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ECLI:DK:OLR:2025:BS0000000312 Kendelse

ØSTRE LANDSRET KENDELSE afsagt den

  1. marts 2025 Sag BS-52648/2024-OLR (
  2. afdeling) Bayer Intellectual Property GmbH og Bayer A/S (advokat Mikkel Vittrup og advokat Peter-Ulrik Plesner for begge) mod Sandoz A/S (advokat Anders Valentin og advokat Patris Hajrizaj) og Sag BS-52678/2024-OLR (
  3. afdeling) Bayer Intellectual Property GmbH og Bayer A/S (advokat Mikkel Vittrup og advokat Peter-Ulrik Plesner for begge) mod Stada Nordic ApS (advokat Jacob Ørndrup) og Sag BS-52702/2024-OLR (
  4. afdeling) Bayer Intellectual Property GmbH og Bayer A/S (advokat Mikkel Vittrup og advokat Peter-Ulrik Plesner for begge) mod Glenmark Pharmaceuticals Nordic AB (advokat Jakob Krag Nielsen og advokat Maria Pilh Arendsdorf Bengtsen) og 2 Sag BS-52530/2024-OLR (
  5. afdeling) Bayer Intellectual Property GmbH og Bayer A/S (advokat Mikkel Vittrup og advokat Peter-Ulrik Plesner for begge) mod Teva Denmark A/S (advokat Nicolaj Bording) Sø- og Handelsretten har den
  6. oktober 2024 afsagt kendelse i
  7. instans i tre forbuds- og påbudssager (sagerne BS-9717/2024-SHR, BS-17450/2024-SHR og BS-19709/2024-SHR) anlagt af Bayer Intellectual Property GmbH og Bayer A/S mod Sandoz A/S, Stada Nordic ApS og Glenmark Pharmaceuticals Nordic AB, som følger: ”Anmodningerne om midlertidige forbud og påbud nægtes fremme. Bayer Intellectual Property GmbH og Bayer A/S skal i fællesskab inden 14 dage betale sagsomkostninger med 1.575.000 kr. til Stada Nordic ApS, 3.500.000 kr. til Glenmark Pharmaceuticals Nordic AB og 3.500.000 kr. til Sandoz A/S. Sagsomkostninger forrentes efter rentelovens § 8 a.” Den
  8. oktober 2024 har Sø- og Handelsretten endvidere afsagt kendelse i
  9. instans i en forbuds- og påbudssag (sag BS-12699/2024-SHR) anlagt af Bayer Intellectual Property GmbH og Bayer A/S mod Teva Denmark A/S, som følger. ”Anmodningerne om midlertidige forbud og påbud nægtes fremme. Bayer Intellectual Property GmbH og Bayer A/S skal i fællesskab inden 14 dage betale sagsomkostninger med 1.000.000 kr. til Teva Denmark A/S. Sagsomkostninger forrentes efter rentelovens § 8 a.” Kendelserne er kæret af Bayer Intellectual Property GmbH og Bayer A/S (i det følgende samlet ”Bayer”) og er sambehandlet i landsretten. Landsdommerne Katja Høegh, Susanne Lehrer og Uffe Sørensen, tillige med sagkyndig dommer Lars Pallisgaard Olsen, har deltaget i sagernes afgørelse. Kæremålene har været behandlet mundtligt. 3 Påstande Bayer har nedlagt følgende påstande: I sag BS-52648/2024-OLR (Sandoz A/S): Påstand 1a (sideordnet med påstand 1b): Principalt: Sandoz A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 30504, eller im-portere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Sandoz A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 30504, eller importere eller besidde det med et sådant for-mål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Sandoz A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 30504, eller impor-tere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Mere subsidiært: Sandoz A/S forbydes i Danmark at udbyde, bringe i omsæt-ning, markedsføre eller anvende lægemidlet Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden føl-gende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 30504, eller importe-re eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. 4 Påstand 1b (sideordnet med påstand 1a): Principalt: Sandoz A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Hexal" i styrkerne 10 mg, 15 mg og 20 mg godkendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 32333, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Sandoz A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Hexal" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 32333, eller importere eller besidde det med et sådant for-mål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Sandoz A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Hexal" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hin-anden følgende dage i patienter, og hvor det er angivet at den terminale halve-ringstid er på 5-13 timer, jf. dansk specialitetsnummer 32333, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Mere subsidiært: Sandoz A/S forbydes i Danmark at udbyde, bringe i omsæt-ning, markedsføre eller anvende lægemidlet Rivaroxaban "Hexal" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske for-styrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden føl-gende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 32333, eller importe-re eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Påstand 2: Principalt: Sandoz A/S påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 30504, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Sandoz A/S. 5 Sandoz A/S skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectu-al Property GmbH og Bayer A/S' advokater. Subsidiært, sideordnet: Sandoz A/S påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 30504, fra samt-lige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Sandoz A/S. Sandoz A/S skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectu-al Property GmbH og Bayer A/S' advokater. Subsidiært, sideordnet: Sandoz A/S påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgi-velse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 30504, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Sandoz A/S. Sandoz A/S skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectu-al Property GmbH og Bayer A/S' advokater. Mere subsidiært: Sandoz A/S påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 30504, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Sandoz A/S. Sandoz A/S skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectu-al Property GmbH og Bayer A/S' advokater. Påstand 3: Principalt: Sandoz A/S påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. 6 dansk specialitetsnummer 30504, i det danske prisregister (www.medicinpriser.dk). Subsidiært, sideordnet: Sandoz A/S påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 30504, i det dan-ske prisregister (www.medicinpriser.dk). Subsidiært, sideordnet: Sandoz A/S påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgi-velse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 30504, i det danske prisregister (www.medicinpriser.dk ). Mere subsidiært: Sandoz A/S påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Sandoz" i styrkerne 10 mg, 15 mg og 20 mg, god-kendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 30504, i det danske prisregister (www.medicinpriser.dk). Påstand 4: Principalt: Sø- og Handelsrettens afgørelse om sagsomkostninger i sag BS9717/2024-SHR ophæves, og Bayer tilkendes sagsomkostninger for Sø- og Handelsretten. Subsidiært: Sø- og Handelsrettens afgørelse om sagsomkostninger i sag BS9717/2024-SHR ændres, således at de tilkendte sagsomkostninger nedsættes. Påstand 5: Sandoz A/S skal tilbagebetale sagsomkostninger til Bayer Intellectual Property GmbH og Bayer A/S med i alt 3.500.000 kr. med tillæg af procesrente fra den
