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`AGILA ET AL - EXHIBIT 1017 (PART 3 OF 4)
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`STATES
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`DEPARTMENT
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`0403
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`TANTl
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`|l
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`UNITED STATES FKTENT AND TRADEMARK OFFICE
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`Electronic Patent
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`
`Application Number:
`
`Filing Date:
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`
`Title of
`
`Invention:
`
`Bendamustine
`
`pharmaceutical
`
`First Named
`
`Inventor/Applicant Name:
`
`0409
`
`

`
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`CP391/CEPH-4391
`DOCKET NO.:
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`May 13,
`
`2011
`
`IN THE
`
`UNITED
`
`STATES
`
`0418
`
`

`
`CP391/CEPH-4391
`DOCKET NO.:
`Application No.:
`11/330,868
`Office Action
`Dated:
`
`May 13,
`
`2011
`
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`
`of
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`

`
`CP391/CEPH-4391
`DOCKET NO.:
`Application No.:
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`Office Action
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`
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`
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`
`89.
`
`(New) The lyophilized
`
`pharmaceutical
`
`0420
`
`

`
`CP391/CEPH-4391
`DOCKET NO.:
`Application No.:
`11/330,868
`Office Action
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`
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`
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`
`This submission
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`accompanies
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`0421
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`
`Electronic Patent
`
`Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`11330868
`
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`
`Title of
`
`Invention:
`
`Bendamustine
`
`First Named
`
`Inventor/Applicant
`
`0422
`
`

`
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`
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`
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`
`in
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`
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`
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`
`evidences
`
`receipt on
`
`0426
`
`

`
`Substitute for
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`
`/PTO
`
`Complete if
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`Known
`
`Application Number
`
`INFORMATION DISCLOSURE
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`/PTO
`
`Complete if
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`
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`INFORMATION DISCLOSURE
`STATEMENT BY
`
`0428
`
`

`
`1
`
`GDR Patent
`
`34727
`
`co- [5—bis— (p-chloroethyl) —amino—
`benzimidazolyl-(2)]-alkane carboxylic
`
`0429
`
`

`
`2
`
`influenced by the heteroaromatic system. As the basicity of
`the nitrogen
`atom is
`correlated
`
`0430
`
`

`
`3
`
`The object
`
`of the
`
`invention
`
`is
`
`0431
`
`

`
`4
`
`alkane dicarboxylic acids such as succhinic acid, glutaric
`acid or adipinic acid. The resulting N1 -substituted
`a, co-
`alkane dicarboxylic acid-2-amino-5-nitro-monoanilides are
`cyclized to the corresponding 1-substituted co-[5-nitro-
`benzimidazolyl-(2)]-alkane carboxylic acids in diluted
`hydrochloric acid and reacted with alcohols such as ethyl
`alcohol in acidic solution to 1-substituted co-[5-nitro-
`benzimidazolyl-(2)]-alkane carboxylic acid esters. The
`preparation of the foregoing alkane carboxylic acid esters
`serving as
`starting
`material
`
`0432
`
`

`
`5
`
`benzimidazole
`
`[bis- (|3-chloroethyl) -aminomethyl ] -
`hydrochloride.
`However,
`
`0433
`
`

`
`6
`
`Example 1:
`a) (3- [ 5-Nitro-1-methyl-benzimidazolyl- ( 2 ) ] -propionic
`ethyl ester
`(II)
`
`37.1 g
`
`(3-[5-Nitro-l-methyl-benzimidazolyl-(2)]-propionic
`
`0434
`
`

`
`7
`
`(3- [ 5-bis ((3-hydroxyethyl) -amino-1-methyl-benzimidazolyl
`(2)]-propionic
`acid
`ethyl
`
`0435
`
`

`
`8
`
`calculated: C 46.23;
`
`H
`
`5.43; N
`
`10.78;
`
`C 46.23;
`
`0436
`
`

`
`9
`
`is prepared
`
`analogue
`
`V.
`Yield: 85% of the theory, colourless crystals from alcohol,
`Fp. 148
`to
`
`0437
`
`

`
`10
`
`Yield: 63.5%
`
`of
`
`the
`
`0438
`
`

`
`11
`
`C18 Hi9N302
`
`. 4)
`(309
`13.59
`N
`calculated: C 69.87; H 6.20;
`C 69.98; H 6.26;
`N
`found:
`
`|3- [5-bis- ((3-hydroxyethyl) -amino-l-phenyl-benzimidazolyl-
`(2)]-propionic
`acid
`
`0439
`
`

