P=~e~vpe a plus sign (+) inside this box --~
`
`PTO/SB/05 (12/97)
`
`O UTILITY
`PATENT APPLICATTON
`TRANSMITTAL
`(Only) for new nonprovisional applications under
`
`Attorney Docket No. XI4173A
`First Named Inventor or Application Identifier
`NIYIKIZA Clet
`Express Mail Label NO.
`
`Application Elements
`See MPEP chapter 60b concerning utility patent
`application contents.
`
`ADDRESS TO :
`
`I. ~ Fee Transmittal Form
`original, and a duplicate for fee processing)
`
`(Submit an
`
`EL832896550 US
`Commissioner for Patents
`Mail Stop Patent Application
`P.O. Box 1450
`Alexandria, VA 22313-1450
`6. D Microfiche Computer Program (Appendix)
`
`. O
`
`]
`
`7.
`
`Nucleotide and/or Amino Acid Sequence Submission
`applicable, all necessary)
`
`Computer Readable Copy
`Paper Copy (identical to computer copy)
`Statement verifying identity of above copies
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`ACCOMPANYING A~PLICATION PARTS
`
`2.
`
`~referred arrangement
`Pages
`~ Specification [Total ~
`set forth below)
`Descriptive title of the Invention
`Cross References to Related Applications
`Statement Regarding Fed sponsored R & D
`Reference to Microfiche Appendix
`Backgroundof the Invention
`Brief Summary of the Invention
`Brief Description of the Drawings (if filed)
`Detailed Description
`Claims
`
`Abstract of the Disclosure
`
`3.
`
`Drawing(s) (35 USC
`113)
`¯ 4. Oath or Declaration
`
`[Total
`Sheets
`[Total
`Pages
`Newly executed (original or copy)
`
`3
`
`Copy from a prior application (37 CFR
`1.63(d)) (for continuation/divisional with
`Box 17 completed) [Note Box 5 below]
`DELETION OF INVENTORIS) Signed
`statement attached deleting
`inventqr(s) named in
`the prior application, see 37 CFR
`1.63(d)(2) and 1.33(b).
`5. ~ Incorporatibn By Reference (useable if Box 4b
`is checked) The entire disclosure of the prior
`application, from which a copy of the oath or
`declaration is supplied under Box 4b, is
`considered as being part of the disclosure of
`the accompanying application and is hereby
`incorporated by reference therein.
`17. If a CONTINUING A~PLICATION, check appropriate box and supply’the requisite information:
`] Continuation ~ Divisional I--] Continuation-in-part (CIP) of prior application No:
`18. CORRESPONDENCE ADDRESS
`
`a.
`
`b.
`
`X
`
`i.
`
`-I
`
`X
`
`X
`
`Assignment Papers (cover sheet & document(s)
`
`37 CFR 3.73(b) Statement ~ Power of
`~when there is an assignee)II Attorney
`English Translation Document (if applicable)
`
`Information Disclosure
`Statement (IDS)/PTO-1449
`Preliminary Amendment
`
`copies of IDS
`Citations
`
`X
`x Return Receipt Postcard (MPEP 503) (Should be
`specifically itemized)
`Small Entity ~ Statement filed in prior
`Statement(s) ~_~ application, Status still
`proper and desired
`Certified Copy of Priority Document(s) (if foreign
`priority is claimed)
`
`~ Othe~ :
`Amendment and Petition to
`Correct Inventorship
`
`ii.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`10/297~821
`
`Correspondence
`address below
`
`Customer Numb ..... Bar’ Code ~i : ;i;25885 ~ or
`¯ labe~ ~ :
`
`[Eli Lilly and Company
`
`ADDRESS
`
`Patent Division
`P.O. Box 6288
`
`CITY
`Indianapolis
`COUNTRY
`U.S.A.
`SUBMITTED BY
`qh~ped or
`Elizabeth A. McGraw
`,Printed Name
`~ ,~./~
`Signature 2~ // I/~ ~_~ .
`"
`~Express Mail" maili~a~l n~er -- ~ L ~ 9~~ ~%
`
`I STATE
`I TELEPHONE
`
`Indiana
`317-277-7443
`
`25885
`PARENT TRADEMARK OFFICE
`46206-6288
`ZIP CODE
`FAX 317-276-3861
`Complete (if applicable)
`Reg. Number
`44, 646
`
`Date
`
`I hereby certify t~a~t~is paper or fee is being deposited wi~h the United States Postal Se~ice "~ress Mail Post Office
`to Addressee" se~ice ~der 37 C.F.R. i.i0 on the date indicaCed~ve ~d is addressed to the Co~issioner for Patents,
`P~ Box 1450, Alexandr~VA 22313-1450.
`~
`
`/
`
`Printed N~e
`
`w/
`
`~
`Si~ature
`
`Sandoz Inc.
