3 0 7 4 5 *
`
`4
`
`..die losung filtriert, im Reaktionsdunnsohiohtverdampfer i .
`eingeengt au£ oa. 8 1 und der Euckstand iDit .24
`1
`verdunnt und "bis
`zur Kxistallisation
`Eeinigung, erfolgt durch. Umkristallisation
`
`0201
`
`AGILA ET AL - EXHIBIT 1017 (PART 2 OF 4)
`
`

`
`2 3 0 7 4 5 4
`
`Erfindungsanspruoh.
`
`zur Herstellung von 4-^T-Methyl-^-bisCZ-ohlor-
`1. Verfahren
`von
`athyl)-T3enzimidazolyl-27-l)uttersaure duroh. Reaktion
`4-^T-Methyl-5-'bis-(2-hydroxyathyl)-benziinidazolyi-27'-
`"buttersaureastern mit
`Thionylohlorid und
`Verseifung des Esters dadurch. gekennzeiohnet, daB man die
`, Reaktion "bei
`
`0202
`
`

`
`GDR Patent
`
`1598
`
`1
`
`77
`
`Method for preparing 4-[l-methyl-5-bis(2-chloroethyl)amino-
`benzimidazolyl-2]-butyric
`acid
`5
`
`Title of
`
`the
`
`0203
`
`

`
`>3
`
`the removal
`
`of
`
`2
`
`the
`
`excessive chlorinating agent
`
`0204
`
`

`
`jr>
`
`3
`
`conducted to a complete conversion by thin film
`chromatographic control. It was found that after a defined
`a
`period of
`time of
`the main
`reaction
`of 10 hours was necessary but 30 hours should not be
`exceeded. Particular advantageous are 16 hours. At the same
`time the solvent of the chlorinating reaction is distilled
`and contaminations
`precipitate
`
`0205
`
`

`
`41
`
`Claims:
`
`4
`
`1. Method for preparing 4-[l-methyl-5-bis-(2-chloroethyl)-
`benzimidazolyl-2]-butyric acid by reaction of 4-[1-
`methyl-5-bis-(2-hydroxyethyl)-benzimidazolyl-2]-butyric
`acid ester with thionyl chloride and subsequent
`esterification of the ester characterized in that the
`reaction is drawn
`to complete
`conversion of the hydroxy
`ethyl groups
`at temperatures
`of -5
`to
`to 30
`hours
`
`30o C
`after-reaction
`
`0206
`
`

`
`<*)
`
`5
`
`Abstract
`
`The invention
`
`relates
`
`to
`
`an
`
`0207
`
`

`
`w
`
`(19) DEUTSCHE DEMOKRATISCHE REPUBLIK
`
`Wirtschaftspatent
`ErieiltgernaeSJ5Absstz 1
`^ / [ § \
`z u r n P®'®" 1
`
`PATENTSCHRIFT
`1592 89
`
`ISSN 0433-6461
`
`(ID
`
`^
`
`desAenderungsgeseces
`6 8 8 1 2
`
`IntCI.3
`3(51) A 61 K
`
`AMI FUER ERFINDUNGS- UND
`
`PATEIMTWESEN
`
`(21) WP A
`
`61 K/
`
`2304 291
`
`(22)
`
`(71)
`
`VEB JENAPHARM,
`(72)
`
`JENA;DD;
`OLTHOFF, UWE.DR.
`
`0208
`
`