`
`12
`
`calculated: C
`
`64.56; H
`
`5.42;
`
`N
`
`found: C
`
`0440
`
`

`
`13
`
`For identification the picrate is made, which crystallizes
`with 1
`M
`crystal
`alcohol.
`
`0441
`
`

`
`14
`
`is prepared
`
`analogue
`
`IV.
`Yield: theoretic
`
`0442
`
`

`
`15
`
`Claim:
`
`GO- [ 5-bis-((3-chloroethy 1) -amino-
`preparing
`of
`1. Method
`benzimidazolyl-(2)]-alkane carboxylic acids substituted
`in 1-position
`of
`the
`
`0443
`
`

`
`1 6
`
`R^snslts j
`
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`ntiais^r
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`§
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`&, 25
`Ms
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`5ffi5
`&&$
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`
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`
`0444
`
`

`
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`
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`result®
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`xnouse.;
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`wst effect A v«' single
`
`dose: O.0S t;« O . S !Rg
`
`5
`
`0445
`
`

`
`c n 7 o
`2 3 5
`PATENTSCHRIFT
`
`/*#-/£
`/
`34727
`
`Wirtschafts patent
`
`Deutsche
`Demolcratische
`Republik
`
`Erieilt sumbt §
`
`5
`
`Absoti
`
`1 des
`
`JCndatungsgeseHej
`
`lun
`
`PatantgeceU
`
`Zusatzpatent zum
`
`0446
`
`

`
`34727
`
`4
`
`3
`•Wachstum von Krebszellen negativ zu beeinflussen,
`,zur Behandlimg von Tutnoren geeignet. Audi die
`Benzimidazolyl-aLkancarbonsauren konnen als Ami-
`nosaureantagonisten und als Purinantagonisten an-
`gesehen -werden,
`und es ist
`von thnen ein hemmcn-
`der EinfluB auf das Wachstum von Krebszellen zu
`erwarten. Die Antikrehswirksamkeit des Grujid-
`korpers soli
`durch die Verknupfung mit der Stidt-
`stofflostgruppe in der 5-SteUung des Benzimidazol-
`wobei aber
`ringes noch
`wesentlich verstarkt werden,
`die Tcxizitat
`der Gesamtverbindung
`
`LO
`niedrig bleiben
`
`belegt;
`p-I5-Bis-(^-chLoratliyl)-amino-l-methyl-
`Die Substanz
`benzimLdazolyl-(2)]-propionsaure-hj,
`
`0447
`
`

`
`5
`
`6
`
`34 727
`
`beredinet: C
`
`46,23;
`
`H 5,43;
`
`N
`
`10,78;
`
`HjO
`
`0448
`
`

`
`1
`azolyl-(2)]-valeraansaure-hydrochlorid
`wird analog
`V
`
`34 727
`
`3
`
`liergesteUt.
`Ausbeule: 38% der Th., farblose Kristalle aus
`Wasser, Fp.
`ITS
`bis 176
`0
`
`C.
`
`Die
`
`Substanz
`
`0449
`
`

`
`9
`PatentansBruch:
`
`34 727
`
`10
`
`N
`02 N_/\/
`Verfahren zur
`
`\ . U
`
`C - <CH2
`Herstellung
`
`)
`
`r
`
`,
`
`-
`
`COOC2
`von
`
`H
`
`5
`
`0450
`
`

