wncaovl
`
`PTO/SBI05 (09-04)
`Approved for use through 07/31/2006. OMB 0651-0032
`US Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`Under the Papenrrork Reduction Act of 1995. no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`
`
`
`
`
`
`
`”‘ °’
`
`Express Mail Label No.
`
`EV63777376-1US
`
`
`
`
`
`‘”'”“
`PATENT APPLICATION
`TRANSMITTAL
`(Only for new nonprovisional applications under 37 C.F. R. 1. 53(b))
`
`
`908LL0llllllllllllllllllllllllllllllllllllllll
`
`9. D Assignment Papers (cover sheet & document(s))
`Name of Assignee
`[Total Pages
`3. X Specification
`
`Both the claims and abstract must start on a new page
`(For infonnation on the preferred arrangement, see MPEP 608.01(5))
`
`1o.E]
`37 C.F.R. 3.73(b) Statement El Power of
`4.E] Drawing(s) (35 u.s.c.113)
`[Total Sheets §
`1
`
`(when there is an assignee)
`Attorney
`
`
`
`English Translation Document (if applicable)
`11.E]
`
`
`
`
`Information Disclosure Statement(PTo/S8108 or PTO-1449)
`CI Copies of citations attached
`
`
`
`12. E]
`
`13. E]
`
`Preliminary Amendment
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`
`
`
`
`
`5. Oath or Declaration
`
`[Total Sheets _ ]
`
`a. D Newly executed (original or copy)
`b. El Copy from a prior application (37 CFR 1.63 (d))
`{for a continuation/divisional with Box 18 completed)
`1. El DELETION OF lNVENTOR(S)
`Signed statement attached deleting inventor(s)
`named in the prior application, see 37 CFR
`1.63(d)(2) and 1.33(b).
`
`
`
`14. IZI
`Return Receipt Postcard (MPEP 503)
`6. X Application Data Sheet. See 37 CFR 1.76
`
`(Should be specifically itemized)
`7. E] CD-ROM or CD-R in duplicate, large table or
`Computer Program (Appendix)
`E] Landscape Table on CD
`
` 16.13
`8. Nucleotide andlor Amino Acid Sequence Submission
`Nonpublication Request under 35 U.S.C. 122(b)(2)(B)(i).
`(if applicable, items a.—c. are required)
`Applicant must attach form PTOlSBl35 or its equivalent.
`a. C] Computer Readable Form (CRF)
`
`b.
`Specification Sequence Listing on:
`17. X Other. Unsigned Declaration
`
`i. E] CD-ROM or CD-R (2 copies); or
`
`ii. I] Paper
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`c. U Statements verifying identity of above copies
`
` 18. It a CONTINUING APPLICATION, check appropriate box, and supply the requisite infonnation below and in the first sentence of the
`specification following the title, or in an Application Data Sheet under 37 CFR 1. 76:
`of prior application No:
`I
`D Continuation-in-part (CIP)
`[J Continuation
`D Divisional
`Art Unit:
`
`Examiner
`Prior application infonnation:
`
`
`
`19. CORRESPONDENCE ADDRESS
`
`
`
`
`
`
`
`15. E]
`
`Certified Copy of Priority Document(s)
`{if foreign priority is claimed)
`
`
`
`
`
`8 Customer Number
`
`OR B Correspondence address below
`
`Name
`
`Address
`
`_ Te'ePh°~e — Fax
`
`N
`
`4
`"’""”Me’
`-
`This collection of information Is required by 37 CFR 1.53(b). The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO to
`process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to complete, including
`gathering, preparing. and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount of
`time you require to complete this form andlor suggestions for reducing this burden, should be sent to the Chief Information Officer. U.S. Patent and Trademark Office.
`U.S. Department of Commerce, P.0. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Mall
`Stop Patent Application. Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`If you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
`
`Registration No.
`
`FRESENIUS KABI 1014-OOO1
`
`~ 2
`
`U,-
`-
`3
`'-
`
`011206
`
`
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utility patent application contents.
`1.
`Fee Transmittal Form (e.g., PTOlSBl17)
`
`(Submit an original and a duplicate for fee processing)
`2. E] Applicant claims small entity status.
`See 37 CFR 1.27.
`
`6_3
`
`]
`
`
`
`ADDRESS To
`
`,'
`
`g%mg-issmgrforratenm
`.
`. ox
`Alexandria VA 22313-1450
`ACCOMPANYING APPLICATIONS PARTS
`
`
`
`
`
`

`
`—L
`
`PTO/SB/17 (12-04v2)
`Approved for use through 07/31/2006. OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`, Under the Papenniork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number
`
`%' R?