`
`— 2
`
`2 3 0 4 2 9
`
`I
`
`bei der chronischen Lympbadenose, de.r lymphoretikulose,
`der Lyphogranulomatose und bei Retikulosen eingefiihrt.
`
`Bendamustinhydrocblorid ist eine relativ instabile Ver-
`L o s u n g e n e r f o l g t n a c h k u r z e r Z e i t
`b i n d u n g . I n w a l 3 r i g e n
`eine nahezu vollstandige Hydrolase der Lost-Halogen-
`gruppen. Deshalb ist'die Herstellvng der Injektionsid-
`sungen erst kurz vor der Injektion moglich. Die kineti-
`soben Untersuchungen zur Chloridhydrolyse der N-Lost-
`gruppe des Bendamustinhydrochlorids ergaben in sauren
`und neutralen Losungen einen Reaktionsablauf, der sich nach
`pseudoerster Reaktionsordnung fiir eine Folgereaktion der
`symmetrisohen Dihalogenidverbindung berechnen lie/3
`(U.
`OLTHOFF, Abstr. Congr. Pharm. Hung. VI, Budapest 1974,
`S». 7 2 ) . D i e C h l o r i d - u n d P r o t o n e n a b s p a l t u n g a u s d e n B -
`Chlorethylgruppen erfolgt unabhangig vom pH -V
`/ert
`und von
`eingesetzten Puffersystemen vollstandig und mit sehr gro­
`wer Geschwindigkeit. Dabei ubertrifft Bendamustinhydro-
`cblorid sogar die besonders reaktionsfahigen Loste N-Me-
`thyl-Lost, Chlorambucil und Uracil-lost. Diese Angaben be-
`griinden die besondere Schwierigkeiten, die sicb der Her-
`stellung stabiler medizinischer Zubereitungen des Benda-
`mustinhydrochlorids entgegenstellen.
`
`W-Lostderivat
`das
`Nach der DBR-Patentschrift VVP 80 967 rau/3
`Bendamustinbydrochlorid s t e r i l , schwebstofffrei und in
`einer fiir die schnelle Auflosung geeigneten KristalLform
`hergestellt v/erden. Die Zubereitungsform i s t eine Trocken-
`ampulle, die eine Mischung von 25 mg Bendamustinhydrocblo-
`rid und 175 mg Ascorbinsaure enthalt. Vor der Anwendung i s t
`der Ampulleninbalt in Wasser zur Injektion aufzulosen. Die
`Ascorbinsaure bat die Aufgaben, ein abfiillfahiges Pulverge-
`miscb berzustellen, sovvie die Haltbarkeit und den pH—irVert
`der InJektionsl'dsung zu sichern. Aufierdem soil
`gerfahigkeit des trockenen Gemisches erreicht warden. Die
`Hydrolysegeschvvindigkeit vyird nach vorliegenden Versuchser-
`gebnissen durch den Ascorbinsaurezusatz nicht beeinflui3t.
`
`0209
`
`

`
`-
`
`3
`
`2 3 0 4 2 9
`
`-
`
`I
`
`Der pH-Wert einer Bendamustinhydrochlorid-Ldsung, der im
`Bereich von 2,4 bis 3,0 liegt., wird durch den its cor bins au-
`rezusatz nicht wesentlich verandert. Der Ascorbinsaure-
`z u s a t z e r f i i l l t d e m n a c h n i c h t d i e
`a n e i n e n S t a b i l i s a t o r
`stellenden Anforderungen.
`Bendamustinhydrochlorid zeigt als
`Festsubstanz nach einiger Lagerungszeit eine rosa bis braun-
`rote Verfarbung, die von der Substanzoberllache ausgebt und
`nach langerer Zeit die gesamte Substanz fiir die Herstellung
`von pharmazeutischen Zubereitungen ungeeignet macht. Auch
`die Mischung mit Ascorbinsaure zeigt diesen Effekt.
`
`'
`
`Weiterhin v/urde vorgeschlagen, die waiBrige Ldsung der Sub­
`stanz Bendamustinhydrochlorid zu lyophilisieren und vor der
`Anwendung in V/asser oder Natriumchloridldsung aufzulosen
`(Herstellungsverfahren des ZIMET, Pharitiazeutisches Qutachten
`IfAr/Nr. 180/80). Das erhaltene Lyophilisat (25 mg/Ampulle)
`weist erbebliche Nachteile fiir einen technologischen Herstel-
`lungsprozefl auf. Insbesondere die extreme Hygroskopizitat
`und die Durchfuhrung des Prozesses unter Inertgas erschv/eren
`die technologische Realisierbarkeit. Aul3erdem wurden v/ahrend
`der Herstellung des Praparates deutliche Zersetzungserschei-
`nungen im Bereich von 5 bis 10 % des Wirkstoffes nachgev/ie-
`sen. Unbefriedigend ist
`auch
`die Feststellung groI3er Mengen
`von Mikropartikeln nach Auflosen des Lyophilisats, die auf
`eine weitere Instabilitat des Systems hinweisen.
`
`Der Nachteil der extremen Hygroskopizitat des Lyophilisats
`kann durch Zusatze von bei Raumtemperatur festen Polyolen,
`behoben vverden. Neben dem hohen
`insbesondere von Mannitol
`technologischen Aufwand sind jedoch weiterhin die Nachteile
`einer erheblichen Zersetzung und des Auftretens von unge-
`Ibsten Mikropartikeln gegeben.
`
`Ziel der Erfindung
`
`'Ziel der Erfindung ist die Herstellung einer stabilen und
`gebrauchsfertigen Injektionslbsung von N-Lostverbindungen
`unter Umgehung der technischen Lbsung als Trockenampulie.
`
`0210
`
`

