Rb. Den Haag, 31-05-2023, nr. C/09/646434

te Haarlem, 2. TEVA NEDERLAND B.V.,

te Haarlem, 3. PHARMACHEMIE B.V.,

te Haarlem,

gedaagden,

advocaat: mr. J.M.J.A. Krens te Amsterdam.

Eiseres zal hierna BMS genoemd worden en gedaagden zullen hierna gezamenlijk Teva c.s. (vrouwelijk enkelvoud) genoemd worden.

De zaak is voor BMS inhoudelijk behandeld door mr. Van der Velden voornoemd, mr. ir. H. Zagers en mr. C. Sijm, advocaten te Amsterdam, en voor Teva c.s. door mr. Krens voornoemd en mr. M.L de Haas, advocaat te Amsterdam.

Het verloop van de procedure blijkt uit:

- de dagvaarding van 8 mei 2023 met producties EP01 t/m EP45;

- de e-mail van 8 mei 2023 van BMS met als bijlage haar proceskostenoverzicht;

- de e-mail van 23 mei 2023 van BMS waarin wordt verwezen naar het vonnis van de voorzieningenrechter in deze rechtbank van 17 mei 2023 in de kort geding procedures tussen BMS en Sandoz & Stada (C/09/644989 KG ZA 23-240 en C/09/644996 KG ZA 23-244) waarin de vorderingen van BMS zijn afgewezen en waartegen BMS hoger beroep heeft ingesteld. Gelet hierop hebben partijen afgesproken dat Teva c.s. in deze procedure geen conclusie van antwoord en producties zal indienen, dat de mondelinge behandeling van 26 mei 2023 geen doorgang hoeft te vinden (of vervangen kan worden door een pro forma zitting) en dat partijen de voorzieningenrechter verzoeken om een vonnis te wijzen dat (uitsluitend) dezelfde redenering zal bevatten als het vonnis van 17 mei 2023 en waarin de vorderingen van BMS worden afgewezen en BMS wordt veroordeeld in de proceskosten conform artikel 1019h Rv1.(ook al is BMS het niet eens met de inhoud van dat vonnis);

- de e-mail van 24 mei 2023 van de rechtbank aan partijen waarin de voorgestelde aanpak wordt bevestigd met dien verstande dat de mondelinge behandeling (verkort) doorgang zal waarbij slechts over de proceskosten zal worden gepleit;

- de e-mail van 25 mei 2023 van Teva c.s. met als bijlage haar proceskostenoverzicht;

- de mondelinge behandeling van 26 mei 2023, waarop de advocaten namens partijen zijn verschenen, de advocaten ten aanzien van de proceskosten hebben gepleit en uiteindelijk een partijafspraak hebben gemaakt dat de door BMS aan Teva c.s. te betalen proceskosten

€ 60.000,- bedragen.

Partijen hebben afgesproken dat na het wijzen van dit vonnis de conclusie van antwoord zoals die door Teva c.s. is geconcipieerd nog tussen partijen zal worden gewisseld en dat die in de hoger beroepsprocedure als processtuk zal worden beschouwd, maar dat daar voor dit vonnis geen acht op is geslagen.

Vonnis is bepaald op heden.

Het vonnis van 17 mei 2023 luidt als volgt:

BMS maakt deel uit van het BMS concern. Dit concern is een farmaceutisch concern dat wereldwijd actief is en zich richt op de ontwikkeling van geneesmiddelen. Sinds 2007 is het BMS concern een wereldwijde samenwerking aangegaan met Pfizer Inc.

BMS brengt – onder meer in Nederland – het geneesmiddel met de merknaam Eliquis® op de markt, met als actieve stof apixaban. Apixaban is een stof die de werking van factor Xa remt. Het remmen van factor Xa helpt de vorming van bloedstolsels te voorkomen. Eliquis® wordt in tabletvorm toegepast als anticoagulans, oftewel bloedverdunner, bij de behandeling van trombo-embolische aandoeningen.

Bristol-Meijers Squibb Company (Verenigde Staten) heeft op 17 september 2002 een internationale PCT-aanvraag ingediend onder nummer WO 03/026652 (hierna: WO 652) getiteld ‘Lactam-containing compounds and derivatives thereof as factor Xa inhibitors’. De aanvraag doet een beroep op het prioriteitsdocument US 60/324165 van 21 september 2001 en bevat – onder meer – de volgende passages:

2.BACKGROUND OF THE INVENTION

(…)

3.Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII

Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors. (…)4.For example, it is preferred to find new compounds with improved factor Xa inhibitory activity and selectivity for factor Xa versus other serine proteases (i.e., trypsin). It is also desirable and preferable to find compounds with advantageous and improved characteristics in one or more of the following categories, but are not limited to: (a) pharmaceutical properties (e.g., solubility, permeability, and amenability to sustained release formulations); (b) dosage requirements (e.g., lower dosages and/or once-daily dosing); (c) factors which decrease blood concentration peak-to-trough characteristics (e.g., clearance and/or volume of distribution); (d) factors that increase the concentration of active drug at the receptor (e.g., protein binding, volume of distribution); (e) factors that decrease the liability for clinical drug-drug interactions (e.g., cytochrome P450 enzyme inhibition or induction); (f) factors that decrease the potential for adverse side-effects (e.g., pharmacological selectivity beyond serine proteases, potential chemical or metabolic reactivity, and limited CNS penetration); and, (g) factors that improve manufacturing costs or feasibility (e.g., difficulty of synthesis, number of chiral centers, chemical stability, and ease of handling).

