`
`
`Case 1:12-cv-00086-RLY-DKL Document 1 Filed 01/20/12 Page 1 of 7 PageID #: 1
`Case 1:12-cv-00086-Ifi-DKL Document 1 Filed 01/20/16Page 1 of 7 PageID #: 1
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE SOUTHERN DISTRICT OF INDIANA
`INDIANAPOLIS DIVISION
`
`ELI LILLY AND COMPANY,
`
`v.
`
`Plaintiff,
`
`ACCORD HEALTHCARE, INC., USA,
`
`Defendant.
`
`vvvvvvvv
`
`
`
`Civil Action No.
`
`I :12 w—tltlaaRLY-DKL
`
`COMPLAINT
`
`Plaintiff Eli Lilly and Company (“Lilly”), by its attorneys, hereby alleges as
`
`follows:
`
`NATURE OF THE ACTION
`
`1.
`
`This is an action for patent infringement under the patent laws of the
`
`United States, Title 35, United States Code, that arises out of the filing by defendant Accord
`
`Healthcare Inc., USA (“Accord”) of an Abbreviated New Drug Application (“ANDA”) with the
`
`US. Food and Drug Administration (“FDA”) seeking approval to manufacture and sell generic
`
`versions of ALIMTA® prior to the expiration of US. Patent No. 7,772,209.
`
`PARTIES
`
`2.
`
`Lilly is a corporation organized and existing under the laws of the State of
`
`Indiana, having its corporate offices and principal place of business at Lilly Corporate Center,
`
`Indianapolis, Indiana 46285.
`
`3.
`
`Upon information and belief, defendant Accord is a wholly owned
`
`subsidiary of Intas Pharmaceuticals Ltd.
`
`ACCORD EX 1000
`
`ACCORD EX 1000
`
`

`

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`4.
`
`Upon information and belief, defendant Accord is a corporation organized
`
`and existing under the laws of the State of North Carolina, having a place of business at 1009
`
`Slater Road, Suite 210»B, Durham, NC, 27703.
`
`JURISDICTION AND VENUE
`
`5.
`
`This Court has subject matter jurisdiction pursuant to 28 U.S.C. §§ 1331,
`
`1338(a), 2201, and 2202.
`
`6.
`
`7.
`
`Venue is proper in this district pursuant to 28 U.S.C. §§ 1391 and 1400(b).
`
`Upon information and belief, Accord is subject to personal jurisdiction in
`
`this District because, among other things, Accord markets, sells, and distributes generic drugs
`
`throughout the United States, including within the State of Indiana and the Southern District of
`
`Indiana. Upon information and belief, Accord has engaged in and maintained systematic and
`
`continuous business contacts within the State of Indiana and the Southern District of Indiana, and
`
`has purposefully availed itself of the benefits and protections of the laws of Indiana.
`
`8.
`
`Upon information and belief, and consistent with its practice with respect
`
`to other generic products, following any FDA approval of Accord’s ANDA No. 203485 for
`
`generic versions of ALIMTA®, Accord will market, distribute, and sell its generic products
`
`throughout the United States and within Indiana and the Southern District of Indiana, and knows
`
`that Lilly will be injured by such actions in Indiana and the Southern District of Indiana. Upon
`
`information and belief, following any FDA approval of ANDA No. 203485, Accord knows and
`
`intends that its generic products will be marketed, distributed, and sold in the United States and
`
`within the State of Indiana and the Southern District of Indiana, and knows that Lilly will be
`
`injured by such actions in Indiana and the Southern District of Indiana.
`
`

`

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`Case 1:12-cv-00086-W-DKL Document 1 Filed Ol/20/tPage 3 of 7 PageID #: 3
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`BACKGROUND
`
`9.
`
`ALIMTA® is a chemotherapy agent used for the treatment of various types
`
`of cancer. ALIMTA® is indicated (in combination with cisplatin) (a) for the treatment of patients
`
`with malignant pleural mesothelioma, or (b) for the initial treatment of locally advanced or
`
`metastatic nonsquamous non-small cell lung cancer. ALIMTA® also is indicated as a single-
`
`agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small
`
`cell lung cancer after prior chemotherapy. ALIMTA® also is indicated for maintenance
`
`treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung
`
`cancer whose disease has not progressed after four cycles of platinum-based first-line
`
`chemotherapy.
`
`10.
`
`Lilly sells ALIMTA® in the United States pursuant to a New Drug
`
`Application that has been approved by the FDA.
`
`11.
`
`United States Patent No. 7,772,209 (“the ’209 patent”), entitled “Novel
`
`Antifolate Combination Therapies,” was duly and legally issued on August 10, 2010. The ’209
`
`patent is attached as Exhibit A hereto.
`
`12.
`
`Lilly is the assignee of the ’209 patent. As set forth in greater detail in the
`
`’209 patent, one or more claims of the ’209 patent, incorporated by reference herein, cover a
`
`method of administering pemetrexed disodium to a patient in need thereof that also involves
`
`administration of folic acid and vitamin B12.
`
`13.
`
`An actual case or controversy exists between Lilly and Accord with
`
`respect to infringement of the ’209 patent.
`
`
`
`