`
`«./
`
`- 4 -
`J a r l e g u n g d e s Wesens d e r E r f i n d u n g
`
`2 3 0 4 2 9 1
`
`d a s
`Die b i s h e r bekannten t e c h n i s c h e n Lbsungen r e a l i s i e r t e n
`I n j e k t i o n s p r a p a r a t e n t w e d e r a l s P u l v e r a b f u l l u n g
`g a b e e i n e s S t a b i l i s a t o r s
`bzw. a n d e r s a r t i g e r H i l f s s t o f f e , Oder
`a l s L y o p h i l i s a t ,
`g g f . u n t e r Z u s a t z von H i l f s s t o f f e n . Durch
`d i e s e Mal3nahraen
`g e l i n g t e s n i c h t bzv/. n u r m i t e r h e b l i c h e n
`N a c h t e i l e n , e i n g e e i g n e t e s
`Die s o e r h a l t e n e n T r o c k e n a b f i i l l u n g e n s i n d d u r c h m a n g e l h a f t e
`chemische und p h y s i k a l i s c h e S t a b i l i t a t
`dem s t e l l t
`Mehraufwand d a r , d e r s i c h a l s
`
`0211
`
`

`
`- 5 -
`
`2 3 0 4 2 9
`
`t
`
`d u n n s c h i c h t c h r o m a t o g r a p h i s c h e n
`raittels e i n e s s p e z i f i s c h e n
`V e r f a h r e n s (Auftragmenge e n t s p r . 0 , 0 2 5 mg B e n d a m u s t i n h y -
`B u t a n o l / E s s i g s a u r e /
`. d r o c h l o r i d , K i e s e l g e l G,
`L a u f m i t t e l :
`V/asser 4 : 1 : 5 , D e t e k t i o n UV 360 nm bz-w. D r a g e n d o r f f - R e a -
`g e n z ) a u f d i e B i l d u n g
`von S p a l t p r o d u k t e n b i n u n t e r s u c h t ,
`B e f u n d e :
`
`B i l d u n g von Abbauprodukten i n :
`Propylenglykol-Losung
`Zeit
`Ethanol—losung
`25 0C
`75 0C
`50 0C
`2 5 0C
`
`* V . S
`
`0 , 5 h
`
`h
`1 , 5 h
`. 2
`
`h
`
`h
`5
`h
`7
`h
`24
`8 Wochen
`
`ohne
`ohne
`ohne
`ohne
`
`ohne
`ohne
`
`Aus p h a r m a k o l o g i s c h e n und f e r t i g u n g s t e c h n i s c h e n
`
`0212
`
`

`
`V v
`
`6
`
`2 3 0 4 2 9
`
`d e n Z u s a t z e i n e s g e e i g n e t e n waI3rigen V e r d i i n n u n g s m i t t e l s .
`( N a t r i u m c h l o r i d l b s u n g Oder Wasser e u r I n j e k t i o n ) s o v e r -
`d t l n n t , dal3 d i e z u r Anwendung kommende Lb sung n u r noch c a .
`P o l y o l , g g f . auch
`1 0 %
`v/eniger e n t h a l t . D i e P o l y o l l b s u n g e n
`s i n d rait
`den angegebenen Verdiinnungsmitteln ohne N a c h t e i l
`f i i r den W i r k s t o f f b e l i e b i g v e r d i i n n b a r . Durch d i e b r e i t e V a -
`r i a t i o n s m b g l i c h k e i t d e s P o l y o l a n t e i l s und d e r Verdunnung
`e r g e b e n s i c b w e i t e r e V o r t e i l e
`f i i r
`d i e Auswahl e i n e r o p t i m a l e n ,
`b e s o n d e r s g u t v e r t r a g l i c h e n I n j e k t i o n s z u b e r e i t u n g . Neben d e r
`H y d r o l y s e e m p f i n d l i c h k e i t s i n d a l s w e i t e r e
`von L i c h t und L u f t s a u e r s t o f f zu b e r i i c k -
`r e n d i e Einwirkungen
`s i c h t i g e n . Trockene Z u b e r e i t u n g e n ' u n d a u c h Lbsungen v e r f a r -
`ben s i c h u n t e r l i c h t -
`b r a u n l i c h . Die Lbsungen i n A l k o h o l e n
`g u t v e r s c h l o s s e n e n Ampullen
`
`0213
`
`