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel lactam-containing compounds and derivatives thereof that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

(…)

5.UTILITY

The compounds of this invention are inhibitors of factor Xa and are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals (i.e., factor Xa-associated disorders). (…)

(…)

6.The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nm. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Ki.

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, Km, for substrate hydrolysis was determined at 25 °C using the method of Lineweaver and Burk. Values of Ki were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 mM - 1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 min and the velocities (rate of absorbance change vs. time) were measured in the time frame of 25-30 min. The following relationship was used to calculate Ki values:

(VO-VS)/VS = I/(Ki (1+ S/Km))

where:

VO is the velocity of the control in the absence of inhibitor;

VS is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

Ki is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

Km is the Michaelis constant.

Compounds tested in the above assay are considered to be active if they exhibit a Ki of ≤ 10 µM. Preferred compounds of the present invention have Ki's of ≤ 1 µM.

More preferred compounds of the present invention have Ki's of ≤ 0.1 µM. Even more preferred compounds of the present invention have Ki's of ≤ 0.01 µM. Still more preferred compounds of the present invention have Ki's of ≤ 0.001 µM.

Using the methodology described above, a number of compounds of the present invention were found to exhibit Ki's of ≤ 10 µM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

(…)

7.Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. (…)

(…)8.Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Ki of less than 10 µM, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.

(…)

9.EXAMPLES

(…)

10.Example 18

1-(4-methoxypheny1)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl-4,5,6,7-tetrahydro-1H-pyrazole-[3,4-c]pyridine-3-carboxamide

(…)

11.Part F. To ester from Part E (4.8 g, 0.009 mol) was added 5% NH3 in ethylene glycol (40 mL) and the mixture was heated to 120 °C for 4 h in sealed vessel. Water was added and the resulting solid was collected. Purification by silica gel chromatography using 0-10% Me0H/ CH2C12 as eluent afforded 3.5 g of a white solid. A portion of the solid was recrystallized from CH2Cl2/ EtOAc to afford 2.5 g of the title compound. The remaining solid and filtrate material was recrystallized from isopropyl alcohol to afford an additional 0.57 g for a total of 3.07 g (68%): (…)

(…)

12.WHAT IS CLAIMED IS:

1. A compound of Formula I:

P4-P-M-M4

I

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;(…)

13.8. A compound according to Claim 1, wherein the compound is selected from the group:

(…)

14.1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl-4,5,6,7-tetrahydro-1H-pyrazole-[3,4-c]pyridine-3-carboxamide;

(…)

15.or a pharmaceutically acceptable salt form thereof.

WO 652 is voortgezet als Europese octrooiaanvraag en uiteindelijk op 12 augustus 2009 verleend onder publicatienummer EP 1 427 415 B1 (hierna: EP 415 of het octrooi) met BMS als octrooihoudster. EP 415 was van kracht, onder meer in Nederland, tot en met 16 september 2022.

EP 415 is het basisoctrooi voor Aanvullend Beschermingscertificaat (NL) 300500 voor ‘Apixaban desgewenst in de vorm van een farmaceutisch aanvaardbaar zout’ (hierna: het ABC). Het ABC is ingegaan op 17 september 2022 en is van kracht tot en met 19 mei 2026.

De ingeroepen conclusies 1-4 van EP 415 luiden in de authentieke Engelse versie als volgt:

1. A compound, which is represented by formula (1):

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, which is represented by the formula (1).

3. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of the formula (1) of claim 1 or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition, comprising: the pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 2.

[formula 1 = apixaban, vzr]

De internationale octrooiaanvraag WO 00/39131 (hierna: WO 131) van 17 december 1999 is voor EP 415 de meest nabije stand van de techniek. WO 131 is gepubliceerd op 6 juli 2000 en getiteld ‘Nitrogen containing heterobicycles as factor Xa inhibitors’. De uitvinders zijn afkomstig uit dezelfde onderzoeksgroep als de uitvinders van EP 415. WO 131 bevat – onder meer – de volgende passages:16.

17.BACKGROUND OF THE INVENTION

(…)

18.Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII

Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors. (…)

19.UTILITY

The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals.. (…)

(…)

20.The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Ki.

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, Km, for substrate hydrolysis was determined at 25°C using the method of Lineweaver and Burk. Values of Ki were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate Ki values:

(VO-VS)/VS = I/(Ki (1+ S/Km))

where:

VO is the velocity of the control in the absence of inhibitor;

VS is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

Ki is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

Km is the Michaelis constant.

Using the methodology described above, a number of compounds of the present invention

were found to exhibit a Ki of <10 µM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

Compounds tested in the above assay are considered to be active if they exhibit a Ki of ≤ 10 µM. Preferred compounds of the present invention have Ki's of ≤ 1 µM. More preferred compounds of the present invention have Ki's of ≤ 0.1 µM. Even more preferred compounds of the present invention have Ki's of ≤ 0.01 µM. Still more preferred compounds of the present invention have Ki's of ≤ 0.001 µM.

(…)

21.Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. (…)

(…)22.Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Ki of less than 10 µM, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.

Bij dagvaarding van 2 juli 2021 heeft Teva Nederland B.V. voor de onderhavige rechtbank een VRO-procedure aanhangig gemaakt tegen BMS, waarin zij de vernietiging vordert van het Nederlandse deel van EP 415 en van het ABC (hierna: de VRO-procedure). Deze procedure is aangehouden hangende de uitspraak van de Grote Kamer van Beroep (hierna GKB) van het Europees Octrooibureau (EOB) inzake G 2/21.