`E; 03
`if%
`+" -
`'
`
`
`
`Effective on 12/08/2004.
`Fees pursuant to the Consolidated Appropriations Act, zoos (H.R. 4818).
`
`FEE TRANSMITTAL
`
`"
`
`for FY 2005
`D Applicant claims small entity status. See 37 CFR 1.27
`
`
`
`
`
`
`
`
`Application Number
`
`°°”'P’°‘° " K"°“’"
`UNKNOWN
`
`Filing Date
`
`January 12, 2008
`
`First Named Inventor
`
`BR'TrA'N
`
`
`
`
`
`
`@TOTAL AMOUNTOF PAYMENT
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`METHOD OF PAYMENT (check all that apply)
`
`I] Check I:I Credit Card E] Money Order
`
`:
`I:I None C] Other (please identify)
`
`Deposit Account Name: Cephalon, Inc.
`
`IX Deposit Account Deposit Account Number: 03-1195
`For the above-identified deposit account, the Director is hereby authorized to: (check all that apply)
`
`IX Charge fee(s) indicated below
`
`[:1 Charge fee(s) indicated below, except for the filing fee
`
`IX Charge any additional fee(s) or underpayments of fee(s)
`Under 37 CFR 1.16 and 1.17
`WARNING: lnforrnatlon on this man may become public. Credit card Information should not be included on this form. Provlde credit card
`lnfonnatlon and authorization on PTO-2038.
`
`Q Credit any overpayments
`
`FEE CALCULATION
`
`BASIC FILING, SEARCH, AND EXAMINATION FEES
`FILING FEES
`SEARCH FEES
`Small Entity
`Small Entity
`Fee(§)
`Fee(§)
`250
`150
`50
`
`1.
`
`Application Type
`Utility
`Design
`Plant
`
`Fee (§)
`300
`
`200
`200
`
`100
`100
`
`Reissue
`Provisional
`
`300
`200
`
`150
`"100
`
`2. EXCESS CLAIM FEES
`
`Fee(§)
`500
`100
`
`300
`
`500
`0
`
`150
`
`250
`0
`
`Fee Description
`Each claim over 20 (including Reissues)
`Each independent claim over 30 (including Reissues)
`Multiple dependent claims
`Total Claims
`
`Extra Claims
`
`Fee Paid (§)
`§2,900.00
`
`Fee Paid (§)
`§3,600.00
`
`EXAMINATION FEES
`Small Entig
`Fee(§)
`100
`65
`80
`
`Fee(§)
`200
`130
`160
`
`600
`0
`
`300
`0
`
`V
`
`Fees Paid (§)
`1,000.00
`
`Small Entity
`
`Fee (§)
`50
`200
`360
`
`Fee (§)
`25
`100
`180
`
`Multiple Dependent Claims
`Fee (§)
`Fee Paid (§)
`
`Fee
`
`Fee Paid (§)
`
`__
`Fees Paid (§)
`
`Fee(§)
`x E
`5_8
`-20 or HP=
`E
`HP = highest number of total claims paid for. if greater than 20.
`lndep. Claims
`Extra Claims
`Fee(§)
`=
`§;0_Q
`1_8
`x
`2_1
`- 3 or HP=
`HP = highest number of independent claims paid for, if greater than 3
`3. APPLICATION SIZE FEE
`
`
`If the specification and drawings exceed 100 sheets of paper (excluding electronically filed sequence or computer
`
`
`listings under 37 CFR l.52(e)), the application size fee due is $250 ($125 for small entity) for each additional 50
`sheets or fraction thereof. See 35 U.S.C. 4l(a)(1)(G) and 37 CFR l.I6(s).
`Total Sheets
`Extra Sheets
`Number of each additional 50 or fraction thereof
`
`
`pg
`- 100 = Q /50 =
`(round up to a whole number) x
`
`
`4. OTHER FEE(S)
`
`
`Non-English Specification, $130 fee (no small entity discount)
`
`Other (e.g., late filing surcharge) :
`
`
`SUBMITTED BY
`
`I Registration No.
`, ;
`Amme , em
`
`38,532
`
`Telephone
`Date
`
`610-736-5463
`January 12, 2006
`
`Name (Printlfype)
`M soon K. Le
`tby the public which is to file (and by the USPTO to process) an application.
`This collection of information is required by 37 CFR 1.136. The information is required to obtain or retain a benefi
`_
`p
`_
`This collection is estimated to take 30 minutes to complete, including gathering, prepanng, and submitting the completed
`Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14.