`Exhibit 1024-0001
`
`Teva – Fresenius
`Exhibit 1024-00001
`
`

`
`type a plus sign (+) inside this box ~
`
`FEE TRANSMITTAL
`
`Effective December 8, 2004
`
`TOTAL AMDUNT OF PAYMENT
`
`($)!360.00
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`METHOD OF PAYMENT (check one)
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`The Commissioner is hereby authorized to charge
`indicated fees and credit any overpayments to:
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`Complete if Known
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`Serial NO.
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`NIYIKIZA Clet
`
`XI4173A
`
`FEE CALCULATION (continued)
`3. ADDITIONAL FEES
`Large
`Large
`Entity
`Entity
`Fee
`Fee ($)
`Code
`¯ 1051
`
`130
`
`Surcharge-late filing fee or oath
`
`Fee Description
`
`Fee Paid
`
`Deposit
`ACcount
`Number
`Deposit
`
`0 5 -- 0 8 4 0
`
`Eli Lilly and Company
`
`1052
`
`50
`
`Surcharge-late provisional filing fee
`or cover sheet.
`
`X
`
`Additional Fee
`Required
`
`37 CFR 1.18 at the time of
`al]owance
`FEE CALCULATION
`
`Code
`
`1011
`
`Iiii
`
`In connection with the filing, search
`and exam fees
`Description
`
`Fee Paid
`
`Fee
`
`Basic filing fee
`(Utility)
`Utility search fee
`
`Utility examination
`
`$300.00
`
`$500.00
`
`300.00
`
`500.00
`
`1053
`
`1251
`1252
`
`1253
`
`1254
`
`1255
`
`1401
`
`130
`
`120
`450
`
`1,020
`
`1,590
`
`2,160
`
`500
`
`Non-English specification
`
`Extension for reply within first month
`
`Extension for reply within second month
`
`Extension for reply within third month
`
`Extension-for reply within fourth month
`
`Extension for reply within fifth month
`
`Notice of Appeal
`
`1311
`
`$200.00
`
`200.00
`
`SUBTOTAL (i)
`
`($) 1,000
`
`Code
`1202
`
`Total claims
`i0 - 20 =
`
`Extra
`
`__ X 50 =
`
`Fee Paid
`($)
`$
`
`Independent
`claims
`
`1201
`
`2
`
`- 3 =
`
`__ X 200 =
`
`$
`
`1203
`
`Multiple
`Dependent
`Claim
`
`Yes
`or
`No
`
`360 = $360
`t(if yes)
`
`1081
`21
`
`Claims and Excess Length Fees
`Total length (spec + drawings)
`i00 = __ excess pages
`
`$__
`No extra charge, for first 100 pages. Must pay
`$250 for each adtl 50 pages (or fraction thereof).
`
`1402
`
`1452
`
`1453
`
`1502
`
`122
`
`1891
`
`500
`
`500
`
`1,500
`
`1,400
`
`130
`
`790
`
`Filing a brief~in support Of an appeal
`
`Petition to revive-unavoidable
`
`Petition to revive-unintentional
`
`Utility issue fee (or reissue)
`
`Petitions to the Colmsissioner ’
`
`Request for Continued Examination (RCE)
`
`Other fee (specify)
`
`Other fee (specify)
`
`Other fee (specify)
`
`Other fee (specify)
`
`SUBTOTAL (2) (S) ~(~0."
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`SUR~I TTED BY
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`Typed or
`Printed Name
`Signature
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`Elizabeth A. McGraw
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`/
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`SUBTOTAL (3)
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`($)
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`Complete (if applicable)
`
`Reg. Number 44,646
`
`Date
`
`Sandoz Inc.
`Exhibit 1024-0002
`
`Teva – Fresenius
`Exhibit 1024-00002
`
`

`
`P=~e~vpe a plus sign (+) inside this box --~
`
`PTO/SB/05 (12/97)
`
`O UTILITY
`PATENT APPLICATTON
`TRANSMITTAL
`(Only) for new nonprovisional applications under
`
`Attorney Docket No. XI4173A
`First Named Inventor or Application Identifier
`NIYIKIZA Clet
`Express Mail Label NO.
`
`Application Elements
`See MPEP chapter 60b concerning utility patent
`application contents.
`
`ADDRESS TO :
`
`I. ~ Fee Transmittal Form
`original, and a duplicate for fee processing)
`
`(Submit an
`
`EL832896550 US
`Commissioner for Patents
`Mail Stop Patent Application
`P.O. Box 1450
`Alexandria, VA 22313-1450
`6. D Microfiche Computer Program (Appendix)
`
`. O
`
`]
`
`7.
`
`Nucleotide and/or Amino Acid Sequence Submission
`applicable, all necessary)
`
`Computer Readable Copy
`Paper Copy (identical to computer copy)
`Statement verifying identity of above copies
`
`ACCOMPANYING A~PLICATION PARTS
`
`2.
`
`~referred arrangement
`Pages
`~ Specification [Total ~
`set forth below)
`Descriptive title of the Invention
`Cross References to Related Applications
`Statement Regarding Fed sponsored R & D
`Reference to Microfiche Appendix
`Backgroundof the Invention
`Brief Summary of the Invention
`Brief Description of the Drawings (if filed)
`Detailed Description
`Claims
`
`Abstract of the Disclosure
`
`3.