Sandoz behoort tot de Sandoz-groep, die zich bezighoudt met de ontwikkeling, productie en distributie van, onder andere, generieke geneesmiddelen. Eén van die geneesmiddelen is de generieke versie van Eliquis (hierna: apixaban Sandoz).

Sandoz heeft op 24 september 2021 marktvergunningen verkregen voor apixaban Sandoz 2,5 mg en 5 mg filmomhulde tabletten.

Op 23 november 2021 heeft BMS aan Sandoz een waarschuwingsbrief gestuurd. Sandoz heeft bij brief van 3 december 2021 aangegeven dat zij zich gewaar is van de intellectuele eigendomsrechten van BMS en dat zij niet de intentie heeft een apixaban product in Nederland te lanceren vóór de expiratie van EP 415 en het ABC.

Sandoz Limited en Teva Pharmaceutical Industries Limited hebben in het Verenigd Koninkrijk een bodemprocedure tegen BMS aanhangig gemaakt en gevorderd dat het Engelse deel van EP 415 (en het daarop gebaseerde parallelle Engelse ABC) nietig wordt verklaard. Op 7 april 2022 heeft Meade J van de High Court of Justice, Business and Property Courts of England and Wales (hierna: de High Court) uitspraak gedaan en beslist dat het Engelse deel van EP 415 nietig is vanwege gebrek aan plausibiliteit en technische bijdrage.23.

Bij brief van 7 april 2022 heeft (de advocaat van) Sandoz aan BMS bericht dat zij van plan is om apixaban Sandoz zo snel mogelijk in Nederland op de markt brengen.

Sandoz heeft apixaban Sandoz laten opnemen in de G-standaard van mei 2022, die op 12 april 2022 is gepubliceerd.

Naar aanleiding van de opname in de G-standaard is BMS in april 2022 een kort geding-procedure gestart tegen Sandoz. In die zaak is op 10 mei 2022 vonnis gewezen.24.De voorzieningenrechter nam aan dat er een gerede kans was dat het octrooi en het daarop gebaseerde certificaat een bodemprocedure niet zouden overleven en heeft een verbod daarom geweigerd. Kort gezegd overwoog hij dat het door BMS gestelde verbeterde effect (meer specifiek: een verbeterde remming van factor Xa door een Ki waarde in het nanomolaire bereik) niet uit de oorspronkelijke aanvrage was af te leiden, noch daarin plausibel was gemaakt, zodat dit effect niet kon worden meegewogen bij de beoordeling van inventiviteit. Bij gebreke van een verbeterd effect als toe te kennen technisch effect aan de verschilmaatregel ten opzichte van WO 131, was er volgens de voorzieningenrechter geen sprake van inventiviteit.

Centrafarm B.V., Centrafarm Services B.V., Centrafarm Nederland B.V. en Stada Service Holding B.V. behoren alle tot de Stada-groep, die zich bezighoudt met de ontwikkeling, productie en distributie van voornamelijk generieke geneesmiddelen. Eén van die generieke geneesmiddelen is Apixaban CF. Apixaban CF is een generieke versie van Eliquis®.

Centrafarm c.s. heeft op 3 januari 2022 marktvergunningen verkregen voor Apixaban CF 2,5 en 5 mg. Centrafarm c.s. heeft op 7 maart 2023 aangekondigd dit product op 18 april 2023 in de G-standaard voor mei 2023 op te nemen en dat zij op 1 mei 2023 op de markt zal komen.

Er zijn verder nietigheidsprocedures tegen buitenlandse delen van EP 415 aanhangig, onder andere in Bulgarije, Denemarken, Finland, Frankrijk, Hongarije, Ierland, Italië, Kroatië, Noorwegen, Polen, Portugal, Slowakije, Spanje, Tsjechië, Zweden en Zwitserland. In al deze landen zijn zustervennootschappen van Teva procespartij. Het Stockholms Tingsrätt, Patent- och marknadsdomstolen in Zweden heeft in een bodemzaak in eerste aanleg het Zweedse deel van EP 415 op 2 november 2022 geldig bevonden. In de Engelse vertaling is daarbij onder meer het volgende overwogen:

According to the court, the skilled person who, with his general knowledge, took part of the patent writing would hold it too probable that apixaban was an fXa inhibitor and in the absence of anything which indicated the opposite would not find grounds for doubt. The mere absence of specific biological data would not have led the skilled person to question the function of apixaban, nor has the investigation in the case revealed anything else that would have given the skilled person reason to doubt the compound’s function as an fXa inhibitor.

(…)

The objective technical problem

The court has concluded above that the problem as formulated in the patent can be considered to have been solved. The objective problem the skilled person is presented with should thus be formulated as the provision of an alternative fXa inhibitor, active as anticoagulants and potentially useful as an active substance for the treatment of thromboembolic conditions.

(…)

In conclusion, it is the court’s assessment that the skilled person with its general knowledge, based on the content of WO 131 and faced with the problem of developing an alternative fXa inhibitor, active as an anticoagulant and potentially useful as an active substance for the treatment of thromboembolic diseases, would not have arrived at the invention according to patent claim 1.

In procedures in Finland en Ierland is onlangs aan Teva als voorlopige voorziening een verbodsmaatregel opgelegd.

In de Verenigde Staten, Canada en Korea heeft BMS met succes de geldigheid verdedigd van de betreffende aan EP '415 equivalente nationale octrooien en er werd geoordeeld dat generieke versies van Eliquis® inbreuk maken.