`the individual case. Any comments on the amount of time you require to complete this form andlor suggestions for reducing this
`application form to the USPTO. Time will vary depending upon
`ark Office. U.S. Department of Commerce, P.O. Box 1450, Alexandna_ VA 22313-1450. DO NOT SEND FEES
`burden, should be sent to the Chief Information Officer, U.S. Patent and Tradem
`P.O. Box 1450, Alexandria. VA 22313-1450.
`
`I! you need assistance in completing this form, call 1-800-PTO-9199 (1-800-786-9199) and select option 2.
`
`FRESENIUS KABI 1014-OOO2
`
`

`
`wncaovl
`
`PTO/SBI05 (09-04)
`Approved for use through 07/31/2006. OMB 0651-0032
`US Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`Under the Papenrrork Reduction Act of 1995. no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`
`
`
`
`
`
`
`”‘ °’
`
`Express Mail Label No.
`
`EV63777376-1US
`
`
`
`
`
`‘”'”“
`PATENT APPLICATION
`TRANSMITTAL
`(Only for new nonprovisional applications under 37 C.F. R. 1. 53(b))
`
`
`908LL0llllllllllllllllllllllllllllllllllllllll
`
`9. D Assignment Papers (cover sheet & document(s))
`Name of Assignee
`[Total Pages
`3. X Specification
`
`Both the claims and abstract must start on a new page
`(For infonnation on the preferred arrangement, see MPEP 608.01(5))
`
`1o.E]
`37 C.F.R. 3.73(b) Statement El Power of
`4.E] Drawing(s) (35 u.s.c.113)
`[Total Sheets §
`1
`
`(when there is an assignee)
`Attorney
`
`
`
`English Translation Document (if applicable)
`11.E]
`
`
`
`
`Information Disclosure Statement(PTo/S8108 or PTO-1449)
`CI Copies of citations attached
`
`
`
`12. E]
`
`13. E]
`
`Preliminary Amendment
`
`
`
`
`
`
`5. Oath or Declaration
`
`[Total Sheets _ ]
`
`a. D Newly executed (original or copy)
`b. El Copy from a prior application (37 CFR 1.63 (d))
`{for a continuation/divisional with Box 18 completed)
`1. El DELETION OF lNVENTOR(S)
`Signed statement attached deleting inventor(s)
`named in the prior application, see 37 CFR
`1.63(d)(2) and 1.33(b).
`
`
`
`14. IZI
`Return Receipt Postcard (MPEP 503)
`6. X Application Data Sheet. See 37 CFR 1.76
`
`(Should be specifically itemized)
`7. E] CD-ROM or CD-R in duplicate, large table or
`Computer Program (Appendix)
`E] Landscape Table on CD
`
` 16.13
`8. Nucleotide andlor Amino Acid Sequence Submission
`Nonpublication Request under 35 U.S.C. 122(b)(2)(B)(i).
`(if applicable, items a.—c. are required)
`Applicant must attach form PTOlSBl35 or its equivalent.
`a. C] Computer Readable Form (CRF)
`
`b.
`Specification Sequence Listing on:
`17. X Other. Unsigned Declaration
`
`i. E] CD-ROM or CD-R (2 copies); or
`
`ii. I] Paper
`
`c. U Statements verifying identity of above copies
`
` 18. It a CONTINUING APPLICATION, check appropriate box, and supply the requisite infonnation below and in the first sentence of the
`specification following the title, or in an Application Data Sheet under 37 CFR 1. 76:
`of prior application No:
`I
`D Continuation-in-part (CIP)
`[J Continuation
`D Divisional
`Art Unit:
`
`Examiner
`Prior application infonnation:
`
`
`
`19. CORRESPONDENCE ADDRESS
`
`
`
`
`
`
`
`15. E]
`
`Certified Copy of Priority Document(s)
`{if foreign priority is claimed)
`
`
`
`
`
`8 Customer Number
`
`OR B Correspondence address below
`
`Name
`
`Address
`
`_ Te'ePh°~e — Fax
`
`N
`
`4
`"’""”Me’
`-
`This collection of information Is required by 37 CFR 1.53(b). The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO to
`process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to complete, including
`gathering, preparing. and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount of
`time you require to complete this form andlor suggestions for reducing this burden, should be sent to the Chief Information Officer. U.S. Patent and Trademark Office.
`U.S. Department of Commerce, P.0. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Mall
`Stop Patent Application. Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`If you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
`
`Registration No.
`
`FRESENIUS KABI 1014-OOO3
`
`~ 2
`
`U,-
`-
`3
`'-
`
`011206
`
`
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utility patent application contents.