`
`Drawing(s) (35 USC
`113)
`¯ 4. Oath or Declaration
`
`[Total
`Sheets
`[Total
`Pages
`Newly executed (original or copy)
`
`3
`
`Copy from a prior application (37 CFR
`1.63(d)) (for continuation/divisional with
`Box 17 completed) [Note Box 5 below]
`DELETION OF INVENTORIS) Signed
`statement attached deleting
`inventqr(s) named in
`the prior application, see 37 CFR
`1.63(d)(2) and 1.33(b).
`5. ~ Incorporatibn By Reference (useable if Box 4b
`is checked) The entire disclosure of the prior
`application, from which a copy of the oath or
`declaration is supplied under Box 4b, is
`considered as being part of the disclosure of
`the accompanying application and is hereby
`incorporated by reference therein.
`17. If a CONTINUING A~PLICATION, check appropriate box and supply’the requisite information:
`] Continuation ~ Divisional I--] Continuation-in-part (CIP) of prior application No:
`18. CORRESPONDENCE ADDRESS
`
`a.
`
`b.
`
`X
`
`i.
`
`-I
`
`X
`
`X
`
`Assignment Papers (cover sheet & document(s)
`
`37 CFR 3.73(b) Statement ~ Power of
`~when there is an assignee)II Attorney
`English Translation Document (if applicable)
`
`Information Disclosure
`Statement (IDS)/PTO-1449
`Preliminary Amendment
`
`copies of IDS
`Citations
`
`X
`x Return Receipt Postcard (MPEP 503) (Should be
`specifically itemized)
`Small Entity ~ Statement filed in prior
`Statement(s) ~_~ application, Status still
`proper and desired
`Certified Copy of Priority Document(s) (if foreign
`priority is claimed)
`
`~ Othe~ :
`Amendment and Petition to
`Correct Inventorship
`
`ii.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`10/297~821
`
`Correspondence
`address below
`
`Customer Numb ..... Bar’ Code ~i : ;i;25885 ~ or
`¯ labe~ ~ :
`
`[Eli Lilly and Company
`
`ADDRESS
`
`Patent Division
`P.O. Box 6288
`
`CITY
`Indianapolis
`COUNTRY
`U.S.A.
`SUBMITTED BY
`qh~ped or
`Elizabeth A. McGraw
`,Printed Name
`~ ,~./~
`Signature 2~ // I/~ ~_~ .
`"
`~Express Mail" maili~a~l n~er -- ~ L ~ 9~~ ~%
`
`I STATE
`I TELEPHONE
`
`Indiana
`317-277-7443
`
`25885
`PARENT TRADEMARK OFFICE
`46206-6288
`ZIP CODE
`FAX 317-276-3861
`Complete (if applicable)
`Reg. Number
`44, 646
`
`Date
`
`I hereby certify t~a~t~is paper or fee is being deposited wi~h the United States Postal Se~ice "~ress Mail Post Office
`to Addressee" se~ice ~der 37 C.F.R. i.i0 on the date indicaCed~ve ~d is addressed to the Co~issioner for Patents,
`P~ Box 1450, Alexandr~VA 22313-1450.
`~
`
`/
`
`Printed N~e
`
`w/
`
`~
`Si~ature
`
`Sandoz Inc.
`Exhibit 1024-0003
`
`Teva – Fresenius
`Exhibit 1024-00003
`
`

`
`type a plus sign (+) inside this box ~
`
`FEE TRANSMITTAL
`
`Effective December 8, 2004
`
`TOTAL AMDUNT OF PAYMENT
`
`($)!360.00
`
`METHOD OF PAYMENT (check one)
`
`The Commissioner is hereby authorized to charge
`indicated fees and credit any overpayments to:
`
`Complete if Known
`
`Serial NO.
`Application Date
`US Nat’ 1 Entry Date
`(if applicable)
`First Named Inventor
`Group Art Unit
`Examiner Name
`Conf. No.
`Attorney Docket Number
`
`NIYIKIZA Clet
`
`XI4173A
`
`FEE CALCULATION (continued)
`3. ADDITIONAL FEES
`Large
`Large
`Entity
`Entity
`Fee
`Fee ($)
`Code
`¯ 1051
`
`130
`
`Surcharge-late filing fee or oath
`
`Fee Description
`
`Fee Paid
`
`Deposit
`ACcount
`Number
`Deposit
`
`0 5 -- 0 8 4 0
`
`Eli Lilly and Company
`
`1052
`
`50
`
`Surcharge-late provisional filing fee
`or cover sheet.