`

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`
`
`COUNT
`
`(Infringement of US. Patent No. 7,772,209)
`
`14.
`
`Lilly incorporates each of the preceding paragraphs as if fully set forth
`
`herein.
`
`15.
`
`By letter dated December 8, 2011 (“Accord’s Notice Letter”), Accord
`
`notified Lilly that it had submitted to the FDA ANDA No. 203485 for Accord’s Pemetrexed
`
`Disodium for Injection, 100 rug/vial and 500 mg/vial products (“Accord’s ANDA Products”).
`
`16.
`
`Accord’s ANDA Products are generic versions of ALIMTA®.
`
`17.
`
`Accord’s ANDA Products contain pemetrexed disodium.
`
`18.
`
`Upon information and belief, the use of Accord’s ANDA Products in
`
`accordance with Accord’s proposed labeling for Accord’s ANDA Products involves
`
`administration of folic acid and vitamin B12.
`
`19.
`
`Upon information and belief, the use of Accord’s ANDA Products in
`
`accordance with and as directed by Accord’s proposed labeling for those products will infringe
`
`one or more claims of the ’209 patent.
`
`20.
`
`Upon information and belief, Accord filed as a part of ANDA No. 203485
`
`a certification of the type described in Section 505(j)(2)(A)(vii)(IV) of the Food, Drug, and
`
`Cosmetic Act (“FDCA”), 21 U.S.C. § 3550)(2)(A)(vii)(IV), with respect to the ’209 patent,
`
`asserting that the claims of the ’209 patent are invalid, unenforceable, and/or not infringed by the
`
`manufacture, use, offer for sale, or sale of Accord’s ANDA Products.
`
`21.
`
`The purpose of ANDA No. 203485 was to obtain approval under the
`
`FDCA to engage in the commercial manufacture, use, offer for sale, and/or sale of Accord’s
`
`ANDA Products prior to the expiration of the ’209 patent.
`
`
`
`

`

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`22.
`
`Accord’s submission of ANDA No. 203485 for the purpose of obtaining
`
`approval to engage in the commercial manufacture, use, offer for sale, and/or sale of Accord’s
`
`ANDA Products prior to the expiration of the ’209 patent is an act of infringement of the ’209
`
`patent under 35 U.S.C. § 271(e)(2)(A).
`
`23.
`
`Upon information and belief, Accord intends to engage in the
`
`manufacture, use, offer for sale, sale, marketing, distribution, and/or importation of Accord’s
`
`ANDA Products and the proposed labeling therefor immediately and imminently upon approval
`
`of ANDA No. 203485, 1'. e. , prior to the expiration of the ’209 patent.
`
`24.
`
`Upon information and belief, Accord has knowledge of the claims of the
`
`’209 patent. Notwithstanding this knowledge, Accord has continued to assert its intent to engage
`
`in the manufacture, use, offer for sale, sale, marketing, distribution, and/or importation of
`
`Accord’s ANDA Products and the proposed labeling therefor immediately and imminently upon
`
`approval of ANDA No. 203485.
`
`25.
`
`Upon information and belief, Accord plans and intends to, and will,
`
`actively induce infringement of the ’209 patent when its ANDA is approved, and plans and
`
`intends to, and will, do so immediately and imminently upon approval.
`
`26.
`
`Upon information and belief, Accord knows that Accord’s ANDA
`
`Products are especially made or adapted for use in infringing the ’209 patent, and that Accord’s
`
`ANDA Products are not suitable for substantial noninfringing use. Upon information and belief,
`
`Accord plans and intends to, and will, contribute to infringement of the ’209 patent immediately
`
`and imminently upon approval of ANDA No. 203485.
`
`
`
`