Op 23 maart 2023 heeft de GKB uitspraak gedaan in de zaak G2/21 aangaande plausibiliteit.25.Hierna zijn enkele overwegingen uit de uitspraak opgenomen:

Referred points of law

I. By interlocutory decision T 116/18 of 11 October 2021 (hereinafter: the referring decision), Technical Board of Appeal 3.3.02 (hereinafter: the referring board) referred the following questions of law to the Enlarged Board of Appeal (hereinafter: the Enlarged Board) for decision under Article 112(1)(a) EPC in combination with Article 22 RPBA 2020:

If for acknowledgement of inventive step the patent proprietor relies on a technical effect and has submitted evidence, such as experimental data, to prove such an effect, this evidence not having been public before the filing date of the patent in suit and having been filed after that date (post-published evidence):

1. Should an exception to the principle of free evaluation of evidence (see e.g. G 3/97, Reasons 5, and G 1/12, Reasons 31) be accepted in that post-published evidence must be disregarded on the ground that the proof of the effect rests exclusively on the post-published evidence?

2. If the answer is yes (the post-published evidence must be disregarded if the proof of the effect rests exclusively on this evidence), can the post-published evidence be taken into consideration if, based on the information in the patent application in suit or the common general knowledge, the skilled person at the filing date of the patent application in suit would have considered the effect plausible (ab initio plausibility)?

3. If the answer to the first question is yes (the post-published evidence must be disregarded if the proof of the effect rests exclusively on this evidence), can the post-published evidence be taken into consideration if, based on the information in the patent application in suit or the common general knowledge, the skilled person at the filing date of the patent application in suit would have seen no reason to consider the effect implausible (ab initio implausibility)?

(…)

Reasons

(…)

56 Hence, evidence submitted by a patent applicant or proprietor to prove a technical effect relied upon for acknowledgement of inventive step of the claimed subject-matter may not be disregarded solely on the ground that such evidence, on which the effect rests, had not been public before the filing date of the patent in suit and was filed after that date.

57 This, however, does not immediately lead to the answering of referred question 1 in the negative, without needing to turn to referred questions 2 and 3 because they are dependent on an affirmative answer to referred question 1. Notwithstanding the specific drafting of the referred questions, the Enlarged Board accepts that the gist of the matter underlying the present referral extends beyond the literal wording of question 1.

(…)

64 The Enlarged Board is aware of the case law cited by the referring board as examples for different approaches to the acceptance of a patent applicant’s or patent proprietor’s reliance on an asserted technical effect (see points VI.(6) to (8) above and points 13.4 to 13.6 of the Reasons for the referring decision). As the volume of decisions on the relevance of post-published evidence, such as experimental data, to prove an alleged technical effect for acknowledgement of inventive step in the context of Article 56 EPC is too big to discuss in detail, the Enlarged Board focusses on a selection of in particular more recent jurisprudence, which the development of the earlier case law appears to culminate in.

[volgt een analyse van enkele beslissingen van de TKB’s aangaande inventiviteit]

Intermediate conclusion

70 The Enlarged Board takes note of the classification done by the referring board in respect of the case law of the boards of appeal concerning the relevance of post-published evidence to prove an asserted technical effect for acknowledgement of inventive step (see points 13.4 to 13.6 of the Reasons for the referring decision).

71 However, when analysing the case law in more detail and irrespective of the conceptual terminologies for what questions 2 and 3 refer to as two distinct plausibility approaches, the Enlarged Board understands from the case law of the boards of appeal as common ground that the core issue rests with the question of what the skilled person, with the common general knowledge in mind, understands at the filing date from the application as originally filed as the technical teaching of the claimed invention.

72 Applying this understanding to the aforementioned decisions, not in reviewing them but in an attempt to test the Enlarged Board's understanding, the Enlarged Board is satisfied that the outcome in each particular case would not have been different from the actual finding of the respective board of appeal. Irrespective of the use of the terminological notion of plausibility, the cited decisions appear to show that the particular board of appeal focussed on the question whether or not the technical effect relied upon by the patent applicant or proprietor was derivable for the person skilled in the art from the technical teaching of the application documents.

Considerations concerning the jurisprudence regarding sufficiency of disclosure

73 As noted in points 11 and 12 above, the referred questions do not require an answer to the issue of sufficiency of disclosure and Article 83 EPC. However, as the terminological notion of plausibility relied upon by the referring board in questions 2 and 3 of the referral and the reasons for it is mainly to be found in the case law of the boards of appeal with regard to the patentability requirement of sufficiency of disclosure, the Enlarged Board accepts the appropriateness of a comparative analysis and comparative considerations in this regard.

74 While the issues of sufficiency of disclosure (Article 83 EPC) and inventive step (Article 56 EPC) and their assessment are clearly to be treated separately and on their own, as correctly pointed out by the referring board in point 13.3.1 of the Reasons of the referring decision, the Enlarged Board is aware of the case law in particular concerning second medical use claims where the notion of "plausibility" has been used. For such claims, the issue of reliance on post-published evidence for a purported technical effect arises in particular in the context of sufficiency of disclosure.

Indeed, a technical effect, which in the case of for example a second medical use claim is usually a therapeutic effect, is a feature of the claim, so that the issue of whether it has been shown that this effect is achieved is a question of sufficiency of disclosure under Article 83 EPC.

[volgt een analyse van enkele beslissingen van de TKB’s aangaande ‘sufficiency of disclosure’ (nawerkbaarheid)]

Intermediate conclusion

77 The reasoned findings of the boards of appeal in the decisions referred to above make clear that the scope of reliance on post published evidence is much narrower under sufficiency of disclosure (Article 83 EPC) compared to the situation under inventive step (Article 56 EPC). In order to meet the requirement that the disclosure of the invention be sufficiently clear and complete for it to be carried out by the person skilled in the art, the proof of a claimed therapeutic effect has to be provided in the application as filed, in particular if, in the absence of experimental data in the application as filed, it would not be credible to the skilled person that the therapeutic effect is achieved. A lack in this respect cannot be remedied by post-published evidence.