`
`X
`
`Additional Fee
`Required
`
`37 CFR 1.18 at the time of
`al]owance
`FEE CALCULATION
`
`Code
`
`1011
`
`Iiii
`
`In connection with the filing, search
`and exam fees
`Description
`
`Fee Paid
`
`Fee
`
`Basic filing fee
`(Utility)
`Utility search fee
`
`Utility examination
`
`$300.00
`
`$500.00
`
`300.00
`
`500.00
`
`1053
`
`1251
`1252
`
`1253
`
`1254
`
`1255
`
`1401
`
`130
`
`120
`450
`
`1,020
`
`1,590
`
`2,160
`
`500
`
`Non-English specification
`
`Extension for reply within first month
`
`Extension for reply within second month
`
`Extension for reply within third month
`
`Extension-for reply within fourth month
`
`Extension for reply within fifth month
`
`Notice of Appeal
`
`1311
`
`$200.00
`
`200.00
`
`SUBTOTAL (i)
`
`($) 1,000
`
`Code
`1202
`
`Total claims
`i0 - 20 =
`
`Extra
`
`__ X 50 =
`
`Fee Paid
`($)
`$
`
`Independent
`claims
`
`1201
`
`2
`
`- 3 =
`
`__ X 200 =
`
`$
`
`1203
`
`Multiple
`Dependent
`Claim
`
`Yes
`or
`No
`
`360 = $360
`t(if yes)
`
`1081
`21
`
`Claims and Excess Length Fees
`Total length (spec + drawings)
`i00 = __ excess pages
`
`$__
`No extra charge, for first 100 pages. Must pay
`$250 for each adtl 50 pages (or fraction thereof).
`
`1402
`
`1452
`
`1453
`
`1502
`
`122
`
`1891
`
`500
`
`500
`
`1,500
`
`1,400
`
`130
`
`790
`
`Filing a brief~in support Of an appeal
`
`Petition to revive-unavoidable
`
`Petition to revive-unintentional
`
`Utility issue fee (or reissue)
`
`Petitions to the Colmsissioner ’
`
`Request for Continued Examination (RCE)
`
`Other fee (specify)
`
`Other fee (specify)
`
`Other fee (specify)
`
`Other fee (specify)
`
`SUBTOTAL (2) (S) ~(~0."
`
`SUR~I TTED BY
`
`Typed or
`Printed Name
`Signature
`
`Elizabeth A. McGraw
`
`/
`
`SUBTOTAL (3)
`
`($)
`
`Complete (if applicable)
`
`Reg. Number 44,646
`
`Date
`
`Sandoz Inc.
`Exhibit 1024-0004
`
`Teva – Fresenius
`Exhibit 1024-00004
`
`

`
`-- EST AVA-1LABLE COPY
`
`WO 02/02093
`
`PCT/US01/14860
`
`NOVEL ANTIFOLATE COMBINATION THERAPIES
`
`5
`
`Potentially, Iife-threatenln£ toxicity remains a major limitation to the Optimal
`
`administration of antifo]ates. (see, generally, Antifolate Drugs ~n Cancer Therapy, edited
`
`by Jackman, A~n L., Humana Press, Totowa, NJ, 1999.) In some cases, a supportive
`
`intervention ~s routinely used to permit safe, maximal dosing. For exan~ple, steroids, such
`
`as dexamethone, can be used to prevent th~ formation of skin rashes caused bythe
`
`10
`
`ant.fro]ate. CAntifo]ate. pg 197.)
`
`Amffo]ates represent one of the nmst thoroughly studied classes of antineop]astic
`
`agents, with -rr~nepterin initially demonstrating clinical a~tivity appro~h+mtely 50 years
`
`ago. Methotrexate was developed shortly thereafter, and today is a standard component
`
`of effective chemotherapeutic regimens for malignancies such as lymphcnna, breast cancer,
`
`15
`
`and head and neck cancer. (Bonnadonna G, Zmmhetti M, Valagussa P. Sequential or
`
`alternating doxorubicin a~d CMF regimens in breast cancer with more than three positive
`
`nodes: Ten year results. JAMA 1995;273(7):542-547; Bonnadonna G, Valagussa P,
`
`¯
`
`Moliterni A, Zambetti M, Bramb~a C. Adjuvant cyclopho~ph+mide, methotrexate, and
`
`fluorouracfl in node-positive breast cancer: The results of 20 years of fi31]ow-up. N EnSJ J
`
`20 Med 1995;332(14):901-906; and Hong WK, Schaefer S, Iasell B, et aL A pro.specfi~
`
`randomized triaJ of methotrexate versus cisplatin in the t~e.+atment of recurrent squamous
`
`ceil carcinoma of th~ head axtd neck Cancer 1983 ;52:206-210.) Antffolates intn~oit one or
`
`several key fo]ate-requking enzymes of the thymidine and pm’ine biosynthetic pathways, in
`
`particular, thymidylate synthase+ (TS), dihydrofo]ate reductase (DHFR), and glycinamide
`
`25
`
`n~oonuCleotide formyltransferase (GARFF), by competing with reduced folates for binding
`
`sites of these enzymes. (Shih C, Habeck LL, Mendelsolm LG, Chen VJ, Schultz RM.