`
`- 7 -
`
`2 3 0 4 2 9 1
`
`und i n Ampullen
`e r f o l g t
`"bei
`
`a b g e f u l l t . D i e Aufbewahrung d e r Ampullen
`T e m p e r a t u r e n von +15 0C b i s +25
`
`0 C .
`
`0214
`
`

`
`-
`
`8
`
`2 3 0 4 2 9 1
`
`E r f i n d u n g s a n s c r u c h
`
`z u r H e r s t e l l u n g s t a b i l e r I n j e k t i o n s l b s u n g e n
`1 . V e r f a h r e n
`von N-Lostverbindungen gekennz-eichnet d a d u r c h , daI3
`N - L o s t d e r i v a t e i n K o n z e n t r a t i o n e n
`von 25 mg/ml b i s zu
`1 0 0 mg/ral i n einem v v a s s e r f r e i e n e i n - o d e r
`m e h r w e r t i g e n
`' A l k o b o l ( P o l j r o l ) g e l b s t w e r d e n , wobei d a s L b s e n , .Ab-
`f i i l l e n und Aufbewabren d e r Lbsung u n t e r I n e r t g a s e r -
`f o l g t , und d i e Lasung v o r d e r m e d i z i n i s c b e n Anwendung
`im V e r h a l t n i s von 1 : 5 b i s
`1 : 2 0 m i t
`einem wafirigen I n -
`j e k t i o n s t r a g e r verdiinnt w i r d .
`
`g e k e n n z e i c h n e t
`2 . V e r f a h r e n n a c h Punkt 1
`W i r k s t o f f B e n z i m i d a z o l - L o s t e , i n s b e s o n d e r e Bendamustin-
`h y d r o c h l o r i d angewendet w e r d e n .
`
`.
`
`n a c h Punkt 1 g e k e n n z e i c h n e t
`3 . V e r f a h r e n
`P o l y o l i n s b e s o n d e r e 1 , 2 - P r o p (
`
`0215
`
`

`
`1
`
`Abstract: The invention relates to a method for producing stable injection solutions
`which can be used for medical treatment. It is the objective to produce a ready to
`use, stable injection solution of N-mustard compounds, avoiding the technical
`N-mustard compounds
`solution of
`a dry ampoule. According
`to the
`invention, the
`used in concentrations of 25mg/ml to 100mg/ml, dissolved in an anhydrous
`monovalent or
`polyvalent
`alcohol (polyol),
`
`0216
`
`

`
`Field of
`
`the
`
`Invention
`
`2
`
`The invention relates to a method for producing injection solutions which may be
`used for
`medical
`treatment.
`
`Characteristic of
`
`the
`
`Background
`
`N-mustard compounds have been used for some years as highly effective
`cytostatics. It is estimated that mustards can be used in the therapy of 70 %
`treated malign tumors. More recent synthesis research was aimed at, for example,
`synthesizing a multivalent antagonist type out of said compound group. In said
`experiments and
`hydrochloride (trial ID IMET 3393),
`
`0217
`
`

`
`3
`
`These data explain particular difficulties encountered in the production of stable
`medical preparations
`out
`of
`
`bendamustine
`
`0218
`
`

`
`found after
`
`the
`
`dissolution of
`
`the
`
`lyophilisate, which
`
`4
`
`0219
`
`