`1.
`Fee Transmittal Form (e.g., PTOlSBl17)
`
`(Submit an original and a duplicate for fee processing)
`2. E] Applicant claims small entity status.
`See 37 CFR 1.27.
`
`6_3
`
`]
`
`
`
`ADDRESS To
`
`,'
`
`g%mg-issmgrforratenm
`.
`. ox
`Alexandria VA 22313-1450
`ACCOMPANYING APPLICATIONS PARTS
`
`
`
`
`
`

`
`—L
`
`PTO/SB/17 (12-04v2)
`Approved for use through 07/31/2006. OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`, Under the Papenniork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number
`
`%' R?
`E; 03
`if%
`+" -
`'
`
`
`
`Effective on 12/08/2004.
`Fees pursuant to the Consolidated Appropriations Act, zoos (H.R. 4818).
`
`FEE TRANSMITTAL
`
`"
`
`for FY 2005
`D Applicant claims small entity status. See 37 CFR 1.27
`
`
`
`
`
`
`
`
`Application Number
`
`°°”'P’°‘° " K"°“’"
`UNKNOWN
`
`Filing Date
`
`January 12, 2008
`
`First Named Inventor
`
`BR'TrA'N
`
`
`
`
`
`
`@TOTAL AMOUNTOF PAYMENT
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`METHOD OF PAYMENT (check all that apply)
`
`I] Check I:I Credit Card E] Money Order
`
`:
`I:I None C] Other (please identify)
`
`Deposit Account Name: Cephalon, Inc.
`
`IX Deposit Account Deposit Account Number: 03-1195
`For the above-identified deposit account, the Director is hereby authorized to: (check all that apply)
`
`IX Charge fee(s) indicated below
`
`[:1 Charge fee(s) indicated below, except for the filing fee
`
`IX Charge any additional fee(s) or underpayments of fee(s)
`Under 37 CFR 1.16 and 1.17
`WARNING: lnforrnatlon on this man may become public. Credit card Information should not be included on this form. Provlde credit card
`lnfonnatlon and authorization on PTO-2038.
`
`Q Credit any overpayments
`
`FEE CALCULATION
`
`BASIC FILING, SEARCH, AND EXAMINATION FEES
`FILING FEES
`SEARCH FEES
`Small Entity
`Small Entity
`Fee(§)
`Fee(§)
`250
`150
`50
`
`1.
`
`Application Type
`Utility
`Design
`Plant
`
`Fee (§)
`300
`
`200
`200
`
`100
`100
`
`Reissue
`Provisional
`
`300
`200
`
`150
`"100
`
`2. EXCESS CLAIM FEES
`
`Fee(§)
`500
`100
`
`300
`
`500
`0
`
`150
`
`250
`0
`
`Fee Description
`Each claim over 20 (including Reissues)
`Each independent claim over 30 (including Reissues)
`Multiple dependent claims
`Total Claims
`
`Extra Claims
`
`Fee Paid (§)
`§2,900.00
`
`Fee Paid (§)
`§3,600.00
`
`EXAMINATION FEES
`Small Entig
`Fee(§)
`100
`65
`80
`
`Fee(§)
`200
`130
`160
`
`600
`0
`
`300
`0
`
`V
`
`Fees Paid (§)
`1,000.00
`
`Small Entity
`
`Fee (§)
`50
`200
`360
`
`Fee (§)
`25
`100
`180
`
`Multiple Dependent Claims
`Fee (§)
`Fee Paid (§)
`
`Fee
`
`Fee Paid (§)
`
`__
`Fees Paid (§)
`
`Fee(§)
`x E
`5_8
`-20 or HP=
`E
`HP = highest number of total claims paid for. if greater than 20.
`lndep. Claims
`Extra Claims
`Fee(§)
`=
`§;0_Q
`1_8
`x
`2_1
`- 3 or HP=
`HP = highest number of independent claims paid for, if greater than 3
`3. APPLICATION SIZE FEE
`
`
`If the specification and drawings exceed 100 sheets of paper (excluding electronically filed sequence or computer
`
`
`listings under 37 CFR l.52(e)), the application size fee due is $250 ($125 for small entity) for each additional 50
`sheets or fraction thereof. See 35 U.S.C. 4l(a)(1)(G) and 37 CFR l.I6(s).
`Total Sheets
`Extra Sheets
`Number of each additional 50 or fraction thereof
`
`
`pg
`- 100 = Q /50 =
`(round up to a whole number) x
`
`
`4. OTHER FEE(S)
`
`
`Non-English Specification, $130 fee (no small entity discount)
`
`Other (e.g., late filing surcharge) :
`
`
`SUBMITTED BY
`
`I Registration No.
