Uitspraken

Het verloop van de procedure blijkt uit:

- het vonnis in de provisionele voorziening van 1 november 2018 en de daarin genoemde gedingstukken.

wherein:

P1 and P2 independently represent hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, amino alkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;

R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radicals, -NO2, -C≡N, CF3, -OR9, -SR9, wherein R9 represents hydrogen and alkyl radicals;

R3 represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical; and

R4 represents radicals as defined by R3 except for hydrogen;
wherein aryl wherever occuring may optionally carry one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl;

wherein heterocycle or heteroaryl may optionally be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo and/or on a secondary nitrogen atom by alkyl, aralkoxycrbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom by oxido and which is attached via a carbon atom;

and the pharmaceutically acceptable salt, ester, or prodrug thereof.

R3 represents alkyl, cycloalkyl, cycloalkylalkyl, isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl, or n-propyl; and

R4 represents aryl, alkyl, aryl, para-substituted aryl, heteroaryl, Phenyl, para-methoxyphenyl, para-cyanophenyl, para-chlorophenyl, para-hydroxyphenyl, para-nitrophenyl, para-fluorophenyl, 2-naphthyl, 3-pyridyl, 3-pyridyl N-oxide, 4‑pyridyl, or 4-pyridyl N-oxide.

(…)

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-fluorophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-nitrophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-chlorophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-acetamidophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-aminophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;
Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-fluorophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-nitrophenylsulfonyl) amino]-1S-(phenylmethyl)propyl] carbamate;

Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-chlorophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl) (4-methoxyphenylsulfonyl) amino]-1S-(4-fluorophenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl) (4-fluorophenylsulfonyl amino]-1S-(4-fluorophenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(butyl)(phenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(cyclohexylmethyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(cyclohexyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Pentanamide, 2S-[[(dimethylamino)acetyl]amino]-N-2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl] -3S-methyl;

Pentanamide, 2S-[[(methylamino)acetyl]amino]-N-2R-hydroxy-3-[(4-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl;

Pentanamide, 2S-[[(dimethylamino)acetyl]amino]-N-2R-hydroxy-3-[(4-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl;

[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine;

2R-hydroxy-3-[(2-methylpropyl)(4-hydroxypnenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine;

[2R-hydroxy-3-[(phenylsulfonyl)(3-methylbutyl) amino]-1S-(phenylmethyl) propylamine;

[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl) amino]-1S-(phenylmethyl)propylamine;

[2R-hydroxy-3-[(phenylsulfonyl)(cyclohexylmethyl)amino]-1S-(phenylmethyl)propylamine;

[2R-hydroxy-3-[(phenylsulfonyl)(cyclohexyl)amino]-1S-(phenylmethyl)propylamine;
4-Pyridinecarboxamide,
N-[2R-hydroxy-3-[[(4-methoxyphenyl) sulfonyl](2-methylpropyl) amino] -1S-(phenylmethyl)propyl];

Benzamide,
N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2,6-dimethyl;

Benzamide,
N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl;

Benzamide,
N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-ethyl;

Benzamide,
N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-chloro;

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester, N-oxide;

Carbamic acid, [2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 4-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2 - methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 4-pyridylmethyl ester, N-oxide;

Carbamic acid, [2R-hydroxy-3-[[(4-chlorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester; or

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 5-pyrimidylmethyl ester.

wherein

P1 represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl or heteroaroyl radicals;
P2 represents hydrogen;
R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with alkyl, halogen, -NO2, -CN, CF3, -OR9 or SR9 radicals, wherein R9 represents hydrogen or alkyl radicals;
R3 represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, aryl, aralkyl or heteroaralkyl radicals; and
R4 represents alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl or aralkyl radicals; and

wherein alkyl, alone or in combination, is a straight-chain or branched-chain hydrocarbon radical having from 1 to 8 carbon atoms; alkenyl, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and from 2 to 8 carbon atoms; alkynyl, alone or in combination, means a straight -chain hydrocarbon radical having one or more triple bonds and from 2 to 10 carbon atoms; cycloalkyl, alone or in combination, is a hydrocarbon ring containing from 3 to 8 carbon atoms; aryl, alone or in combination, means a phenyl or naphthyl radical optionally substituted with alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano or haloalkyl radicals; heterocyclyl or heterocycloalkyl means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having one or more nitrogen, oxygen or sulphur heteroatoms, which is optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy or oxo radicals, or on a secondary nitrogen atom by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl radicals, or on a tertiary nitrogen atom by oxido radical; and heteroaryl means an aromatic heterocyclyl radical which is optionally substituted as defined above with respect to the definition of heterocyclyl;
wherein aryl wherever occuring may optionally carry one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl;
wherein heterocycle or heteroaryl may optionally be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo and/or on a secondary nitrogen atom by alkyl, aralkoxycrbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom by oxido and which is attached via a carbon atom;
and the pharmaceutically acceptable salt, ester, prodrug thereof.

(…)

P1 represents alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;

P2 represents hydrogen;

R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radicals, -NO2, -C≡N, CF3, -OR9, -SR9, wherein R9 represents hydrogen and alkyl radicals;

R3 represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical; and
R4 represents radicals as defined by R3 except for hydrogen;

wherein aryl wherever occurring may optionally carry one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl;
wherein heterocycle or heteroaryl may optionally be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo and/or on a secondary nitrogen atom by alkyl, aralkoxycrbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom by oxido and which is attached via a carbon atom;
and the pharmaceutically acceptable salt, prodrug or ester thereof.

R2 represents cycloalkylalkyl, aralkyl, alkyl, benzyl, cyclohexylmethyl, 2‑naphthylmethyl, para-fluorobenzyl, para-methoxybenzyl, isobutyl, or n-butyl;

R3 represents alkyl, cycloalkyl, cycloalkylalkyl, isobmyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl, or n-propyl; and

R4 represents aryl, alkyl, aryl, para-substituted aryl, heteroaryl, phenyl, para-methoxyphenyl, para-cyanophenyl, para-chlorophenyl, para-hydroxyphenyl, para-nitrophenyl, para-fluorophenyl, 2-naphthyl, 3-pyridyl, 3-pyridyl N-oxide, 4‑pyridyl, or 4-pyridyl N-oxide.

waarbij:

P1 en P2 onafhankelijk waterstof, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, amino alkanoyl, en mono- en di-gesubstitueerde aminocarbonyl- en mono- en di-gesubstitueerde aminoalkanoylgroepen voorstellen, waarbij de substituenten zijn gekozen uit alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkylgroepen, of waar genoemd aminoalkanoylgroep di-gesubstitueerd is, genoemde substituenten samen met het stikstofatoom waaraan ze zijn gehecht een heterocycloalkyl- of heteroarylgroep vormen;