`

`Case 1:12-cv-00086-RLY-DKL Document 1 Filed 01/20/12 Page 6 of 7 PageID #: 6
`Case 1:12-cv-00086-li-DKL Document 1 Filed 01/20/16Page 6 of 7 PageID #: 6
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`27.
`
`The foregoing actions by Accord constitute and/or will constitute
`
`infringement of the ’209 patent, active inducement of infringement of the ”209 patent, and
`
`contribution to the infringement by others of the ’209 patent.
`
`28.
`
`Upon information and belief, Accord is without a reasonable basis for
`
`believing that it will not be liable for infringing the ’209 patent, actively inducing infringement
`
`of the ’209 patent, and/or contributing to the infringement by others of the ’209 patent.
`
`29.
`
`Unless Accord is enjoined from infringing the ’209 patent, actively
`
`inducing infringement of the ’209 patent, and contributing to the infringement by others of the
`
`’209 patent, Lilly will suffer irreparable injury. Lilly has no adequate remedy at law.
`
`WHEREFORE, Lilly requests the following relief:
`
`(a)
`
`A judgment that Accord has infringed the ’209 patent and/or will infringe,
`
`actively induce infringement of, and/or contribute to infringement by others of the ’209 patent;
`
`(b)
`
`A judgment ordering that the effective date of any FDA approval for
`
`Accord to make, use, offer for sale, sell, market, distribute, or import Accord’s ANDA Products,
`
`or any product the use of which infringes the ’209 patent, be not earlier than the expiration date
`
`of the ’209 patent, inclusive of any extensi0n(s) and additional period(s) of exclusivity;
`
`(c)
`
`A preliminary and permanent injunction enjoining Accord, and all persons
`
`acting in concert with Accord, from making, using, selling, offering for sale, marketing,
`
`distributing, or importing Accord’s ANDA Products, or any product the use of which infringes
`
`the ’209 patent, or the inducement of or contribution to any of the foregoing, prior to the
`
`expiration date of the ’209 patent, inclusive of any extension(s) and additional period(s) of
`
`exclusivity;
`
`

`

`Case 1:12-cv-00086-RLY-DKL Document 1 Filed 01/20/12 Page 7 of 7 PageID #: 7
`Case 1:12-cv-00086-li-DKL Document 1 Filed 01/20/16Page 7 of 7 PageID #: 7
`
`(d)
`
`A judgment declaring that making, using, selling, offering for sale,
`
`marketing, distributing, or importing of Accord’s ANDA Products, or any product the use of
`
`which infringes the ’209 patent, prior to the expiration date of the ’209 patent, infringes, will
`
`infringe, will actively induce infringement of, and/or will contribute to the infringement by other
`
`of the ’209 patent;
`
`(e)
`
`A declaration that this is an exceptional case and an award of attorneys’
`
`fees pursuant to 35 U.S.C. § 285;
`
`(f)
`
`An award of Lilly’s costs and expenses in this action; and
`
`(g)
`
`Such further and other relief as this Court may deem just and proper.
`
`Dated: January 20, 2012
`
`Respectfully submitted,
`
`M. ’71 Chi/MUD!
`
`J
`B
`
`Carroll, No. 4187-49
`ES & THORNBURG LLP
`
`11 South Meridian Street
`
`Indianapolis, IN 46204
`(317) 236-1313
`jan.carroll@btlaw.com
`Attorneyfor Plaintiff
`Eli Lilly and Company
`
`OF COUNSEL:
`Bruce R. Genderson
`
`Adam L. Perlman
`
`Ellen E. Oberwetter
`Dov P. Grossman
`David M. Krinsky
`Megan A. Hughes
`WILLIAMS & CONNOLLY LLP
`725 Twelfth Street, NW.
`Washington, DC 2005
`(202) 434-5000
`
`INDSOZ J'MC 1202829vl
`
`
`
`