`
`Multiple fo]ate enzym~ i~h+bition: Mechanism of a novel py~rolopyrimidine-based
`
`antifolate LY231514 (MTA). Advan F.nzym~ Regul, 1998; 38:135-152 and Shih C, Clmn
`
`VJ, Gossett LS, et al+ LY231514, a pyrrolo[2,3-d]pyrJmidine-based antffolate that intn’bits
`
`30 multip]e fo]ate-requiring enzymes. Cancer Res 1997;57:1116-1123.) Several antifolate
`
`drugs are currently in devetopmem. Examples of antffo]ates that have thymidylate
`
`Sandoz Inc.
`Exhibit 1024-0005
`
`Teva – Fresenius
`Exhibit 1024-00005
`
`

`
`WO o2102093
`
`PCT/USOIII 4~0
`
`-2-
`
`synthase inh~iting ("FSI") characteristics include 5-fluorottracil and Tonmdex®. An
`
`example of an antifolate that has dihydrofolate reductase inhibiting ("DHI:~")
`
`characteristic is Methotrexate@. An example of an autifolate that has glycinamide
`
`nq~onucleotide formyltrausferase inh~iting ("GARFFF’) characteristics is Lome.trexol.
`
`5 Many of these antifolate drugs intffbit more than one biosynthetic pathway. For example
`
`Lometrexol is also an ktWoitor of dihydrofolate reductase and pemctrexed disodiurn
`
`(Alirnta®, Eli Lilly and Company, lndimaapoli~, IN) ~ demonstrated thymidylate
`
`synthase, ch~ydrofolate reductase, and glycinamide n’bonucleotide formyltransferase
`
`inhibition.
`
`10
`
`A limitation to the development of these drugs is that the cytotoxic activity and
`
`subsequent effectiveness of antifolates may be associated with substantial toxicity for some
`
`patients. Additionally antifolates as a class are associated with sporadic severe
`
`mylosuppression with gastrointestinal toxicity which, though infrequent, catrie~ a high risk
`
`of mortality. The inability to control these toxicities led to the abandonment of clinical
`
`15
`
`development of some antifolates and has complicated the clinical development of others,
`
`such as Lometrexol and raltitrexed. (Jacknmu AL, Calvert AFI Folate-Based Thymidylate
`
`Synthase lnh~itors as Auticancer Drugs. Ann Oncol 1995;6(9):871-881; Laohavinij S,
`
`Wedge SR, Lind MJ, et al. A phase I clittieal study of the antipurine antifolate Lometrexol
`
`(DDATHF) given with oral folie acid. l.uvest New Drugs 1996;14:325-335; and Maughan
`
`20
`
`TS, James RD, Kerr D, et al., on behalf of the British MRC Co]orectal Cancer Working
`
`Party. Preliminary results of a rtmlticenter randomi~,exl trial comparing 3 chenmtherapy
`
`regimem (deGramont, Lokich, aud raltiu’exed) in metastatic colorectal cancer. Proc
`
`ASCO 1999;18:Abst 1007.)
`
`Initially, folio acid was used as a treatment for toxicities associated with GAR-FFI
`
`25
`
`see, e.g.U.S. Pat. No. 5,217,974. Folio acid has been shown to lower homocysteine
`
`levels (see e.g. Homoeysteine Lowering Trialist’s Collaboration. Lowering blood
`
`homocysteine with folio acid based supplements: meta-analysis of randomized trials. BMJ
`
`1998;316:894-898 and Naurath HJ, Joosten E, Riezler R, Stabler SP, Allen RH,
`
`Lindenbaum J. Effects of vitamin B 12, folate and vitan~ B6 supplements in elderly
`
`30
`
`people with normal serum vitamin concentrations, lancet 1995 ;346:85-89), and
`
`homocysteine levels have been shown to be a predictor of cytotoxic events related to the
`
`Sandoz Inc.
`Exhibit 1024-0006
`
`Teva – Fresenius
`Exhibit 1024-00006
`
`

`
`AVAILABLE !30PY
`
`WO 02~020~3
`
`PCT/US0 I/14860
`
`-3-
`
`use of GARFT inh~itors, see e.g.U.S. Pat. No. 5,217,974. However, even with this
`
`treatment, cytotoxic activity of GARFT inh~itors and antffolates as a class remains a
`
`s~rious concern in the development of antif~lates as pharmaceutical drugs. The ability to
`
`lower cytotoxic activity would represent an important advance in the use of these agents.
`
`5
`
`Surprisingly and unexpectedly, we have now discovered that certain toxic effects
`
`such as mortality and noahematologie events, such as skin rashes and fatigue, caused by
`
`antffolates, as a class, can be signifieamly reduced by the presence of a methyknalonic acid
`
`lowering agent, without adversely affecting therapeutic efficacy. The present invention
`
`thus provides a method for improving the tt~apeutic utility of antifolate drugs by
`
`10
`
`adminiL~tering to the host undergoing treatment with a methylmalonie acid lowering agent.
