Rb. Den Haag, 10-12-2021, nr. C/09/617057 / KG ZA 21-810

Bayer maakt deel uit van de Bayer Groep. De Bayer Groep is een wereldwijd opererende onderneming die zich met name richt op biowetenschappen in gezondheidszorg en landbouw. Zij ontdekt, ontwikkelt, produceert en verkoopt onder meer geneesmiddelen voor humaan gebruik, waaronder oncologische geneesmiddelen.

De Bayer Groep brengt onder meer in Nederland het receptgeneesmiddel Nexavar® op de markt (hierna: Nexavar). Het werkzame bestanddeel van Nexavar is sorafenib (N-(4-chloor-3-(trifluormethyl)fenyl-N'-(4-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)ureum) dat als tosylaat (het zout van p-tolueensulfonzuur) aan de patiënt wordt toegediend. Het geneesmiddel is beschikbaar in de vorm van filmomhulde tabletten met 200 mg werkzame stof.

Sorafenib is een proteïnekinaseremmer. Proteïnekinaseremmers blokkeren specifieke enzymen die proteïnekinasen worden genoemd. Deze enzymen worden aangetroffen in bepaalde receptoren op het oppervlak van kankercellen, waar ze betrokken zijn bij de groei en verspreiding van kankercellen, en in de bloedvaten die de tumoren van bloed voorzien. Het gebruik van Nexavar zorgt ervoor dat deze enzymen, waaronder RAF-kinase, worden geblokkeerd, waardoor de groei van kankercellen wordt verminderd en de bloedtoevoer wordt afgesneden.

Volgens de SmPC is Nexavar geïndiceerd voor:

Voor alle voornoemde indicaties is Nexavar aangewezen als weesgeneesmiddel. De daaruit voortvloeiende periode van 10 jaar marktexclusiviteit is enkel nog geldend voor indicatie (C).

De stof sorafenib werd aanvankelijk beschermd door Europees octrooi EP 1 140 840 (hierna: het basisoctrooi) van Bayer en naderhand tot 20 juli 2021 door ABC1.met nummer 300242.

Bayer heeft op 3 december 2002 een internationale PCT-aanvraag ingediend, gepubliceerd onder nummer WO 03/047579 A1 voor ‘Aryl urea compounds in combination with other cytostatic or cytotoxic agents for treating human cancers’ (hierna: WO 579 of de moederaanvrage) met een beroep op het prioriteitsdocument US 334,609 van 3 december 2001 (hierna: US 609). WO 579 is voortgezet als Europese octrooiaanvraag onder publicatienummer EP 1 450 799 (hierna: EP 799). Van EP 799 is een tweede generatie divisional afgesplitst onder publicatienummer EP 1 769 795 (hierna: EP 795).

De onderhavige procedure ziet op een derde generatie divisional afgesplitst van EP 795, te weten EP 2 305 255 B1 (hierna: EP 255) voor ‘Aryl urea compounds in combination with other cytostatic or cytotoxic agents for treating human cancers’. EP 255 is verleend op 22 augustus 2012 onder inroeping van het prioriteitsdocument US 609 van 3 december 2001. EP 255 is van kracht tot 2 december 2022.

De conclusies van EP 255 luiden in de authentieke Engelse versie als volgt:

1. Use of an aryl urea compound and 5-fluorouracil or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a cancer, wherein said aryl urea compound is a tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.

2. The use according to claim 1, wherein said cancer is mediated by ref kinase.

3. The use of claim 1, wherein said cancer is colon, gastric, lung, pancreatic, ovarian, prostate, leukemia, melanoma, hepatocellular, renal, glioma, mammary, or head and neck cancer.

4. The use of claim 1, wherein said medicament is administered in a therapeutically effective amount to a patient in need thereof by oral delivery or by intravenous injection or infusion.

5. The use of claim 1, wherein said medicament is administered in a therapeutically effective amount to a patient in need thereof in the form of a tablet, a liquid, a topical gel, an inhaler or in the form of a sustained release composition.

6. The use of claim 1, wherein the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea is administered to a patient at an oral, intravenous, intramuscular, subcutaneous or parenteral dosage which can range from about 0.1 to about 300 mg/kg of total body weight.

7. The use of claim 1 for inhibiting the proliferation of cancer cells in a patient.

8. The use of claim 1, wherein said aryl urea compound is administered simultaneously with 5-fluorouracil or a pharmaceutically acceptable salt thereof.

9. The use of claim 8, wherein said aryl urea compound and 5-fluorouracil or a pharmaceutically acceptable salt thereof are administered in the same formulation or in separate formulations.

10. The use of claim 1, wherein said aryl urea compound is administered sequentially with 5-fluorouracil or a pharmaceutically acceptable salt thereof, in any order.

11. The use of claim 1, wherein said aryl urea compound is administered in tandem with 5-fluorouracil or a pharmaceutically acceptable salt thereof wherein said aryl urea compound can be administered to a patient once or more per day for up to 28 consecutive days with the concurrent or intermittent administration of 5-fluorouracil or a pharmaceutically acceptable salt thereof over the same total time period.

12. Aryl urea compound, which is a tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.

Deze conclusies luiden in de onbestreden Nederlandse vertaling als volgt:

1. Gebruik van een arylureumverbinding en 5-fluoruracil of een farmaceutisch aanvaardbaar zout daarvan voor de bereiding van: een geneesmiddel voor de behandeling van een kanker, waarbij de arylureumverbinding een tosylaatzout van N-(4-chloor-3-(trifluormethyl)fenyl-N'-(4-(N-methylcarbamoyl)-4-pyridyloxy)fenyl)ureum is.