  10. november 2024 og indtil betaling sker. I sag BS-52530/2024-OLR (Teva Denmark A/S): Påstand 1: Principalt: Teva Denmark A/S forbydes i Danmark at udbyde, bringe i omsæt-ning, markedsføre eller anvende lægemidlet Rivaroxaban "Teva" i styrkerne 10 7 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 31578, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Teva Denmark A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Teva"i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor riva-roxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 31578, eller importere eller besidde det med et så-dant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Teva Denmark A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Teva"i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af trombo-emboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 31578, eller impor-tere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Mere subsidiært: Teva Denmark A/S forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Teva" i styr-kerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboem-boliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hin-anden følgende dage i patienter, og hvor det er angivet at den terminale halve-ringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 31578, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Påstand 2: Principalt: Teva Denmark A/S påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Teva" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 31578, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Teva Denmark A/S. Teva Denmark A/S skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. 8 Subsidiært, sideordnet: Teva Denmark A/S påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Teva" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 31578, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Teva Denmark A/S. Teva Denmark A/S skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Subsidiært, sideordnet: Teva Denmark A/S påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Teva" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i pa-tienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 31578, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Teva Denmark A/S. Teva Denmark A/S skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Mere subsidiært: Teva Denmark A/S påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Teva" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgi-velse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 31578, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Teva Denmark A/S. Teva Denmark A/S skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Påstand 3: Principalt: Teva Denmark A/S påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Teva" i styrkerne 10 mg, 15 mg og 20 mg god-kendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 31578, i det danske prisregister (www.medicinpriser.dk). 9 Subsidiært, sideordnet: Teva Denmark A/S påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Teva" i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 31578, i det dan-ske prisregister (www.medicinpriser.dk). Subsidiært, sideordnet: Teva Denmark A/S påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Teva" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgi-velse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 31578, i det danske prisregister (www.medicinpriser.dk ). Mere subsidiært: Teva Denmark A/S påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Teva" i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 31578, i det danske prisregister (www.medicinpriser.dk). Påstand 4: Principalt: Sø- og Handelsrettens afgørelse om sagsomkostninger i sag BS12699/2024-SHR ophæves, og Bayer tilkendes sagsomkostninger for Sø- og Handelsretten. Subsidiært: Sø- og Handelsrettens afgørelse om sagsomkostninger i sag BS12699/2024-SHR ændres, således at de tilkendte sagsomkostninger nedsættes. Påstand 5: Teva Denmark A/S skal tilbagebetale sagsomkostninger til Bayer Intellectual Property GmbH og Bayer A/S med i alt 1.000.000 kr. med tillæg af procesrente fra den
  11. november 2024 og indtil betaling sker. I sag BS-52678/2024-OLR (Stada Nordic ApS): Påstand 1a (sideordnet med påstand 1b): Principalt: Stada Nordic ApS forbydes i Danmark at udbyde, bringe i omsæt-ning, markedsføre eller anvende lægemidlet Rivaroxaban "Stada" i styrkerne 15 mg og 20 mg som hårde kapsler godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 10 32493, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Stada Nordic ApS forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Stada" i styrkerne 15 mg og 20 mg som hårde kapsler godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller min-dre, jf. dansk specialitetsnummer 32493, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Stada Nordic ApS forbydes i Danmark at udbyde, brin-ge i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som hårde kapsler, godkendt/anvendt til be-handling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 32493, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Mere subsidiært: Stada Nordic ApS forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som hårde kapsler, godkendt/anvendt til behand-ling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk speciali-tetsnummer 32493, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Påstand 