R2 alkyl-, aryl-, cycloalkyl-, cycloalkylalkyl- en aralkylgroepen voorstelt, waarbij de groepen optioneel zijn gesubstitueerd met een groep gekozen uit alkyl- en halogeengroepen, -NO2, -CN, CF3, -OR9 of SR9, waarbij R9 waterstof en alkylgroepen voorstelt;

R3 waterstof, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl en mono- en di-gesubstitueerde aminoalkylgroepen voorstelt, waarbij genoemde substituenten zijn gekozen uit alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, en heterocycloalkylalkylgroepen, of in het geval van een di-gesubstitueerde aminoalkylgroep vormen genoemde substituenten, samen met het stikstofatoom waaraan ze zijn gehecht, een heterocycloalkyl- of een heteroarylgroep; en

R4 groepen voorstelt zoals gedefinieerd door R3, met uitzondering van waterstof;

waarbij aryl, wanneer het voorkomt, optioneel één of meer substituenten kan dragen, gekozen uit alkyl, alkoxy, halogeen, hydroxy, amino, nitro, cyano, haloalkyl;

waarbij heterocyclus of heteroaryl optioneel op één of meer koolstofatomen gesubstitueerd kan zijn door halogeen, alkyl, alkoxy, oxo en/of op een secundair stikstofatoom door alkyl, aralkoxycarbonyl, alkanoyl, fenyl of fenylalkyl of op een tertiair stikstofatoom door oxido en dat is gehecht via een koolstofatoom;

en het farmaceutisch aanvaardbare zout, ester, of prodrug daarvan.

R2 cycloalkylalkyl, aralkyl, alkyl, benzyl, cyclohexylmethyl, 2-naftylmethyl, para-fluorobenzyl, para-methoxybenzyl, isobutyl, of n-butyl voorstelt;

R3 alkyl, cycloalkyl, cycloalkylalkyl, isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n‑butyl, of n-propyl voorstelt; en

R4 aryl, alkyl, aryl, para-gesubstitueerd aryl, heteroaryl, fenyl, para-methoxyfenyl, para-cyanofenyl, para-chlorofenyl, para-hydroxyfenyl, para-nitrofenyl, para-fluorofenyl, 2-naftyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, of 4-pyridyl N-oxide voorstelt.
(…)

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(fenylsulfonyl)amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-methoxyfenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-fluorofenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-nitrofenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-chlorofenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-acetamidofenylsulfonyl)amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-aminofenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(4-methoxyfenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-fluorofenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-nitrofenylsulfonyl) amino]-1S-(fenylmethyl)propyl] carbamaat;
Fenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-chlorofenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl) (4-methoxyfenylsulfonyl) amino]-1S-(4-fluorofenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(2-methylpropyl) (4-fluorofenylsulfonyl) amino]-1S-(4-fluorofenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(butyl)(fenylsulfonyl) amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(cyclohexylmethyl)(fenylsulfonyl)amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(cyclohexyl)(fenylsulfonyl)amino]-1S-(fenylmethyl)propyl]carbamaat;

Fenylmethyl[2R-hydroxy-3-[(propyl)(fenylsulfonyl)amino]-1S-(fenylmethyl)propyl]carbamaat;

Pentanamide, 2S-[[(dimethylamino)acetyl]amino]-N-2R-hydroxy-3-[(3-methylpropyl)(4-methoxyfenylsulfonyl)amino]-1S-(fenylmethyl)propyl] -3S-methyl;

Pentanamide, 2S-[[(methylamino)acetyl]amino]-N-2R-hydroxy-3-[(4-methylbutyl)(fenylsulfonyl)amino]-1S-(fenylmethyl)propyl]-3S-methyl;

Pentanamide, 2S-[[(dimethylamino)acetyl]amino]-N-2R-hydroxy-3-[(4-methylbutyl)(fenylsulfonyl)amino]-1S-(fenylmethyl)propyl]-3S-methyl;

[2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propylamine;

2R-hydroxy-3-[(2-methylpropyl)(4-hydroxypnenyl)sulfonyl]amino-1S-(fenylmethyl)propylamine;

[2R-hydroxy-3-[(fenylsulfonyl)(3-methylbutyl) amino]-1S-(fenylmethyl) propylamine;

[2R-hydroxy-3-[(fenylsulfonyl)(2-methylpropyl) amino]-1S-(fenylmethyl)propylamine;

[2R-hydroxy-3-[(fenylsulfonyl)(cyclohexylmethyl)amino]-1S-(fenylmethyl)propylamine;

[2R-hydroxy-3-[(fenylsulfonyl)(cyclohexyl)amino]-1S-(fenylmethyl)propylamine;

4-Pyridinecarboxamide,
N-[2R-hydroxy-3-[[(4-methoxyfenyl) sulfonyl](2-methylpropyl) amino] -1S-(fenylmethyl)propyl];

Benzamide,
N-[2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-2,6-dimethyl;

Benzamide,
N-[2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-2-methyl;

Benzamide,
N-[2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-2-ethyl;

Benzamide,
N-[2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-2-chloro;

Carbamidezuur, [2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamidezuur, [2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 3-pyridylmethyl ester, N-oxide;

Carbamidezuur, [2R-hydroxy-3-[[fenylsulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamidezuur, [2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 4-pyridylmethyl ester;

Carbamidezuur, [2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2 - methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 4-pyridylmethyl ester, N-oxide;

Carbamidezuur, [2R-hydroxy-3-[[(4-chlorofenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamidezuur, [2R-hydroxy-3-[[(4-nitrofenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamidezuur, [2R-hydroxy-3-[[(4-fluorofenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamidezuur, [2R-hydroxy-3-[[(4-hydroxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 3-pyridylmethyl ester; of

Carbamidezuur, [2R-hydroxy-3-[[(4-methoxyfenyl)sulfonyl](2-methylpropyl)amino]-1S-(fenylmethyl)propyl]-, 5-pyrimidylmethyl ester
is.