2. Gebruik volgens conclusie 1, waarbij de kanker wordt gemedieerd door ref-kinase.

3. Gebruik volgens conclusie 1, waarbij de kanker colon-, maag-, long-, pancreas-, ovarium-, prostaatkanker, leukemie, melanoom, hepatocellulaire kanker, nierkanker, glioom, borst-, of hoofd-halskanker is.

4. Gebruik volgens conclusie 1, waarbij het: geneesmiddel in een therapeutisch effectieve hoeveelheid aan een patiënt die daaraan behoefte heeft, wordt toegediend door middel van orale afgifte of door middel van intraveneuze injectie of infusie.

5. Gebruik volgens conclusie 1, waarbij het geneesmiddel in een therapeutisch effectieve hoeveelheid aan een patiënt die daaraan behoefte heeft, wordt toegediend in de vorm van een tablet, een vloeistof, een topische gel, een inhalator of in de vorm van een preparaat met aanhoudende afgifte.

6. Gebruik volgens conclusie 1, waarbij het tosylaatzout van N-(4-chloor-3-(trifluormethyl)fenyl-N'-(4-(N-methylcarbamoyl)-4-pyridyloxy)fenyl)ureum aan een patiënt wordt toegediend in een orale, intraveneuze, intramusculaire, subcutane of parenterale dosering die kan variëren van ongeveer 0,1 tot ongeveer 300 g/kg totaal lichaamsgewicht.

7. Gebruik volgens conclusie 1 voor het remmen van de proliferatie van kankercellen in een patiënt.

8. Gebruik volgens conclusie 1, waarbij de arylureumverbinding wordt toegediend gelijktijdig met 5-fluoruracil of een farmaceutisch aanvaardbaar zout daarvan.

9. Gebruik volgens conclusie 8, waarbij de arylureumverbinding en 5-fluoruracil of een farmaceutisch aanvaardbaar zout daarvan worden toegediend in dezelfde formulering of in aparte formuleringen.

10. Gebruik volgens conclusie 1, waarbij de arylureumverbinding sequentieel met 5-fluoruracil of een farmaceutisch aanvaardbaar zout daarvan wordt toegediend, in willekeurige volgorde.

11. Gebruik volgens conclusie 1, waarbij de arylureumverbinding wordt toegediend in tandem met 5-fluoruracil of een farmaceutisch aanvaardbaar zout daarvan, waarbij de arylureumverbinding één of meer malen per dag gedurende tot 28 opeenvolgende dagen aan een patiënt kan worden toegediend met de gelijktijdige of intermitterende toediening van 5-fluoruracil of een farmaceutisch aanvaardbaar zout daarvan over dezelfde totale periode.

12. Arylureumverbinding, die een tosylaatzout van N-(4-chloor-3-(trifluormethyl)fenyl-N'-(4-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)ureum is.

Bayer beroept zich in de onderhavige procedure enkel op conclusie 12 van EP 255 (hierna ook alleen: conclusie 12).

In de authentieke Engelse versie van de beschrijving van EP 255 is - voor zover hier van belang - het volgende opgenomen:

Field of the invention

[0001] This invention relates to aryl urea compounds namely the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, also in combination with cytotoxic or cytostatic agents, namely 5-fluorouracil, and their use in treating raf kinase mediated diseases such as cancer.

(…)

Summary of the Invention

[0004] Generally, it is the overall object of the present invention to provide 5-fluorouracil in combination with sorafenib tosylate raf kinase inhibitors which will serve to (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, (2) provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5) provide for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, (7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

(…)

[0006] The present invention relates to a combination comprising an aryl urea compound which is sorafenib tosylate with at least one other chemotherapeutic (a) cytotoxic agent or (b) cytostatic agent which is 5-fluorouracil or pharmaceutically acceptable salts of any component.

[0007] A cytotoxic or cytostatic agent and (1) a substituted bridged aryl urea compound, or (2) a substituted bridged aryl urea compound having at least one bridged aryl urea structure with substituent(s) on the remote ring, or (3) a γ-carboxyamide substituted bridged aryl urea compound, or (4) a compound or a pharmaceutically acceptable salt of a compound of formula I

        A - D - B     (I)

is described

(…)

[0015] The invention relates to sorafenib tosylate per se.

(…)

[0060] For purposes of the experiments herein described in the Examples, the aryl urea compound (compound A) is a tosylate salt of of N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.

EXAMPLES

Animals

[0061] Ncrnu/nufemale mice (…) were used for allin vivostudies invovling the DLD-1 and NCI-H460 tumor models. Female CB-17 SCID mice (…) were used for studies involving the Mia-PaCa-2 tumor model. (…)

Compounds

[0062] Compound A (lot 9910071) was used in all studies. Compound A is a dry powder with a color ranging from white to ivory or light yellow. (…)

[0063] Camptosar® (…).

[0064] Gemzar® (Gemcitabine HCI) (…).

[0065] Navelbine® (vinorelbine tartrate) (…).

[0066] DOX (Doxorubicin HCl) (…).

[0067] Gefinitib (ZD1839) (4-(3-chloro-4-fluoroanilino)7-methoxy-6-(3-morpholinopropoxy)quinazoline (…).