`
`5
`
`the bendamustine
`that N-mustard compounds of
`found
`It has now been
`hydrochloride type do not undergo an alcoholysis reaction. The use of anhydrous
`solvents is required in order to avoid decomposition caused by the mentioned
`sensitivity to hydrolysis. Under these conditions, bendamustine hydrochloride, for
`example, is chemically stable for long periods of time in the mentioned group of
`solvents and does not form the monohydroxy and dihydroxy or monoalkoxy or
`dialkoxy derivatives
`known
`from
`
`aqueous
`
`In order to examine the stability, bendamustine hydrochloride in a concentration of
`25 mg/ ml was dissolved in ethanol and 1,2-propylene glycol and the solution was
`stored at room temperature, as well as at increased temperatures (50° C,
`
`0220
`
`

`
`For pharmacological
`
`reasons
`
`and
`
`for
`
`6
`
`0221
`
`

`
`7
`
`Exemplary embodiments:
`
`Example 1:
`
`Bendamustine hydrochloride
`
`is
`
`dissolved under
`
`0222
`
`

`
`-
`
`.
`
`CLAIMS
`
`8
`
`1. Method for producing stable injection solutions of N-mustard compounds,
`characterized in that N-mustard derivatives in concentrations
`of 25 mg/ ml to
`100mg/ml are dissolved in an anhydrous monovalent or polyvalent alcohol
`(polyol), wherein
`the
`solution
`
`is
`
`0223
`
`

`
`1 0 / 0 7 / 2 0 0 8 1 4 : 3 9 FAX BIO 738 6530
`
`CEPHALON LEGAL
`
`RECEIVED
`• USPTO main CENTR/SLP90CGEWTER
`OCT 0 7
`2008
`
`Approvttd For
`
`PTO/SB/Oea (01-08)
`use
`through
`
`US. Patenl and
`Under lha
`
`0224
`
`

`
`1 0 / 0 7 / 2 0 0 8 1 4 : 3 9 FAX
`
`610 738 6590
`
`CEPHALON LEGAL
`
`•» USPTO main
`
`@ 0 0 1 / 0 0 6
`
`Attorney Docket
`
`No.:
`
`CP39fi>
`
`RECEIVED
`CENTRAL FAX
`
`CENTER
`OCT 0 7 2008
`
`IN THE
`
`UNITED
`
`STAfES PATENT
`
`In Re Application
`
`of:
`
`0225
`
`

`
`
`
`UNITED STATES
`PATENT
`AND
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`OFFICE
`TRADEMARK
`a
`II
`UNITED STATES DEPARTMENT OF COMMERCE
`1
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www.uspto.goV
`
`APPLICATION NO.
`
`F ING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONF {MATION NO.
`
`11/330,868
`
`01/12/2006
`
`Jason Edward Brittain
`
`CP391
`
`9998
`
`05/28/2009
`
`7590
`
`27573
`Ross J. Oehler
`CEPHALON, Inc.
`41 MOORES ROAD
`PO BOX 4011
`FRAZER, PA 19355
`
`SOROUSH, AU
`
`1616
`
`MAIL DATE
`
`05/28/2009
`
`PAPER NUMBER
`
`DELIVERY MODE
`
`PAPER
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`PTOL—90A (Rev. 04/07)
`
`0226
`
`

`
`Application No.
`
`11/330,868
`Office Action Summary
`
`Applicant(s)
`
`BRITTAIN ET
`
`Examiner
`
`— The MAILING
`
`DATE of
`
`ALI SOROUSH
`communication
`
`this
`
`0227
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`Restriction to
`
`0228
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`Inventions I
`
`0229
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`obtaining agency
`
`0230
`
`

`
`Application/Control Number:
`Art Unit:
`
`1616
`
`11/330,868
`
`overlapping subject
`
`matter and
`
`there
`
`0231
`
`

`
`Application/Control Number:
`Art Unit:
`
`1616
`
`11/330,868
`
`The election
`
`of
`
`an
`
`invention may
`
`0232
`
`

`
`Application/Control Number:
`Art Unit:
`
`1616
`
`11/330,868
`
`such species.
`
`In addition,
`
`these species
`
`are
`
`0233
`
`

`
`Application/Control Number:
`Art Unit:
`
`1616
`
`11/330,868
`
`requirement will
`
`result in
`
`the loss
`
`of
`
`0234
`
`

`
`Application/Control Number:
`Art Unit:
`
`1616
`
`11/330,868
`
`The examiner
`
`has
`
`required
`
`Where applicant
`
`0235
`
`

