Uitspraken

“1. Use of pemetrexed disodium in the manufacture of a medicament for use in combination therapy for inhibiting tumor growth in mammals wherein said medicament is to be administered in combination with vitamin B12 or a pharmaceutical derivative thereof, said pharmaceutical derivative of vitamin B12 being hydroxocobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-chlorocobalamin perchlorate, azidocobalamin, chlorocobalamin or cobalamin.

“1. Toepassing van pemetrexed dinatrium bij het bereiden van een geneesmiddel voor toepassing bij combinatietherapie voor het remmen van tumorgroei bij zoogdieren, waarbij het geneesmiddel dient te worden toegediend in combinatie met vitamine B12 of een farmaceutisch derivaat daarvan, waarbij het farmaceutisch derivaat van vitamine B12 hydroxocobalamine, cyaan-10-chloorcobalamine, aquocobalamine perchloraat, aquo-10-chloorcobalamine perchloraat, azidocobalamine, chloorcobalamine of cobalamine is.

“ [0001] Potentially, life-threatening toxicity remains a major limitation to the optimal administration of antifolates. (see, generally, Antifolate Drugs in Cancer Therapy , edited by Jackman, Ann L., Humana Press, Totowa, NJ, 1999.) In some cases, a supportive intervention is routinely used to permit safe, maximal dosing. For example, steroids, such as dexamethone, can be used to prevent the formation of skin rashes caused by the antifolate. ( Antifolate , pg 197.)

[0002] 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, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 1995;332(14):901-906; and Hong WK, Schaefer S, Issell B, et al A prospective randomized trial of methotrexate 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 of the thymidine and purine biosynthetic pathways, in particular, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), by competing with reduced folates for binding sites of these enzymes. (Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM. Multiple folate enzyme inhibition: Mechanism of a novel pytrolopyrimidine-based antifolate LY231514 (MTA). Advan Enzyme Regul, 1998; 38:135-152 and Shih C, Chen VJ, Gossett LS, et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolaten 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-fluorouracil and Tomudex®. An example of an antifolate that has dihydrofolate reductase inhibiting ("DHFRI'') characteristic is Methotrexate®. An example of an antifolate that has glycinamide 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, IN) has demonstrated thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase inhibition.

[0003] 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, carries a high risk of mortality. The inability to control these toxicities led to the abandonment of clinical development of some antifolates and has complicated the clinical development of others, such as Lometrexol and raltitrexed. (Jackman AL, Calvert AH Folate-

Based Thymidylate Synthase Inhibitors as Anticancer Drugs. Ann Oncol 1995;6(9):871-881; Laohavinij S, Wedge SR, Lind MJ, et al. A phase I clinical study of the antipurine antifolate Lometrexol (DDATHF) given with oral folic acid. Invest New Drugs 1996;14:325-335; and Maughan TS, James RD, Kerr D, et al., on behalf of the British MRC Colorectal Cancer Working Party. Preliminary results of a multicenter randomized trial comparing 3 chemotherapy regimens (deGramont, Lokich, and raltitrexed) in metastatic colorectal cancer. Proc ASCO 1999;18:Abst 1007.)

[0004] Initially, folic acid was used as a treatment for toxicities associated with GARFTI see, e.g. U.S. Pat. No. 5,217,974. Folic acid has been shown to lower homocysteine levels (see e.g. Homocysteine Lowering Trialist's Collaboration. Lowering blood homocysteine with folic 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). The role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate LY 231514 (pemetrexed) was discussed in Worzalla et al. (Anticancer Research 18: 3235-3240 (1998) Worzalla JF, Chuan S and Schultz RM). EP-A-0546870 relates to nutrient compositions which are intended to prevent and cure infectious diseases and which are intended to be administered to patients being administered with anticancer drugs to prevent and treat infectious diseases due to immunosuppression induced by the anticancer drug therapy. The compositions of EP-A-0546870 are characterized in that they comprise a certain amount of retinoid compound(s) such as vitamin A which is indicated as being responsible for the immunoreactivity. Effects of vitamin B12, folate and vitamin B6 supplements in elderly 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 use of GARFT inhibitors, see e.g. U.S. Pat. No. 5,217,974. However, even with this treatment, cytotoxic activity of GARFT inhibitors and antifolates as a class remains a serious concern in the development of antifolates as pharmaceutical drugs. The ability to lower cytotoxic activity would represent an important advance in the use of these agents.

[0005] Surprisingly and unexpectedly, we have now discovered that certain toxic effects such as mortality and nonhematologic events, such as skin rashes and fatigue, caused by antifolates, as a class, can be significantly reduced by the presence of a methylmalonic acid lowering agent as vitamin B12, without adverse adversely affecting therapeutic efficacy. The present invention thus generally relates to a use in the manufacture of a medicament for improving the therapeutic utility of antifolate drugs by administering to the host undergoing treatment with a methylmalonic acid lowering agent as vitamin B12. 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 methylmalonic acid, such as treatment with vitamin B12, reduces mortality and nonhematologic events, such as skin rashes and fatigue events previously associated with the antifolate drugs. Thus, the present invention generally relates to a use in the manufacture of a medicament for reducing the toxicity associated with the administration of an antifolate to a mammal by administering to said mammal an effective amount of said antifolate in combination with a methylmalonic acid lowering agent as vitamin B12.