Vehicles

(…)

Tumor Lines

(…)

Tumor Xenograft Experiments

(…)

Results

Combination of compound A and cytotoxic/cytostatic agents

(…)

Example 1

[0074] In the first study, Camptosar® was administered i.p at 40 mg/kg/dose. Compound A was administered p.o. on a qd x 9 schedule at 80 mg/kg/dose. All treatment was initiated on Day 7 post-implant when all animals had small but established DLD-1 human colon tumor xenografts averaging 108 mg in size. Control tumors grew progressively in all animals with an average doubling time of 4.4 days. The evaluation endpoint used to calculate the growth delay parameters was time to three mass doublings. The median time for the tumors in the untreated control group to attain that size was 10.4 days.

[0075] Camptosar® was well tolerated as a single agent with minimal weight loss and no lethality. The 40 mg/kg dose level produced a TGS of 71% with no complete or partial tumor regressions.

[0076] Compound A was also well tolerated as a single agent producing no significant weight loss and no lethality at 80 mg/kg/dose. Compound A produced a TGS of 100%.

[0077] There was no increase in weight loss and no lethality associated with the combination of Camptosar® with compound A. The anti-tumor efficacy of the concurrent therapy was at least additive producing a 229% TGS. This was associated with 3 PR's.

Example 2

[0078] The second study evaluated Gemzar®, administered i.p at 120 mg/kg/dose on a q4d x 3 schedule and compound A, administered p.o. on a qd x 9 schedule at 40 mg/kg/dose. All treatment was initiated on Day 7 post-implant when all animals had small but established MiaPaCa-human pancreatic tumor xenografts averaging 108 mg in size. Control tumors grew progressively in all animals with an average doubling time of 4.1 days. The evaluation endpoint used to calculate the growth delay parameters was time to two mass doublings. The median time for the tumors in the untreated control group to attain that size was 5.8 days.

[0079] Gemzar® was well tolerated as a single agent with no weight loss and no lethality. This dose level produced a TGS of 154% with no complete or partial tumor regressions. Compound A was also well tolerated as a single agent producing no significant weight loss and no lethality at the 80 mg/kg dose level. Compound A produced TGS of 112%.There was no increase in weight loss and no lethality associated with the combination of Gemzar® with Compound A. The anti-tumor efficacy of the concurrent therapy of 120 mg/kg Gemzar and 40 mg/kg Compound A was at least additive producing a 222% TGS. This was associated with 2 PR's.

Example 3

[0080] The third example demonstrates the effect of the combination of Compound A, administered p.o. on a qd x 9 schedule at 40 mg/kg/dose and Navelbine®, administered i.v. on a q4d x 3 schedule at 6.7 mg/kg/dose. All treatment was initiated on Day 6 post-implant when all animals had small but established NCI-H460 human non-small cell lung tumor xenografts averaging 100 mg in size. Control tumors grew progressively in all animals with an average doubling time of 3.1 days. The evaluation endpoint used to calculate the growth delay parameters was time to three mass doublings. The median time for the tumors in the untreated control group to attain that size was 7.4 days. The 6.7 mg/kg dose level of Navelbine was an approximate maximum tolerated dose producing an average 19% weight loss during the treatment period as a single agent. This was associated with a 32% TGS. Compound A was well tolerated with no significant weight loss and produced a TGS of 104%. The combination of these treatments was well tolerated with no lethality and an average weight loss of 14% (less than that produced by Navelbine alone). The antitumor efficacy of this combination was also approximately additive with a TGS of 133%.

Example 4

[0081] The fourth example demonstrates the effect of the combination of Compound A, administered p.o. on a qd x 9 schedule at 40 mg/kg/dose and DOX, administered i.v. on a q4d x 3 schedule at 4 mg/kg/dose. All treatments were initiated on Day 6 post-implant when all animals had small but established tumors averaging 66 mg in size. Control tumors grew progressively in all animals with an average doubling time of 3.7 days. The evaluation endpoint used to calculate the growth delay parameters was time to four mass doublings. The median time for the tumors in the untreated control group to attain that size was 14.5 days.The 4 mg/kg dose level of DOX was well tolerated producing an average 5% weight loss during the treatment period as a single agent. This was associated with a 43% TGS. Compound A was well tolerated with no significant weight loss and produced a TGS of 46%. The combination of these treatments was tolerated with no lethality and an average weight loss of 12%. The antitumor efficacy of this combination was also approximately additive with a TGS of 133%.

Example 5

[0082] The fifth example demonstrates the effect of the combination of Compound A, administered p.o. on a qd x 9 schedule at 80 mg/kg/dose and Gefinitib (Iressa<®>), administered p.o. on a qd x 9 schedule at 150 mg/kg/dose. All treatment was initiated on Day 15 post-implant when all animals had small but established A549 human non-small cell lung tumor xenografts averaging 110 mg in size. Control tumors grew progressively in all animals with an average doubling time of 10.5 days. The evaluation endpoint used to calculate the growth delay parameters was time to one mass doubling. The 150 mg/kg dose level of Iressa<®>was well tolerated producing no weight loss and no lethality during the treatment period as a single agent. This treatment was associated with a 101% TS and 1 PR. Compound A was also well tolerated as a single agent with no weight loss or lethality and produced a TGS of 218% with 1 CR and 2 PRs. The combination of these treatments was tolerated with one non-specific death out of 10 mice and an average 10% weight loss. The antitumor efficacy of this combination was approximately additive with a TGS of 314%. This treatment also produced 6 CR's and 3 PR's.