`

`Case 1:12-cv-00086-RLY-DKL Document 1-1 Filed 01/20/12 Page 1 of 9 PageID #: 8
`Case 1:12-cv-00086-Ifi-DKL Document 1—1 Filed 01/20/
`Page 1 of 9 PageID #: 8
`
`USOO7772209B2
`
`(12)
`
`United States Patent
`Niyikiza
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 7,772,209 B2
`Aug. 10, 2010
`
`ANTIFOLATE COMBINATION THERAPIES
`
`W0
`
`WO 95/27723
`
`10/1995
`
`Inventor: Clot lelkiza, Indianapolis, IN (US)
`
`OTHER PUBLICATIONS
`
`(54)
`
`(75)
`
`(73)
`
`(*)
`
`(21)
`
`(22)
`
`(65)
`
`(62)
`
`(50)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`
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`C
`
`,
`
`,
`'
`l'
`L'
`ompany Indianapo ls
`IEblIi(Ullsl)y and
`-
`-
`-
`-
`subjw. to any madame“. the term 0m“
`patent IS extended or adjusted under 35
`U'S'C' 1540)) by 162 days.
`
`:
`
`'
`Asstgnee
`-
`_
`N'mce'
`
`.
`Appl. No" 11/776,329
`.
`Filed:
`
`Jul. 11’ 2007
`
`Prior Publlcation Data
`US 2mg/0032948 A1
`Feb. 7, 2008
`.
`.
`Relamd U'S' Amman” Data
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`
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`A61K 31/70
`(2006.01)
`A61K 31/685
`(2006.01)
`A61K 31/50
`(2006.01)
`A61K 31/525
`(2006.01)
`A61K 31/519
`U.S. c1.
`........................... 514/52; 514/77; 514/249;
`514,251; 514/265‘1
`Field of Classification Search ................... 514/52,
`514/77, 249, 251, 265.1
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`(Continued)
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`Primary Examiner—Kevin Weddington
`(74) Attorney, Agent, or Firm—Elizabeth A. McGraw
`
`(57)
`
`ABSTRACT
`
`A method ofadministering an antifolate to a manunal in need
`thereof, comprising administering an effective amount ofsaid
`antifolate in combination with a methylmalonic acid lower-
`ing agent.
`
`22 Claims, No Drawings
`
`

`

`
`
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`Vestnik Akademii Medicinskich Nauk SSSR (1979), vol. 1: 72-78.
`
`* cited by examiner
`
`