[0006] Additionally, we have discovered that the combination of a methylmalonic acid lowering agent as vitamin B12 and folic acid synergistically reduces the toxic events associated with the administration of antifolate drugs. Although, the treatment and prevention of cardiovascular disease with folic acid in combination with vitamin B12 is known, the use of the combination for the treatment of toxicity associated with the administration of antifolate drugs was unknown heretofore.

[0007] Furthermore, the present invention generally relates to a use in the manufacture of a medicament for inhibiting tumor growth in mammals by administering to said mammals an effective amount of an antifolate in combination with a methylmalonic acid lowering agent.

[0008] Furthermore, the present invention generally relates to a use in the manufacture of a medicament for inhibiting tumor growth in mammals by administering 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.

[0009] Furthermore the present invention generally relates to the use of a methylmalonic acid lowering agent as vitamin B12, alone or in combination with a FBP binding agent, for lowering the mammalian toxicity of an antifolate. A preferred FBP binding agent is folic acid.

[0010] The invention specifically provides the use of the antifolate pemetrexed disodium in the manufacture of a medicament for use in combination therapy for inhibiting tumor growth in mammals wherein said medicament is to be administered in combination with a methylmalonic acid lowering agent selected from vitamin B12 and pharmaceutical derivatives thereof.

(…)

[0022] The terms "antifolate" and ''antifolate drug' generally refer to a chemical compound which inhibits at least one key folate-requiring enzyme of the thymidine or purine biosynthetic pathways, preferably thymidylate synthase ("TS"), dihydrofolate reductase ("DHFR"), or glycinamide ribonucleotide formyltransferase ("GARFT"), by competing with reduced folates for binding sites of these enzymes. The "antifolate" or ''antifolate drug" for use in this invention is Pemetrexed Disodium (ALIMTA0), as manufactured by Eli Lilly & Co.”

Teva en Actavis Group PTC (hierna ook “Actavis”) maken onderdeel uit van de Teva groep. De Teva groep houdt zich onder andere wereldwijd bezig met de verhandeling van diverse generieke farmaceutische producten. Teva is de Nederlandse entiteit binnen de Teva groep die verantwoordelijk is voor de verhandeling van de generieke farmaceutische producten.

Een van deze producten betreft ARMISARTE, een generiek geneesmiddel met als actieve stof pemetrexed diacid (hierna in het Nederlands: pemetrexed dizuur), welk middel wordt voorgeschreven in combinatie met een vitaminesupplement dat bestaat uit foliumzuur, oraal toegediend, en vitamine B12, toegediend via intramusculaire injectie. Het is een medicijn voor de behandeling van twee typen longkanker.

Verenigd Koninkrijk

“We write to you in your capacity as owner of the Dutch part of European patent EP 1 313 508.

As you are aware, Actavis Group PTC ehf (“Actavis”) holds a marketing authorization granted through the centralized procedure for the medicinal product Armisartó for the treatment of lung cancer (…). This letter pertains to the use of this marketing authorization in the Netherlands.

Teva Nederland B.V. ("Teva Nederland") takes the position that Armisarte@ falls outside the scope of protection of the Dutch part of European patent EP 1 313 508. (…)

(…)

In an effort to be transparent and to open communication with you, we hereby inform you that Armisarte will be listed in the so-called “G-Standaard” of Z-Index for May 20l7 in name of Teva Pharma B.V. The G-Standaard for May 2C)17 will be published on Wednesday April 19, 2017.

In view of the above, we request a confirmation from you in writing ultimately by 19 April 2017 that Eli Lilly, (…) shall refrain from enforcing and relying upon the Dutch part of EP 1 313 508 in any way against Teva Nederland, Teva Pharma B.V. and Actavis in relation to the marketing of Armisarte in the Netherlands and/or any customers, such as wholesale companies and/or pharmacists.

In the event that you would take the position that the marketing of Armisarte does infringe the Dutch part of EP 1 313 508 and you intend to enforce this patent, i.e. the above requested confirmation is not provided, Teva Nederland considers it be in the interest of both parties to resolve the dispute about the non-infringement in an orderly and timely fashion, also offering the preliminary relief judge sufficient time to render a decision. Therefore, in that situation, Teva Nederland seeks a confirmation in writing ultimately by 19 April 2017 that you will initiate preliminary injunction proceedings (a socalled

‘Kort Geding’) in the Netherlands against Teva Nederland relying upon the Dutch part of EP 1 313 508 and that the parties will jointly approach the preliminary relief judge to arrange for a litigation scheme.”