`
`Kl.:12p.
`
`9
`
`34727
`
`IPK.: C07d2
`
`Testergebnisse:
`
`Tabelle 1
`
`Einzeldosis
`
`Anzahl
`d. Injek-
`mg
`tionen
`
`Gesamt-
`dosis
`
`Anzahl der
`
`Versuchstiere
`
`mg
`
`Asc. +
`Asc. -
`Subat.
`Kontr.
`
`QT
`Subst. -
`Kontr.
`
`Versuchs-
`bewertung
`
`0,5
`0,35
`0,25
`0,25
`0,1
`0,1
`0,05
`0,05
`0,025
`0,01
`
`6
`23
`33
`19
`23
`22
`31
`20
`14
`a
`
`3
`8,05
`8,25
`4,75
`2,3
`2,2
`1,55
`1,0
`0,35
`0,08
`
`3
`3
`3
`
`3
`3
`3
`3
`3
`3
`
`10
`3
`3
`10
`3
`10
`3
`10
`3
`10
`
`3
`3
`3
`3
`3
`3
`3
`3
`3
`3
`
`1,13
`2,1
`2,6
`2,01
`2,11
`1,4
`1,3
`1,93
`1,61
`0,78
`
`++ (tox.)
`+ +/+ H—h
`+ + +
`++/+ + +
`+ +/+'- +
`+ +/+++
`+ +
`+ + /+ + +
`+/+ +
`
`LDso i.
`
`p.:
`
`1,33
`
`mg/20
`
`g
`
`mg/kg
`Maus; 65,5
`Wirksamste Einzeldosis: 0,05 bis 0,35 mg
`
`Testergebnisse:
`
`0451
`
`

`
`A
`
`ibe
`hi­
`nd
`ibt
`hie
`die
`so
`&-
`>!e
`'c-
`iin
`jni
`ert
`in.
`rur
`ib-
`
`K'.: 12 p,
`
`9
`
`34 727
`
`IPK.: C07d
`
`g&
`
`Tafce11e
`
`:
`
`Testergebnisse
`
`Binzel-
`dosis
`(mg)
`
`Ani-ahl
`der In- '
`jektionen
`
`Aniahl der
`Cesnmt-
`dosis
`(mg)
`
`Versuchstlere
`
`Asc.-
`Kor{r.
`
`Asc. -|-
`Subst.
`
`Subst.-
`Kcntr.
`
`Vcrsu:Ks-
`bewertung
`
`1
`
`0,5
`
`0,25
`
`0.1
`
`3
`
`9
`
`33
`
`30
`
`3
`
`4,5
`
`8,25
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`10
`
`3
`
`3
`
`3
`
`3
`
`3
`
`0,26
`
`2,29
`
`4,54
`
`2,04
`
`to*.
`r ++
`++
`
`+f+
`
`+++
`
`+-r*
`
`>r-
`>i~
`e-
`nit
`0-
`o-
`hn
`n-
`IKt
`is-
`HI
`!z-
`
`0,1
`
`0.05
`
`0,05
`
`0,05
`
`0,025
`
`0,025
`
`29
`
`32
`
`22
`
`29
`
`15
`
`13
`
`2,9
`
`1,6
`
`1,1
`
`1,45
`
`0,375
`
`0,325
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`10
`
`3
`
`10
`
`3
`
`3
`
`3
`
`3
`
`2,08
`
`2,56
`
`1.45
`
`2,88
`
`1,06
`
`0,71
`
`+-M-
`
`+-r
`
`tif
`
`n
`
`IDs) i.
`
`p.:
`
`mg/20g Mous; 71 mg/kg Mans
`1,42
`Wirteamste Einzeldosis: 0,05
`bis 0,5
`
`mg (3,5 bis
`
`35% der LOso)
`
`Ti
`
`1
`
`0452
`
`