National legal framework and jurisprudence with regard to the reliance on a technical effect for inventive step

[volgt een analyse van de jurisprudentie in enkele EPO landen waaronder Nederland]

Intermediate conclusion

86 Like the EPC, none of the legal systems of the EPC Contracting States provide for an explicit patentability requirement for what the referring decision discusses and addresses with what is referred to in questions 2 and 3 under the term "plausibility".

87 Notwithstanding the fact that the aforementioned decisions were taken on the decisive facts of the case in hand and the particular submissions made by the parties to those proceedings, the Enlarged Board recognises a certain degree of common ground that the courts of the EPC Contracting States, when confronted with the examination of an asserted technical effect in the assessment of inventive step and with the question whether a patent proprietor may rely on post-published evidence to confirm that technical effect, ponder on the technical teaching of the claimed subject-matter that the person skilled in the art, with the common general knowledge in mind, understands from the patent application.

Concluding considerations

88 As already mentioned in points 55 to 59 above, the proceedings under the EPC are governed by the principle of free evaluation of evidence which is also known in various EPC Contracting States with a civil law system.

89 The principle of free evaluation of evidence depicts a universally applicable principle of both procedural and substantive law in assessing any means of evidence submitted by a party in proceedings under the EPC, be it an administrative department of the EPO or a board of appeal as the competent judicial body reviewing decisions of such administrative departments pursuant to Article 106(1) EPC.

90 As the principle of free evaluation of evidence is enshrined in the right of each party to proceedings under EPC to give evidence in appropriate form pursuant to Articles 113(1) and 117(1) EPC, it may not be used to disregard evidence per se insofar as it is submitted and relied upon by a party in support of an inference which is challenged as to its plausibility and is decisive for the final decision.

91 Hence, evidence submitted by a patent applicant or proprietor to prove a purported technical effect relied upon for acknowledgement of inventive step of the claimed subject-matter may not be disregarded solely on the ground that such evidence, on which the effect rests, had not been public before the filing date of the patent in suit and was filed after that date.

92 The term "plausibility" that is found in the case law of the boards of appeal and relied upon by the referring board in questions 2 and 3 of the referral and the reasons for it, does not amount to a distinctive legal concept or a specific patent law requirement under the EPC, in particular under Article 56 and 83 EPC. It rather describes a generic catchword seized in the jurisprudence of the boards of appeal, by some national courts and by users of the European patent system.

93 The relevant standard for the reliance on a purported technical effect when assessing whether or not the claimed subject-matter involves an inventive step concerns the question of what the skilled person, with the common general knowledge in mind, would understand at the filing date from the application as originally filed as the technical teaching of the claimed invention. The technical effect relied upon, even at a later stage, needs to be encompassed by that technical teaching and to embody the same invention, because such an effect does not change the nature of the claimed invention.

94 Hence, a patent applicant or proprietor may rely upon a technical effect for inventive step if the skilled person, having the common general knowledge in mind, and based on the application as originally filed, would consider said effect as being encompassed by the technical teaching and embodied by the same originally disclosed invention.

95 The Enlarged Board is aware of the abstractness of some of the aforementioned criteria. However, apart from the fact that the Enlarged Board, in its function assigned to it under Article 112(1) EPC, is not called to decide on a specific case, it is the pertinent circumstances of each case which provide the basis on which a board of appeal or other deciding body is required to judge, and the actual outcome may well to some extent be influenced by the technical field of the claimed invention. Irrespective of the actual circumstances of a particular case, the guiding principles set out above should allow the competent board of appeal or other deciding body to take a decision on whether or not post-published evidence may or may not be relied upon in support of an asserted technical effect when assessing whether or not the claimed subject-matter involves an inventive step.

Order

For these reasons it is decided that the questions of law referred to the Enlarged Board of Appeal are answered as follows:

1. Evidence submitted by a patent applicant or proprietor to prove a technical effect relied upon for acknowledgement of inventive step of the claimed subject-matter may not be disregarded solely on the ground that such evidence, on which the effect rests, had not been public before the filing date of the patent in suit and was filed after that date.

2. A patent applicant or proprietor may rely upon a technical effect for inventive step if the skilled person, having the common general knowledge in mind, and based on the application as originally filed, would derive said effect as being encompassed by the technical teaching and embodied by the same originally disclosed invention.

Op 4 mei 2023 heeft de England and Wales Court of Appeal (Civil Division) uitspraak gedaan.26.Lord Justice Arnold gaf daarbij de unanieme opinie. De beslissing van Meade J. werd daarin bekrachtigd. Arnold analyseert naast de Engelse jurisprudentie ook de uitspraak G 2/21:

G 2/21

43. In G 2/21 the Enlarged Board of Appeal considered three questions about the circumstances in which it was permissible to rely on post-published evidence of a technical effect in support of inventive step. The first question asked whether such evidence had to be disregarded on the ground that proof of the effect rested exclusively on the post-published evidence. The Enlarged Board’s answer was that evidence submitted by a patent applicant or proprietor to prove a technical effect relied on in support of inventive step may not be disregarded solely on the ground that such evidence had not been made public before the filing date of the patent and was filed after that date.

