Rb. Den Haag, 01-03-2017, nr. C/09/526079 / KG ZA 17-129

Lilly is onderdeel van het Lilly concern dat wereldwijd opereert en actief is op het gebied van onderzoek, ontwikkeling en verhandeling van nieuwe innovatieve geneesmiddelen.

Lilly brengt onder meer het geneesmiddel ALIMTA op de markt. Dit geneesmiddel wordt toegepast bij de behandeling van bepaalde longkankers (tumorgroei). De actieve stof in Alimta is pemetrexed. Het antifolaat pemetrexed werd aanvankelijk beschermd door Europees octrooi EP 0 432 677 (hierna: EP 677), dat mede op naam van Lilly stond. EP 677 is het basisoctrooi voor Aanvullend Beschermingscertificaat 300181 voor ‘pemetrexed, desgewenst in de vorm van een farmaceutisch aanvaardbaar zout’ (hierna: het ABC). Het ABC was van kracht tot en met 9 december 2015.

Daarnaast is Lilly houdster van het Europees octrooi EP (NL) 1 313 508 (hierna: EP 508 of het octrooi) voor een ‘Combination containing an antifolate and methylmalonic acid lowering agent’. De aanvraag voor EP 508 werd ingediend op 15 juni 2001 met beroep op de prioriteitsdata 30 juni 2000, 27 september 2000 en 18 april 2001 op basis van een drietal Amerikaanse octrooiaanvragen. De verlening van EP 508 is gepubliceerd op 18 april 2007. Het octrooi is van kracht tot en met 14 juni 2021.

EP 508 is getiteld “Combination containing an antifolate and methylmalonic acid lowering agent” (waarvan de Nederlandse vertaling luidt: “Samenstelling welke een antifolaat en methylmalonzuur verlagend middel bevat”). De conclusies van het octrooi luiden in de authentieke Engelse versie:

“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.

2. Use according to claim 1 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, and a folic binding protein binding agent selected from folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid and (6R)-5-forinyl-5,6,7,8-tetrahydrofohc acid or a physiologically available salt or ester thereof.

3. Use according to claim 2 wherein the folic binding protein binding agent is folic acid.

4. Use according to any one of claims 1 to 3 wherein the vitamin B12 or pharmaceutical derivative thereof is vitamin B12, cobalamin or chlorocobalamin.

5. Use according to any one of claims 1 to 3 wherein the vitamin B 12 or pharmaceutical derivative thereof is selected from vitamin B12 or hydroxocobalamin.

6. Use according to any one of claims 1 to 5 wherein the medicament, the vitamin B12 or pharmaceutical derivative thereof and optionally the folic binding protein binding agent are to be administered simultaneously, separately or sequentially.

7. Use according to any one of claims 1 to 6 wherein the medicament is to be administered after administration of the vitamin B12 or pharmaceutical derivative thereof.

8. Use according to any one of claims 1 to 7 wherein the medicament is to be administered after the folic binding protein binding agent.

9. Use according to any one of claims 2 to 8 wherein the medicament is to be administered after pretreatment with the vitamin B12 or pharmaceutical derivative thereof followed by folic acid.

10. Use according to any one of claims 1 to 9 wherein vitamin B12 or pharmaceutical derivative thereof is to be administered as an intramuscular injection.

11. Use according to any one of claims 2 to 10 wherein the folic binding protein binding agent is to be administered orally as a tablet.

12. A product containing pemetrexed disodium, 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, and, optionally, a folic binding protein binding agent selected from the group consisting of folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid and (6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a physiologically available salt or ester thereof, as a combined preparation for the simultaneous, separate or sequential use in inhibiting tumor growth.

13. A product according to claim 12 wherein the vitamin B12 or pharmaceutical derivative thereof is vitamin B12, cobalamin or chlorocobalamin and, if present, the folic binding protein binding agent is folic acid.

14. A product according to claim 12 wherein the vitamin B12 or pharmaceutical derivative thereof is vitamin B12 or hydroxocobalamin and, if present, the folic binding protein binding agent is folic acid.”

In de onbestreden Nederlandse vertaling luiden de conclusies als volgt:

“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.

2. Toepassing volgens conclusie 1, 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, en een foliumbindend eiwit bindend middel gekozen uit foliumzuur, (6R)-5-methyl-5,6,7,8-tetrahydrofoliumzuur en (6R)-5-formyl-5,6,7,8-tetrahydrofoliumzuur of een fysiologisch aanvaardbaar zout of ester daarvan.