1b (sideordnet med påstand 1a): Principalt: Stada Nordic ApS forbydes i Danmark at udbyde, bringe i omsæt-ning, markedsføre eller anvende lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter godkendt/anvendt til indgi-velse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 32493, eller importere eller besidde det med et sådant for-mål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Stada Nordic ApS forbydes i Danmark at udbyde, brin-ge i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter god-kendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalve-ringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 32493, eller im- 11 portere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Stada Nordic ApS forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter, god-kendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 32493, eller importere eller besidde det med et sådant for-mål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Mere subsidiært: Stada Nordic ApS forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er an-givet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 32493, eller importere eller besidde det med et sådant for-mål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Påstand 2a (sideordnet med påstand 2b): Principalt: Stada Nordic ApS påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Stada" i styrkerne 15 mg og 20 mg som hårde kaps-ler godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hin-anden følgende dage, jf. dansk specialitetsnummer 32493, fra samtlige kom-mercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapote-ker, hvortil levering er foretaget af Stada Nordic ApS. Stada Nordic ApS skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Subsidiært, sideordnet: Stada Nordic ApS påbydes at tilbagekalde allerede ske-te leverancer af lægemidlet Rivaroxaban "Stada" i styrkerne 15 mg og 20 mg som hårde kapsler godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 32493, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Stada Nordic ApS. Stada Nordic ApS skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. 12 Subsidiært, sideordnet: Stada Nordic ApS påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som hårde kapsler, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 513 timer, jf. dansk specialitetsnummer 32493, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Stada Nordic ApS. Stada Nordic ApS skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Mere subsidiært: Stada Nordic ApS påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som hårde kapsler, godkendt/anvendt til behandling af tromboemboliske for-styrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden føl-gende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 32493, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusa-poteker, hvortil levering er foretaget af Stada Nordic ApS. Stada Nordic ApS skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Påstand 2b (sideordnet med påstand 2a): Principalt: Stada Nordic ApS påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 32493, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Stada Nordic ApS. Stada Nordic ApS skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Subsidiært, sideordnet: Stada Nordic ApS påbydes at tilbagekalde allerede ske-te leverancer af lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 32493, fra samtlige kommercielle aftagere, herunder hospi- 13 taler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Stada Nordic ApS. Stada Nordic ApS skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Subsidiært, sideordnet: Stada Nordic ApS påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 32493, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Stada Nordic ApS. Stada Nordic ApS skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Mere subsidiært: Stada Nordic ApS påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter, godkendt/anvendt til behandling af tromboembo-liske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinan-den følgende dage i patienter, og hvor det er angivet at den terminale halve-ringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 32493, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Stada Nordic ApS. Stada Nordic ApS skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Påstand 3a (sideordnet med påstand 3b): Principalt: Stada Nordic ApS påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Stada" i styrkerne 15 mg og 20 mg som hårde kapsler godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 32493, i det danske prisregister (www.medicinpriser.dk). Subsidiært, sideordnet: Stada Nordic ApS påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Stada" i styrkerne 15 mg og 20 mg som hårde kapsler godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk speciali-tetsnummer 32493, i det danske prisregister (www.medicinpriser.dk). 14 Subsidiært, sideordnet: Stada Nordic ApS påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som hårde kapsler, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden føl-gende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 32493, i det danske prisregister (www.medicinpriser.dk). Mere subsidiært: Stada Nordic ApS påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som hårde kapsler, godkendt/anvendt til behandling af tromboemboliske forstyrrel-ser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende da-ge i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 32493, i det danske prisre-gister (www.medicinpriser.dk). Påstand 3b (sideordnet med påstand 3a): Principalt: Stada Nordic ApS påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmover-trukne tabletter godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 32493, i det dan-ske prisregister (www.medicinpriser.dk). Subsidiært, sideordnet: Stada Nordic ApS påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 32493, i det danske prisregister (www.medicinpriser.dk). Subsidiært, sideordnet: Stada Nordic ApS påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter, godkendt/anvendt til behandling af tromboembo-liske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinan-den følgende dage