`, ;
`Amme , em
`
`38,532
`
`Telephone
`Date
`
`610-736-5463
`January 12, 2006
`
`Name (Printlfype)
`M soon K. Le
`tby the public which is to file (and by the USPTO to process) an application.
`This collection of information is required by 37 CFR 1.136. The information is required to obtain or retain a benefi
`_
`p
`_
`This collection is estimated to take 30 minutes to complete, including gathering, prepanng, and submitting the completed
`Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14.
`the individual case. Any comments on the amount of time you require to complete this form andlor suggestions for reducing this
`application form to the USPTO. Time will vary depending upon
`ark Office. U.S. Department of Commerce, P.O. Box 1450, Alexandna_ VA 22313-1450. DO NOT SEND FEES
`burden, should be sent to the Chief Information Officer, U.S. Patent and Tradem
`P.O. Box 1450, Alexandria. VA 22313-1450.
`
`I! you need assistance in completing this form, call 1-800-PTO-9199 (1-800-786-9199) and select option 2.
`
`FRESENIUS KABI 1014-OOO4
`
`

`
`CP391
`
`PATENT
`
`BENDAMUSTINE PHARMACEUTICAL COMPOSITIONS
`
`5
`
`10
`
`15
`
`20
`
`25
`
`FIELD OF THE INVENTION
`
`The present invention pertains to the field of pharmaceutical compositions for the
`
`treatment of various disease states, especially neoplastic diseases and autoimmune
`
`diseases. Particularly, it relates to pharmaceutical formulations comprising nitrogen
`
`mustards, particularly the nitrogen mustard bendarnustine, e.g., bendarnustine HCl.
`
`BACKGROUND OF THE INVENTION
`
`The present invention claims the benefit of and priority to US Serial No.
`
`60/644,354, filed January 14, 2005, entitled, “Bendamustine Pharmaceutical
`
`Compositions,” which is incorporated herein by reference in its entirety, including figures
`
`and claims.
`
`The following description includes information that may be useful in
`
`understanding the present invention. It is not an admission that any such information is
`
`prior art, or relevant, to the presently claimed inventions, or that any publication
`
`specifically or implicitly referenced is prior art.
`
`Because of their high reactivity in aqueous solutions, nitrogen mustards are
`
`difficult to formulate as pharmaceuticals and are often supplied for administration in a
`
`lyophilized form that requires reconstitution, usually in water, by skilled hospital personal
`
`prior to administration. Once in aqueous solution, nitrogen mustards are subject to
`
`degradation by hydrolysis, thus, the reconstituted product should be administered to a
`
`patient as soon as possible after its reconstitution.
`
`Bendarnustine, (4-{5-[Bis(2-ch1oroethyl)arnino]-1-methyl-2-benzimidazolyl}
`
`butyric acid, is an atypical structure with a benzimidazole ring, whose structure includes
`
`an active nitrogen mustard (see Formula I, which shows bendarnustine hydrochloride).
`
`FRESENIUS KABI 1014-OOO5
`
`

`
`CP391
`
`PATENT
`
`CI/fl
`N
`I CE
`
`C:
`
`N
`
`"{
`
`Formula I
`
`o
`
`-”°'
`
`Bendamustine was initially synthesized in 1963 in the German Democratic
`
`'
`
`Republic (GDR) and was available from 1971 to 1992 in that location under the name
`
`Cytostasan®. Since that time, it has been marketed in Germany under the tradename
`
`Ribomustin®. It has been widely used in Germany to treat chronic lymphocytic
`
`leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, and breast
`
`cancer.
`
`10
`
`15
`
`Due to its degradation in aqueous solutions (like other nitrogen mustards),
`
`bendamustine is supplied as a lyophilized product. The current lyophilized formulation of
`
`bendamustine (Ribomustin®) contains bendamustine hydrochloride and mannitol in a
`
`sterile lyophilized form as a white powder for intravenous use following reconstitution.
`
`The finished lyophilisate is unstable when exposed to light. Therefore, the product is
`
`stored in brown or amber-colored glass bottles. The current lyophilized formulation of
`
`bendamustine contains degradation products that may occur during manufacturing of the
`
`drug substance and/or during the lyophilization process to make the finished drug product.