`
`We have discovered that increased levels of methylmalonic acid is a predictor of toxic
`
`events in patients that receive an antifolate drug and that treatment for th~ increased
`
`methylmalonic acid, such as treatment with vitamin B 12, reduces mortality and
`
`nonhematologic events, such as skin rashes and fatigue events previously associated with
`
`15
`
`the anfifolate drugs.
`
`Additionally, we have discovered that the combm" ation of a methyimalonie acid
`
`lowering agent and folie acid synergistically reduced the toxic events associated with the
`
`admlni.~tration of antffolate drugs. Although, the treatn-=nt and prevention of
`
`cerdiovaseular disease with folic acid in combination with vitamin B12 is known, the use
`
`20
`
`of the combination for the trea~t of toxicity associated With the adminisu~ion of
`
`antffolate drugs was unknown heretofore.
`
`The present invention relates to a method of administering an antifolate to a
`
`mammal in need thereof, comprising administering an effective amount of said antffolate in
`
`combination with a methylmalonie acid lowering agent.
`
`25
`
`Furthermore, the pz~sent invention relates to a method of reducing the toxicity
`
`associated with the admini.~tration of an antifolate to a matm=-ual comprising admini.~tering
`
`to said mammal an effective amount of said antifolate in combination with a methylmaloaic
`
`acid lowering agent.
`
`Fttrthermore, the present invention relates to a method of inh~iting tumor growth
`
`30
`
`in maunoals comprising admini.~tering to said rnamrrml.~ an effective amount of an
`
`antifolate in combination with a methytmalonic acid lowering agent.
`
`Sandoz Inc.
`Exhibit 1024-0007
`
`Teva – Fresenius
`Exhibit 1024-00007
`
`

`
`WO 02/02093
`
`PCT/US01/14860
`
`¯
`
`Furthermore, the present invention relates to a method of admini.~tering an
`
`antifolate to a mammal in need thereof, comprising administering an effective amount of
`
`said antifolate in combination with a rnethytmalonic acid lowering agent and a FBP binding
`
`agent. A preferred FBP binding agent is folio acid.
`
`5
`
`Furthermore, the present invention relates to a method of reducing the toxicity
`
`associated with the adrni~i.ctration of an antifolate to a ma~n~al comprising aclvaiui.~tering
`
`to said matmt~al an effective amount of said antifolate in combination with a methylmalomc
`
`¯ acid lowering agent and a FBP binding agent. A preferred FBP binding agent is folie acid.
`
`Furthermore, the present invention relates to a method of inh~’biting minor growth
`
`10
`
`in.mammals comprising ad,,fi,,i.ctering to said mammals an effective amount of an
`
`antifolate in combination with a methylmalonic acid lowering agent and a I:rBp binding
`
`agent. A preferred FBP binding agent is folic acid.
`
`Furthem~re, the present invention relates to the use of a methylmalonic acid
`
`lowering agent, alone or in combination with a P’BP binding agent, in the preparation of a
`
`15 medicament useful in lowering the rrmrnrnallan toxicity of an antffolate. A preferred FBP
`
`binding agent is folie acid.
`
`Furthermore, the present invention relates to the use of a n~thylmalonie acid
`
`lowering agent in the preparation of a medicament useful in lowering the ma ..... ~a_lian
`
`toxicity associated with an antifolate, and the rrexlieament is aclr~ini.~tered in combination
`
`20 with an autifolate.
`
`Purthermore, the present invention relates to the use of a n’~thylmalonic acid
`
`lowering agent in the preparation of a medicament useful in lowering the rnarrmaalian
`
`toxicity associated with an antifolate, and the medicament is administered in combination
`
`with an antifolate and a FBP binding agent.
`
`25
`
`Fttrthermore, the present invention relates to the use of a methylmalonic acid
`
`lowering agent in the manufacture of a medicament for use in a method of intn’biting tumor
`
`growth in mammals, which method comprises adn2uJstering said methylmalonic acid
`
`lowering agent in combination with an antifolate.
`
`Furthermore, the present invention relates to a product containing a methylmalonic
`
`30
`
`acid lowering agent, an antifolate and optionally a FBP binding agent as a combined
`
`preparation for the simultaneous, separate or sequential use in inln’biting tumour growth.
`
`Sandoz Inc.
`Exhibit 1024-0008
`
`Teva – Fresenius
`Exhibit 1024-00008
`
`

`
`. .VA LAB. LE COPY
`
`WO 02/02093
`
`PtL-’T/US0 I/! 4860
`
`-5-
`
`The current invention con~ms the discovery that administration of a
`
`raethylmalonic acid loweri~ agent in combination with aa antifolate drug reduces the
`
`toxicity of t]~ said mtifolate drug.
`
`The term ’~nhibit" as it relates to matifolate drugs refers to proht’bitmg, alleviating,
`
`¯ 5
`
`ameliorating, halting, restraining, slowing or reversing the progression of, or reducing
`
`tumor growth.