De stand van de techniek

De navolgende publicaties behoren voor EP 255 tot de stand van de techniek.

De op 20 juli 2000 gepubliceerde internationale octrooiaanvraag WO 00/42012, waaruit het basisoctrooi EP 840 (zie 2.6) is voortgevloeid (hierna: Riedl). Riedl is getiteld “omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors”. Het Abstract Riedl et al., opgenomen in het blad “Proceedings of the American Association for Cancer Results” (volume 42 onder nummer #4956 op blz. 923) in maart 2001, luidt als volgt:

[Deze afbeelding wordt zo spoedig mogelijk toegevoegd.]

Het artikel van Kumar et al., genaamd “Drugs targeted against protein kinases”, opgenomen in het blad “Expert Opinion, Emerging Drugs” (volume 6, nummer 2, blz. 303-315) van oktober 2001 (hierna: Kumar). In deze publicatie is in een tabel – onder meer – de volgende informatie opgenomen:

(…)

[Deze afbeelding wordt zo spoedig mogelijk toegevoegd.]

(…)

[Deze afbeelding wordt zo spoedig mogelijk toegevoegd.]

Het artikel van Lyons et al., genaamd “Discovery of a novel Raf kinase inhibitor”, opgenomen in het vakblad Endocrine-Related Cancer in 2001 (nummer 8, blz. 219-225) (hierna: Lyons). Daarin is - onder meer - opgenomen:

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[Deze afbeelding wordt zo spoedig mogelijk toegevoegd.]

[Deze afbeelding wordt zo spoedig mogelijk toegevoegd.]

Handboeken

Op de prioriteitsdatum was over farmaceutische zouten de volgende informatie voorhanden. Daarin wordt onder meer gesproken over de pKa-waarde. De pKa-waarde is de zuur-base-dissociatieconstante en ziet op de neiging van een ioniseerbare groep om in een waterige oplossing te ioniseren en is dus maatgevend voor de sterkte van een zure of basische groep (hoe sterker het zuur, hoe lager de pKa-waarde en hoe sterker de base, hoe hoger de pKa-waarde).

In het handboek van M.E. Aulton, “Pharmaceutics: The Science of

Dosage Form Design”, Churchill Livingstone, 1988, 223-253 (hierna: Aulton), is – onder meer – opgenomen:

(…)

THE CONCEPT OF PREFORMULATION

(…)

However, a knowledge of two fundamental properties is mandatory for a new compound:

1. intrinsic solubility (Co),

2 dissociation constant (pKa).

These will immediately determine (a) the need and (b) the possibility of making more soluble salts of the drug to eliminate solubility-related poor bio-availability, particularly from solid dosage forms.

(…)

2 SOLUBILITY

(…)

Salts

A major improvement in solubility can be achieved by selection of a salt. (…)

(…)

[Deze afbeelding wordt zo spoedig mogelijk toegevoegd.]

(…)

Dissolution

(…)

Common ion effect

A common interaction with solvent, which is often overlooked, is the common ion effect. The addition of a common ion often reduces the solubility of a slightly soluble electrolyte (Long & McDevitt, 1952). This ‘salting out’ results from the removal of water molecules as solvent due to the competing hydration of other ions. (…)

Hydrochloride salts often exhibit suboptimal solubility in gastric juice due to the abundance of

Cl ions. (…)

Where a hydrochloride salt exhibits suboptimal solubility then the next logical choice is probably a salt of toluene sulphonic acid (tosylate: pKa -1.34).

In de publicatie Bastin et al., “Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities”, Organic Process Research & Development 2000, vol. 4, 427-435 (hierna: Bastin) is – onder meer – opgenomen:

Abstract:

Selection of an appropriate salt form for a new chemical entity provides the pharmaceutical chemist and formulation scientist with the opportunity to modify the characteristics of the potential drug substance and to permit the development of dosage forms with good bioavailability, stability, manufacturability, and patient compliance. Salts are most commonly employed for modifying aqueous solubility, (…)

(…)

Investigations into the Possibilities of Salt Formation

(…) Invariably, the first information generated for each candidate is the calculated pKa value of each ionisable group in the molecule.(…) (…) Knowledge of the pKa value enables potential salt forming agents (counterions) to be selected, for each candidate, based on lists that are available in the literature.(…) For the formation of a stable salt, it is widely accepted that there should be a minimum difference of about 3 units between the pKa value of the group and that of its counterion, especially when the drug substance is a particularly weak acid or base. Occasionally, exceptions may be found where a salt has an acceptable stability, despite there being a smaller difference in the pKa values.

(…)

[Deze afbeelding wordt zo spoedig mogelijk toegevoegd.]

(…)

Choice of the Salt Former

(…) For weakly basic drug substances. salts of an inorganic acid (e.g., hydrochloride, sulphate, or phosphate), a sulphonic acid (mesylate or isethionate), a carboxylic acid (acetate, maleate or fumarate), a hydroxyacid (citrate or tartrate), or possibly an amino acid (arginine or lysine) could be considered.

In het handbook A.R. Gennaro (Chairman editorial board), “Remington: the Science en Practice of Pharmacie”, 2000, 704-705 (hierna: Remington) is – onder meer – de volgende tabel opgenomen:

[Deze afbeelding wordt zo spoedig mogelijk toegevoegd.]