waarbij

P1 alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl of heteroaroylgroepen voorstelt;
P2 waterstof voorstelt;
R2 alkyl, aryl, cycloalkyl, cycloalkylalkyl of aralkylgroepen voorstelt, waarbij de groepen optioneel zijn gesubstitueerd met alkyl, halogeen, -NO2, -CN, CF3, -OR9 of SR9 groepen, waarbij R9 waterstof of alkylgroepen voorstelt;
R3 alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, aryl, aralkyl of heteroaralkylgroepen voorstelt; en
R4 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl of aralkylgroepen voorstelt; en

waarbij alkyl, alleen of in combinatie, een rechte-keten of vertakte-keten koolwaterstofgroep is met van 1 tot 8 koolstofatomen; alkenyl, alleen of in combinatie, een rechte-keten of vertakte-keten koolwaterstofgroep betekent met één of meer dubbele bindingen en van 2 tot 8 koolwaterstofatomen; alkynyl, alleen of in combinatie, een rechte-keten koolwaterstofgroep betekent met één of meer drievoudige bindingen en van 2 tot 10 koolwaterstofatomen; cycloalkyl, alleen of in combinatie, een koolwaterstofring is, bevattende van 3 tot 8 koolwaterstofatomen; aryl, alleen of in combinatie, een fenyl- of naftylgroep betekent, optioneel gesubstitueerd met alkyl, alkoxy, halogeen, hydroxy, amino, nitro, cyano of haloalkylgroepen; heterocyclyl of heterocycloalkyl een verzadigde of gedeeltelijk onverzadigde monocyclische, bicyclische of tricyclische heterocyclus betekent met één of meer stikstof-, zuurstof- of zwavelheteroatomen, die op één of meer koolwaterstofatomen optioneel gesubstitueerd zijn door halogeen, alkyl, alkoxy of oxogroepen, of een secundair stikstofatoom door alkyl, aralkoxycarbonyl, alkanoyl, fenyl of fenylalkylgroepen, of op een tertiair stikstofatoom door oxidogroep; en heteroaryl een aromatische heterocyclylgroep betekent die optioneel is gesubstitueerd zoals hierboven gedefinieerd met betrekking tot de definitie van heterocyclyl;
waarbij aryl, wanneer het voorkomt, optioneel één of meer substituenten kan dragen, gekozen uit alkyl, alkoxy, halogeen, hydroxy, amino, nitro, cyano, haloalkyl;
waarbij heterocyclus of heteroaryl optioneel op één of meer koolstofatomen gesubstitueerd kan zijn door halogeen, alkyl, alkoxy, oxo en/of op een secundair stikstofatoom door alkyl, aralkoxycarbonyl, alkanoyl, fenyl of fenylalkyl of op een tertiair stikstofatoom door oxido en dat is gehecht via een koolstofatoom;
en het farmaceutisch aanvaardbare zout, ester, of prodrug daarvan.

(…)

waarbij:

P1 alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, en mono- en di-gesubstitueerde aminocarbonyl- en mono- en di-gesubstitueerde aminoalkanoylgroepen voorstelt, waarbij de substituenten zijn gekozen uit alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylgroepen, of waar genoemde aminoalkanoylgroep di-gesubstitueerd is, genoemde substituenten samen met het stikstofatoom waaraan ze zijn gehecht een heterocycloalkyl- of heteroarylgroep vormen;
P2 waterstof voorstelt;

R2 alkyl, aryl, cycloalkyl, cycloalkylalkyl en aralkylgroepen voorstelt, waarbij de groepen optioneel gesubstitueerd zijn met een groep gekozen uit alkyl- en halogeengroepen, -NO2, -C≡N, CF3, -OR9, -SR9, waarbij R9 waterstof- en alkylgroepen voorstelt;

R3 waterstof, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl en mono- en di-gesubstitueerde aminoalkylgroepen voorstelt, waarbij genoemde substituenten zijn gekozen uit alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, en heterocycloalkylalkylgroepen, of in het geval van een di-gesubstitueerde aminoalkylgroep vormen genoemde substituenten, samen met het stikstofatoom waaraan ze zijn gehecht, een heterocycloalkyl- of een heteroarylgroep; en

R4 groepen voorstelt zoals gedefinieerd door R3, met uitzondering van waterstof;

waarbij aryl, wanneer het voorkomt, optioneel één of meer substituenten kan dragen, gekozen uit alkyl, alkoxy, halogeen, hydroxy, amino, nitro, cyano, haloalkyl;
waarbij heterocyclus of heteroaryl optioneel op één of meer koolstofatomen gesubstitueerd kan zijn door halogeen, alkyl, alkoxy, oxo en/of op een secundair stikstofatoom door alkyl, aralkoxycarbonyl, alkanoyl, fenyl of fenylalkyl of op een tertiair stikstofatoom door oxido en dat is gehecht via een koolstofatoom;
en het farmaceutisch aanvaardbare zout, prodrug of ester daarvan.

R2 cycloalkylalkyl, aralkyl, alkyl, benzyl, cyclohexylmethyl, 2-naftylmethyl, para-fluorobenzyl, para-methoxybenzyl, isobutyl, of n-butyl voorstelt;

R3 alkyl, cycloalkyl, cycloalkylalkyl, isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl, of n-propyl voorstelt; en

R4 aryl, alkyl, aryl, para-gesubstitueerd aryl, heteroaryl, fenyl, para-methoxyfenyl, para-cyanofenyl, para-chlorofenyl, para-hydroxyfenyl, para-nitrofenyl, para-fluorofenyl, 2-naftyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, of 4-pyridyl N-oxide voorstelt.

(…)

BRIEF DESCRIPTION OF THE INVENTION

[0008] The present invention is directed to virus inhibiting compounds and compositions. More particularly, the present invention is directed to retroviral protease inhibiting compounds and compositions, to the use of such compounds for preparing medicaments for inhibiting proteases, especially for inhibiting HIV protease and for treating a retroviral infection such as HIV infection and for treating AIDS, to processes for preparing the compounds and to intermediates useful in such processes. The subject compounds are characterized as sulfonamide-containing hydroxyethylamine inhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention provides retroviral protease inhibitor compounds represented by the Formula I:

wherein:

(…)

[0010] Preferred compounds thereof are those wherein P1 and P2 independently represent hydrogen, alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkoxycarbonyl, aroyl, heteroaroyl, alkanoyl, cycloalkanoyl, 3-pyridylmethyloxycarbonyl, 3-pyridylmethyloxycarbonyl N-oxide, 4-pyridylmethyloxycarbonyl, 4-pyridylmethyloxycarbonyl N-oxide, 5-pyrimidylmethyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, 2-propyloxycarbonyl, benzyloxycarbonyl, cycloheptylcarbonyl, cyclohexylcarbonyl, cyclopentylcarbonyl, benzoyl, 2-substituted benzoyl, 4-pyridylcarbonyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2-chlorobenzoyl, 2-ethylbenzoyl, 2,6-dimethylbenzoyl, 2,3-dimethylbenzoyl, 2,4-dimethylbenzoyl, or 2,5-dimethylbenzoyl;

R2 represents cycloalkylalkyl, aralkyl, alkyl, benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-flurobenzyl, para-methoxybenzyl, isobutyl, or n-butyl;

R3 represents alkyl, cycloalkyl, cycloalkylalkyl, isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl, or n-propyl; and

R4 represents aryl, alkyl and heteroaryl, aryl, para-substituted aryl, heteroaryl, phenyl, para-methoxyphenyl, para-cyanophenyl, para-chlorophenyl, para-hydroxyphenyl, para-nitrophenyl, para-fluorophenyl, 2-naphthyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, or 4-pyridyl N-oxide.