`
`As used l~erein, the term "effective amotmt" refers to an amotmt of a compound or
`
`drug, which is capable of performing the intended result. For example, an effective
`
`rex)urn of an antifolat¢ drug that is admini.~tered in an effort to reduce tuner growth is
`
`10
`
`that amount which is required to reduce tumor growtlz
`
`As used herein, tl~ term"toxieity" refers to a toxic event associated with the
`
`~u’ation on an antifolate. Such events inel~d~e-, but are not l~r~ted to, neutrop6"nia,
`
`thrombopenia, toxic death, fatigue, anorexia, nausea, skin ra.~h, infection, diarrhea,
`
`mueositis, and anemia. For further explanation of the types of toxicity experienced by
`
`15
`
`patients receiving autifolates, see, generally, Ant~f0]ate Drugs in Cancer Therapy.
`
`Preferably, toxicity refers to toxic death, fatigue, neutropenia, thrombopenia, and
`
`As used herein, the term"nonhematologic event" refers to the occurrence of
`
`rash or fatigue due to the adrr~i.m’ation of an antifolate.
`
`20
`
`As used herein, the term ’~n combination with" refers to the administration of the
`
`n~thytmalonie acid lowering agent, the antifolate drug, and optionally the folio acid; in any
`
`order such that sufficient levels of methylmalonie acid lowering agent and optionally folk:
`
`acid are present to reduce the toxicity of an antifolate in a mau~-ual. The admi~i.~tration of
`
`the eompaunds maybe simultaneous as a single composition or as two separate
`
`25
`
`compositions or can be administered sequentially as separate compositions such that an
`
`effective amoum of the agent first admires" tered is in the patient’s body when the sex, ond
`
`and/or third agent is adm~ni.~tered. The antifolate drug may be adrrfni.~tered to the
`
`~ first, followed by treatn~nt with the rnethylmalonic acid lowering agent.
`
`Alternatively, the naai~r~l may be admini.ctered the antifolate drug simxdtaneously with the
`
`30 methylmalonic acid lowering agent. Preferably, the manm~ is pretreated with the
`
`methylmalonie acid lowering agent and then treated with the antifolate. If folio acid is to
`
`Sandoz Inc.
`Exhibit 1024-0009
`
`Teva – Fresenius
`Exhibit 1024-00009
`
`

`
`WO 02/02093
`
`be admi~i.¢tered in addition to the me.thylmalonic acid lowering agent, the folic acid may be
`
`adi~tered at any time prior, post, or simultaneously to the a~nistration of either the
`
`rr~thylmaloaic acid lowering agent or the amffolate. Preferably, the mammal is pretreated
`
`with the methylmalonic acid, and then treated with folic acid, followed by treatmet~t with
`
`5
`
`the aatifolate compound.
`
`The terms "aatifolate" and "antifolate drug" refer to a chemical compound which
`
`inhibits at least one key folate-requiring enzyme of the thymidiae or purine biosynthetic
`
`pathways, preferably thymidylate synthase ("I’S"), dihydrofolate reductase (’~)HFR"), or
`
`glycinamide ribonueleotide formyltransferase ("GARFF"), by competing with reduced
`
`10
`
`folates for binding sites of these enzymes. ,Preferred examples of antifolates include 5-
`
`fluorouracil, as manufactured by Glaxo; Tomud_ex®, as mamffactured by Zeaeca;
`
`Methotrexate@, as rnaau!actured by Lederle; Lometrexol®, as manufactured by Tularfl~;
`
`pyrido[2,3-d]pyrimidiae derivatives descn-bed by Taylor et at in U.S. Pat. Nos. 4684653,
`
`4833145, 4902796, 4871743, and 4882,334; derivatives desen’bed by Akimoto in U.S.
`
`15
`
`Pat. No. 4997838; thymidylate synthase tnhibitors as found in EPO application 239,362;
`
`and most preferred, Pemetrexed Sodium (AI~IMTA), as manufactured by Eli l.illy & Co.
`
`The terms "methylmalonic acid" and "’MMA" refer to a structural isomer of
`
`sueciaic acid present in minute amounts in healthy human urine.
`
`The term "rtmthylmz/_onic acid lowering agent" refers to a substrate, which lowers
`
`20
`
`the concentration of m~thylmaloaie acid in a mammal. A preferred example of such a
`
`substrate is vitamin B 12. For methods of determining methylmalonie acid and substrates
`
`therefore, see, e.g., Matchar DB, Feussner JR, Millington DS, et al. Isotope dilution assay
`
`for urinary methylmalonic acid in the diagnosis of vitamin B 12 deficiency. A prospective
`
`clinical evaluation. Ann Intern Med 1987; 106: 707-710; Norman F_J, Morrison JA.
`
`25
`
`Screening elderly populations for cobalamia (vitamin B 12) deficiency using tt~ urinary
`
`methylmaloaic acid assay by gas chromatography mass spectrometry. Am J Med 1993; 94:
`
`589-594; Norman EJ. Gas Chromatography mass speetrornetry screening of urinary
`
`methylmalozic acid: early detection of vitamin B 12 (cobalamin) deficiency to prevent
`
`permanent neurologic disability. GC./MS News 1984; 12:120-129; Martin DC, Francis J,
`
`30
`
`Protetch J, Huff FJ. Time dependency of cognitive recovery with cobalarnin replacement:
`
`report of a pilot study. JAGS 1992; 40: 168-172; Norman F_J, Cronin C. Cobalamia
`
`Sandoz Inc.