Teva c.s. en haar generiek

Teva c.s. is onderdeel van de wereldwijd opererende Teva Groep, met Europees hoofdkantoor in Nederland.

Op 11 maart 2019 is aan Teva een Nederlandse handelsvergunning verleend voor Sorafenib Teva 200 mg, filmomhulde tabletten met sorafenibtosylaat, een generieke versie van Nexavar (hierna: de generiek).

De advocaat van Bayer heeft op 4 april 2019 een brief gezonden aan Teva om haar te wijzen op de exclusieve rechten van Bayer en bevestiging te vragen dat Teva deze zal respecteren. Bij brief van 12 april 2019 heeft Teva Bayer bericht dat zij tot het verlopen van het ABC op 20 juli 2021 (zie 2.6) niet de intentie heeft om met de generiek op de markt te komen in Nederland.

In verband met de naderende expiratie van het ABC, heeft de advocaat van Bayer Teva op 8 april 2021 een brief gezonden, waarin nogmaals is gewezen op de exclusieve rechten van Bayer, met name op EP 255, met het verzoek te bevestigen dat Teva zich van inbreuk zal onthouden. Daarna heeft tussen partijen overleg plaatsgevonden dat niet heeft geleid tot overeenstemming.

Teva heeft op 17 augustus 2021 haar generiek laten opnemen in de G-standaard, welke opname effectief is geworden per 1 september 2021. Pharmachemie wordt als productverantwoordelijke voor de generiek vermeld.

Buitenlandse procedures

Binnen Europa zijn buitenlandse delen van EP 255 het onderwerp (geweest) van verschillende procedures tussen enerzijds Bayer en anderzijds aanbieders van generiek sorafenib wegens (niet-)inbreuk op EP 255.

Zo heeft Ratiopharm GmbH (onderdeel van de Teva Groep) in februari 2020 een nietigheidsprocedure, gericht op het Duitse deel van EP 255, aanhangig gemaakt. Het Bundespatentgericht heeft op 1 april 2021 respectievelijk 21 april 2021 twee voorlopige opinies uitgebracht, waarin conclusie 12 niet inventief is geacht. Op 29 september 2021 heeft de mondelinge behandeling voor het Bundespatentgericht plaatsgevonden. De Duitse rechter heeft bij die gelegenheid mondeling geoordeeld dat conclusie 12 van het Duitse deel van EP 255 nietig is wegens gebrek aan inventiviteit. Uit de voorlopige opinies en het zittingsverslag van de mondelinge behandeling volgt dat de Duitse rechter daarbij is uitgegaan van Lyons. De schriftelijke gronden van de beslissingen worden verwacht binnen twee à drie maanden na 29 september 2021.

In het Verenigd Koninkrijk hebben Teva Pharmaceutical Industries Ltd en Teva UK Ltd in maart 2020 een nietigheidsprocedure, gericht op het Engelse deel van EP 255, aanhangig gemaakt. Op 8 oktober 2021 heeft de High Court of Justice – Patents Court vonnis gewezen en geoordeeld dat conclusie 12 van het Engelse deel van EP 255 niet geldig is wegens gebrek aan inventiviteit in het licht van Lyons. In de beslissing zijn – ondermeer – de volgende overwegingen opgenomen:

(…)

The Patent

7. The Patent is entitled ‘Aryl urea compounds in combination with other cytostatic or cytotoxic agents for treating human cancers’. It has a priority date of 3 December 2001. The field of the invention is described as follows in [0001], where the principal chemical entity is sorafenib:

[0001] This invention relates to aryl urea compounds namely the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, also in combination with cytotoxic or cytostatic agents, namely 5-fluorouracil, and their use in treating raf kinase mediated diseases such as cancer.

8. Under the heading ‘Summary of the Invention’ in [0004], the Patent explains: ‘Generally, it is the overall object of the present invention to provide 5-fluorouracil in combination with sorafenib tosylate raf kinase inhibitors which will serve to…’ and then there are 8 listed benefits in the treatment of tumours.

9. Although the Detailed Description starts with a general Markush formula I (A-D-B), with very wide ranges of suitable groups then being described, by [0015] the Patent states ‘The invention relates to sorafenib tosylate per se’.

(…)

11. [0060] [0060] confirms that all the experiments reported in the Examples were performed using sorafenib tosylate, also referred to as Compound A. The experiments were conducted on female mice implanted with tumor fragments (human colon, human pancreatic, human non-small cell lung and one unidentified tumor type). Treatment was initiated once the tumors were established. The treatment in each example comprised the administration of (a) a particular cytotoxic or cytostatic agent (b) Compound A as a single agent and then (c) the concurrent therapy of both, with the percent tumour growth suppression (%TGS) measured. The picture presented by the Examples is that although Compound A on its own produced appreciable levels of TGS (e.g. 100%, 112%, 104% etc), when administered in combination, the levels of TGS were significantly better (equivalents being 229%, 222%, 133% etc). Accordingly, conclusions were drawn under each example that the anti-tumor efficacy of the concurrent therapy was either approximately additive or at least additive.

(…)

14. Claims 2-11 are all use claims dependent on claim 1, directly or indirectly. (…)

15. Claim 12 is to:

‘Aryl urea compound, which is a tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.’