[0011] Further preferred compounds are those of formula I, wherein

R2 represents cycloalkylalkyl, aralkyl, alkyl, benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-fluorobenzyl, para-methoxybenzyl, isobutyl, or n-butyl;

R3 represents alkyl, cycloalkyl, cycloalkylalkyl, isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl, or n-propyl; and

R4 represents aryl, alkyl, aryl, para-substituted aryl, heteroaryl, phenyl, para-methoxyphenyl, para-cyanophenyl, para-chlorophenyl, para-hydroxyphenyl, para-nitrophenyl, para-fluorophenyl, 2-naphthyl, 3-pyridyl, 3-pyridyl-N-oxide, 4-pyridyl or 4-pyridyl-N-oxide.

[0012] Preferred compounds are the following ones:

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-fluorophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-nitrophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl) (4-chlorophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl) (4-acetamidophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl) (4-aminophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-methoxyphenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-fluorophenylsulfonyl) amino]-1S-(phenylmethyl) propyl] carbamate;

Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-nitrophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (4-chlorophenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl) (4-methoxyphenylsulfonyl) amino]-1S-(4-fluorophenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-fluorophenylsulfonyl) amino]-1S-(4-fluorophenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(butyl) (phenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(cyclohexylmethyl) (phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(cyclohexyl) (phenylsulfonyl) amino]-1S-(phenylmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(propyl) (phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;

Pentanamide, 2S-[[(dimethylamino)acetyl]amino]-N-2R-hydroxy-3-[(3-methylpropyl) (4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl;

Pentanamide, 2S-[[(methylamino)acetyl]amino]-N-2R-hydroxy-3-[(4-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl;

Pentanamide, 2S-[[(dimethylamino)acetyl]amino]-N-2R-hydroxy-3-[(4-methylbutyl) (phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl;

[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine;

2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine;

[2R-hydroxy-3-[(phenylsulfonyl) (3-methylbutyl)amino]-1S-(phenylmethyl)propylamine;

[2R-hydroxy-3-[(phenylsulfonyl) (2-methylpropyl) amino] -1S-(phenylmethyl)propylamine;

[2R-hydroxy-3-[(phenylsulfonyl) (cyclohexylmethyl)amino]-1S-(phenylmethyl)propylamine;

[2R-hydroxy-3-[(phenylsulfonyl)(cyclohexyl)amino]-1S-(phenylmethyl)propylamine;

4-Pyridinecarboxamide, N-[2R-hydroxy-3-[[(4-methoxyphenyl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl];

Benzamide, N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2,6-dimethyl;

Benzamide, N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl;

Benzamide, N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-ethyl;

Benzamide, N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-chloro;

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester, N-oxide;

Carbamic acid, [2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino-]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 4-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 4-pyridylmethyl ester, N-oxide;

Carbamic acid, [2R-hydroxy-3-[[(4-chlorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester;

Carbamic acid, [2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester; or

Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 5-pyrimidylmethyl ester.

[0013] Other compounds according to the present invention are those represented by the formula:

wherein

(…)

[0014] Among these compounds are preferred wherein P1 represents alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkoxycarbonyl, aroyl, heteroaroyl, alkanoyl or cycloalkanoyl radicals;

R2 represents alkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with halogen, -OR<9> or -SR<9> radicals, wherein R<9> represents hydrogen or alkyl radicals;
R3 represents alkyl, cycloalkyl or cycloalkylalkyl radicals; and
R4 represents alkyl, aryl or heteroaryl radicals.

[0015] Further preferred are compounds wherein P1 represents - 3-pyridylmethyloxycarbonyl, 3-pyridylmethyloxycarbonyl N-oxide, 4-pyridylmethyloxycarbonyl, 4-pyridylmethyloxycarbonyl N-oxide, 5-pyrimidylmethyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, 2-propyloxycarbonyl, benzyloxycarbonyl, cycloheptylcarbonyl, cyclohexylcarbonyl, cyclopentylcarbonyl, benzoyl, 2-substituted benzoyl, 4-pyridylcarbonyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2-chlorobenzoyl, 2-ethylbenzoyl, 2,6-dimethylbenzoyl, 2,3-dimethylbenzoyl, 2,4-dimethylbenzoyl or 2,5-dimethylbenzoyl radicals;

R2 represents benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-fluorobenzyl, paramethoxybenzyl, isobutyl or n-butyl radicals;
R3 represents isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl or n-propyl radicals; and R4 represents phenyl, para-methoxyphenyl, para-cyanophenyl, para-chlorophenyl, para-hydroxyphenyl, para-nitrophenyl, para-fluorophenyl, 2-naphthyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl or 4-pyridyl N-oxide radicals.

[0016] Also preferred are compounds of the above formula II wherein P1 represents heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl or heteroaroyl radicals;

R2 represents alkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with halogen, -OR<9> or -SR<9> radicals, wherein R<9> represents hydrogen or alkyl radicals;
R3 represents alkyl, cycloalkyl or cycloalkylalkyl radicals; and
R4 represents alkyl, aryl or heteroaryl radicals; and

wherein heterocyclyl or heterocycloalkyl means a 5-6 ring membered heterocycle or a benzfused 5-6 ring membered heterocycle having one or two nitrogen, oxygen or sulphur heteroatoms; and heteroaryl means an aromatic 5-6 ring membered heterocycle or an aromatic benzfused 5-6 ring membered heterocycle having one or two nitrogen, oxygen or sulphur heteroatoms.

[0017] Also preferred are those compounds wherein

P1 represents heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl or heteroaroyl radicals;
R2 represents benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-fluorobenzyl, paramethoxybenzyl, isobutyl or n-butyl radicals;
R3 represents isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl or n-propyl radicals; andwherein heterocyclyl or heterocycloalkyl means a 5-6 ring membered heterocyle having one or two nitrogen, oxygen or sulphur heteroatoms; and heteroaryl means an aromatic 5-6 ring membered heterocycle having one or two nitrogen, oxygen or sulphur heteroatoms.

[0018] Another group of compounds according to the invention comprises a retroviral protease inhibiting compound according to claim 1 having the formula

wherein:

(…)

[0019] Among these are those preferred wherein

R2 represents cycloalkylalkyl, aralkyl, alkyl, benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-fluorobenzyl, para-methoxybenzyl, isobutyl, or n-butyl;

R3 represents alkyl, cycloalkyl, cycloalkylalkyl, isobmyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl, or n-propyl; and
R4 represents aryl, alkyl, aryl, para-substituted aryl, heteroaryl, phenyl, para-methoxyphenyl, para-cyanophenyl, para-chlorophenyl, para-hydroxyphenyl, para-nitrophenyl, para-fluorophenyl, 2-naphthyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, or 4-pyridyl N-oxide.