44. Although the referring Board of Appeal only asked its second and third questions on the premise that the answer to the first question was yes, the Enlarged Board considered them anyway. In its decision to refer (T 116/18 Sumitomo/Insecticide compositions, unreported, 11 October 2021) the referring Board had identified what it regarded as two divergent lines of Board of Appeal case law. The first line, represented by decisions such as Johns Hopkins and BMS/Dasatinib, it labelled “ab initio plausibility”. The second line, represented by decisions such as Ipsen, it labelled “ab initio implausibility”. The distinction it saw between these two lines was that, in the first, post-published evidence could be taken into account if, based on the information in the application and the skilled person’s common general knowledge, the skilled person would have considered the technical effect plausible. In the second line, post-published evidence could be taken into account if, based on the information in the application and the skilled person's common general knowledge, the skilled person would not have considered the technical effect implausible.

45. The Enlarged Board began its consideration of these questions by observing at [58] that it considered "the conceptional notion inherent in the term 'plausibility', which is often used as a generic catchword, as not being a distinct condition of patentability and patent validity, but a criterion for the reliance on a purported technical effect". This observation chimes with what Lord Sumption said in Warner-Lambert at [23] and [36].

46. From [60] onwards, the Enlarged Board embarked on an analysis of the "jurisprudence regarding the reliance on a technical effect for inventive step". It began with some "general considerations", referring among other cases to Ipsen. At [66]-[68] it considered cases in the "ab initio plausibility" or "type I" line of case law identified by the referring Board, including Johns Hopkins and BMS/Dasatinib. In [69] it considered cases in the "ab initio implausibility" or "type II" line. It expressed its "intermediate conclusion" as follows:

[volgen paragrafen 70-72 van G 2/21, zie 2.21]

47. In other words, the Enlarged Board regarded the two lines of case law as being reconcilable. In each case, the core question being addressed was what the technical teaching of the application was to the skilled person with the common general knowledge in mind at the filing date, and whether the technical effect relied upon by the patent applicant or proprietor was derivable from the application.

48. Although the reference was only concerned with inventive step, at [73]-[76] the Enlarged Board considered the case law of the Boards of Appeal regarding sufficiency, in particular in the context of second medical use claims. It expressed its "intermediate conclusion" on those cases at [77] as follows:

[volgt paragraaf 77 van G 2/21, zie 2.21]

49. In my view it is tolerably clear that the Enlarged Board's reference to "a claimed therapeutic effect" means a therapeutic effect which is asserted as the basis for a second medical use claim.

50. At [78]-[85] the Enlarged Board turned to consider decisions of courts of EPC contracting states "with regard to the reliance on technical effect for inventive step". In particular, at [84]-[85] it considered judgments of the UK courts, including Warner-Lambert and the judgment under appeal in the present case. It expressed its "intermediate conclusion" as follows:

[volgen paragrafen 86-87 van G 2/21, zie 2.21]

51. In other words, the Enlarged Board interpreted the decisions of the national courts as approaching matters in a similar manner to the Board of Appeal decisions which it had encapsulated in [71]-[72].

52. At [88]-[95] the EBA set out its "concluding considerations", including the following:

[volgen paragrafen 92-95 van G 2/21, zie 2.21]

53. It is clear from these observations as well as the Enlarged Board's earlier reasoning that the fundamental consideration when a court or tribunal is considering whether a claimed invention involves an inventive step is whether the technical effect asserted by the patent applicant or proprietor is derivable by the skilled person from the application as filed read with the common general knowledge. It is perhaps worth adding that this passage (and in particular the last sentence of [93]) confirms that the parties in this case were correct to agree that the issues of inventive step and sufficiency should be assessed by reference to the Application and not the Patent.

[Na de analyse van de jurisprudentie, past Arnold deze toe op de zaak:]

BMS's case on plausibility

81. Prior to trial BMS was ordered to, and did, serve a statement of its case on plausibility which it subsequently amended in minor respects. It is not necessary for present purposes to set this out, but for reasons that will appear it is important to note that there was no averment that the skilled team reading the Application with the benefit of their common general knowledge would interpret the Application as disclosing (whether explicitly or implicitly) that apixaban (or any compounds of the invention) had been tested and found to have nanomolar Kis

(…)

90. Before turning to consider these grounds, it is important to note that BMS does not contend that the invention claimed in claim 1 of the Patent involved an inventive step and was sufficiently disclosed in the Application on the basis that the technical problem solved, and the technical contribution made, by the invention was merely the identification of a new chemical compound. On the contrary, BMS contends that the claimed invention involves an inventive step and was sufficiently disclosed because apixaban is an effective factor Xa inhibitor, as has subsequently been confirmed.

Grounds 1-4

91. These grounds can be considered together since they are essentially alternative submissions. The starting point here is that it is common ground that the majority judgment in Warner-Lambert is binding on this Court at least in cases involving claims to second medical uses, and it is not suggested by BMS that G 2/21 would justify this Court in departing from Warner-Lambert in such a case. Equally, however, it is common ground that there is a factual difference between Warner-Lambert and the present case since claim 1 of the Patent is a claim to a single chemical compound. The question is whether that factual difference means that the present case is legally distinguishable from Warner-Lambert, as BMS argues.