`
`Application/Control Number:
`Art Unit:
`
`1616
`
`11/330,868
`
`Any inquiry
`
`concerning this
`
`communication or
`
`0236
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`1 1 3 3 0 8 6 8
`
`• Rejected
`
`Allowed
`
`G Claims renumbered
`
`0237
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`1 1 3 3 0 8 6 8
`
`• Rejected
`
`Allowed
`
`G Claims renumbered
`
`0238
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`1 1 3 3 0 8 6 8
`
`• Rejected
`
`Allowed
`
`G Claims renumbered
`
`0239
`
`

`
`Attorney Docket
`
`No.
`
`CP391
`
`IN THE
`
`UNITED STATES
`
`PATENT
`
`0240
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`IN THE
`
`CLAIMS
`
`1. (Currently amended) A
`
`0241
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`6. (Currently amended)
`
`A
`
`0242
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`14. (Currently amended)
`
`A
`
`0243
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`21. (Original)
`
`A
`
`pharmaceutical
`
`0244
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`28. (Currently amended) A
`
`0245
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`is no more
`
`than
`
`0.2%
`
`0246
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`36. (Currently amended) A
`
`0247
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`41. (Original)
`
`A
`
`method
`
`0248
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`49. (Original) A
`
`method
`
`0249
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`iii) holding
`
`at
`
`-50
`
`0250
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`63. (Original) A
`
`method
`
`0251
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`said dosage
`
`form
`
`comprises
`
`0252
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`PATENT
`
`78. (Original) The
`
`preparation
`
`0253
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`Discussion of
`
`the
`
`0254
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`Claims 1-24,
`
`31-35,
`
`0255
`
`

`
`DOCKET NO.:
`CP391
`Application No.:
`
`11/330,868
`Office Action
`
`Dated:
`
`May 28,
`
`2009
`
`Accordingly, reconsideration
`
`0256
`
`

`
`Electronic Acknowledgement Receipt
`
`EFSID:
`
`5478884
`
`Application Number:
`
`11330868
`
`International Application
`
`Number:
`
`Confirmation Number:
`
`0257
`
`

`
`Multipart Description/PDF
`
`files
`
`in .zip
`
`description
`
`Document Description
`
`Response to
`
`Election
`
`/
`
`0258
`
`

`
`Approved
`
`for
`
`PTO/SB/06
`use
`
`(07-06)
`
`0259
`
`

`
`
`
`UNITED STATES
`PATENT
`AND
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`OFFICE
`TRADEMARK
`a
`II
`UNITED STATES DEPARTMENT OF COMMERCE
`1
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www.uspto.goV
`
`APPLICATION NO.
`
`F ING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONF {MATION NO.
`
`11/330,868
`
`01/12/2006
`
`Jason Edward Brittain
`
`CP391
`
`9998
`
`08/19/2009
`
`7590
`
`27573
`Ross J. Oehler
`CEPHALON, Inc.
`41 MOORES ROAD
`PO BOX 4011
`FRAZER, PA 19355
`
`SOROUSH, AU
`
`1616
`
`MAIL DATE
`
`08/19/2009
`
`PAPER NUMBER
`
`DELIVERY MODE
`
`PAPER
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`PTOL—90A (Rev. 04/07)
`
`0260
`
`

`
`Application No.
`
`11/330,868
`Office Action Summary
`
`Applicant(s)
`
`BRITTAIN ET
`
`Examiner
`
`— The MAILING
`
`DATE of
`
`ALI SOROUSH
`communication
`
`this
`
`0261
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`0262
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`Claims 1-6,
`
`0263
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1
`
`USPQ 459
`
`obviousness under
`
`0264
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`conditions. More
`
`0265
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`drugs. For
`
`the
`
`0266
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`800-786-9199 (IN
`
`0267
`
`

`
`Application/Control No.
`
`Notice of
`
`Applicant(s)/Patent Under
`Reexamination
`BRITTAIN ET
`
`11/330,868
`References Cited
`
`0268
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`11330868
`
`• Rejected
`
`Allowed
`
`G Claims renumbered
`
`0269
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`11330868
`
`• Rejected
`
`Allowed
`
`G Claims renumbered
`
`0270
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`11330868
`
`•
`
`Rejected
`
`Allowed
`
`G Claims renumbered
`
`0271
`
`