3. Toepassing volgens conclusie 2, waarbij het foliumbindende eiwitbindende middel foliumzuur is.

4. Toepassing volgens een of meer van de conclusies 1-3, waarbij het vitamine B12 of het farmaceutische derivaat daarvan vitamine B12, cobalamine of chloorcobalamine is.

5. Toepassing volgens een of meer van de conclusies 1-3, waarbij het vitamine B12 of het farmaceutische derivaat daarvan is gekozen uit vitamine B12 of hydroxocobalamine.

6. Toepassing volgens een of meer van de conclusies 1-5, waarbij het geneesmiddel, het vitamine B12 of het farmaceutische derivaat daarvan en eventueel het foliumbindende eiwitbindende middel tegelijkertijd, afzonderlijk of achtereenvolgens dienen te worden toegediend.

7. Toepassing volgens een of meer van de conclusies 1-6, waarbij het geneesmiddel dient te worden toegediend na toediening van het vitamine B12 of het farmaceutische derivaat daarvan.

8. Toepassing volgens een of meer van de conclusies 1-7, waarbij het geneesmiddel na het foliumbindende eiwitbindende middel dient te worden toegediend.

9. Toepassing volgens een of meer van de conclusies 2-8, waarbij het geneesmiddel dient te worden toegediend na voorbehandeling met het vitamine B12 of het farmaceutische derivaat daarvan gevolgd door foliumzuur.

10. Toepassing volgens een of meer van de conclusies 1-9, waarbij het vitamine B12 of het farmaceutische derivaat daarvan als een intramusculaire inspuiting dient te worden toegediend.

11. Toepassing volgens een of meer van de conclusies 2-10, waarbij het foliumbindend eiwitbindend middel als een tablet oraal dient te worden toegediend.

12. Product dat pemetrexed dinatrium, 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, en eventueel een foliumbindend eiwitbindend middel gekozen uit de groep bestaande uit foliumzuur, (6R)-5-methyl-5,6,7,8-tetrahydrofoliumzuur en (6R)-5-formyl-

5,6,7,8-tetrahydrofoliumzuur, of een fysiologisch aanvaardbaar zout of ester daarvan, als een gecombineerd preparaat voor gelijktijdige, afzonderlijk of achtereenvolgend gebruik bij remmen van tumorgroei, bevat.

13. Product volgens conclusie 12, waarbij het vitamine B12 of het farmaceutische derivaat daarvan vitamine B12, cobalamine of chloorcobalamine is en, indien aanwezig, het foliumbindende eiwitbindende middel foliumzuur is.

14. Product volgens conclusie 12, waarbij het vitamine B12 of farmaceutisch derivaat daarvan vitamine B12 of hydroxocobalamine is en, indien aanwezig, het foliumbindend eiwitbindend middel foliumzuur is.”

In de authentieke Engelse versie van de beschrijving van het octrooi is voorts - voor zover hier van belang - het volgende opgenomen:

“[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.”

Na de verlening van EP 508 is door Teva Pharmaceuticals Industry (hierna: Teva) oppositie ingesteld bij het EOB.1.De oppositieafdeling van het EOB (hierna: OD) heeft bij de mondelinge behandeling op 18 november 2010 de oppositie afgewezen en het octrooi in stand gelaten zoals verleend. In de schriftelijke beslissing van de OD ter zake (gedateerd 27 december 2010) is - voor zover in de onderhavige procedure relevant - opgenomen:

“1 SUMMARY OF FACTS AND SUBMISSIONS

(…)

Proprietor of the patent (P): Eli Lilly, Indianapolis (US)

Opponent 1 (O1) : Teva Pharmaceutical Industries Ltd., Petah Tqva (IL)

(…)

The following documents have been cited by the parties:

(…)

D8(a) and D8 (b): "Metabolism at a Glance", edited by Blackwell Science (1998 edition), pages 54-57.

D09: Niyikiza C et al.: "L Y231 514 (MTA): relationship of vitamin metabolite profile to toxicity", American Society of Clinical Oncology (ASCO) Meeting Abstract No.2139 (1998).

(…)

D12: Worzalla et al.: "Role of Folic acid in Modulating the Toxicity and Efficacy of the

Multitargeted Antifolate, L Y231 514", Anticancer Research (1998), 18: 3235 -3240.