92. In my judgment the answer to that question is no. (…)

Ground 5

98. The Claimants object that this ground raises a new case which was not advanced below, and argue that BMS should not be given permission to advance the new case on appeal because it would have affected the evidence given at trial. Counsel for BMS denied that the case was a new one. He did not argue that, if it was new, BMS should nevertheless be permitted to advance it on appeal. The judge's view, as he made clear when BMS applied to him for permission to appeal, was that BMS had not advanced any case that the Application impliedly disclosed that apixaban had a nanomolar Ki at trial. This Court should be slow to question the judge's view given that he was best placed to know what case BMS ran at trial, but in any event I consider he was plainly correct and that this is a new case. As noted above, BMS's statement of case on plausibility did not aver that the skilled team reading the Application with the benefit of their common general knowledge would interpret the Application as disclosing (whether explicitly or implicitly) that apixaban (or any compounds of the invention) had been tested and found to have nanomolar Kis. Nor did BMS adduce any evidence to that effect, put that proposition to any of the Claimants' witnesses or advance such a case in submissions. Instead, the case which BMS advanced at trial was that the Application impliedly disclosed that apixaban had been tested and found to have a Ki of <10 µM.

99. I would add that this ground cannot assist BMS anyway. If the judge was correct that the Application did not impliedly disclose that apixaban had been tested and found to have a Ki of <10 µM, as I consider that he was for the reasons explained below, it necessarily follows that it did not impliedly disclose that apixaban had been tested and found to have a nanomolar Ki.

Ground 6

100. Ground 6 amounts to a bald assertion that the judge was wrong in his evaluation of plausibility. As BMS's own submissions to the judge correctly recognised, however, plausibility involves a multi-factorial evaluation. It follows that this Court is only justified in intervening if the judge has made an error of law or principle: compare Actavis Group PTC EHF v ICOS Corp [2019] UKSC 15, [2019] Bus LR 1318 at [78]-[81] (Lord Hodge) and see Re Sprintroom Ltd [2019] EWCA Civ 932, [2019] BCC 1031 at [72]-[78] (McCombe, Leggatt and Rose LJJ). Counsel for BMS sought to get round this difficulty by arguing that the limited matters which BMS now relied upon merely involved interpretation of the Application and thus could be reviewed by this Court. I accept this point so far as the passage at page 170 line 28-32 is concerned, but counsel for BMS made no serious attempt to argue that the judge had misinterpreted that passage.re Rather, he concentrated his submissions on Example 18, and in particular the statements I have highlighted in paragraph 74 above. He stressed that much more of apixaban was made than was reported in any other Example and that a second recrystallisation step was performed unlike in any other Example.

101. There is no dispute as to what Example 18 says, however, or what the highlighted statements mean. The issue is what the skilled team would think the patentee's reason was for making 3 g of apixaban given that no explanation is given in the Application. Counsel for BMS argued that the skilled team would infer that this was because early results had been favourable and the patentee wanted to take work on the compound forwards. The problem with this argument is that the judge made a finding, based on the expert evidence, that the skilled team reading Example 18 would think that, although that was a possible explanation, there were other possible reasons why the patentee had made such a large quantity of apixaban. Counsel for BMS did not submit that the judge's finding as to the existence of other possible reasons which would occur to the skilled reader based on their common general knowledge and their reading of the Application was not open to him on the evidence. It follows that the skilled team would not draw the inference for which BMS contend. I would add that BMS's argument presupposes that the patentee had carried out a prior synthesis of apixaban to that reported in Example 18, whereas there is no hint of that in the Application.

102. Counsel for BMS also argued that the judge had not taken into account the second recrystallisation performed in Example 18. It is true that the judge did not mention this, but it does not assist BMS. It is clear from Example 18 that the extra step of recrystallisation was performed in order to increase the yield. Thus this adds nothing of substance to the disclosure that a much greater quantity of apixaban was made than of any other compound.

103. It follows that the judge made no error in his assessment of the significance of Example 18. Indeed, I agree with it.

104. Counsel for BMS's final argument was that the judge had failed to consider the combined effect of the passage at page 170 lines 28-32 and Example 18. This argument goes nowhere for two reasons. First, the judge explicitly considered the cumulative effect of the points relied upon by BMS and held that the whole was no greater than the sum of the parts.

105. Secondly, as the judge rightly held, there is nothing in the Application to link the assay results briefly summarised at page 170 lines 28-32 with apixaban. Apixaban may have been one of the compounds tested, but it may not. One does not know because, for whatever reason, the Application does not identify which compounds have been tested, nor does it reveal the actual results which have been obtained. Thus the Application does not disclose either expressly or impliedly that apixaban has been tested and found to have Ki of <10 µM (let alone nanomolar Ki). In the absence of any theory based on e.g. its structure or any data in the specification, there is simply nothing in the Application to support the assertion that apixaban is a factor Xa inhibitor, let alone a factor Xa inhibitor of sufficient potency to be useful in therapy. The assertion is not plausible because the Application gives the skilled team no reason for thinking that there is a reasonable prospect that the assertion will prove to be true. It is therefore speculative. It follows that the invention claimed in claim 1 of the Patent made no technical contribution to the art. It is irrelevant that BMS subsequently proved that the assertion was well founded and limited the claim to apixaban.

Conclusion

106. For the reasons given above I would dismiss this appeal.

BMS vordert een inbreukverbod en een verbod tot onrechtmatig handelen door aan te zetten tot inbreuk, met nevenvorderingen (opgave, recall en rectificatie) en met veroordeling van Sandoz/Centrafarm in de volledige proceskosten.

Ter onderbouwing van haar (neven)vorderingen stelt BMS – samengevat – dat Apixaban Sandoz en Apixaban CF voldoen aan de kenmerken van conclusies 1 tot en met 4 van EP 415 alsmede onder het ABC vallen. Door de opname in de mei-editie 2022 respectievelijk 2023 van de G-standaard en de verhandeling sedertdien is er een concrete dreiging van directe inbreuk (dan wel handelt Sandoz/Centrafarm onrechtmatig ten opzichte van BMS), waarmee BMS recht heeft op en belang bij de voorlopige maatregelen.