`
`Currently bendamustine is formulated as a lyophilized powder for injection with
`
`100 mg of drug per 50 mL vial or 25 mg of drug per 20 mL vial. The vials are opened and
`
`20
`
`reconstituted as close to the time of patient administration as possible. The product is
`
`reconstituted with 40 mL (for the 100 mg presentation) or 10 mL (for the 25 mg
`
`presentation) of Sterile Water for Injection. The reconstituted product is further diluted
`
`into 500 mL, q.s., 0.9% Sodium Chloride for Injection. The route of administration is by
`
`intravenous infusion over 30 to 60 minutes.
`
`25
`
`Following reconstitution with 40 mL Sterile Water for Injection, vials of
`
`bendamustine are stable for a period of 7 hours under room temperature storage or for 6
`
`days upon storage at 2-8°C. The 500 mL admixture solution must be administered to the
`
`patient within 7 hours of vial reconstitution (assuming room temperature storage of the
`
`admixture).
`
`FRESENIUS KABI 1014-0006
`
`

`
`CP391
`
`PATENT
`
`The reconstitution of the present bendamustine lyophilized powder is difficult.
`
`Reports from the clinic indicate that reconstitution can require at least fifieen minutes and
`
`may require as long as thirty minutes. Besides being burdensome and time-consuming for
`
`the healthcare professional responsible for reconstituting the product, the lengthy exposure
`
`of bendamustine to water during the reconstitution process increases the potential for loss
`
`of potency and impurity formation due to the hydrolysis of the product by water.
`
`Thus, a need exists for lyophilized formulations of bendamustine that are easier to
`
`reconstitute and which have a better impurity profile than the current lyophilate
`
`(lyophilized powder) formulations of bendamustine.
`
`German (GDR) Patent No. 34727 discloses a method of preparing co-[5-bis-(B-
`
`chloroethyl)-arnino-benzimidazolyl-(2)]-alkane carboxylic acids substituted in the 1-
`
`position.
`
`German (GDR) Patent No. 80967 discloses an injectable preparation of y-[1-
`
`methyl-5—bis-(B-ch1oroethyl)-amino—benzimaidazolyl-(2)]-butric acid hydrochloride.
`
`German (GDR) Patent No. 159877 discloses a method for preparing 4-[1-methyl-
`
`5-bis (2-chloroethyl) amino-benzimidazolyl-2)-butyric acid.
`
`German (GDR) Patent No. 159289 discloses an injectable solution of
`
`bendamustine.
`
`Ribomustin® bendamustine Product monograph (updated 1/2002)
`
`hgp://wwwribosepharm.de/pdf/ribomustin bendamustin/productmonographpdf provides
`
`information about Ribomustin® including product description.
`
`Ni et al. report that the nitrosourea SarCNU was more stable in pure tertiary
`
`butanol than in pure acetic acid, dimethyl sulfoxide, methylhydroxy, water or in
`
`TBA/water mixtures (Ni et al. (2001) Int]. J. Phamaceutics 226:39-46).
`
`Lyophilized cyclophoshamide is known in the art see e. g., US Patent Nos.
`
`5,418,223; 5,413,995; 5,268,368; 5,227,374; 5,130,305; 4,659,699; 4,537,883; and
`
`5,066,647.
`
`The lyophilized nitrogen mustard Ifosfarnide is disclosed in International
`
`Publication No. WO 2003/066027; US Pat. Nos. 6,613,927; 5,750,131; 5,972,912;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`5,227,373; and 5,204,335.
`
`FRESENIUS KABI 1014-OOO7
`
`

`
`CP391
`
`PATENT
`
`Teagarden et al. disclose lyophilized formulations of prostaglandin E-1 made by
`
`dissolving PGE-1 in a solution of lactose and tertiary butyl alcohol (US Pat. No.
`
`5,770,230).
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to stable pharmaceutical compositions of
`
`nitrogen mustards, in particular lyophilized bendamustine and its use in treatment of
`
`various disease states, especially neoplastic diseases and autoimmune diseases.
`
`An embodiment of the invention is a pharmaceutical composition of bendamustine
`
`10
`
`containing not more than about 0.5% to about 0.9% (area percent of bendamustine) HP1,
`
`as shown in Formula II,
`
`Ho/H
`r”©£”w}o~
`N\
`
`Cl
`
`Formula II
`
`at the time of release or where the HP1 is the amount of HP1 present at time zero afier
`
`reconstitution of a lyophilized pharmaceutical composition of bendamustine as described
`
`herein. In a preferred embodiment is a pharmaceutical composition of bendamustine
`
`containing not more than about 0.5% (area percent of bendamustine) HP1, preferably not
`
`more than about 0.45%, more preferably not more than about 0.40%, more preferably not
`
`more than about 0.35%, even more preferably not more than 0.30%.