D13: "Clinical Chemistry: principle, procedures, correlation", third edition (1996), published by Lippincott: pages 61 8-627.

(…)

D19: Barak, et al.: "Vitamin B12 as a Possible Adjunct in Prevention of Methotrexate Hepatotoxicity", Biochemical Archives (1985), vol. 1: 139 -142.

D20: Arsenyan, et al.: "Influence of Methylcobalamin on the Antineoplastic Activity of

Methotrexate", Pharmaceutical Chemistry Journal (1978), vol. 10: 1299 -1304.

D21: Maysishecheva, N.y., et al.: "Antitumor Activity of Methotrexate When Used in Combination with Cobalamine Derivatives", Eksperimentalnaya Onkologija (1982), vol. 4, no. 5: 29-33.

(…)

D22: Sofyina, Z.P., et al.: "Possibility of Potentiating the Antineoplastic Action of Folic Acid Antagonist by Methylcobalamine Analogs", Vestnik Akademli Medicinskich Nauk SSSR (1979), vol. 1: 72-78.

(…)

D23: McDonald, A.C., et al.: "Clinical Phase I Study of L Y231 514, a Multitargeted Antifolate, Administered by Daily x 5 q 21 Schedule", Annals of Oncology(1996), vol. 7: 85, Abstract No. 291.

(…)

D26: Abstract No.907, Zervos et al.: "Functional folate status as a prognostic indicator of toxicity in clinical trials of the multitargeted antifolate L Y231514", Proceedings of ASCO, Vol.16, 1997, page 256a.

(…)

D28: Calvert, Hilary: "An Overview of Folate Metabolism: Features Relevant to the Action of Toxicities of Antifolate Anticancer Agents", Seminars in Oncology, Vol.26, No.2, Suppl. 6 (1999), pages 3-10.

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REASONS FOR THE DECISION

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5 Inventive step(Article 100(a) in conjunction with Article 56 EPC)

Document D28, which constitutes the closest prior art, is a scientific article in which the action and toxicities of antifolate anticancer agents, including pemetrexed is discussed. D28 discloses the antitumor properties of pemetrexed (MTA) as well as its toxicity. This toxicity is correlated to an increase in homocysteine levels (page 9, left-hand column, paragraph 1). D28 further teaches that any functional deficiency either in B12 or folate will result in an increase in the plasma level of homocysteine (page 8, right-hand column).

The problem to be solved by the present invention is to reduce the toxicity associated with the administration of pemetrexed disodium in cancer patients.

The proposed solution is to use vitamin B12 alone or in association with folic acid.

The OD is convinced that the above-mentioned problem was solved in the light of the experimental data described on paragraphs [0034] to [0056] of the patent in suit (see point 3 above "insufficiency of disclosure").

During oral proceedings, O1 has argued lack of inventive step based on D28 taken alone or in combination with D9 in view of the general knowledge D13.

D28 teaches that the toxicity of pemetrexed is correlated to an increase in homocysteine plasma levels; said increase of homocysteine plasma level being known to be correlated with vitamin B12 deficiency. Consequently, the solution to the problem of the toxicity of pemetrexed, i.e. the administration of vitamin B12 was thus obvious in view of D28 based on the disclosure of pages 8-9 and Fig.8 (see point 5.1 above).

Alternatively, according to O1 D28 can be combined with D9 (reference 17 of D28).

D9 discloses a study concerning the problem of toxicity of pemetrexed. Neutropenia, thrombocytopenia, mucositis and diarrhea are mentioned as toxic side effects related to high level of homocysteine. The skilled person starting from D28/D9 and knowing that the pemetrexed toxicity is related to homocysteine would have been prompted by D13 to use vitamin B12 to lower the homocysteine blood level, and thus, the toxic effects thereof, since D13 teaches that an improved vitamin B12 status normalizes homocysteine levels in blood, which is in fact common general knowledge. According to O1, by administering vitamin B12 to correct homocysteine level and thereby the toxic effects of pemetrexed, the opposed patent did nothing more than apply standard knowledge.

The OD cannot follow this line of arguments.