`
`Application/Control No.
`
`Search Notes
`
`Applicant(s)/Patent Under
`Reexamination
`
`11330868
`
`Class
`
`Search Notes
`EAST (See search
`
`0272
`
`

`
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`
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`
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`FORM PTO-1449
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`
`Application Number
`INFORMATION DISCLOSURE
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`
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`
`APPLICANT
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`
`

`
`FORM PTO-1449
`
`Attorney Docket
`
`CP391
`
`Application Number
`INFORMATION DISCLOSURE
`STATEMENT BY
`
`11/330,868
`
`APPLICANT
`
`0279
`
`

`
`FORM PTO-1449
`
`Attorney Docket
`
`CP391
`
`Application Number
`INFORMATION DISCLOSURE
`STATEMENT BY
`
`11/330,868
`
`APPLICANT
`
`0280
`
`

`
`FORM PTO-1449
`
`Attorney Docket
`
`CPS 91
`
`Application Number
`INFORMATION DISCLOSURE
`STATEMENT BY
`
`11/330,868
`
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`
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`
`

`
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`
`1 0 / 0 7 / 2 0 0 8 1 4 : 3 9 F A X
`
`B I O 7 3 8 6 5 9 0
`
`C E P H A L O N L E G A L
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`
`USPTO
`
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`
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`m a i n CENTRMWWeENTER
`OCT 0 7 2008
`
`PTO/SB/Oea (OI-OB)
`use
`
`through
`
`0282
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`IN THE
`
`UNITED
`
`0283
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`This listing
`
`2009
`
`of
`
`claims
`
`0284
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`6. (Currently Amended)
`
`A
`
`0285
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`14. (Previously Presented)
`
`0286
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`dimethyl sulfoxide,
`
`hexafluoroacetone,
`
`0287
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`32. (Currently Amended)
`
`A
`
`0288
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`46. (Currently Amended)
`
`ATfee
`
`0289
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`vii) holding for about 5 t o about 4 0 hours t o form a bendamustine o r bendamustine
`hydrochloride
`lyophilized
`
`0290
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`wherein said
`
`HP1
`
`HP1
`
`0291
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`throughout primary
`
`drying
`
`0292
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`neoplastic agents
`
`wherein
`
`0293
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`74. (Previously Presented)
`
`A
`
`0294
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`The finality
`
`of the
`
`restriction requirement
`
`REMARKS
`
`0295
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`PATENT
`
`August 19,
`
`2009
`
`0% HP1.
`
`The Applicants
`
`disagree
`
`0296
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`The desirability
`
`of keeping
`
`the amount
`
`0297
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11 /330,868
`Office Action
`Dated:
`
`August 19,
`
`2009
`
`That CCI-779
`
`and
`
`0298
`
`

`
`Electronic Acknowledgement Receipt
`
`EFSID:
`
`6469688
`
`Application Number:
`
`11330868
`
`International Application
`
`Number:
`
`Confirmation Number:
`
`0299
`
`

`
`2
`
`1410313_1.PDF
`
`yes
`
`16
`
`197824
`
`Multipart Description/PDF
`
`files
`
`in .zip
`
`description
`
`99b4544e2d6ed5b7db71870dac20e61cd3
`d973b8
`
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`
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`
`Reconsideration-After
`
`0300
`
`

`
`IRAN.LET
`Doc Code:
`Document Description:
`
`Transmittal Letter
`
`Approved
`
`for
`
`0301
`
`

`
`Privacy Act
`
`Statement
`
`The Privacy
`
`Act
`
`of
`
`1974 (P.L.
`
`93-579)
`
`0302
`
`

`
`Approved
`
`for
`
`PTO/SB/06
`use
`
`(07-06)
`
`0303
`
`

`
`
`
`UNITED STATES
`PATENT
`AND
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`OFFICE
`TRADEMARK
`a
`II
`UNITED STATES DEPARTMENT OF COMMERCE
`1
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www.uspto.goV
`
`APPLICATION NO.
`
`F ING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONF {MATION NO.
`
`1 1/330, 868
`
`01/12/2006
`
`Jason Edward Brittain
`
`CP391
`
`9998
`
`02/18/2010
`
`7590
`
`27573
`Ross J. Oehler
`CEPHALON, Inc.
`41 MOORES ROAD
`PO BOX 4011
`FRAZER, PA 19355
`
`SOROUSH, AU
`
`1616
`
`MAIL DATE
`
`02/18/2010
`
`PAPER NUMBER
`
`DELIVERY MODE
`
`PAPER
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`PTOL—90A (Rev. 04/07)
`
`0304
`
`