[datum]

Geachte [naam geadresseerde],

RECTIFICATIE

De Voorzieningenrechter van de rechtbank te Den Haag heeft ons bij vonnis d.d. [datum vonnis] bevolen u het volgende mede te delen:

Wij hebben inbreuk gemaakt op het Europees octrooi EP 1 313 508 van Eli Lilly and Co. te Indianapolis, Indiana, Verenigde Staten, door inbreukmakende pemetrexed producten te verhandelen.

De Voorzieningenrechter van de rechtbank te Den Haag heeft ons bevolen om met onmiddellijke ingang iedere inbreuk op dit octrooi, waaronder de vervaardiging en verhandeling van de inbreukmakende pemetrexed producten, onmiddellijk te staken en gestaakt te houden. Tevens heeft de Voorzieningenrechter van de rechtbank te Den Haag ons bevolen om de reeds geleverde inbreukmakende pemetrexed producten terug te nemen en de koopprijs en transportkosten te vergoeden.

In het licht van het voorgaande mogen wij de inbreukmakende pemetrexed producten niet langer produceren en verhandelen zo lang het octrooi van kracht is. Wij hebben onze afnemers inmiddels verzocht om de door ons verkochte en/of geleverde inbreukmakende pemetrexed producten aan ons te retourneren.

Hoogachtend,

[gedaagde]

-------- [handtekening]

--------- [naam van een statutair bevoegd vertegenwoordiger]

dan wel een mededeling die de voorzieningenrechter van de rechtbank te Den Haag in goede justitie vaststelt;

[datum]

Geachte [naam geadresseerde],

RECTIFICATIE

De Voorzieningenrechter van de rechtbank te Den Haag heeft ons bij vonnis d.d. [datum vonnis] bevolen u het volgende mede te delen:

Wij hebben inbreuk gemaakt op het Europees octrooi EP 1 313 508 van Eli Lilly and Co. te Indianapolis, Indiana, Verenigde Staten, door inbreukmakende pemetrexed producten te verhandelen.

De Voorzieningenrechter van de rechtbank te Den Haag heeft ons bevolen om met onmiddellijke ingang iedere inbreuk op dit octrooi, waaronder de vervaardiging en verhandeling van de inbreukmakende pemetrexed producten, onmiddellijk te staken en gestaakt te houden. Tevens heeft de Voorzieningenrechter van de rechtbank te Den Haag ons bevolen om de reeds geleverde inbreukmakende pemetrexed producten terug te nemen en de koopprijs en transportkosten te vergoeden.

In het licht van het voorgaande mogen wij de inbreukmakende pemetrexed producten niet langer produceren en verhandelen zo lang het octrooi van kracht is. Wij hebben onze afnemers inmiddels verzocht om de door ons verkochte en/of geleverde inbreukmakende pemetrexed producten aan ons te retourneren.

Hoogachtend,

[gedaagde]

-------- [handtekening]

--------- [naam van een statutair bevoegd vertegenwoordiger]

dan wel een mededeling die de voorzieningenrechter van de rechtbank te Den Haag in goede justitie vaststelt;

Ter onderbouwing van haar vordering in 3.1 onder 1 en de nevenvorderingen onder 3 tot en met 7 stelt Lilly dat met publicatie in de G-standaard en het feitelijk aanbieden op de markt van Armisarte door Teva directe dan wel indirecte inbreuk op EP 508 wordt gemaakt. Teva biedt Armisarte aan in een combinatietherapie met B12 voor de behandeling van tumorgroei bij een zoogdier, welke combinatietherapie als uitvinding door EP 508 wordt beschermd. Omdat Teva het rechtstreeks verkregen voortbrengsel van de werkwijze in Nederland gebruikt en op de markt brengt en verhandelt, met de wetenschap dat het voor de geoctrooieerde indicatie gebruikt gaat worden in combinatie met vitamine B12, is sprake van de fictieve vervaardigingsstap (benodigd nu EP 508 een Swiss-type claim betreft). Daarmee is aan alle vereisten voor directe inbreuk voldaan. Nu de werkzame stof pemetrexed is, maakt het geen verschil of het gaat om pemetrexed dinatrium of pemetrexed dizuur zodat Teva letterlijke inbreuk maakt. Als dat niet het geval is, dan maakt Teva directe inbreuk door equivalentie. De oplossing van zowel de zout- als zuurvorm van pemetrexed in een zout- of glucoseoplossing voor infusie resulteert in het werkzame pemetrexed, namelijk het pemetrexed anion. De verschillen in hulpstoffen van Armisarte ten opzichte van Alimta hebben evenmin invloed op de werkzaamheid. Daarmee is het geneesmiddel Armisarte equivalent aan een geneesmiddel dat pemetrexed dinatrium bevat. Teva maakt daarnaast indirecte inbreuk op het octrooi, daar zij wezenlijke bestanddelen levert voor de toepassing van de geoctrooieerde uitvinding, pemetrexed dinatrium althans een equivalent daarvan, evenals productie/toedieningsinstructies aan andere personen dan degenen die bevoegd zijn om de uitvinding in Nederland toe te passen.

Subsidiair stelt Lilly dat Teva directe dan wel indirecte inbreuk maakt op conclusies 12-14 van EP 508.