D9 is an abstract which relates to pemetrexed (LY231514 or MTA) and the relationship of vitamin metabolite profile to toxicity. The abstract reports that three vitamin metabolites were measured: homocysteine, cystathioine and methyl malonic acid. D9 reports that there was a strong correlation between baseline homocysteine levels and the development of number toxicities such as neutropenia, thrombocytopenia, mucositis or diarrhea. Toxicity was seen in all patients with increased level of homocysteine. No correlation between those toxicities and the remaining pre-specified predictors, namely methylmalonic acid (MMA) and cystathionine was seen.

The strong correlation between homocysteine level and pemetrexed toxicity is also reported in other documents, for example in D10, D26 or D27. It was therefore well established, at the priority date of the patent, that the toxicity of pemetrexed is correlated to an increase in homocysteine plasma levels.

However, it appears that vitamin B12 is not the only marker of an increased level of homocysteine.

As can be appreciated from D8 and D13, homocysteine requires folate to convert to methionine. If no folate is present then homocysteine levels rise. Cystathionine is the deficiency marker for vitamin B6. If vitamin B6 is deficient then cystathioine levels rise.

Methyl malonic acid (MMA) is the deficiency marker for vitamin B12. However, vitamin B12 is also involved as a cofactor in the conversion of homocysteine to methionine. Thus, in some cases a vitamin B12 deficiency will also cause increased homocysteine as well as increased MMA.

This is in line with the teaching of D29 where it can be seen that folate deficiency is only associated to elevated serum level of homocysteine, whereas vitamin B12 deficiency is associated to elevation of serum level homocysteine and MMA (page 242, Table VII; page 244, left-hand column paragraphs 2-4).

The OD is therefore of the opinion that since D9 teaches that there is no correlation between pemetrexed toxicity and the marker for vitamin B12 deficiency (MMA), the skilled person would have concluded that vitamin B12 was not involved in the toxicity observed in pemetrexed treatment. He would thus have found no motivation to use vitamin B12 given that the known marker for its deficiency was uncorrelated.

Consequently, starting from D28, the skilled person faced with the problem of reducing pemetrexed toxicity would have ruled out the involvement of vitamin B12 in view of the teaching of D9 and therefore would not have used this vitamin to reduce said toxicity.

The OD considers that the skilled person would have rather used folic acid since in the absence of correlation between the pemetrexed toxicity and MMA as reported in D9, the elevated level of homocysteine described in said document would have been recognised as the marker for folate deficiency. In addition, the solution to the problem of pemetrexed toxicity has been already proposed in D12 and D26 as being the combined treatment of pemetrexed with folic acid.

During the procedure, additional arguments against inventive step were based on the combination of documents D19 with D23; D21 (or D20 or D22) in combination with the skilled person's common technical knowledge.

Documents D20-D22 describe the increase of the antitumor effect of the folic antagonist methotrexate when combined with vitamin B12. These documents however do not address the problem of the present invention, namely the toxicity of the antifolate drugs.

Document D19 relates to the use of vitamin B12 as a mean of protecting methotrexate hepatotoxicity. However, liver toxicity is generally not associated with pemetrexed treatment (see the opposed patent, Table 1 or D9). In the clinical phase I study of pemetrexed reported in D23, only one patient out of thirty two had hepatic toxicity.

In view of the foregoing, it is the OD's opinion that the subject-matter of the patent

in suit does involve an inventive step and thus fulfills the requirements of Article 56

EPC.

(…)”

Teva heeft tegen de beslissing van de OD beroep aangetekend, maar heeft dit beroep vervolgens eenzijdig ingetrokken.

De navolgende publicaties behoren voor het octrooi tot de stand van de techniek.

Worzalla et al. (D12): "Role of Folic acid in Modulating the Toxicity and Efficacy of the Multitargeted Antifolate, L Y231 514", Anticancer Research (1998), 18: 3235 -3240. Daarin is - onder meer - opgenomen:“Abstract. We studied the effects of folic acid on modulating the toxicity and antitumor efficacy of LY231514

(pemetrexed, voorzieningenrechter). Using several human tumor cell lines adapted to growth in low folate medium, folic acid was shown to be 100- to 1000-fold less active than folinic acid at protecting cells from LY231514-induced cytotoxicity. The lethality of LY231514 was compared in mice maintained on standard diet or low folate diet. The LD50 occurred at 60- and 250-fold lower doses of LY231514 in DBA/2 and CD1 nu/nu mice, respectively, maintained on low folate diet compared to standard diet. The L5178Y/TK-/HX-murine lymphoma was much more sensitive to the antitumor action of LY231514 compared to wild type L5178Y-S tumors. For mice on low folate diet, LY231514 at 0.3 and 1 mg/kg (qd x 10, i.p.) produced 100% inhibition of L5178Y/TK-/HX-lymphoma growth, and significant lethality occurred at