`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(12) INTERNATIONAL
`APPLICATION
`PUBLISHED
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`20 July 2006 (20.07.2006)
`
`
`
`(10) International Publication Number
`
`WO 2006/076620 A2
`
`(51)
`
`(21)
`
`International Patent Classification:
`
`Not classified
`
`International Application Number:
`Ir’C'I'/US2006/001308
`
`(22)
`
`International Filing Date: 13 January 2006 (13.01.2006)
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`English
`
`English
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE. AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FT,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
`LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI,
`NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`SK. SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US,
`UZ, VC, VN, YU, ZA, ZM, ZW.
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`(74)
`
`Priority Data:
`60/644,354
`1 1/330,8 68
`
`14 January 2005 (14.01.2005)
`12 January 2006 (12.01.2006)
`
`US
`US
`
`except US):
`all designated States
`(for
`Applicant
`CEPHALON, INC.
`[U-S/US]; 41 Moores Road, P.O.
`Box 401 1, Frazer, Pennsylvania 19355 (US).
`
`Inventors; and
`Inventors/Applicants (for US only): BRITTAIN, Jason,
`Edward [US/US]; 1580 Chiswick Court, El Cajon, Cal-
`ifornia 92020 (US). FRANKLIN, Joe, Craig [US/US];
`3708 45th Street, Tulsa, Oklahoma 74135 (US).
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, M7,, NA, SD, SL, S7,, T7,, UG, ZM,
`ZW), Eurasian (AIVI, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`Agent: MILLER, Suzanne, E.; Woodcock Washburn
`LLP, One Liberty Place — 46th Floor, Philadelphia, Penn-
`sylvania 19103 (US).
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes and Abbreviations ” appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: BENDAMUSTINE PHARMACEUTICAL COMPOSITIONS
`
`HP1 information after 24 hours stored at 5"C in Various
`Alcohol/Water Co-Solvents
`
`HPI(2Area)
`
`
`
`Methanol
`
`Ethanol
`
`Propanol
`
`El 07. (v/V)
`I 5% (V/V)
`10% (v/v)
`2oz (v/v)
`
`E 30% (v/v)
`
`Iso-
`propanol
`
`(57) Abstract: The present invention provides pharmaceutical formulations of lyophilized bendamustine suitable for pharmaceuti-
`cal use. The present invention further provides methods of producing lyophilized bendamustine. The pharmaceutical formulations
`can be used for any disease that is sensitive to treatment with bendaniustine, such as neoplastic diseases.
`
`0453
`
`
`
`WO2006/076620A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`0453
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`BENDAMUSTINE PHARMACEUTICAL COMPOSITIONS
`
`FIELD OF
`The present
`
`THE
`invention pertains
`
`INVENTION
`to
`
`0454
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Bendamustine was
`
`initially synthesized
`
`in
`Republic (GDR)
`
`0455
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`increases the
`
`potential for
`
`loss
`
`of
`
`potency and
`
`0456
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`The present
`
`invention is
`
`directed
`
`to
`
`nitrogen mustards,
`
`0457
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`CI
`
`CI
`
`N
`
`N
`
`COOCH2CH3
`
`N I
`Formula IV.
`
`Yet another
`
`embodiment
`
`of the
`
`is
`invention
`5
`bendamustine wherein
`
`0458
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`of the
`
`invention,
`
`the dosage
`
`form
`
`can be
`
`about 5
`
`to
`
`0459
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`The bendamustine
`
`product
`
`herein contains
`
`not
`
`0460
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Still another
`
`embodiment of
`
`the
`
`0461
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`In a
`
`preferred
`
`method for
`
`preparing
`
`a
`
`0462
`
`

`
`WO 2006/076620
`
`treatment with
`
`PCT/US2006/001308
`
`composition. Some conditions
`said pharmaceutical
`treatment with
`the
`
`amenable
`compositions
`
`0463
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`hours; ramping
`
`to about
`
`-15
`
`0
`
`C
`
`over
`
`0464
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Fig. 3
`
`shows
`
`HP1
`
`(Formula II)
`
`formation
`alcohol/water co-solvents
`
`0465
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`% of
`
`un-degraded
`
`active,
`
`preferably at
`
`least
`
`about
`
`0466
`
`