i patienter, og hvor det er angivet at den terminale halve-ringstid er på 5-13 timer, jf. dansk specialitetsnummer 32493, i det danske pris-register (www.medicinpriser.dk). Mere subsidiært: Stada Nordic ApS påbydes omgående at afregistrere den indmeldte pris for Rivaroxaban "Stada" i styrkerne 10 mg, 15 mg og 20 mg som filmovertrukne tabletter, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden føl- 15 gende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 59 timer for unge voksne, jf. dansk specialitetsnummer 32493, i det danske prisregister (www.medicinpriser.dk). Påstand 4: Principalt: Sø- og Handelsrettens afgørelse om sagsomkostninger i sag BS17450/2024-SHR ophæves, og Bayer tilkendes sagsomkostninger for Sø- og Handelsretten. Subsidiært: Sø- og Handelsrettens afgørelse om sagsomkostninger i sag BS17450/2024-SHR ændres, således at de tilkendte sagsomkostninger nedsættes. Påstand 5: Stada Nordic ApS skal tilbagebetale sagsomkostninger til Bayer Intellectual Property GmbH og Bayer A/S med i alt 1.575.000 kr. med tillæg af procesrente fra den
  12. november 2024 og indtil betaling sker. I sag BS-52702/2024-OLR (Glenmark Pharmaceuticals Nordic AB): Påstand 1: Principalt: Glenmark Pharmaceuticals Nordic AB forbydes i Danmark at udby-de, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaxa i styr-kerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 33573, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Glenmark Pharmaceuticals Nordic AB forbydes i Dan-mark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaxa i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor riva-roxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 33573, eller importere eller besidde det med et så-dant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Subsidiært, sideordnet: Glenmark Pharmaceuticals Nordic AB forbydes i Dan-mark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaxa i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den termi-nale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 33573, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. 16 Mere subsidiært: Glenmark Pharmaceuticals Nordic AB forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Rivaxa i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 33573, eller importere eller besidde det med et sådant formål, så længe dansk patent nr. DK/EP 1 845 961 er i kraft. Påstand 2: Principalt: Glenmark Pharmaceuticals Nordic AB påbydes at tilbagekalde alle-rede skete leverancer af lægemidlet Rivaxa i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 33573, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Glenmark Pharmaceuticals Nordic AB. Glenmark Pharmaceuticals Nordic AB skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Subsidiært, sideordnet: Glenmark Pharmaceuticals Nordic AB påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaxa i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 33573, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Glenmark Pharmaceuticals Nordic AB. Glenmark Pharmaceuticals Nordic AB skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Subsidiært, sideordnet: Glenmark Pharmaceuticals Nordic AB påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaxa i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 33573, fra samtlige kommercielle aftagere, herun-der hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er fore-taget af Glenmark Pharmaceuticals Nordic AB. 17 Glenmark Pharmaceuticals Nordic AB skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Mere subsidiært: Glenmark Pharmaceuticals Nordic AB påbydes at tilbagekalde allerede skete leverancer af lægemidlet Rivaxa i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i pa-tienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge voksne, jf. dansk specialitetsnummer 33573, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Glenmark Pharmaceuticals Nordic AB. Glenmark Pharmaceuticals Nordic AB skal samtidig sende kopi af alle tilbagekaldelser til Bayer Intellectual Property GmbH og Bayer A/S' advokater. Påstand 3: Principalt: Glenmark Pharmaceuticals Nordic AB påbydes omgående at afregistrere den indmeldte pris for Rivaxa i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage, jf. dansk specialitetsnummer 33573, i det danske prisregister (www.medicinpriser.dk). Subsidiært, sideordnet: Glenmark Pharmaceuticals Nordic AB påbydes omgå-ende at afregistrere den indmeldte pris for Rivaxa i styrkerne 10 mg, 15 mg og 20 mg godkendt/anvendt til indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, hvor rivaroxaban har en plasmakoncentrationshalveringstid på 10 timer eller mindre, jf. dansk specialitetsnummer 33573, i det danske prisregister (www.medicinpriser.dk). Subsidiært, sideordnet: Glenmark Pharmaceuticals Nordic AB påbydes omgå-ende at afregistrere den indmeldte pris for Rivaxa i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgivelse højst en gang dagligt i mindst fem på hinanden følgende dage i pa-tienter, og hvor det er angivet at den terminale halveringstid er på 5-13 timer, jf. dansk specialitetsnummer 33573, i det danske prisregister (www.medicinpriser.dk ). Mere subsidiært: Glenmark Pharmaceuticals Nordic AB påbydes omgående at afregistrere den indmeldte pris for Rivaxa i styrkerne 10 mg, 15 mg og 20 mg, godkendt/anvendt til behandling af tromboemboliske forstyrrelser ved indgi-velse højst en gang dagligt i mindst fem på hinanden følgende dage i patienter, og hvor det er angivet at den terminale halveringstid er på 5-9 timer for unge 18 voksne, jf. dansk specialitetsnummer 33573, i det danske prisregister (www.medicinpriser.dk). Påstand 4: Principalt: Sø- og Handelsrettens afgørelse om sagsomkostninger i sag BS19709/2024-SHR ophæves, og Bayer tilkendes sagsomkostninger for Sø- og Handelsretten. Subsidiært: Sø- og Handelsrettens afgørelse om sagsomkostninger i sag BS19709/2024-SHR ændres, således at de tilkendte sagsomkostninger nedsættes. Påstand 5: Glenmark Pharmaceuticals Nordic AB skal tilbagebetale sagsomkostninger til Bayer Intellectual Property GmbH og Bayer A/S med i alt 3.500.000 kr. med tillæg af procesrente fra den