16. Although it was not flagged in advance, an issue of construction of claim 12 emerged in closing submissions when I raised the point with Bayer’s counsel that the parties did not even agree on the question I had to address. Whilst Bayer naturally addressed the issue of which salts to include in a salt screen, their submissions appeared to be focussed on claim 12 as proposed to be amended – in other words Bayer was contending that to establish that unamended claim 12 was invalid Teva still needed to prove that it was obvious not just to make sorafenib tosylate but also to characterise it and then use it for oral administration to treat cancer.

16. Mr Mitcheson QC for Bayer sought to justify this argument by reference to what he submitted was the invention:

15 …..The invention in this case is not about making

16 sorafenib tosylate alone. As Teva point out, the patent

17 itself does not tell you how to do that, and the experts did

18 not know how to either, the experts who were called, and the

19 patent is not directed to a medicinal chemist, it is directed

20 to a formulator. Nor does the prior art tell you how to make

21 the tosylate, nor do the CGK textbooks that everyone has

22 relied upon. That is because the technical contribution in

23 this case is not just making sorafenib tosylate, it is making

24 and then using sorafenib tosylate for oral administration to

25 treat cancer, and to obtain sufficient bioavailability to do so.

(…)

20. My task is to undertake a ‘normal construction’ of claim 12. It is unnecessary for me to set out the standard authorities but I have in mind Actavis v Lilly [2017] UKSC 48, Icescape v Ice-World [2019] FSR 5 and Liqwd Inc v L’Oreal UK Ltd [2018] EWHC 1394 (Pat), Birss J.

21. Of course, each case turns on its own facts. In this case, I am entirely satisfied that unamended claim 12 does claim just the compound. I say that for the following reasons:

i. First, I remind myself that the words of these claims form part of the ‘unilateral statement by the patentee, in words of his own choosing, addressed to those likely to have a practical interest in the subject matter of his invention.’ (per Lord Diplock in Catnic).

Second, in claims 1-11, the patentee had the ability to and did claim a variety of particular uses of sorafenib tosylate. These uses appear to me to cover the general statements in the specification of the ‘invention’ (save for one which I address below) in, for example, [0004], [0006] et seq., [0016]-[0017].

Third, the exception is [0015] which reads ‘The invention relates to sorafenib tosylate per se.’ This is a clear signal that the patentee wishes to claim the sorafenib tosylate compound as is and without any limitation to a particular use.

Fourth, consistent with that signal in [0015], claim 12 appears to be worded so as to claim sorafenib tosylate per se.

Fifth, the skilled person reading the Patent and the claims would understand claim 12 in effect to be a sweep-up general claim. Claims 1-11 claim the particular uses in focus in the specification i.e. to treat cancer (and particular forms) along with 5-fluorouracil or a pharmaceutically acceptable salt thereof and via various forms of administration. Having read those claims, it would be apparent to the skilled person that in claim 12 the Patentee is claiming sorafenib tosylate per se i.e. without any restriction as to use.

Sixth, the skilled person would also be aware that if the Patentee had wished to formulate a claim to the invention as characterised by Mr Mitcheson QC it could easily have been done, but did not.

Seventh, assuming claim 12 to be valid, I am quite sure that if a third party managed to find a use for sorafenib tosylate which fell outside claims 1-11, they would have been sued for infringement of claim 12 and one of the alleged acts of infringement would have been simply making sorafenib tosylate.

Eighth, this case seems to me to be materially different to the class-type cases such as Pharmacia and Idenix, where a particular activity is the defining characteristic of the class. There is no class here, nor any need to construe claim 12 so that it is limited to a particular activity or effect. Indeed, it is readily apparent that the patentee worded claim 12 deliberately broadly so that it was not limited to any particular use, activity or effect. Furthermore, my construction of claim 12 creates no inconsistency with the description of the invention in the specification. To the contrary: as I have indicated, my construction is entirely consistent with [0015].

Ninth, I asked Mr Mitcheson QC how the Court was to assess ‘sufficient bioavailability’. His answer was you have to put it [i.e. the formulated drug] into animals to ascertain it is bioavailable and also ‘you have to do enough to believe this product is worth giving to the subjects’, but these explanations were the same point as his main argument, just in a different guise.

Tenth, as illustrated by Bayer’s proposed amendment to claim 12, if Bayer had wanted to introduce a limitation into claim 12, it could have done so. In the end, no such limitation was before me.

Overall, I find Mr Mitcheson QC’s submission to be a classic instance of Angora cat behaviour by a patentee: in this instance because only validity is in issue, the claim is presented as being narrow.

22. For all these reasons, I concluded that the ‘target’ for the obviousness attack is the compound sorafenib tosylate per se.

(…)

The Skilled Person or Team

24. As appears below, the parties and the evidence concentrated very much on the CGK and characteristics of the Skilled Formulator. Whilst the Skilled Formulator is the most important member of the team, to implement the Patent the Skilled Team would have to cover a wider set of related disciplines. In particular, the Skilled Team would need medicinal chemists to make the sorafenib free base and then to make various salts of sorafenib which the Skilled Formulator selected for his or her salt screen. There was, however, no dispute over the identity of the Skilled Team. In his evidence, Professor Frijlink referred simply to the ‘formulator’, but all such references were to and should be read as referring to the Skilled Formulator.

(…)

Obviousness

(…)

Lyons

Disclosure

(…)

121. As Professor Frijlink said, Lyons as a document would have been of more interest to a clinician than a formulator. However, the Lyons paper would have sparked the interest of medicinal chemists working in this area.