≥ 3 mg/kg. For mice on standard diet, LY231514 produced > 95% inhibition of tumor growth at 30 to 300 mg/kg, but all mice died at 800 mg/kg. Folic acid supplementation was demonstrated to preserve the antitumor activity of LY231514 while reducing toxicity. The combination of folic acid with LY231514 may provide a mechanism for enhanced clinical antitumor selectivity.

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Materials and Methods

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Mice. (…) Mice were housed in temperature and humidity controlled rooms. Mice were fed either standard laboratory rodent chow (Purina Chow #5001) or folic acid-deficient diet containing 1% succinylsulfathiazole (Purina Chow #5831C-2); both diets were purchased from Ralston Purina Co. (St. Louis, MO, USA). The average content of folates from natural sources in both diets was found to be 0.03 ppm, whereas the standard diet was analyzed to contain 7.3 ppm of added folic acid. (…). ”

A.L. Jackman (ed), Antifolate Drugs in Cancer Therapy, 1999, Humana Press. Totowa, NJ. In hoofdstuk 8 van deze uitgave, getiteld “Preclinical Pharmacology Studies and the Clinical Development of a Novel Multitargeted Antifolate, MTA (LY231514)” is - onder meer - opgenomen (pagina 190 en 191):

“2.6. The in Vivo Antitumor Effects and the Role of Folic Acid in Modulating the Efficacy and Toxicity of MTA

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To evaluate the importance of dietary folate in modulating the toxicity of MTA (pemetrexed, voorzieningenrechter), LD50 values were determined in mice maintained on standard diet (SD) or on a special lowfolate diet (LFD) (35). MTA was administered ip daily for 10 d. It is estimated that mice on LFD consumed an average of approx 0.003 mg/kg/d of folic acid vs 0.75-1.5 mg/kg/d for mice on SD. Thus mice on SD had a daily intake of approx 250-500 times more folic acid than mice on LFD. MTA was more toxic to several different strains of mice maintained on LFD (Table 6), with the LD50 values being 30- to 250-fold lower than mice maintained on SD. A similar effect had been observed for antipurine antifolates such as lometrexol. The MTD of lometrexol on LFD was 1000- to 5000-fold lower than in mice maintained on SD (36). DHFR inhibitors such as methotrexate had a similar effect but to a lesser extent (50- to 100-fold, J.F. Worzalla, unpublished observation). The therapeutic index of MTA against the L5178Y/TK-/HX-tumor was greatly diminished when the mice were put on a LFD (2 wk) with no folate supplementation. Good antitumor activity was observed at 0.3 mg/kg and 1.0 mg/kg (ip daily X 10) doses only, and significant toxicity was observed for MTA at higher doses (Fig. 4). However, if daily folic acid supplementation (15 mg/d/mouse, po) was given in conjunction with MTA, excellent antitumor dose-response (10 mg/kg to 1000 mg/kg, with antitumor activity ranging from 80 to 100%) and no lethality were observed. This antitumor dose response (with folate supplementation) is identical to the dose response that was observed for MTA on mice fed with SD (Fig. 3). These data suggest that folate supplementation not only modulates the toxicity but also slightly enhances the antitumor response of MTA.”

In hoofdstuk 12 van deze uitgave, getiteld “Preclinical and Clinical Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitors Lometrexol and LY309887”, wordt - onder meer - vermeld (pagina 269, 270, 276 en 277):

“8. THE EFFECT OF LFD AND DIETARY FOLATE SUPPLEMENTATION ON THE EFFICACY AND TOXICITY OF LOMETREXOL AND LY309887

In mice on a LFD for 2 wk, the toxicity of lometrexol and LY309887 increased 300-1000-fold. Antitumor activity cannot be assessed because of the lethality of these agents. Oral supplementation with folic acid (0.6-600 mg/kg) restores sensitivity to the antitumor activity of both GARFT inhibitors. High doses of folic acid (>600 mg/kg) eliminated both toxicity and antitumor activity.