  13. november 2024 og indtil beta-ling sker. Bayer har over for alle de indkærede påstået, at forbud og påbud skal meddeles uden sikkerhedsstillelse, subsidiært mod en af retten fastsat sikkerhed. Sandoz A/S (”Sandoz”) har over for Bayers forbuds- og påbudspåstande 1-3 nedlagt påstand om afvisning, subsidiært stadfæstelse, og har over for Bayers påstand 4 om sagsomkostninger nedlagt påstand om stadfæstelse. For det til-fælde, at der meddeles forbud og påbud, har Sandoz subsidiært påstået, at San-doz tilkendes sagsomkostninger, og mere subsidiært at hver part bærer egne sagsomkostninger. Over for Bayers påstand 5 om tilbagebetaling har Sandoz påstået frifindelse. Sandoz har endvidere nedlagt påstand om, at forbud og påbud i givet fald be-tinges af en sikkerhedsstillelse fastsat efter landsrettens skøn. Teva Denmark A/S (”Teva”) har over for Bayers forbuds- og påbudspåstande 1-3 nedlagt påstand om afvisning, subsidiært stadfæstelse, og mere subsidiært at forbud og påbud betinges af en sikkerhedsstillelse på ikke under 200 mio. kr. Teva har over for Bayers påstand 4 om sagsomkostninger nedlagt påstand om stadfæstelse. Over for Bayers påstand 5 om tilbagebetaling har Teva påstået frifindelse Stada Nordic ApS (”Stada”) har over for Bayers forbuds- og påbudspåstande 1-3 nedlagt påstand om afvisning, subsidiært stadfæstelse, og mere subsidiært at forbud og påbud betinges af en sikkerhedsstillelse fastsat efter landsrettens skøn. Over for Bayers påstand 4 om sagsomkostninger har Stada nedlagt på-stand om stadfæstelse. Over for Bayers påstand 5 om tilbagebetaling har Stada påstået frifindelse. 19 Glenmark Pharmaceuticals Nordic AB (”Glenmark”) har over for Bayers forbudspåstand 1 nedlagt påstand om afvisning, subsidiært stadfæstelse, og mere subsidiært at forbud betinges af en sikkerhedsstillelse efter landsrettens skøn. Over for Bayers påbudspåstande 2-3 har Glenmark påstået stadfæstelse, subsi-diært at påbud betinges af en sikkerhedsstillelse fastsat efter landsrettens skøn. Glenmark har over for Bayers påstand 4 om sagsomkostninger nedlagt påstand om stadfæstelse, subsidiært at Glenmark tilkendes sagsomkostninger, mere subsidiært at hver part bærer egne omkostninger. Over for Bayers påstand 5 om tilbagebetaling har Glenmark påstået frifindelse. Supplerende sagsfremstilling Stridspatentet Af beskrivelsen i stridspatentet fremgår: ”[0001] The present invention relates to the field of blood coagulation, more specifically it relates to a method of treating a thromboembolic disorder by administering a direct factor Xa inhibitor once daily in oral dosage form to a patient in need thereof, wherein the factor Xa inhibitor has a plasma concentration half life indicative of a bid or tid administration interval, e.g. of 10 hours or less. [0002] Blood coagulation is a protective mechanism of the organism which helps to "seal" defects in the wall of the blood vessels quickly and reliably. Thus, loss of blood can be avoided or kept to a minimum. Haemostasis after injury of the blood vessels is effected mainly by the coagulation system in which an enzymatic cascade of complex reactions of plasma proteins is triggered. Numerous blood coagulation factors are involved in this process, each of which factors converts, on activation, the respectively next inactive precursor into its active form. At the end of the cascade comes the conversion of soluble fibrinogen into insoluble fibrin, resulting in the formation of a blood clot. In blood coagulation, traditionally the intrinsic and the extrinsic pathways, which end in a joint reaction path, are distinguished. Here factor Xa, which is formed from the proenzyme factor X, plays a key role, since it connects the two coagulation paths. The activated serine protease Xa cleaves prothrom-bin to thrombin. The resulting thrombin, in turn, cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant. In addition, thrombin is a potent effector of platelet aggregation which likewise contributes significantly to haemostasis. [0003] Maintenance of normal haemostasis - the balance between bleeding and thrombosis - is subject to a complex regulatory mechanism. Uncontrolled activation of the coagulant system or defective inhibition of the activation processes may cause formation of local thrombi or em-bolisms in vessels (arteries, veins) or in heart cavities. This may lead to serious disorders, such as myocardial infarction, angina pectoris (in-cluding unstable angina), vascular re-occlusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic at-tacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep vein thromboses; herein below, these disorders are collectively al- 20 so referred to as thromboembolic disorders. In addition, in the case of consumption coagulopathy, hypercoagulability may - systemically - re-sult in disseminated intravascular coagulation. [0004] These thromboembolic disorders are the most frequent cause of morbidity and mortality in most industrialised countries. Estimates place the annual incidence of VTE in excess of 1 case per 1,000 persons [White, RH. The epidemiology of venous thromboembolism. Circula-tion 107 (Suppl.1),14-18

(2003)]. About 1.3 - 4.1 persons in 1,000 experi-ence a first stroke [Feigin, V.L., Lawes, C.M., Bennett, D.A., Anderson, C.S. Lancet Neurol. 2, 43-53
(2003)], and about 5 in 1,000 persons a myocardial infarction annually [Fang, J, Alderman, M.H. Am. J. Med 113, 208-214