`
`WO 2006/076620
`WO 2006/076620
`
`PCT/US2006/001308
`PCT/US2006/001308
`
`mg/m
`about 100-150
`2
`about 100-150 mg/m2 on days 1 and 2 with repetition of the cycle about every 4
`
`on
`
`Weeks.
`
`As used herein "neoplastic" refers to a neoplasm, which is an abnormal growth,
`
`such growth occurring because of a proliferation of cells not subject to the usual
`
`limitations of growth. As used herein, "anti-neoplastic agent" is any compound,
`
`composition, admixture, co-mixture, or blend which inhibits, eliminates, retards, or
`
`reverses the neoplastic phenotype of a cell.
`
`As used herein "hyperproliferation" is the overproduction of cells in response
`
`to a particular growth factor. "Hyperproliferative disorders" are diseases in which the
`
`10
`
`cells overproduce in response to a particular growth factor. Examples of such
`
`"hyperproliferative disorders" include diabetic retinopathy, psoriasis, endometriosis,
`
`cancer, macular degenerative disorders and benign growth disorders such as prostate
`
`enlargement.
`
`As used herein, the term “vial” refers to any walled container, whether rigid or
`
`15
`
`flexible.
`
`"Controlling" as used herein means putting process controls in place to
`
`facilitate achievement of the thing being controlled. For example, in a given case,
`
`"controlling" can mean testing samples of each lot or a number of lots regularly or
`
`randomly; setting the concentration of degradants as a release specification; selecting
`
`process conditions, e.g., use of alcohols and/or other organic solvents in the pre-
`
`lyophilization solution or dispersion, so as to assure that the concentration of
`
`degradants of the active ingredient is not unacceptably high; etc. Controlling for
`
`degradants by setting release specifications for the amount of degradants can be used
`
`to facilitate regulatory approval of a pharmaceutical product by a regulatory agency,
`
`such as the U.S. Food and Drug Administration and similar agencies in other countries
`
`20
`
`25
`
`or regions ("agency").
`
`The term "pharmaceutically acceptable” as used herein means that the thing
`
`that is pharmaceutically acceptable, e.g., components, including containers, of a
`
`pharmaceutical composition, does not cause unacceptable loss of pharmacological
`
`30
`
`activity or unacceptable adverse side effects. Examples of pharmaceutically
`
`acceptable components are provided in The United States Pharmacopeia (USP), The
`
`National Formulary (NF), adopted at the United States Pharmacopeial Convention,
`
`held in Rockville, Md. in 1990 and FDA Inactive Ingredient Guide 1990, 1996 issued
`
`-14-
`
`0467
`
`0467
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`by the U.S. Food
`
`and
`
`Drug
`
`Administration, (both
`
`0468
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`therapeutic effect
`
`of
`
`the
`
`API.
`
`0469
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`The term
`
`"release" or
`
`"at release"
`
`means
`
`product
`the drug
`specifications and
`
`0470
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`One family
`
`of antineoplastic
`
`agents
`
`which
`
`the compounds
`
`0471
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`consisting ofTaiho
`
`4181-A, aclarubicin,
`
`actinomycin
`
`0472
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`chlorsulfaquinoxalone, Chemes
`
`CHX-2053,
`
`0473
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`TT-82, Kyowa
`
`Hakko
`
`UCN-01,
`
`Kyowa Hakko
`
`0474
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Fluorouracil, Mitaxantrone
`
`CMF
`
`Cyclopho sphamide,
`Methotrexate, Fluorouracil
`
`Breast cancer
`
`NFL
`
`Mitoxantrone, Fluorouracil,
`Leucovorin
`
`Sequential Dox-CMF
`
`0475
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Doxorabicin, Vinblastine,
`Bleomycin, Etoposide,
`Prednisone
`
`CNOP
`
`Cyclophosphamide,
`Mitoxantrone, Vincristine,
`Prednisone
`
`Non-Hodgkin's
`
`Cyclophosphamide,
`Vincristine, Methotrexate,
`Leucovorin, Cytarabine
`COMLA
`
`Dexamethasone, Cisplatin,
`
`DHAP
`
`ESHAP
`
`0476
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Cyclophosphamide,
`Etoposide, Cytarabine,
`Bleomycin, Vincristine,
`Methotrexate, Leucovorin,
`Septra
`
`M2
`
`Vincristine, Carmustine,
`Cyclophosphamide,
`Melphalan, Prednisone
`
`Melphalan, Prednisone
`
`MP
`
`0477
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`about 2-80
`
`mg/mL,
`
`preferably
`
`about
`
`0478
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`and 6)
`
`cooling
`
`the
`
`solution to
`
`about 1
`
`0
`
`C
`
`0479
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`ranging from
`
`about 10
`
`to
`
`about
`
`600 microns.
`place very
`
`The warming
`gradually, over
`
`0480
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`The lyophilized
`
`formulations
`
`of
`
`0481
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`CCS
`CCS
`
`CCS
`CCS
`
`CCS
`CCS
`
`CCS
`CCS
`CCS
`CCS
`
`CCS
`CCS
`CCS
`CCS
`
`CCS
`CCS
`CCS
`CCS
`
`Precipitate
`CCS
`CCS
`CCS
`
`Precipitate
`CCS
`CCS
`CCS
`
`Precipitate
`CCS
`CCS
`CCS
`
`Precipitate
`CCS
`CCS
`CCS
`
`CCS
`CCS
`CCS
`CCS
`
`CCS
`CCS
`
`20%
`30%
`n-PropanoI (v/v/)
`5%
`10%
`20%
`30%
`Iso-propanol (v/v)
`5%
`10%
`20%
`30%
`n-Butanol (v/v)
`5%
`10%
`
`CCS
`CCS
`2 layers
`20%
`30%
`2 layers
`Tert-Butanol (v/v)
`5%
`10%
`20%
`30%
`CCS stands
`
`CCS
`CCS
`
`CCS
`CCS
`2 layers
`2 layers
`
`CCS
`CCS
`2 layers
`2 layers
`
`CCS
`CCS
`CCS
`CCS
`for
`
`CCS
`CCS
`CCS
`CCS
`clear
`
`0482
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`pharmaceutical use.
`
`However, during
`
`the
`
`manufacturing
`aqueous solutions
`
`0483
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`HO^i
`HO'^V
`
`^
`
`N
`
`HO-^i
`.N
`
`O,
`
`N
`N
`\
`Bendamustine Dimer
`
`0'
`
`O,
`
`OH
`
`N
`N
`\
`
`(BM1
`
`0484
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Figures 3
`
`and
`
`4
`
`show the
`
`amount
`
`of
`
`0485
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Table 6.
`
`HPLC stability
`
`results for
`
`various
`
`n-propyl alcohol
`
`concentrations
`period. HP1 and
`
`0486
`
`