`
`Application No.
`
`Applicant(s)
`
`11/330,868
`Office Action Summary
`
`— The MAILING
`
`DATE of
`
`BRITTAIN ET
`
`AL.
`
`Examiner
`
`ALI SOROUSH
`communication
`
`this
`
`0305
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`0306
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`0307
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`2005/0020615 A1,
`
`0308
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`Ascertainment of the Difference
`
`0309
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`CCI-779 are
`
`0310
`
`

`
`Application/Control Number:
`
`11/330,868
`Art Unit:
`
`1616
`
`If attempts
`
`to
`
`0311
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`11330868
`
`Examiner
`
`All SOROUSH
`
`Cancelled
`
`Restricted
`
`• Rejected
`
`Allowed
`
`G Claims renumbered
`
`in
`
`0312
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`11330868
`
`Examiner
`
`All SOROUSH
`
`Cancelled
`
`Restricted
`
`• Rejected
`
`Allowed
`
`G Claims renumbered
`
`in
`
`0313
`
`

`
`Application/Control No.
`
`Index of
`
`Claims
`
`Applicant(s)/Patent Under
`Reexamination
`
`11330868
`
`Examiner
`
`All SOROUSH
`
`Cancelled
`
`Restricted
`
`• Rejected
`
`Allowed
`
`G Claims renumbered
`
`in
`
`0314
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`IN THE
`
`UNITED
`
`STATES
`
`0315
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`This listing
`
`of
`
`claims
`
`0316
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`bendamustine, at
`
`time
`
`0317
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`14. (Previously Presented)
`
`A
`
`0318
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`21. (Original) A
`
`pharmaceutical
`
`0319
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`32. (Previously Amended)
`
`A
`
`0320
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`46. (Previously Amended)
`
`A
`
`0321
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`wherein said
`
`lyophilized
`
`powder contains
`
`0322
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`57. (Canceled)
`
`58. (Canceled)
`
`59. (Previously Presented)
`
`A
`
`0323
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`61. (Original) A
`
`lyophilized
`
`0324
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`76. (Original) A
`
`pharmaceutical
`
`0325
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`Claims 1-4,
`
`6-24,
`
`31-35,
`
`REMARKS
`
`0326
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`PATENT
`
`February 18,
`
`2010
`
`As Jacob
`
`fails
`
`to
`
`0327
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`note that
`
`Jacob
`
`instructs that
`
`0328
`
`

`
`DOCKET NO.:
`CP391/CEPH-4391
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`February 18,
`
`2010
`
`Date: April 1,
`
`2010
`
`0329
`
`

`
`1
`
`Abstract: The invention relates to a method for producing stable injection solutions
`which can be used for medical treatment. It is the objective to produce a ready to
`use, stable injection solution of N-mustard compounds, avoiding the technical
`solution of
`a
`dry
`ampoule. According
`
`to
`
`0330
`
`

`
`Field of
`
`the
`
`Invention
`
`2
`
`The invention relates to a method for producing injection solutions which may be
`used for
`medical
`treatment.
`
`Characteristic of
`
`0331
`
`

`
`3
`
`These data explain particular difficulties encountered in the production of stable
`medical preparations
`out
`of
`
`bendamustine
`
`0332
`
`

`
`found after
`
`the
`
`dissolution of
`
`the
`
`lyophilisate,
`
`4
`
`0333
`
`

`
`5
`
`the bendamustine
`that N-mustard compounds of
`found
`It has now been
`hydrochloride type do not undergo an alcoholysis reaction. The use of anhydrous
`solvents is required in order to avoid decomposition caused by the mentioned
`sensitivity to hydrolysis. Under these conditions, bendamustine hydrochloride, for
`example, is chemically stable for long periods of time in the mentioned group of
`solvents and does not form the monohydroxy and dihydroxy or monoalkoxy or
`dialkoxy derivatives
`known from aqueous
`solutions.
`
`In order to examine the stability, bendamustine hydrochloride in a concentratio