`
`Another embodiment of the invention is a lyophilized preparation of bendamustine
`
`containing not more than about 0.1 % to about 0.3 % bendamustine dimer as shown in
`
`Fonnula III at release or at time zero after reconstitution
`
`15
`
`20
`
`25
`
`Ho/H
`
`Ho’\|
`N
`
`N
`
`o
`
`HO/uN N>—\—()>_oI N?—\fOH
`
`N\
`
`Fonnula III.
`
`-4-
`
`FRESENIUS KABI 1014-OOO8
`
`

`
`CP391
`
`PATENT
`
`Yet another embodiment of the invention is a lyophilized preparation of
`
`bendamustine containing not more than about 0.5%, preferably 0.15% to about 0.5%,
`
`bendamustine ethylester, as shown in Formula IV at release or at time zero afier
`
`reconstitution
`
`COOCHZCH3
`
`N I
`
`Formula IV.
`
`CI
`
`%
`
`Cl
`
`Yet another embodiment of the invention is a lyophilized preparation of
`
`bendamustine wherein the concentration of bendamustine ethylester (Formula IV) is no
`
`more than 0.2%, preferably 0.1%, greater than the concentration of bendamustine
`
`ethylester as found in the drug substance used to make the lyophilized preparation.
`
`In another embodiment of the invention is a lyophilized preparation of
`
`bendamustine containing not more than about 0.5% to about 0.9% (area percent of
`
`bendamustine) HP1 at the time of drug product release. In a preferred embodiment is a
`
`lyophilized preparation of bendamustine containing not more than about 0.50% (area
`
`percent of bendamustine) I-IP1, preferably not more than about 0.45%, more preferably
`
`not more than about 0.40%, more preferably not more than about 0.35%, even more
`
`preferably not more than 0.30%. An aspect of this embodiment is lyophilized
`
`preparations of bendamustine containing not more than about 0.5% to about 0.9%,
`
`preferably 0.5%, (area percent of bendamustine) HP1 at the time of release of drug
`
`product where the lyophilized preparation is packaged in a vial or other pharmaceutically
`
`acceptable container.
`
`In yet another aspect of the invention, the lyophilized preparations of
`
`bendamustine are stable with respect to the amount of HP1 for at least about 6 months,
`
`preferably 12 months, preferably 24 months, to about 36 months or greater when stored at
`
`about 2° ‘to about 30°. Preferred temperatures for storage are about 5° C and about room
`
`10
`
`15
`
`20
`
`25
`
`temperature.
`
`FRESENIUS KABI 1014-0009
`
`

`
`CP391
`
`PATENT
`
`Another embodiment of the invention is a pharmaceutical dosage form that
`
`includes a pharmaceutical composition of bendamustine containing not more than about
`
`0.5% to about 0.9% HP1, preferably not more than about 0.50%, preferably not more than
`
`about 0.45%, more preferably not more than about 0.40%, more preferably not more than
`
`about 0.35%, even more preferably not more than 0.30%, where the HP1 is the amount of
`
`HP1 present at release or at time zero after reconstitution of a lyophilized preparation of
`
`bendamustine of the present invention. In preferred aspects of the invention, the dosage
`
`form can be about 5 to about 500 mg of bendamustine, about 10 to about 300 mg of
`
`bendamustine, about 25 mg of bendamustine, about 100 mg of bendamustine, and about
`
`10
`
`200 mg of bendamustine.
`
`Yet another embodiment of the invention is a pharmaceutical dosage form that
`
`includes a lyophilized preparation of bendamustine containing not more than about 0.5%
`
`to about 0.9%, preferably 0.5%, I-IP1. Preferred dosage forms can be about 5 to about 500
`
`mg of bendamustine, about 10 to about 300 mg of bendamustine, about 25 mg of
`
`bendamustine, about 100 mg of bendamustine, and about 200 mg of bendamustine.
`
`In still another embodiment, the invention includes a pharmaceutical composition
`
`of bendamustine including bendamustine containing not more than about 0.5% to about
`
`0.9% (area percent of bendamustine), preferably not more than about 0.50%, preferably
`
`not more than about 0.45%, more preferably not more than about 0.40%, more preferably
`
`not more than about 0.35%, even more preferably not more than 0.30%, and a trace
`
`amount of one or more organic solvents, wherein said HP1 is the amount of HP1 present
`
`at release or time zero afier reconstitution of a lyophilized pharmaceutical composition of
`
`bendamustine as disclosed herein. In different aspects of this embodiment, the organic
`
`solvent is selected from one or more of tertiary butanol, n-propanol, n-butanol,
`
`isopropanol, ethanol, methanol, acetone, ethyl acetate, dimethyl carbonate, acetonitrile,
`
`dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, l-pentanol, methyl acetate,
`
`carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl
`
`sulfone, acetic acid, and cyclohexane. Preferred organic solvents include one or more of
`
`ethanol, methanol, propanol, butanol, isopropanol, and tertiary butanol. A more preferred
`
`organic solvent is tertiary butanol, also known as TBA, t-butanol, tert-butyl alcohol or
`
`tertiary butyl alcohol.