`
`WO 2006/076620
`
`20% Methanol
`
`30% Methanol
`
`97.65
`
`24 hours
`99.56
`0 hours
`99.31
`3 hours
`98.99
`6 hours
`24 hours
`98.31
`0 hours
`3 hours
`6 hours
`24 hours
`
`1.85
`
`PCT/US2006/001308
`
`0.18
`0.22
`0.38
`0.50
`1.15
`
`99.59
`99.43
`99.25
`98.65
`
`0.11
`0.11
`0.12
`0.16
`
`0.18
`0.27
`0.34
`0.76
`
`0.10
`0.11
`0.11
`0.13
`
`Table 9.
`
`HPLC
`
`stability
`
`results
`
`0487
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`development was
`
`changed
`
`and
`
`0488
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Ingredients
`Bendamustine HC1
`Mannitol
`Butanol
`Water, q.s.
`
`to
`
`Concentration
`about 2-40
`
`mg/mL
`about 0-50
`5
`
`0489
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`about 2-50
`
`mg/mL
`about 0-50
`
`Bendamustine HC1
`
`mg/mL
`about 0.5-99
`
`%
`
`0490
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Examples are
`
`in
`
`no way
`
`to
`
`be considered
`
`to
`
`0491
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`back to
`
`in 1 min
`20%B
`
`20%B
`hold at
`Run time:
`Post run
`
`for 4
`30 min
`time:
`
`min
`
`5
`
`0492
`
`

`
`WO 2006/076620
`
`Gradient:
`
`PCT/US2006/001308
`
`% Phase Time (min.)
`
`0.0
`7.0
`11.0
`15.0
`30.0
`31.0
`
`A
`
`% Phase B
`82
`60
`60
`20
`20
`82
`
`18
`40
`40
`80
`80
`18
`
`Sample preparation-
`
`dissolve the
`
`drug
`
`0493
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`The retention
`
`times for
`
`some Bendanxustine
`described above
`
`impurities
`are
`
`0494
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`03C08
`
`97.61
`
`1.24
`
`0.19
`
`0.46
`
`0.02
`
`Example 2-
`
`Solubility
`The solubility
`
`of bendamustine
`
`HC1
`
`(bendamustine)
`
`in
`
`0495
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`concentration of
`
`TBA for the final
`
`formulation and
`
`is
`regardless of
`
`0496
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`bendamustine
`
`is
`
`higher in
`
`a
`
`30% TBA/water
`
`saturated
`
`0497
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`10% iso-propanol,
`
`20%
`
`iso-propanol produced
`
`either
`
`0498
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Major impurities
`
`introduced
`
`during
`
`compounding, fill,
`
`0499
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`The literature
`
`reports that
`
`forms
`TB A adopts different crystal
`freeze rate. In some TBA solutions,
`
`0500
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`Step
`
`Description
`
`Time (Hour)
`
`0
`
`Pressure
`Temperature (
`(Microns)
`1
`Hold
`Ramp
`
`2
`
`3
`
`4
`
`Hold
`
`5
`
`0.25
`
`8
`
`Ramp
`
`6
`
`Hold
`
`0501
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`each, instance herein
`
`any
`
`terms "comprising",
`of the
`"consisting of
`
`"consisting essentially
`may
`
`0502
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`What is
`
`claimed is:
`
`1. A pharmaceutical
`
`composition of
`
`bendamustine
`0.9% (area
`
`percent of
`
`0503
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`8. The lyophilized
`
`preparation according
`with respect
`
`to claim 6, wherein
`the amount
`
`said preparation
`of
`
`to
`
`0504
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`18. A pharmaceutical
`
`dosage
`
`form comprising
`
`the
`
`0505
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`26. In a method for
`
`obtaining
`
`agency
`
`approval for
`
`0506
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`CI
`
`CI
`
`N
`
`N
`
`COOCH2CH3
`
`N
`I
`Formula IV
`than 0.2%
`greater
`
`is no more
`
`than
`
`the concentration
`found in
`
`0507
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`36. A method
`
`of
`
`preparing a
`
`bendamustine lyophilized
`a) dissolving
`
`bendamustine
`
`0508
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`43. A method
`
`according
`
`to claim
`
`36,
`
`wherein an
`
`excipient
`lyophilization.
`
`44. A method
`
`0509
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`52. A method according
`
`to
`
`wherein
`claim 36
`i) freezing the
`
`step b)
`pre-lyophilization solution
`
`0510
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`pressure of
`
`about 13.5
`
`psi
`
`in a pharmaceutically acceptable
`
`0511
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`67. A method of treating
`
`according
`
`to claim
`
`62
`
`further
`dissolved preparation
`
`0512
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`75. A pharmaceutical dosage form
`
`according to
`
`claim
`
`72,
`pharmaceutically acceptable
`
`0513
`
`