The therapeutic indexes (LD10/ED90) of LY309887 and lometrexol were determined over a range of supplemental folic acid doses in two antitumor models, the human xenograft GC3 colon and the murine mammary tumor C3H (Table 6). The data show that increasing folic acid supplementation doses from 0.0 to 6-15 mg/kg/d resulted in an enhanced therapeutic index ranging from 6 to 60 for LY309887 in both models. Furthermore, the ability to delay regrowth of the GC3 tumors over a broad dose range was only seen at the higher doses of folate supplementation. A small but modest increase in lometrexol's therapeutic index to 2-5 was also observed. Higher doses of folic acid supplementation resulted in less robust increases in the therapeutic index.

Lilly vordert samengevat en na vermindering van eis - dat de voorzieningenrechter bij vonnis uitvoerbaar bij voorraad:

1. Sandoz zal bevelen iedere directe en indirecte inbreuk op EP 508 en/of het gebruik maken van tussenpersonen die zulke handelingen verrichten en/of onrechtmatig handelen, te staken en gestaakt te houden, op straffe van verbeurte van een dwangsom van € 100.000,- voor iedere dag dat Sandoz het bevel niet nakomt of een dwangsom van € 100.000,- voor ieder product waarmee Sandoz het bevel niet nakomt;

2. Sandoz zal veroordelen in de volledige kosten van de procedure conform artikel 1019h Rv.

Primair stelt Lilly zich op het standpunt dat Sandoz direct en/of indirect inbreuk maakt op alle conclusies van het octrooi wanneer zij pemetrexed Sandoz op de markt zou brengen. Subsidiair betoogt Lilly dat Sandoz in dat geval directe dan wel indirecte inbreuk maakt op conclusies 12-14 van EP 508.

Sandoz betoogt ten verwere dat de door Lilly gevraagde voorziening moet worden geweigerd omdat een serieuze, niet te verwaarlozen kans bestaat dat het Nederlandse deel van EP 508 in een bodemprocedure zal worden vernietigd. Haar verweer houdt - zakelijk weergegeven - het navolgende in.

Nieuwheid

Volgens Sandoz is Worzalla (vergelijk r.o. 2.9.1) nieuwheidschadelijk voor het onderhavige octrooi, nu Worzalla in zijn studie met muizen concludeert dat de toediening van foliumzuur de bijwerkingen van pemetrexed vermindert terwijl de werkzaamheid behouden blijft. Worzalla gebruikte daarbij de algemene vakkennis dat een adequaat vitamine B12 niveau nodig is om te beschikken over voldoende functioneel folaat voor een aantal biochemische processen in de cel. Hij zorgde er daarom voor dat het dieet van de muizen twee keer zoveel vitamine B12 bevatte dan gebruikelijk. Daarmee is in Worzalla de combinatietherapie nieuwheidsschadelijk geopenbaard.

Inventiviteit

Sandoz baseert haar betoog dat het octrooi inventiviteit mist allereerst op de algemene vakkennis zoals verwoord in het handboek van Jackman (zie r.o. 2.9.2). Daaruit leert de vakman dat hij naast folaat ook vitamine B12 moet toedienen wanneer hij de bijwerkingen van pemetrexed wil verminderen, waarbij de vakman de onderzoeksresultaten met betrekking tot lometrexol in zijn afwegingen zal betrekken.

Voorts volgt het gebrek aan inventiviteit uit Calvert (vergelijk r.o. 2.9.3). Calvert openbaart dat toediening van foliumzuur de bijwerkingen van antifolaten zoals pemetrexed vermindert en dat er een sterke correlatie bestaat tussen de bijwerkingen van pemetrexed en het homocysteïne niveau van de patiënt. Het homocysteïne gehalte wordt zowel beïnvloed door folaat als vitamine B12 en een functioneel tekort van deze beide zal derhalve leiden tot een stijging van het homocysteïne gehalte. Zonder inventieve denkarbeid zal de gemiddelde vakman uit Calvert distilleren dat bij de toediening van pemetrexed ook vitamine B12 moet worden toegediend, al dan niet in combinatie met de algemene vakkennis uit Jackman.

Ten slotte is het octrooi in het licht van Worzalla niet inventief, als dit al niet nieuwheidsschadelijk is, op dezelfde gronden als genoemd in r.o. 3.3.1, al dan niet in combinatie met de algemene vakkennis uit Jackman of met Calvert.

Op de stellingen van partijen wordt hierna, voor zover van belang, nader ingegaan.