`
`15
`
`20
`
`25
`
`30
`
`FRESENIUS KABI 1014-0010
`
`

`
`CP391
`
`PATENT
`
`The present invention involves a method for obtaining agency approval for a
`
`bendamustine product, the improvement which includes setting a release specification for
`
`bendamustine degradants at less than about 4.0%, preferably about 2.0 % to about 4.0 %,
`
`(area percent bendamustine) or otherwise to achieve the pharmaceutical compositions
`
`described herein. An aspect of this embodiment is a method for obtaining agency
`
`approval for a bendamustine product which includes setting a release specification for
`
`HP1 to be less than or equal to 1.5% (area percent Bendamustine). The bendamustine
`
`product herein contains not more than about 0.5% (area percent of bendamustine) HP1 at
`
`release.
`
`Another embodiment is a method for obtaining agency approval for a
`
`bendamustine product, the improvement which includes setting a shelf-life specification
`
`for bendamustine degradants at less than about 7.0%, preferably about 5.0% to about
`
`7.0%, (area percent bendamustine) where the product is stored at about 2°C to about
`
`30°C. Preferred temperatures for storage are about 5°C and about room temperature. The
`
`bendamustine product herein contains not more than about 0.5% (area percent of
`
`bendamustine) HP1 at release.
`
`Another embodiment of the invention is a process for manufacturing a lyophilized
`
`preparation of bendamustine which includes controlling for the concentration of
`
`bendamustine degradants in the final product, such that the concentration of bendamustine
`
`degradants is less than about 4.0%, preferably no more than about 2.0 % to about 4.0 %,
`
`(area percent of bendamustine) at release or otherwise to achieve the pharmaceutical
`
`compositions described herein. The bendamustine product herein contains not more than
`
`about 0.5% to about 0.9%, preferably about 0.5%, (area percent of bendamustine) HP1 at
`
`release.
`
`The present invention discloses a process for manufacturing a lyophilized
`
`preparation of bendamustine which comprises controlling for the concentration of
`
`bendamustine degradants in the final product, such that, at release, the concentration of
`
`HP1 is less than 0.9%, preferably 0.5%, (area percent of bendamustine) and, at the time of
`
`10
`
`15
`
`20
`
`25
`
`product expiration, the concentration of bendamustine degradants is less than about 7.0%,
`
`30
`
`preferably no more than about 5.0% to about 7.0%; wherein said product is stored at about
`
`2°C to about 30°C.
`
`FRESENIUS KABI 1014-0011
`
`

`
`CP39 1
`
`PATENT
`
`Another embodiment of the invention is a bendamustine pre-lyophilization
`
`solution or dispersion comprising one or more organic solvents where the solution or
`
`dispersions include at least one stabilizing concentration of an organic solvent which
`
`reduces the level of degradation of bendamustine so that the amount of HP1 produced
`
`during lyophilization from about 0 to 24 hours does not exceed about 0.5% to about 0.9%
`
`(area percent of bendamustine) preferably 0.50%, preferably 0.45%, more preferably
`
`0.40%, more preferably 0.35%, even more preferably 0.30%. An aspect of this
`
`embodiment is the lyophilized powder produced from the pre-lyophilization solution or
`
`dispersion.
`
`Still another embodiment of the invention is a bendamustine pre-lyophilization
`
`solution or dispersion comprising one or more organic solvents where the solution or
`
`dispersions include at least one stabilizing concentration of an organic solvent which
`
`reduces the level of degradation of bendamustine so that the amount of bendamustine
`
`ethylester produced during lyophilization from about 0 to 24 hours does not exceed about
`
`0.5% (area percent bendamustine). An aspect of this embodiment is the lyophilized
`
`powder produced from the pre-lyophilization solution or dispersion.
`
`Still another embodiment of the invention is a bendamustine pre-lyophilization
`
`solution or dispersion comprising one or more organic solvents where the solution or
`
`dispersions include at least one stabilizing concentration of an organic solvent which
`
`reduces the level of degradation of bendamustine so that the amount of benda