Het verschil tussen verbinding 7 en darunavir bestaat in de aan de linkerzijde gesitueerde P1 substituent groep. In verbinding 7 is die groep een aralkoxycarbonyl, meer precies een benzyloxycarbonyl, die de volgende structuur kent:

In darunavir is de P1 substituent groep een heterocyclyloxycarbonyl. De specifieke P1 groep omvat een gefuseerde bis-tetrahydrofuran, gebonden aan een zuurstof atoom en een carbonyl groep en heeft de volgende structuur:

(…)

19. On the other hand, in HGS’s patent at issue in the main proceedings, the antibody is defined functionally, but not structurally, the definition thus covering an unknown number of otherwise unspecified antibodies. This is the broadest way of claiming an antibody. Furthermore, the specification for that patent does not contain any example of an antibody having been made or tested. Finally, nor does that patent contain any structural description of antibodies which might function as therapeutic antibodies.

(…)

24. By its three questions, which it is appropriate to consider together, the referring court asks, in essence, whether Article 3(a) of Regulation No 469/2009 must be interpreted as meaning that, in order for an active ingredient to be regarded as ‘protected by a basic patent in force’ within the meaning of that provision, the active ingredient must be identified in the claims of the patent by a structural formula, or whether the active ingredient may also be considered to be protected where it is covered by a functional formula in the patent claims.

(…)

33. On the other hand, as is apparent from the response given by the Court to questions 1 to 5 in the case which gave rise to the judgment in Medeva, for the purpose of determining whether a product is ‘protected by a basic patent in force’ within the meaning of Article 3(a) of Regulation No 469/2009, recourse may not be had to the rules governing infringement proceedings, such as, in the main proceedings, those laid down in section 60 of the UK Patents Act 1977.

34. By finding that Article 3(a) of Regulation No 469/2009 precludes the grant of an SPC relating to active ingredients which are not specified in the claims of a basic patent (see Medeva, paragraph 25, and the orders in Case C-630/10 University of Queensland and CSL [2011] ECR I‑12231, paragraph 31, and Case C-6/11 Daiichi Sankyo [2011] ECR I‑12255, paragraph 30), the Court emphasised the key role played by the claims for the purpose of determining whether a product is protected by a basic patent within the meaning of that provision.

(…)

36. In the main proceedings, it is common ground that the active ingredient tabalumab, namely LY2127399, is not expressly named in the claims of HGS’s patent. Moreover, it would appear that it is not otherwise specified in the descriptions or specifications of that patent and cannot, therefore, be identified as such.

(…)

39. With regard to the question whether the use of a functional definition may alone be sufficient, it should be noted that Article 3(a) of Regulation No 469/2009 does not, in principle, preclude an active ingredient which is given a functional definition in the claims of a patent issued by the EPO being regarded as protected by the patent, on condition that it is possible to reach the conclusion on the basis of those claims, interpreted inter alia in the light of the description of the invention, as required by Article 69 of the EPC and Protocol on the interpretation of that provision, that the claims relate, implicitly but necessarily and specifically, to the active ingredient in question.

(…)

41. Moreover, it should be recalled that the SPC is designed simply to re‑establish a sufficient period of effective protection of the basic patent by permitting the holder to enjoy an additional period of exclusivity on the expiry of that patent, which is intended to compensate, at least in part, for the delay to the commercial exploitation of his invention by reason of the time which has elapsed between the date on which the application for the patent was filed and the date on which the first MA in the European Union was granted (…).

42. As stated in recital 4 in the preamble to Regulation No 469/2009, the purpose of that additional period of exclusivity is to encourage research and, to that end, it is designed to ensure that the investments put into such research are covered.

43. In the light of the objective of Regulation No 469/2009, the refusal of an SPC application for an active ingredient which is not specifically referred to by a patent issued by the EPO relied on in support of such an application may be justified – in circumstances such as those in the main proceedings and as observed by Eli Lilly – where the holder of the patent in question has failed to take any steps to carry out more in-depth research and identify his invention specifically, making it possible to ascertain clearly the active ingredient which may be commercially exploited in a medicinal product corresponding to the needs of certain patients. In such a situation, if an SPC were granted to the patent holder, even though – since he was not the holder of the MA granted for the medicinal product developed from the specifications of the source patent – that patent holder had not made any investment in research relating to that aspect of his original invention, that would undermine the objective of Regulation No 469/2009, as referred to in recital 4 in the preamble thereto.

44. In the light of the foregoing considerations, the answer to the questions referred is that Article 3(a) of Regulation No 469/2009 must be interpreted as meaning that, in order for an active ingredient to be regarded as ‘protected by a basic patent in force’ within the meaning of that provision, it is not necessary for the active ingredient to be identified in the claims of the patent by a structural formula. Where the active ingredient is covered by a functional formula in the claims of a patent issued by the EPO, Article 3(a) of that regulation does not, in principle, preclude the grant of an SPC for that active ingredient, on condition that it is possible to reach the conclusion on the basis of those claims, interpreted inter alia in the light of the description of the invention, as required by Article 69 of the EPC and the Protocol on the interpretation of that provision, that the claims relate, implicitly but necessarily and specifically, to the active ingredient in question, which is a matter to be determined by the referring court.

(…)

In een beslissing van 17 oktober 2017 (hierna: de Sitagliptine zaak) heeft het Bundespatentgericht (hierna: BPatG) prejudiciële vragen gesteld aan het HvJ EU. In de beslissing is - onder meer - opgenomen:

(…)

1. Die Beschwerdeführerin ist Inhaberin des am 24. April 1987 angemeldeten und am 25. Juni 2014 erteilten europäischen Patents EP 1 084 705 (DE 597 13 097), das inzwischen durch Zeitablauf erloschen ist. Das Patent betrifft ein Verfahren zur Senkung des Blutglukosespiegels bei Säugern durch die Verabreichung sogenannter DP IV-Inhibitoren. Der Einsatz dieser Wirkstoffgruppe ist auf die Hemmung des Enzyms Dipeptidyl-Peptidase IV gerichtet, wodurch eine Regulation des Blutzuckerspiegels bei Diabetes mellitus-Patienten erreicht wird. Der zu dieser Wirkstoffklasse zählende Wirkstoff Sitagliptin wurde nach dem Anmeldetag des Grundpatents von einer Lizenznehmerin entwickelt, die hierfür ein Patent erhalten hat, auf dessen Basis ihr ein ergänzendes Schutzzertifikat erteilt wurde (...).

Am 17. Dezember 2014 beantragte die Beschwerdeführerin beim Deutschen Patent- und Markenamt (DPMA) auf Grundlage des Deutschen Teils des Europäischen Patents die Erteilung eines ergänzenden Schutzzertifikats für das Erzeugnis “Sitagliptin in allen dem Schutz des Grundpatents unterliegenden Formen”, hilfsweise für “Sitagliptin, insbesondere Sitagliptin Phosphatmonohydrat”. Hinsichtlich der erforderlichen arzneimittelrechtlichen Genehmigung für das Inverkehrbringen stütze sie sich dabei auf die Zulassungen des Arzneimittels Januvia (EU/1/07/383/001-018) vom 21. März 2007 durch die Europäische Arzneimittel-Agentur (EMA).