`
`WO 2006/076620
`
`PCT/US2006/001308
`
`1/6
`
`n
`
`-aj -aj
`
`13 B
`& >
`> >
`tiZ o o
`
`CS2 CO H
`
`C5
`CO
`
`^3^
`(M
`
`CJ o
`0> U
`t-4 0} a CD E-<
`
`cd
`
`cz>
`2s -
`
`o
`co
`
`o
`lO
`
`CD O
`CO
`
`O
`o o o
`Cvi
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`

`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(12) INTERNATIONAL APPLICATION
`PUBLISHED
`
`UNDER
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`
`I October 2009 (01.10.2009) (10) International Publication Number
`
`WO 2009/120386 A2
`
`(51)
`
`(21)
`
`International Patent Classification:
`A6IK 9/19 (2006.01)
`
`(81)
`
`International Application Number:
`PCT/US2009/001956
`
`(22)
`
`International Filing Date:
`
`26 March 2009 (26.03.2009)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`61/039,752
`
`26 March 2008 (26.03.2008)
`
`US
`
`except US):
`all designated States
`0”or
`Applicant
`CEPHALON, INC. [US/US]; 41 Moores Road, P.o. Box
`4011, Frazer, PA 19355 (US).
`
`Inventors; and
`Inventors/Applicants (for US only): COOPER, Martin,
`Ian [GB/GB]; 29 West Hill Road, Foxton, Cambridge
`CB22 GSZ
`(GB). COURVOISIER, Laurent, D.
`[FR/US]; 212 Turnberry Drive, Thorndale, PA 19372
`(US). EDDLESTON, lVIark [GB/GB]; 17 Harlech Rise,
`Chilwell, Nottingham NG9 5PD
`NICKEAN,
`Robert, E.
`[US/US];
`16 Houndstooth Lane, Chester
`Springs, PA 19425 (US).
`
`(74)
`
`Agent: HRUBIEC, Robert, T.; Cephalon Inc.,
`Moores Road, P.O. Box 401 1, Frazer, PA 19355 (US).
`
`41
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`A0, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ,
`EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, l\/IN, MW, MX, MY, MZ, NA, NG, NI, NO,
`NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG,
`SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA,
`UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind ofregional protection available): ARIPO (BW, GH,
`GM, KE, LS, MVV, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR),
`OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML,
`MR, NE, SN, TD, TG).
`Published:
`
`without international search report and to be republished
`upon receipt ofthat report (Rule 48.2(g))
`
`(54) Title: NOVEL SOLID FORMS OF BENDAMUSTINE HYDROCHLORIDE
`
` nun‘: vuaanx
`2-Tll8a- sale
`
`FIG. 2
`
`(57) Abstract: Novel solid Forms ofbendamustine hydrochloride are described, as well as methods of their preparation and use.
`
`0520
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`WO2009/120386A2l||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`0520
`
`