`Exhibit 1024-0010
`
`Teva – Fresenius
`Exhibit 1024-00010
`
`

`
`BEST AVAILABLE C FY
`
`WO 02/02093
`
`PCTIUS011 ! 4860
`
`-7-
`
`deficiency. Neuro],1996; 47:310-311; Rasmussen K, Moelby I, Jensen MK_ Studies on
`
`methylmalonic acid in humans; Savage DG, Lindenbaum J, Stabler SP, AIlen RH.
`
`Sensitivity of rnethylma]onic acid and total homocysteine determination for diagnosing
`
`coba]amin and folate deficiency. AmJ Meal 1994; 96: 239-246.
`
`The term "vitamin B 12" refers to ’vitamin B12 and its pharmaceutical derivatives,
`
`such as hydroxocobalamin, cyano- 10-chlorocobalamin, aquocobalamin perchlorate, aquo-
`
`10-chiorocobalamin perchlorate, azidocobalal~ill, chlorocobalamin, and coba]amin
`
`Preferably the term refers to vitamin B12, cobalamin, and chlorocoba~amin.
`
`The dosage generally will be provided in the form of a vita-fi,, supplement, namely
`
`10
`
`as a tablet adwinistered oraIly, such as a sustained release formulation, as an aqueous
`
`solution added to dr~a~ kin~ water, or as an aqueous pazenteral formulation. Preferably the
`
`methylmalonic acid lowering agent is ad,,fi,istered as an intramuscular injection
`
`formulation Such formulations are known in the art and are con’maercially available.
`
`The ski~led artisan wRl appreciate that the methyknalonic lowering agents are
`
`15
`
`effective over a wide dosage range. For example, when cobalamin is used as the
`
`..
`
`n~thylmalonic Iowering agent, the dosage of cobalm-dn may fail within the range of about
`
`0.2 gg to about 3000 ~.g of coba]amin from once davy for a month to once every nine
`
`weeks for a year. Preferably, cobalamin will be dosed as an intramuscular injection of
`
`about 500 ~,g to about 1500 ~.g adsninistered from about every 24 hours to about every
`
`20
`
`1680bore’s. Preferably, it is an intramusa~ar injection of about 1000 ~tg adrrdnistered
`
`initially from about 1 to about 3 weeks prior to ada~tration of the antifolate and
`
`repeated from about every 24 hours to about every 1680 hours, regardless of when
`
`treatment with the antifolate is started and cominued mtil the administration of the
`
`antifolate is discontinued. Most preferred is an intram~cular injection of about 1000 t~g
`
`25
`
`admini.~tered initi~y from about 1 to abom 3 weeks prior to the first administration of the
`
`antifolate and repeated every 6 to 12 weeks, preferably about every 9 weeks, and
`
`continued until the discontinuation of the antifolate ad~inistrations..However, it will be
`
`understood that the amount of the methylmalonic acid lower~g agent actually
`adrnlni.~tered will be determined by a physician, in the light of the relevant circumstances,
`
`30 including the condition to be treated, the chosen route of administration, the actual agent
`
`Sandoz Inc.
`Exhibit 1024-0011
`
`Teva – Fresenius
`Exhibit 1024-00011
`
`

`
`AVAILABLE
`
`WO 02/~2093
`
`PCT/US0 i I! 486O
`
`-8-
`
`adrr~istered, the age, weight, and response of the individual patient, and the severity of
`
`the patient’s symptoms, and therefore the above dosage ranges are not intended to limit
`
`the scope of the invention in any way. In some instances dosage levels below the lower
`
`limit of the aforesaid range may he more than adequate, wl~e in other cases still larger
`
`5
`
`doses may be employed without causing any harmful side effect.
`
`The term"FBP binding agent" as used herein refers to a folic binding protein
`
`binding agent which includes folk: acid, (6R)-5-methyl-5,6,7,8-tel~ahydrofolie acid, and
`
`(6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a phYsiologically-available salt or ester
`
`thereof. This latter compound is the (6R)-ison-~r of leucovorin as disclosed in J. Am.
`
`10 Chem Soe., 74, 4215 (1952). Both of the tetrahydrofolie acid compounds are in the
`
`unnatural configuration at the 6-position. They are 10-20 fold more efficient in binding
`
`the folate binding protein compared with their respective (6S)--ison~r, see Ratnam, et.
`
`al., Folate and Antifolate Transport in Mau-t~a/ian Ceils Symposium, Mar. 21-22, 1991,
`
`Bethesda, ME). These eompotmds are usual~ prepared as a mixture with their natural
`
`15
`
`form (6S) of diastereon~rs by non-stereoselective reduction from the corresponding
`
`dehydro precursors followed by separation through chromatogr