Mit Beschluss vom 12. April 2017 hat die Patentabteilung 44 des DPMA den Antrag zurückgewiesen, da die Erteilungsvoraussetzung gemäß Art. 3 (a) der Verordnung (EG) Nr. 469/20009 des Europäischen Parlaments und des Rates vom 6. Mai 2009 über das ergänzende Schutzzertifikat für Arzneimittel (im Folgenden: AMVO) nicht erfüllt sei. Zur Begründung hat die Patentabteilung insbesondere ausgeführt, in den Ansprüchen des Grundpatents werde das verfahrensgegenständliche Erzeugnis ausschließlich funktionell definiert. Zwar erfülle das Erzeugnis als ein DP IV-Inhibitor die funktionelle Definition des Grundpatents, jedoch fehle es im Grundpatent an jeglicher spezifischen Offenbarung von Sitagliptin, so dass der konkrete Wirkstoff dem Fachmann nicht zur Verfügung gestellt werde. Von den zahlreichen, unter die funktionelle Definition “DP IV-Inhibitoren” fallenden Wirkstoffen würden im Grundpatent lediglich Alanyl-Pyrrolidid, Isoleucyl-Thiazolidid, N-Valyl-Prolyl und O-Benzoyl Hydroxylamin konkret genannt. Der Hinweis der Antragstellerin, es handle sich vorliegend um eine Grundlagenerfindung, welche die neue Wirkstoffklasse der DP IV-Inhibitoren zur Behandlung des Diabetes-mellitus erstmals zur Verfügung gestellt und damit die spätere Entwicklung des Wirkstoffs Sitagliptin erst möglich gemacht habe, könne die Erteilung des beantragten Schutzzertifikats nicht rechtfertigen. Maßgeblich sei vielmehr, dass der Schutzgegenstand des Grundpatents gerade nicht dem später entwickelten Arzneimittel entspreche, das die Genehmigung zum Inverkehrbringen erhalten habe, auf den sich der vorliegende Erteilungsantrag stütze. Es würde den Zielen der AMVO widersprechen, ein Schutzzertifikat für ein Erzeugnis zu erteilen, das vom Grundpatent nicht zur Verfügung gestellt werde.

Gegen diesen Beschluss richtet sich die Beschwerde der Antragstellerin, mit der sie ihr Begehren auf Erteilung eines ergänzenden Schutzzertifikats weiterverfolgt, zuletzt für das Erzeugnis “Sitagliptin”.

(...)

6. Vor dem Hintergrund, dass sich die Möglichkeit einer Schutzzertifikatserteilung nach den Zielen der AMVO nur auf Grundpatente für neue Arzneimittel bzw. Wirkstoffe und Wirkstoffkombinationen bezieht und nicht auf Stoffgruppen, die erst den Ausgangspunkt für die spätere Entwicklung eines spezifischen Wirkstoffs schaffen, sind diese vom Gerichtshof formulierten Anforderungen nach Ansicht des Senats nur dann erfüllt, wenn der fragliche Wirkstoff (oder die Wirkstoffkombination) in den Patentansprüchen. so spezifiziert ist, dass er als solcher identifizierbar ist und dem Fachmann dadurch tatsächlich zur Verfügung gestellt wird.

7. lm vorliegenden Fall besteht der Schutzgegenstand des Grundpatents aber ausschließlich in der Lehre, über eine Beeinflussung der Dipeptidyl-Peptidase zur Senkung des krankhaft überhöhten Blutzuckerspiegels - verallgemeinernd - Inhibitoren der Dipeptidyl-Peptidase einzusetzen, sowie darin, zu diesem Zweck die in der Beschreibung des Patents konkret benannten Stoffe - zu denen Sitagliptin nicht gehört - heranzuziehen (vgl. hierzu die zur Prioritätsanmeldung des Grundpatents ergangene Entscheidung des Bundesgerichtshofs, GRUR 2013, 1210, Rdn. 28 - Dipeptidyl-Peptidase-Inhibitoren). Der hier verfahrensgegenständliche Wirkstoff Sitagliptin gehört somit nicht zum Schutzgegenstand des Grundpatents. Er fällt zwar in dessen Schutzbereich - der bloße Umstand, dass der zum Prioritätstag des Grundpatents noch nicht entwickelte Wirkstoff Sitagliptin - ebenso wie

eine Vielzahl weiterer Wirkstoffe - unter die funktionelle Definition der Wirkstoffklasse in Anspruch 2 des Grundpatents fällt, mag somit in Verletzungsklagen relevant werden, erfüllt aber nach Auffassung des Senats nicht die Vorgaben des EuGH zum Erfordernis einer spezifischen Identifizierbarkeit des Erzeugnisses in den Ansprüchen des Grundpatents gemäß Art. 3 (a) AMVO. Denn das Grundpatent stellt dem Fachmann neben den explizit genannten Verbindungen - wie bspw. dem DP IV-Inhibitor Isoleucyl-Thiazolidid - nur eine Zielstruktur (DP IV) zur Verfügung, nicht jedoch den Wirkstoff Sitagliptin. Dieser wurde erst später von einer Lizenznehmerin durch entsprechende Forschungsleistungen entwickelt, durch ein eigenes Grundpatent geschützt und hat erst dann eine Genehmigung zum Inverkehrbringen als Arzneimittel erhalten.

8. Wenn die Beschwerdeführerin vorträgt, mit seinen in ,“Eli Lilly” formulierten Grundsätzen habe der Gerichtshof lediglich klarstellen wollen, dass sich der fragliche Wirkstoff als eine Verkörperung des Kerns des erfinderischen Beitrags des Grundpatents darstellen müsse, wie er durch die funktionelle Charakterisierung des Patentanspruchs ausgedrückt werde, teilt der Senat diese Interpretation nicht. Vor dem Hintergrund seiner auch in “Eli Lilly” zitierten Entscheidung “Medeva” (vgl. EuGH, GRUR 2014, 163, Rdn. 34 f. - Eli Lilly) hat der Gerichtshof nach Auffassung des Senats vielmehr deutlich gemacht, dass der fragliche Wirkstoff als zum Schutzgegenstand des Grundpatents gehörend, spezifisch identifizierbar sein muss (vgl. EuGH, GRUR 2014, 163, Rdn. 35 - Eli Lilly). Dementsprechend hat der EuGH auch das ihm vom britischen High Court of Justice als Prüfungskriterium für die Anwendung des Art. 3 (a) AMVO vorgeschlagene Konzept des sogenannten “inventive advance” (High Court, [2012] EWHC 2545 (Pat), Rdn. 75 ff. - Actavis/

Sanofi,) bei der Auslegung dieser Vorschrift nicht aufgegriffen, sondern stattdessen im Rahmen der Auslegung des Art. 3 (c) AMVO berücksichtigt (vgl. EuGH, GRUR Int. 2014, 153, Rdn. 41 f. -Actavis/Sanofi).