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`US 7,772,209 B2
`
`1
`ANTIFOLATE COMBINATION THERAPIES
`
`This application is a divisional of application Ser. No.
`11/288,807, filed 29 Nov., 2005 now abandoned, which is a
`divisional of application Ser. No. 10/297,821 filed 12 May,
`2002, now US. Pat. No. 7,053,065, which claims priority
`under 35 USC 371, for PCT/USOl/l 4860, filed 15 Jun., 2001,
`which claims the priority ofU.S. provisional applications No.
`60/215,310, filed 30 Jun., 2000, No. 60/235,859, filed 27
`Sep., 2000, and No. 60/284,448, filed 18 Apr., 2001.
`Potentially, life-threatening toxicity remains a major limi-
`tation to the optimal administration of antifolatcs. (sec, gen-
`erally, Antifolate Drugs in Cancer Therapy, edited by Jack-
`man, Ann 1..., Humana Press, Totowa, N.J., 1999.) In some
`cases, a supportive intervention is routinely used to permit
`safe, maximal dosing. For example, steroids, such as dexam-
`ethone, can be used to prevent the formation of skin rashes
`caused by the antifolate. (Antifalate, pg 197.)
`Antifolates represent one of the most thoroughly studied
`classes of antineoplastic agents, with aminopterin initially
`demonstrating clinical activity approximately 50 years ago.
`Methotrexate was developed shortly thereafter, and today is a
`standard component of effective chemotherapeutic regimens
`for malignancies such as lymphoma, breast cancer, and head
`and neck cancer. (Bonnadonna G, Zambetti M, Valagussa P.
`Sequential or alternating doxorubicin and CMF regimens in
`breast cancer with more than three positive nodes: Ten year
`results. JAMA 1995;273(7):542-547; Bonnadonna G, Vala-
`gnssa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant
`cyclophosphamide, methotrexate, and fluorouracil in node-
`positive breast cancer: The results of20 years offollow-up. N
`Engl J Med 1995; 332(14):901-906; and Hong W K, Schaefer
`S, Issell B, et al. A prospective randomized trial of methotr-
`exate versus cisplatin in the treatment of recurrent squamous
`cell carcinoma of the head and neck. Cancer 1983; 52:206-
`210.) Antifolates inhibit one or several key folate-requiring
`enzymes ofthe thymidine and purine biosynthetic pathways,
`in particular, thymidylate synthase (TS), dihydrofolate reduc-
`tase (DHFR), and glycinamide ribonucleotide formyltrans-
`ferase (GARFT), by competing with reduced folates for bind-
`ing sites ofthese enzymes. (Shih C, l-Iabeck L L, Mendel sohn
`L G, ChenV J, Schultz R M. Multiple folate enzyme inhibi-
`tion: Mechanism of a novel pyrrolopyrimidine-based anti-
`folate LY231514 (MTA). Advan Enzyme Regul, 1998;
`38:135~152 and Shih C, Chen V J, Gossett L S, et a].
`LY231514, a pyrrolo[2,3—d]pyrimidine-based antifolate that
`inhibits multiple folate-requiring enzymes. Cancer Res 1997;
`57:1116-1123.) Several antifolate drugs are currently in
`development. Examples of antifolates that have thymidylate
`synthase inhibiting (“TSI”) characteristics include 5-fluorou-
`racil and Tomudex®. An example of an antifolate that has
`dihydrofolate reductase inhibiting (“DHFRI”) characteristic
`is Methotrexate®. An example of an antifolate that has gly-
`cinamide
`ribonucleotide
`formyltransferase
`inhibiting
`(“GARFTI”) characteristics is Lometrexol. Many of these
`antifolate drugs inhibit more than one biosynthetic pathway.
`For example Lometrexol is also an inhibitor of dihydrofolate
`reductase and pemetrexed disodium (Alimta®, Eli Lilly and
`Company, Indianapolis, Ind.) has demonstrated thymidylate
`synthase, dihydrofolate reductase, and glycinamidc ribo-
`nucleotide formyltransferase inhibition.
`A limitation to the development of these drugs is that the
`cytotoxic activity and subsequent effectiveness of anti folates
`may be associated with substantial toxicity for some patients.
`Additionally antifolates as a class are associated with spo-
`radic severe mylosuppression with gastrointestinal toxicity
`which, though infrequent, canies a high risk ofmortality. The
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`inability to connol these toxicities led to the abandonment of
`clinical development of some antifolates and has complicated
`the clinical development of others, such as Lornetrexol and
`raltitrexed.
`(Jackman A L, Calvert A H FolateoBased
`”thymidylate Synthase Inhibitors as Anticancer Drugs. Ann
`Oncol 1995; 6(9):871-881; Laohavinij S, Wedge S R, Lind M
`J, et al. A phase I clinical study of the antipurine antifolate
`Lornetrexol (DDATHF) given with oral folic acid. Invest New
`Drugs 1996; 14:325-335; and MaughanT S, James R D, Kerr
`D, et al., on behalf of the British MRC Colorectal Cancer
`Working Party. Preliminary results of a multicenter random—
`ized trial comparing 3 chemotherapy regimens (deGramont,
`Lokich, and raltitrexed) in metastatic colorectal cancer. Proc
`ASCO 1999; 18:Abst 1007.) Initially, folic acid was used as
`a treatment for toxicities associated with GARF‘Tl see, e.g.
`US. Pat. No. 5,217,974. Folic acid has been shown to lower
`homocysteine levels (see e.g. Homocysteine Lowering Trial-
`ist’s Collaboration. Lowering blood homocysteine with folic
`acid based supplements: meta-analysis of randomized trials.
`BMJ 1998; 316:894-898 and Naurath H J, Joosten E, Riezler
`R, Stabler S P, Allen R H, Lindenbaum J. Effects ofvitamin B
`12, folate and vitamin BG supplements in elderly people with
`normal serum vitamin concentrations. Lancet 1995; 346:85-
`89), and homocysteine levels have been shown to be a pre-
`dictor ofcytotoxic events related to the use ofGARFT inhibi-
`tors, seee.g. US. Pat. No. 5,217,974. However, evenwith this
`treatment, cytotoxic activity of GARFT inhibitors and anti-
`folates as a class remains a serious concern in the develop-
`ment of antifolates as pharmaceutical drugs. The ability to
`lower cytotoxic activity would represent an important
`advance in the use of these agents.