Sandoz/Centrafarm voert verweer en betoogt onder meer dat EP 415 ongeldig is vanwege gebrek aan inventiviteit. EP 415 betreft een selectie-uitvinding, daar het een verbinding onder bescherming stelt (die later de stofnaam apixaban heeft gekregen) die in WO 131 al is geopenbaard (als een van de mogelijkheden van de daarin beschreven Markush-formules). In de oorspronkelijke aanvraag (WO 652) is het technisch effect van apixaban niet plausibel gemaakt, laat staan een ten opzichte van de in WO 131 geopenbaarde groep verbindingen verrassend effect. Daarmee is er een gerede kans dat de Nederlandse rechter in een bodemprocedure het Nederlandse deel van EP 415 nietig zal verklaren (evenals het daarop gebaseerde ABC), zodat de vorderingen van BMS moeten worden afgewezen, aldus Sandoz/Centrafarm. Voorts verzoekt Sandoz/Centrafarm BMS te veroordelen in de volledige en evenredige kosten van het geding op de voet van artikel 1019h Rv, te voldoen binnen vijf werkdagen na de datum van dit vonnis, bij gebreke waarvan voormeld bedrag wordt vermeerderd met de wettelijke rente als bedoeld in artikel 6:119 BW27.vanaf de zesde werkdag na datum van dit vonnis tot de dag van volledige betaling.

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

Bevoegdheid

De voorzieningenrechter

in de zaak C/09/644989 KG ZA 23-240

wijst de vorderingen af;

veroordeelt BMS in de kosten van het geding, tot op heden aan de zijde van Sandoz begroot op € 60.676,-, één en ander te voldoen binnen vijf werkdagen na de datum van dit vonnis en – voor het geval voldoening van de kosten niet binnen de gestelde termijn plaatsvindt – te vermeerderen met de wettelijke rente als bedoeld in artikel 6:119 BW over de kosten te rekenen vanaf de zesde werkdag na de datum van dit vonnis tot aan de dag van volledige betaling;

verklaart de proceskostenveroordeling uitvoerbaar bij voorraad;

en in de zaak C/09/644996 KG ZA 23-244

wijst de vorderingen af;

veroordeelt BMS in de kosten van het geding, tot op heden aan de zijde van Centrafarm c.s. begroot op € 60.676,-, één en ander te voldoen binnen vijf werkdagen na de datum van dit vonnis en – voor het geval voldoening van de kosten niet binnen de gestelde termijn plaatsvindt – te vermeerderen met de wettelijke rente als bedoeld in artikel 6:119 BW over de kosten te rekenen vanaf de zesde werkdag na de datum van dit vonnis tot aan de dag van volledige betaling;

verklaart de proceskostenveroordeling uitvoerbaar bij voorraad;

BMS vordert - samengevat - een inbreukverbod en een verbod tot onrechtmatig handelen door aan te zetten tot inbreuk, met nevenvorderingen (opgave, recall en rectificatie) en met veroordeling van Teva in de volledige proceskosten.

Ter onderbouwing van haar (neven)vorderingen stelt BMS – samengevat – dat Apixaban Sandoz en Apixaban CF voldoen aan de kenmerken van conclusies 1 tot en met 4 van EP 415 alsmede onder het ABC vallen. Door de opname in de juni editie 2023 van de G-standaard is er een concrete dreiging van directe inbreuk (dan wel handelt Teva onrechtmatig ten opzichte van BMS), waarmee BMS recht heeft op en belang bij de voorlopige maatregelen.

Teva c.s. voert verweer strekkende tot afwijzing van de vorderingen van BMS, met veroordeling van BMS in de proceskosten op grond van artikel 1019h Rv, vermeerderd met de wettelijke rente, uitvoerbaar bij voorraad

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

Partijen zijn het erover eens dat in dit vonnis een zelfde oordeel dient te worden gegeven als in het vonnis van 17 mei jl. Hoewel BMS het niet met de inhoud van dat vonnis eens is, begrijpt zij dat in deze zaak op dezelfde wijze zal worden geoordeeld door de voorzieningenrechter en geeft zij er de voorkeur aan om alle zaken in een keer in beroep voor te leggen. Conform de wens van partijen en nu hij voorshands geen reden ziet om daarvan af te wijken, zal de voorzieningenrechter om dezelfde redenen als hiervoor weergegeven in het vonnis van 17 mei jl. de gevraagde voorziening afwijzen. Kort gezegd, is er een gerede kans dat de bodemrechter het octrooi van BMS ongeldig zal achten.

Proceskosten

Partijen hebben een proceskostenafspraak gemaakt. Deze houdt in dat BMS zal worden veroordeeld in de proceskosten van Teva c.s. ten bedrage van € 60.000,-. Genoemd bedrag zal daarom aan Teva c.s. worden toegewezen.

De voorzieningenrechter

wijst de vorderingen af;

veroordeelt BMS in de kosten van deze procedure aan de zijde van Teva c.s. tot dusverre begroot op € 60.000,-, vermeerderd met de wettelijke rente over deze kosten als deze niet binnen veertien dagen na betekening van dit vonnis zijn voldaan;

verklaart dit vonnis uitvoerbaar bij voorraad;

wijst het meer of anders gevorderde af.

Dit vonnis is gewezen door mr. E.F. Brinkman en in het openbaar uitgesproken op

31 mei 2023.