
`9/199: 9/190.
`wows/21371
`9/1994 WIPO.
`95/1171
`1/1995 WtPo.
`95/110132
`1/1995 wn>o.
`85/12944
`2/1995 WIPO.
`
`OTHER PUBLICATIONS
`
`\
`
`Remington's Pharmaceutical Sciences 16th Ed (1980) pp.
`1355-1368. 305—306. 1535—1545.
`‘w-
`Shepherd Othcro Sclerosis
`llO/Suppl
`1555~563(1994)
`Micronimd Lenojitrate.
`Kondo Biol. Pharm Bull. 16(8):?