122. Thus, as Professor Buckton explained, the Skilled Formulator would take comfort from the disclosure in Lyons that it was possible to formulate sorafenib as an oral tablet. Although the BAY code specifically refers to the free base, the Skilled Formulator would not have concluded that Lyons was disclosing that the free base had been used.S/he would have thought that sorafenib could have been formulated as the free base or a salt.

123. Bayer pointed out that Lyons contains no direction to the skilled person to tosylate as the appropriate salt of sorafenib to use. As a result, Bayer submits that Teva’s case is essentially a CGK-alone case. They remind me of the warning by Birss J. in Accord v Medac, in this passage: (…)

124. Although I entirely agree with those observations, in my view they are not apposite in this case. Lyons does not contain any ‘inconvenient’ details. It discloses that a chemical entity identified by the BAY code showed promising therapeutic effect against four types of cancer. Then the question is: what would the Skilled Team do next?

125. It is true that Lyons contains no direction to use tosylate. Equally it contains no direction to use either any salt of sorafenib or the free base – Lyons is deliberately uninformative as to the form of BAY 43-9006 actually administered.

126. This is not a CGK-alone case. The starting point is Lyons. I find that Lyons provided the Skilled Team with a strong (but not irresistible) motivation to investigate this chemical entity with a view to identifying a formulated drug, preferably for oral administration to humans. The point is that from the starting point of Lyons, the Skilled Team (and the Skilled Formulator in particular) had their CGK routine tests, considerations and analysis to work with.

What would the Skilled Team do having considered Lyons?

127. The following points did not appear to me to be in dispute but in any event, I find the Skilled Team, having read Lyons, would take the following steps:

i. First, since Lyons reported initial results from Phase 1 clinical trials of BAY 43-9006, they would follow up relevant references including Riedl and Strumberg. The Riedl reference gave the Skilled Team the chemical formula for sorafenib. The Strumberg reference would have been followed up because it reported on pharmacokinetic aspects of the Phase 1 clinical trial. It revealed the dose range of between 50-400mg.

Second, the medicinal chemists in the team would be tasked with finding a way to make the sorafenib free base. They would be able to make it (as Bayer admitted in correspondence), albeit initially in relatively small quantities.

Third, I believe it was common ground that the Skilled Formulator would then seek to characterise the sorafenib free base.

The Skilled Formulator would then find that the sorafenib free base was (a) weakly basic; (b) largely insoluble with a predicted and experimental solubility of 0.00171 mg/mL in water (the experts agreed this was a very low solubility); (c) with a calculated pKa in the range of 2.03-4.5 and 11.55-11.84. The two pKa ranges reflect the fact that sorafenib has both basic and acidic characteristics, but I am satisfied that the Skilled Formulator would decide to focus on its ability as a weak base to form salts, not least because (a) as Professor Frijlink pointed out, Aulton stated that drugs with a pKa of over 10 would not be suitable for salt selection and (b) the aim is to improve solubility at a pH found in the gastro-intestinal tract.

(…)

Based on these characteristics, the Skilled Formulator would decide to carry out a salt screen, in the expectation that they would find a sorafenib salt which would have improved characteristics and in particular improved solubility. Again, s/he would be encouraged by the knowledge from Lyons that the drug was administered orally in tablet form, and that form gave sufficient bioavailability (itself reflecting both solubility and permeability).

(…)

134. In order to form a salt, Professor Buckton stated that the general rule was that the pKa of the acid and base should differ by at least two and preferably three pKa units. This was reflected in passages he cited from Bastin and Berge. Then, he said that the Skilled Formulator developing an oral dosage form would ordinarily want to use a counterion which has been previously approved by the regulatory authorities. He pointed out that these considerations mean that there was a limited list of counterions to select from, especially if the NCE has a low pKa. In addition, for weak bases with a pKa of less than about 3, he stated that the salts formed can have poor physical stability in the solid state and can easily disproportionate back to the free form with atmospheric moisture or when in contact with excipients in a drug product. Even then, salt formation was still the first choice for improving solubility, albeit that a greater focus is placed on the pKa difference in order to improve stability.

135. So, Professor Buckton opined, in screening for an oral dosage form of an NCE with very low solubility, the Skilled Formulator would first identify acids with suitable pKa values which were already in use. Common acids were identified in books such as Aulton and Bighley and in journal articles such as Berge, Gould and Bastin and he said that the acids mentioned in those texts were indicative of the counterions commonly used by the Skilled Formulator in a salt screen.

136. In cross-examination, he was challenged with extracts from his reports in other pieces of litigation where he was content with a difference of 2 pKa units between acid and base. These challenges seemed to me to go nowhere for three reasons: first, because, as Professor Buckton explained, those reports were considering different circumstances; second, because Professor Frijlink agreed that the skilled formulator would want a difference of 2 units, although on occasion he suggested a difference of 1 would do; third, because of Professor Buckton’s point that stability was likely to be improved by a greater difference in pKa units.

137. On that third point, in cross-examination Professor Buckton gave a clear explanation of the technical reasons behind his ‘at least 2 and preferably 3’ range, by reference to the pKa range for sorafenib (2.03-4.5). In essence, he explained that if the pKa was at the lower end of the range, the acid has to have a pKa which is much lower because ‘we are in the region where it is going to be very difficult to get a salt to hold together. If we are at the 4.5 pKa… that becomes a little less critical.’ Hence he explained that if the drug substance has a pKa of around 6 or 7, then he would use his general rule of 2 as a difference; if around 4.5, he would be looking for an acid with a pKa difference of 2.5; if around 2, then he would be looking for a pKa difference of 3; and the purpose of the greater difference at the lower pKa values was to achieve a stable salt.