(2002)]. [0005] The anticoagulants, i.e. substances for inhibiting or preventing blood coagulation, which are known from the prior art have various, of-ten severe disadvantages. Accordingly, in practice, an efficient treat-ment method or prophylaxis of thromboembolic disorders is very diffi-cult and unsatisfactory. [0006] In the therapy and prophylaxis of thromboembolic disorders, use is firstly made of heparin, which is administered parenterally (intra-venously or subcutaneously). Owing to more favourable pharmacoki-netic properties, preference is nowadays more and more given to low-molecularweight heparin. Since heparin inhibits a plurality of factors of the blood coagulation cascade at the same time, the action is non-selective. Moreover, there is a high risk of bleeding. [0007] A second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indanediones, and especially com-pounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives which inhibit the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver in a non-selective manner. Owing to the mechanism of action, however, the on-set of the action is very slow (latency to the onset of action 36 to 48 hours). It is possible to administer the compounds orally; however, ow-ing to the high risk of bleeding and the narrow therapeutic index, a time-consuming individual adjustment and monitoring of the patient are required. [0008] Recently, a novel therapeutic approach for the treatment and prophylaxis of thromboembolic disorders has been described. This novel therapeutic approach aims to inhibit factor Xa [cf. WO-A-99/37304; WOA-99/06371; J. Hauptmann, J. Stürzebecher, Thrombosis Research 1999, 93, 203; S.A.V. Raghavan, M. Dikshit, "Recent advances in the status and targets of antithrombotic agents" Drugs Fut. 2002, 27, 669-683; H.A. Wieland, V. Laux, D. Kozian, M. Lorenz, "Approaches in anticoagulation: Rationales for target positioning" Curr. Opin. Investig. Drugs 2003, 4, 264271; U.J. Ries, W. Wienen, "Serine proteases as tar-gets for antithrombotic therapy" Drugs Fut. 2003, 28, 355-370; L.-A. Linkins, J.I. Weitz, "New anticoagulant therapy" Annu. Rev. Med. 2005, 56, 63-77 ]. It has been shown that, in animal models, various both pep-tidic and nonpeptidic compounds are effective as factor Xa inhibitors. 21 [0009] In general, oral application is the preferable route of administra-tion of a drug, and a less frequent dose regimen is desirable. In particu-lar, once daily oral application is preferred due to favourable conve-nience for the patient and for compliance reasons. However, this goal is sometimes difficult to achieve depending on the specific behaviour and properties of the drug substance, especially its plasma concentration half life. "Half life" is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50 % (Goodman and Gillmans "The Pharmacological Basis of Therapeutics" 7th Edition, Macmillan Publishing Company, New York, 1985, p 27). [0010] When the drug substance is applied in no more than a therapeutically effective amount, which is usually preferred in order to minimize the exposure of the patient with that drug substance in order to avoid potential side effects, the drug must be given approximately every half live (see for example: Malcolm Rowland, Thomas N. Tozer, in "Clinical Pharmacokinetics, Concepts and Applications", 3rd edition, Lea and Febiger, Philadelphia 1995, pp 83). [0011] In the case of multiple dose application the target plasma concentration (approximate steady state) can be reached after 3 to 5 half lives (Donald J. Birkett, in "Pharmacokinetics Made Easy", McGraw-Hill Education: 2000; p 20). At steady state the concentrations of drugs which rise and fall during each interdose interval are repeated identically in each interdose interval (Goodman and Gillmans "The Pharmacological Basis of Therapeutics" 7th Edition, Macmillan Publishing Company, New York, 1985, p 28). [0012] Surprisingly, it has now been found in patients at frequent medication that once daily oral administration of a direct factor Xa inhibitor with a plasma concentration half life time of 10 hours or less demonstrated efficacy when compared to standard therapy and at the same time was as effective as after twice daily (bid) administration. [0013] The present invention relates to the use of an oral dosage form of a direct factor Xa inhibitor for the manufacture of a medicament for the treatment of a thromboembolic disorder administered once daily for at least five consecutive days, wherein said inhibitor has a plasma concentration half life of 10 hours or less when orally administered to a human patient. [0014] In a preferred embodiment, the present invention relates to 5Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]- 1,3oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide (I), a low molecular weight, orally administrable direct inhibitor of blood clotting factor Xa (see WO-A 01/47919) as the active ingredient. [0015] Compound (I) is an active site directed, competitive, direct factor Xa inhibitor [E. Perzborn, J. Strassburger, A. Wilmen, J. Pohlmann, S. Roehrig, K.-H. Schlemmer, A. Straub; J Thromb Haemost 2005 ; DOI: 10.1111/j.1538-7836.2005.01166.x]. (I) acts directly on factor Xa, that means independently from a cofactor (such as Antithrombin III, the co- 22 factor of heparins). The antithrombotic effect is attributed to the inhibi-tion of factor Xa. [0016] Furthermore, (I) binds to the active site of factor Xa in the S1- and S4 pockets [S. Roehrig et al. 228th ACS National Meeting, Philadelphia, August 22-26, 2004, MEDI-156]. [0017] For (I) a plasma concentration half life of 4-6 hours has been demonstrated at steady state in humans in a multiple dose escalation study (D. Kubitza et al, Multiple dose escalation study investigating the pharmacodynamics, safety, and pharmacokinetics of Bay 59-7939, an oral, direct Factor Xa inhibitor, in healthy male subjects. Blood 2003, 102: Abstract 3004) [0018] In a clinical study in patients undergoing total hip replacement (THR), the efficacy of (I) is measured by the occurrence of deep vein thrombosis (DVT) after THR surgery. According to the Sixth ACCP Consensus Conference on Antithrombotic Therapy (Chest 2001; 119: 132S-175S) the DVT rate (prevalence) after THR surgery is as follows: Prevalence (%) 54.2 30.1 (95 % Confidence intervall) (50-58) (27- 33) Placebo Low dose heparin LMWH * 16.1 (15-17) * LMWH = Low Molecular Weight Heparin [0019] After 7 to 9 days of once daily administration of 30 mg (I) to 73 patients undergoing THR surgery, a DVT rate of 12.3 % has been observed (LMWH comparator was 16.8 %). Administration of (I) was also safe and well tolerated. [0020] The once daily dose of (I) was also compared to different doses of (I) which have been administered twice daily (bid). By comparing the total daily doses administered it could also be demonstrated that after once daily administration efficacy on one hand and major bleeding, an expected side effect on the other hand, match well the expected effects after twice daily administration (for