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44. Thirdly, Prof [X] gives some evidence about the relationship between darunavir and the Patent. In summary, he says that darunavir is covered by claims 1, 2, 5, 10 and 11, but is not disclosed in the Patent. The closest compound to darunavir that is disclosed in the Patent is a compound which is disclosed in [0012] at lines 32-33 and also included in claim 4 as the seventh compound listed (“Compound 7”). Darunavir itself does not fall within the scope of claim 4. There are no biological data on Compound 7 in the Patent.

45. The difference between Compound 7 and darunavir is the P1 substituent group. In Compound 7, it is an aralkoxycarbonyl, specifically benzyloxycarbonyl, which has the following structure:

46. By contrast, in darunavir, the P1 substituent group is a heterocyclyloxycarbonyl. Even assuming the skilled reader opts for the heterocyclyloxycarbonyl substituent group over the other groups for P1 listed in the claims, Prof [X] 's evidence is that he is then faced with a choice of at least 8 x 1036 possibilities for that group alone. The specific P1 group in darunavir comprises a fused bis-tetrahydrofuran, joined to an oxygen atom and a carbonyl group. It is represented by the following structure:

47. None of the compounds individually disclosed in the Patent contain this specific heterocyclyloxycarbonyl substituent, or indeed anything similar to it. Prof [X] ’s evidence is that it is an unusual substituent and one which he had not previously encountered.

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98. An important point of detail is the time at which and the circumstances in which the national authority has to determine whether a product is protected by a basic patent. The appellants do not suggest that the exercise for the skilled person of determining whether a product is protected by a basic patent should be performed in ignorance of the product in question. The judge accepted the respondents’ submission that the question whether a product is protected by claims in a basic patent falls to be judged when the product is known, and when it has been authorised to be placed on the market as a medicinal product. I did not understand Ms […] to challenge that proposition. I consider it to be correct. That conclusion still leaves open the question of what is the necessary exercise for determining whether the product is protected by the patent. The two candidates which remain are (a) asking whether it is clear that the product is claimed as such; and (b) asking whether the product is one which is sufficiently identified. A test which goes further and asks whether the active ingredient is specifically disclosed is not advanced by the appellants.

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100. The Lilly requirement stems from the CJEU's decision in Medeva that all members of a combination of active ingredients which is the subject of a SPC must be specified in the wording of the claims. The requirement follows, at least according to the Advocate General's reasoning, from the fact that the product the subject of the SPC is to be protected "as such" by the basic patent. Medeva was not a case about how closely each component of the combination needs to be specified in the claims. Rather it was a case which ruled out a SPC where some of the products were not specified in the claims at all. It was a case in which one had a plain mis-match between the basic patent and the SPC. If there is a mis-match between the product the subject of the SPC and that protected as such by the patent, one can see how infringement rules could lead to an incorrect result. That is because the infringement rules do not require matching in this way. A claim to a single active ingredient is infringed by a combination of that product and another active: but the patent does not protect the combination product as such.

101. In the case of a SPC with a single active ingredient, the reasoning in Medeva requires that the basic patent protect that active ingredient as such. The reasoning is not informative as to how specifically the claims must focus on the active ingredient, or what underlies the requirement that they should do so.

102. It is not clear to me that the CJEU's judgment in Eli Lilly takes the matter much further. Eli Lilly was specifically concerned with functional claims. Functional claims and structural claims are fundamentally different in terms of what they require the skilled person to do in order to determine whether a particular product is specified by a claim. A structural claim simply requires one to read the claim and the specification, look at the structure of the product and decide whether it is a product specified in the claims. Functional claims, by contrast, require one to perform a functional test on the product. For example a claim to an antibody by reference to a binding ability normally requires one to perform a practical test to determine whether the antibody actually binds to something else.

103. Medeva therefore left a substantial unanswered question as to whether a product could be specified by a functional claim at all. It might be thought that it was simply too difficult for a patent office, operating the simple, transparent and objective system set up by the SPC Regulation, to work out whether a particular antibody was one specified in the claim. Problems of that nature do not arise in the case of Markush claims.
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105. Such help as the judgment in Eli Lilly gives as to what underlies the specificity requirement is to be found, not in its core reasoning, but in paragraph [43] of the judgment. That paragraph appears to be one designed to give the national court assistance in arriving at its judgment in the main proceedings. It is true that that paragraph is in the context, additionally, of an application for a SPC based on a third party’s marketing authorisation. But the first part of the paragraph seems to me to indicate, albeit without great clarity, that the court considers that at least one way of preventing or hindering the marketing authorisations of third parties from being used as the basis for SPCs is to insist on a high degree of specificity in the basic patent. That might help to prevent a patentee spreading the net in his patent claims widely and unspecifically, and subsequently fastening on a competitor’s successfully marketed drug to obtain an extended term which he has not earned. That is a consideration which does not only arise in the context of functional claims, and lends force to the suggestion that the requirement for a high degree of specificity is a general one.

106. If it is right that there is a general requirement that the active ingredient which is the subject of the SPC must be identified, the question arises of how specific the claims must be. I agree with Mr [Q] that there is a spectrum of specificity indicated by the factual scenarios in the various decided cases and references. I would regard it as plain that a Markush claim can in some circumstances amount to a sufficiently precise claim for the purposes of Article 3(a), for example where individual substituents are identified in the specification, or where classes of such substituents are set out, and the skilled person would be able to determine the extent of those classes. However I do not think one can extract from the reasoning in Eli Lilly the proposition that an active ingredient is adequately identified by a Markush formula however broadly that formula is framed and however obscure the particular substituent required to form the active ingredient the subject of the SPC. I think it is at least arguable that that substituent must be amongst those which the skilled person would be able to identify based on his common general knowledge at the priority date. I say so for two reasons.

107. My first reason for considering that proposition to be arguable is the insight which paragraph [43] of Eli Lilly gives into the CJEU’s thinking concerning the purpose of the requirement for the active ingredient to be identified. If the objective is to ensure that the patent proprietor has come close to an actual realisation of the product, then the fact that the relevant substituents cannot be arrived at from a reading of the specification and the common general knowledge may be highly relevant.