138. Furthermore, as I indicated, Professor Buckton’s range was supported by passages in both Bastin: ‘for the formation of a stable salt, it is widely accepted that there should be a minimum difference of about 3 units between the pKa value of the group and that of its counterion, especially where the drug substance is a particularly weak acid or base’ and Berge: ‘particularly important is the relative strength of the acid or base…these factors determine whether or not formation occurs and are a measure of the stability of the resulting salt’.

(…)

Bayer heeft in Portugal een bodemprocedure aanhangig gemaakt en een voorlopig inbreukverbod gevraagd wegens verlening van een generieke marktvergunning aan Sandoz, Teva en Pharos (hierna: Sandoz c.s.). Dit verbod is door de Portugese rechter geweigerd. De namens Sandoz c.s. ingestelde tegenvordering tot nietigverklaring van het Europese deel van EP 255 is op procedurele gronden niet toelaatbaar geacht. Zowel Bayer als Sandoz c.s. heeft hoger beroep ingesteld.

Verder heeft Bayer onder meer in Spanje en in Frankrijk voorlopige verbodsprocedures aanhangig gemaakt. Bij vonnis van 19 juli 2021 respectievelijk29 september 2021 hebben de Spaanse en Franse rechter het voorlopig inbreukverbod geweigerd omdat naar voorlopig oordeel conclusie 12 van het Spaanse respectievelijk Franse deel van EP 255 ongeldig is wegens gebrek aan inventiviteit.

In Finland, Estland, Roemenië en Slowakije is op dit moment wel een inbreukverbod van kracht.

Bayer vordert – samengevat – een verbod inbreuk te maken op het Nederlandse deel van EP 255, met nevenvorderingen (verwijdering van de generiek uit de G-standaard en het informeren van derden), alles versterkt met een dwangsom, en een volledige proceskostenveroordeling op de voet van artikel 1019h Rv3..

Ter onderbouwing van haar (neven)vorderingen stelt Bayer – verkortweergegeven – dat Teva c.s. inbreuk maakt op conclusie 12 van EP 255 door opname van de generiek in de G-standaard.

Teva c.s. voert verweer en betoogt dat de door Bayer gevraagde voorziening moet worden geweigerd omdat een serieuze, niet te verwaarlozen kans bestaat dat conclusie 12 in een bodemprocedure zal worden vernietigd. Haar verweer houdt – zakelijk weergegeven – het volgende in.

Het gegeven dat de verbodsvorderingen van Bayer in de Duitse en Engelse bodemprocedures (vergelijk onder 2.20.1 en 2.20.2) zijn afgewezen (evenals in de Franse en Spaanse kortgedingprocedures, zie onder 2.20.4), is al voldoende om aan te nemen dat er een serieuze, niet te verwaarlozen kans bestaat dat conclusie 12 van het Nederlandse deel van EP 255 in een Nederlandse bodemprocedure eveneens zal worden vernietigd. Het gaat om beslissingen van gezaghebbende buitenlandse rechterlijke colleges op basis van vergelijkbare nietigheidsargumenten.

Wanneer de voorzieningenrechter deze buitenlandse beslissingen onvoldoende acht om de vorderingen van Bayer direct af te wijzen, voert Teva c.s. de volgende nietigheidsverweren.

Teva c.s. betoogt dat Bayer geen prioriteit kan ontlenen aan US 609 omdat sorafenibtosylaat, oftewel ‘dezelfde uitvinding’ als geclaimd in conclusie 12, al in een eerdere octrooiaanvraag van Bayer is geopenbaard. Het gaat om een octrooiaanvraag die is ingediend op 10 september 2001 (genaamd: Uday). Uday en Riedl (zie 2.13.1) zijn beide een continuation van hetzelfde Amerikaanse octrooi en zijn inhoudelijk identiek. Omdat Bayer ten onrechte een beroep doet op de prioriteit van US 609, moet de geldigheid van conclusie 12 worden beoordeeld aan de hand van de beschikbare stand van de techniek op 3 december 2002, de datum van indiening van de moederaanvrage (zie 2.7). De artikelen die (naar de auteurs) Lowinger en Hotte worden genoemd, zijn dan nieuwheidsschadelijk voor conclusie 12 van EP 255.

Als geoordeeld wordt dat Bayer met recht een beroep doet op de prioriteit van US 609, dan is conclusie 12 niet nieuw in het licht van Riedl. Riedl openbaart sorafenibtosylaat namelijk direct en ondubbelzinnig, door zowel (de structuurformule van) sorafenib (als één van de 103 gesynthetiseerde arylureumverbindingen die vallen onder een Markush formule (formule I)), als p-tolueensulfonzuur (het zuur dat leidt tot de vorming van een tosylaatzout) (als één van de 24 genoemde farmaceutisch aanvaardbare zouten van de arylureumverbindingen) te openbaren.

Teva c.s. voert verder aan dat conclusie 12 inventiviteit mist in het licht van Lyons (zie 2.13.3), zo nodig in combinatie met Riedl (dan wel Kumar) en de algemene vakkennis van de gemiddelde vakman. Ook uitgaande van Kumar of Riedl is conclusie 12 niet inventief, als deze documenten al niet nieuwheidsschadelijk zijn.

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