`
`WO 2009/120386
`WO 2009/120386
`
`PCT/US2009/001956
`PCT/US2009/001956
`
`NOVEL SOLID
`FORMS
`OF BENDAMUSTINE
`NOVEL SOLID FORMS OF BENDAMUSTINE HYDROCHLORIDE
`
`HYDROCHLORIDE
`
`10
`
`FIELD OF THE INVENTION
`
`10
`
`FIELD OF
`
`THE
`
`This invention pertains to bendamustine—containing compositions, pharmaceutical
`
`compositions comprising bendamustine, processes to reproducibly make them, and
`
`methods of treating patients using them.
`
`BACKGROUND OF THE INVENTION
`
`15
`
`20
`
`25
`
`Active pharmaceutical ingredients (APIS) can be prepared in a variety of different
`
`forms, for example, chemical derivatives, solvates, hydrates, co—crystals, or salts. APIs
`
`may also be prepared in different solid forms, in that they may be amorphous, may exist as
`
`different crystalline polymorphs, and/or in different solvation or hydration states. By
`
`varying the form of an API, it is possible to vary the physical properties thereof. For
`
`instance, solid forms of an API typically have different solubilities such that a more
`
`thermodynamically stable solid form is less soluble than a less thermodynamically stable
`
`solid form. Solid forms can also differ in properties such as shelf-life, bioavailability,
`
`morphology, vapor pressure, density, color, and compressibility. Accordingly, variation
`
`of the solid state of an API is one of many ways in which to modulate the physical and
`
`pharmacological properties thereof.
`
`Bendamustine, 4- { 5- [Bis(2-chloroethyl)amino] - 1 -methyl-2-benzimidazolyl}
`
`butyric acid:
`
`0/“j
`J/N]i:j:N
`
`CI
`
`O OH .HC|
`
`Bendarnustine Hydrochloride
`
`- was initially synthesized in 1963 in the German Democratic Republic (GDR) and was
`
`available from 1971 to 1992 there under the tradename Cytostasan®. See, e. g., W.
`
`-1-
`
`0521
`
`0521
`
`

`
`WO 2009/120386
`
`PCT/US2009/001956
`
`Ozegowski and
`
`D.
`
`Krebs,
`
`IMET 3393
`
`0522
`
`

`
`WO 2009/120386
`
`PCT/US2009/001956
`
`Solid forms
`
`of
`
`bendamustine
`
`hydrochloride
`
`0523
`
`

`
`WO 2009/120386
`WO 2009/120386
`
`PCT/US2009/001956
`PCT/US2009/001956
`
`OF
`BRIEF DESCRIPTION
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`THE
`
`FIG. 1 is a ‘H NMR spectrum of bendamustine hydrochloride
`
`FIG. 2 is an X—ray Powder Diffractogram (XRPD) of bendamustine hydrochloride
`
`Form 1
`
`FIG. 3 is a Differential Scanning Calorimetry (DSC) Therrnogram of bendamustine
`
`hydrochloride Form 1
`
`FIG. 4 is a Therrno—Gravimetric Analysis (TGA) Thermograrn of bendamustine
`
`hydrochloride Form 1
`
`FIG. 5 is a Gravimetric Vapor Sorption (GVS) trace of bendamustine
`
`10
`
`hydrochloride Form 1
`
`FIG. 6 is an X-ray Powder Diffractogram of bendamustine hydrochloride Form 2
`
`FIG. 7A is a DSC Thermogram of bendamustine hydrochloride Form 2
`
`FIG. 7B is a DSC Thermogram of bendamustine hydrochloride Form 2 using a 2
`°C per minute heating rate.
`
`15
`
`20
`
`FIG. 8 is a TGA Thermogram of bendamustine hydrochloride Form 2
`
`FIG. 9 is a GVS trace of bendamustine hydrochloride Form 2
`
`FIG. 10 is an X—ray Powder Diffractogram of bendamustine hydrochloride Form 3
`
`FIG. 11 is an X-ray Powder Diffractogram of bendarnustine hydrochloride Form 4
`
`FIG. 12 is a DSC Thermogram of bendamus