108. My second reason for considering that proposition to be arguable is the view expressed by the BPatG in the Sitagliptin reference that the functional formula in that case and the Markush formula in the present case are factually indistinguishable for the purposes of Article 3(a). Whilst I consider that there are significant points of distinction relevant to Article 3(a) between the two classes of case, the BPatG does not agree. It would therefore appear likely that a German court would take the view that a Markush formula may, at least in a case like the present, fail to provide protection within the meaning of Article 3(a). A decision by this court that a Markush formula will always be adequate for that purpose would therefore lead to conflicting decisions at least in these two member states.

109. Like the judge, however, I am concerned with what I see as a fundamental defect with the “identification” test. The CJEU jurisprudence to date seems to take it as read that a claim can identify active ingredients with specificity. However that is not the function of claims in patents. Instead, claims are concerned with setting the limits to the monopoly. A further defect of the focus on the claim is that claims can be manipulated by skilful drafting to protect combinations, without distinguishing between genuine combinations of products which work together in a new and advantageous way so as to constitute an inventive advance, and mere collocations of products giving rise to their separate individual effects. I agree with the judge that a far better test would be to ask whether the product the subject of the SPC embodies the core inventive advance of the basic patent.

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114. In case it would assist the Court of Justice I will express my provisional conclusion. Left to myself, I would have concluded that darunavir was a product protected by the claims of the patent. In the case of a product with a single active ingredient and a patent with a claim which identifies a number of compounds by means of a Markush formula, all of which compounds embody the core inventive technical advance of the patent, the test should be whether the skilled person, considering the claims of the patent on the one hand and the structure of the product in question on the other, would immediately recognise that the active ingredient in question is one of those specified by the formula. On the facts of the present case as found by the judge, that test is satisfied. However, for the reasons I have given, it is not clear that this is the correct approach in EU law.

115. I would therefore propose that this court should stay the present appeal proceedings and refer the following question to the CJEU:

“Where the sole active ingredient the subject of a supplementary protection certificate issued under [the SPC Regulation] is a member of a class of compounds which fall within a Markush definition in a claim of the patent, all of which class members embody the core inventive technical advance of the patent, is it sufficient for the purposes of Article 3(a) of the SPC Regulation that the compound would, upon examination of its structure, immediately be recognised as one which falls within the class (and therefore would be protected by the patent as a matter of national patent law) or must the specific substituents necessary to form the active ingredient be amongst those which the skilled person could derive, based on their common general knowledge, from a reading of the patent claims?”

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46. It follows from the above that the subject matter of the protection conferred by an SPC must be restricted to the technical specifications of the invention covered by the basic patent, such as claimed in that patent.

46. With regard to the implementation of that rule, it must in the first place be stated that, in accordance with a principle shared by the patent laws of the Member States and reflected in Article 1 of the Protocol on the Interpretation of Article 69 of the EPC, the claims of a patent are to be interpreted from the perspective of a person skilled in the art and, therefore, the issue whether the product which is the subject of the SPC necessarily falls under the invention covered by that patent must be assessed from that perspective.

46. To that end, it is necessary to ascertain whether a person skilled in the art can understand without any doubt, on the basis of their general knowledge and in the light of the description and drawings of the invention in the basic patent, that the product to which the claims of the basic patent relate is a specification required for the solution of the technical problem disclosed by that patent.

46. In the second place, having regard to the objective of Regulation No 469/2009, recalled in paragraph 39 above, for the purposes of assessing whether a product falls under the invention covered by a basic patent, account must be taken exclusively of the prior art at the filing date or priority date of that patent, such that the product must be specifically identifiable by a person skilled in the art in the light of all the information disclosed by that patent.

46. Were it to be accepted that such an assessment could be made taking into account results from research which took place after the filing date or priority date of the basic patent, an SPC could enable its holder unduly to enjoy protection for those results even though they were not yet known at the priority date or filing date of that patent, what is more outside any procedure for the grant of a new patent. That would, as pointed out in paragraphs 40 and 41 above, run counter to the objective of Regulation No 469/2009.

46. Therefore, for the purposes of determining whether a product which is the subject of an SPC is protected by a basic patent, within the meaning of Article 3(a) of that regulation, that product must be identifiable specifically by a person skilled in the art in the light of all the information disclosed by the basic patent and of the prior art at the filing date or priority date of that patent.

46. Having regard to all the foregoing considerations, a product is ‘protected by a basic patent in force’ within the meaning of Article 3(a) of Regulation No 469/2009 in so far as, if that product is not expressly mentioned in the claims of the basic patent, one of those claims relates to it necessarily and specifically. For that purpose, that product must, from the point of view of a person skilled in the art and in the light of the description and drawings of the basic patent, necessarily fall under the invention covered by that patent. The person skilled in the art must be able identify that product specifically in the light of all the information disclosed by that patent, on the basis of the prior art at the filing date or priority date of the patent concerned.

46. Such an interpretation of Article 3(a) of Regulation No 469/2009 must also be upheld in a situation, such as that at issue in the case in the main proceedings, where the products which are the subject of a SCP [bedoeld zal zijn: SPC, voorzieningenrechter] are composed of several active ingredients which have a combined effect.

46. Thus, as regards the issue whether a claim such as claim 27 of the basic patent in fact covers a combination such as the TD/emtricitabine combination which is the subject of the SPC at issue, it falls to the referring court to determine whether the general expression ‘other therapeutic ingredients’, associated with the term ‘optionally’, satisfies the requirement that the claims of the basic patent must relate necessarily and specifically to the product.

46. In particular, it is for the referring court to ascertain, in accordance with the considerations in paragraphs 47 to 51 above, whether, from the point of view of a person skilled in the art, the combination of active ingredients of which the product which is the subject of the SPC at issue consists necessarily falls under the invention covered by that patent, and whether each of those active ingredients is specifically identifiable on the basis of the prior art at the filing date or priority date of that patent.

46. In the present case it is apparent, first, from the information in the order for reference that the description of the basic patent at issue contains no information as to the possibility that the invention covered by that patent could relate specifically to a combined effect of TD and emtricitabine for the purposes of the treatment of HIV. Consequently, it does not seem possible that a person skilled in the art, on the basis of the prior art at the filing date or priority date of that patent, would be able to understand how emtricitabine, in combination with TD, necessarily falls under the invention covered by that patent. The onus is nevertheless on the referring court to check whether such is indeed the case. Secondly, it is also for that court to establish whether emtricitabine is specifically identifiable by that person skilled in the art in the light of all the information contained in that patent, on the basis of the prior art at the filing date or priority date of the patent in question.

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The answer given by the Court in Case C-121/17 is specific to combination products. This Court’s question in the present case relates to a basic patent which protects products consisting of a single active ingredient by means of a class formula where all members of the class embody the core inventive concept of the patent. The court considers that the reference remains necessary to resolve the dispute in the main proceedings.

Eenzelfde verzoek heeft het HvJ EU ook gedaan aan het BPatG in de Sitagliptine zaak (zie onder 2.13). Ook het BPatG heeft aangegeven zijn verwijzing te handhaven.