`Surprisingly and unexpectedly, we have now discovered
`that certain toxic effects such as mortality and nonhemato-
`logic events, such as skin rashes and fatigue, caused by anti-
`folates, as a class, can be significantly reduced by the pres-
`ence of a methylmalonic acid lowering agent, without
`adversely afl'ecting therapeutic eflicacy. The present inven-
`tion thus provides a method for improving the therapeutic
`utility of antifolate drugs by administering to the host under-
`going treatment with a methylmalonic acid IOWering 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 the increased methyl-
`malonic acid, such as treatment with vitamin B12, reduces
`mortality and nonhematologic events, suchas skin rashes and
`fatigue events previously associated with the antifolate drugs.
`Additionally, we have discovered that the combination ofa
`methylmalonic acid lowering agent and folic acid synergisti—
`cally reduces the toxic events associated with the administra-
`tion of antifolate drugs. Although, the treatment and preven-
`tion of cardiovascular disease with folic acid in combination
`with vitamin B12 is knOWn, the use ofthe combination for the
`treatment of toxicity associated with the administration of
`antifolate drugs was unknown heretofore.
`The pres-t invention relates to a method of administering
`an antifolate to a mammal in need thereof, comprising admin-
`istering an effective amount of said antifolate in combination
`with a methylmalonic acid lowering agent.
`Furthermore, the present invention relates to a method of
`reducing the toxicity associated with the administration of an
`antifolate to a mammal comprising administering to said
`mammal an effective amount of said antifolate in combina-
`tion with a methylmalonic acid lowering agent.
`Furthermore, the present invention relates to a method of
`inhibiting tumor growth in mammals comprising administer~
`ing to said mammals an effective amount of an antifolate in
`combination with a methylmalonic acid lowering agent.
`
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`US 7,772,209 B2
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`3
`Furthermore, the present invention relates to a method of
`administering an antifolate to a mammal in need thereof,
`comprising administering an effective amount of said anti~
`folate in combination with a methylmalonic acid lowering
`agent and a FBP binding agent. A preferred FBP binding
`agent is folic acid.
`Furthermore, the present invention relates to a method of
`reducing the toxicity associated with the administration of an
`antifolate to a mammal comprising administering to said
`mammal an effective amount of said antifolate in combina-
`tion with a methylmalonic acid lowering agent and a FBP
`binding agent. A preferred FBP binding agent is folic acid.
`Furthermore, the present invention relates to a method of
`inhibiting tumor growth in mammals comprising administer-
`ing to said mammals an effective amount of an antifolate in
`combination with a methylmalonic acid lowering agent and a
`FBP binding agent. A preferred FBP binding agent is folic
`acid.
`Furthermore, the present invention relates to the use of a
`methylmalonic acid lowering agent, alone or in combination
`with a FBP binding agent, in the preparation ofa medicament
`useful in lowering the mammalian toxicity of an antifolate. A
`preferred FBP binding agent is folic acid.
`Furthermore, the present invention relates to the use of a
`methylmalonic acid lowering agent in the preparation of a
`medicament useful in lowering the mammalian toxicity asso-
`ciated with an antifolate, and the medicament is administered
`in combination with an antifolate.
`Furthermore, the present invention relates to the use of a
`methylmalonic acid lowering agent in the preparation of a
`medicament useful in lowering the mammalian toxicity asso-
`ciated with an antifolate, and the medicament is administered
`in combination with an antifolate and a FBP binding agent.
`Furthermore, the present invention relates to the use of a
`methylmalonic acid lowering agent in the manufacture of a
`medicament foruse in a method of inhibiting tumor growth in
`mammals, which method comprises administering said meth-
`ylmalonic acid lowering agent in combination with an anti-
`folate.
`
`Furthermore, the present invention relates to a product
`containing a methylmalonic acid lowering agent, an anti-
`folate and optionally a FBP binding agent as a combined
`preparation for the simultaneous, separate or sequential use in
`inhibiting tumour growth.
`The current invention concerns the discovery that admin-
`istration of a methylmalonic acid lowering agent in combi-
`nation with an antifolate drug reduces the toxicity ofthe said
`antifolate drug.
`The term “inhibit" as it relates to antifolate drugs refers to
`prohibiting, alleviating, ameliorating, halting, restraining,
`slowing or reversing the progression of, or reducing tumor
`growth.
`As used herein, the term “effective amount" refers to an
`amount ofa compound or drug, which is capable ofperform-
`ing the intended result. For example, an effective amount of
`an antifolate drug that is administered in an effort to reduce
`tumor growth is that amount which is required to reduce
`tumor growth.
`As used herein, the term “toxicity" refers to a toxic event
`associated with the administration on an antifolate. Such
`events include, but are not limited to, neutropenia, throm-
`bopenia, toxic death, fatigue, anorexia, nausea, skin rash,
`infection, diarrhea, mucositis, and anemia. For firrther expla-
`nation of the types of toxicity experienced by patients receiv-
`ing antifolates, see, generally, Antifolate Drugs in Cancer
`Therapy. Preferably, toxicity refers to toxic death, fatigue,
`neutropcnia, thrombopenia, and mucositis.
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