a discussion of further details see the experimental part). [0021] For the purpose of the present invention as disclosed and de-scribed herein, the following terms and abbreviations are defined as fol-lows. [0022] The term "treatment" includes the therapeutic and/or prophylac-tic treatment of thromboembolic disorders. [0023] The term "direct factor Xa inhibitor" means an inhibitor that acts directly on factor Xa, independently of a cofactor (such as Antithrombin III, the cofactor of heparins). The antithrombotic effect is hereby attributed to the inhibition of factor Xa. 23 [0024] The term "thromboembolic disorders" includes in particular disorders as the acute coronary syndrome spectrum as ST Segment Eleva-tion Myocardial Infarction (STEMI) (also known as Q-wave MI), Non ST Segment Elevation Myocardial Infarction (NSTEMI) (also known as Non Q-wave MI) and unstable angina (UA), as well as stable angina pectoris, vascular re-occlusions and restenoses after angioplasty or aor-to-coronary bypass, peripheral arterial occlusion disorders, pulmonary embolisms, or deep vein thromboses, renal thrombosis, transitory is-chaemic attacks and stroke, inhibition of tumor growth and develop-ment of metastasis, treatment of disseminated intravascular coagulation (DIC) and the socalled "economy class syndrome", especially in pa-tients with risk of venous thrombosis, atherosclerotic diseases, inflam-matory diseases, as rheumatic diseases of the musculoskeletal system, Alzheimer's disease, inhibition of old-age macula-degeneration, diabet-ic retinopathy, diabetic nephropathy and other microvascular diseases. [0025] Included are also disorders derived from cardiogenic thromboembolism, for instance cerebral ischemic diseases, stroke, systemic embolism and ischemic attacks, especially in patients with acute, intermittent or persistent arrhythmia of the heart such as atrial fibrillation or alongside cardioversion, or in patients with valvular heart disease or artificial heart valves. [0026] Moreover, included are also disorders derived from thromboembolic complications which can arise within patients with microangio-pathic hemolytic anaemia, extracorporal circulation such as hemodialy-sis, or prosthetic heart valves as well as from thromboembolic compli-cation, e.g. venous thromboembolism in tumor patients, in particular in patients undergoing surgical interventions, chemotherapy or radiother-apy. [0027] Preferred is the treatment of acute coronary syndrome spectrum as ST Segment Elevation Myocardial Infarction (STEMI), Non ST Seg-ment Elevation Myocardial Infarction (NSTEMI) and unstable angina, reocclusions after angioplasty or aortocoronary bypass, peripheral arte-rial occlusion disorders, pulmonary embolisms or deep vein throm-boses, transitory ischaemic attacks and stroke. [0028] Particularly preferred is the treatment of acute coronary syn-drome spectrum as ST Segment Elevation Myocardial Infarction (STE-MI), Non ST Segment Elevation Myocardial Infarction (NSTEMI) and unstable angina, reocclusions after angioplasty or aortocoronary by-pass, pulmonary embolisms or deep vein thromboses and stroke. [0029] The term "oral dosage forms" is used in a general sense to reference pharmaceutical products administered orally. Oral dosage forms are recognized by those skilled in the art to include such forms as liquid formulations, granules, gelcaps, hard gelatine capsules or sachets filled with granules, and tablets releasing the active compound rapidly or in a modified manner. [0030] Tablets are preferred, in particular tablets rapidly releasing the active compound. In the context of the present invention, rapid-release 24 tablets are in particular those which, according to the USP release method using apparatus 2 (paddle), have a Q value (30 minutes) of 75 %. [0031] Very particularly preferred are rapid-release tablets containing 5Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)- phenyl]-1,3oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide as active ingredient. Preparation of such tablets is for example described in PCT/04/01289. [0032] The amount of active ingredient in the formulation will depend on the severity of the condition, and on the patient to be treated, as well as the compound employed. In the case of (I) as active ingredient, a dose of 1 to 100 mg, preferentially 2 to 50 mg, particularly preferred 5 to 30 mg can be applied. [0033] The term "once daily" is well known by those skilled in the art and means administration of the drug once a day and includes the administration of one dosage form as well as administration of two or more dosage forms simultaneously or consecutively within a short time period. [0034] The invention is illustrated, but in no way limited, by the follow-ing example: Experimental part (clinical trial) Example 1 …” Forløbet ved Den Europæiske Patentmyndighed frem til udstedelsen af stridspatentet Bayers oprindelige patentansøgning vedrørende det efterfølgende udstedte EP 1 845 961 indeholdt følgende kravsæt: “1. A method of treating a thromboembolic disorder comprising administering a direct factor Xa inhibitor no more than once daily for at least five consecutive days in an oral dosage form to a patient in need thereof, wherein said inhibitor has a plasma concentration half life of 10 hours or less when orally administered to a human patient. 2. The method of claim 1, wherein one dosage form is administered. 3. The use of an oral dosage form of a direct factor Xa inhibitor for the manufacture of a medicament for the treatment of a thromboembol-ic disorder administered once daily for at least five consecutive days, wherein said inhibitor has a plasma concentration half life of 10 hours or less when orally administered to a human patient. 4. The method or use as claimed in any of Claims 1 to 3, wherein the thromboembolic disorder is ST Segment Elevation Myocardial Infarction (STEM!), Non ST Segment Elevation Myocardial Infarction 25 (NSTEMl), unstable angina, reocclusion after angioplasty or aortocoronary bypass, pulmonary embolisms, deep vein thromboses or stroke. 5. The method or use as claimed in any of Claims 1 to 4, wherein the oral dosage form is a rapid-release tablet. 6. The method or use as claimed in any of Claims 1 to 5, wherein the direct factor Xa inhibitor is 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4morpholinyl)phenyl]-l,3-oxazolidin-5- yl}methyl)-2thiophenecarboxamide. 7. A packaged pharmaceutical composition comprising a container containing a rapid-release tablet comprising 5-Chloro-N-({(5S)-2oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide, said container furthermore containing in-structions for using said rapid-release tablet to treat a thromboem-bolic disorder. 8. The packaged pharmaceutical composition of claim 7, comprising a container containing a rapid-release tablet comprising 5-Chloro-N({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)- phenyl]-l,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide, said container furthermore containing instructions for administering said rapid-release tablet at a frequency of once daily.” I forbindelse med prøvningen af Bayers ansøgning anførte Examining Division ved Den Europæiske Patentmyndighed (”EPO”) i et brev af 26. juli 2010 til Bay-er blandt andet følgende: ”3 The subject-matter of claims 1, 2 and 4-6 (as dependent on claims 1-2) concerns a method of treatment of the human or an-imal body by therapy, which is excluded from patentability (Ar-ticle 53 (c) EPC). The claims as presently formulated are thus not allowable and should be either suppressed or reworded in the form of a product for use in such a method according to Ar-ticles 54
(5)EPC (Guidelines C-IV, 4.8). 4 Furthermore, claim 3 does not meet the requirements of Article 84 EPC in that the matter for which protection is sought is not clearly defined. The functional statement "wherein said in-hibitor has a plasma concentration half life of 10 hours or less when orally administered to a human patient" does not enable the skilled person to determine which structural technical fea-tures are necessary for a compound to fall within the scope of the claim. In a second aspect present claim 3 (and also claims 4-6 as far as they depend on claim 3) do not meet the requirements of Art. 84 because of the feature "once daily for at least five consecutive days". Some passages of the description refer to a dosage regi- 26 men of "no more than once daily for at least five consecutive days". This difference in the terminology conveys the impres-sion that the subject-matter for which protection is sought in claim 3 may include dosage regimens comprising administra-tion of more than once daily, thereby resulting in lack of clarity of claims 3-
  1. It is also noted that if dosage regimens of more than once daily for at least five consecutive days are not exclud-ed from the scope of the claims then not only the once daily dosage regimen but also the bid and tid dosage regimens dis-closed in D2 would be novelty destroying for present claims 3 and 5-6 (see paragraph below). Thus, in order to meet the re-quirements of Art. 84 and to avoid further objections under Art. 54 EPC it is suggested to reformulate present claim 3 by includ-ing the feature "no more than once daily for at least five con-secutive days". 5 The subject- matter of present claims 3 and 5-8 does not meet the requirements of the EPC with respect to novelty (Art. 54) for the following reasons. D1 discloses factor Xa inhibitors, including the compound of present claims 6-8 (see example 44 in D1) for the treatment of various thromboembolic disorders. D1 is novelty destroying for the pharmaceutical compositions of present claims 7 and
  2. It is noted that the feature relating to the instructions is not regarded as a distinctive feature over pharmaceutical compositions comprising the same active agent. D2 and D3 also disclose the compound BAY 59-7939 in connection with the treatment of thromboembolic disease whereby they are also novelty destroying for present claims 7 and
  3. Furthermore, D2 discloses a dosage regimen of administration of 5 mg orally once daily for 5 days. Thus, D2 is also novelty destroying for present claims 3 and 5-
  4. 6 No inventive step (Art. 56 EPC) can be recognised for that subject-matter of the claims which is not novel, namely for that of present claims 3 and 5-
  5. The subject- matter of present claim 4 a dependent on claim 3 does also not involve an inventive step because it merely consist in the selection of particularly pre-ferred embodiments which fall within the customary practice followed by those skilled in the art. Thus, the requirements of Art. 56 EPC are also not met. 7 The applicant is invited to file a new claims which take account of the above comments and objections.” Bayer sendte den
  6. januar 2011 et tilrettet kravsæt til Examining Division og anførte herom: ”Claim Amendments 27 We deleted originally filed claims 1 and 2 and renumbered originally filed claim 3 as new claim
  7. We included originally filed claims 5 and 6 in originally filed claim 3 (new claim 1). Furthermore, we added "no more than" to claim 3 (new claim 1) as suggested by the examiner. We amended originally filed claim 4 (new claim 2) by deleting "method". Furthermore, we deleted originally filed claims 7 and
  8. Novelty and Inventive step 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (rivaroxaban) is administered in form of a rapid-release tablet which means that nearly all rivaroxaban is available to a human patient at once and the elimination of rivaroxaban from the plasma is started. Surprisingly, rivaroxaban can be administered no more than once daily (od) for at least five consecutive days, even though rivaroxaban has a plasma concentration half life of 10 hours or less when orally administered to a human patient (see also page 3 line 15 to 18, foreign countries text) . It is well known to a person skilled in the art that usually this half life is not sufficient for a once daily administration. It had been demonstrated by preclinical investigations that the k i value for free factor Xa is 0 4 nM which would be equivalent to a plasma concentration of approximately 0.17 µg/L of unbound rivaroxaban. The administration of 10 mg rivaroxaban once daily in phase II studies resulted in free plasma concentrations at trough of 0.91 µg/L which is approximately 5-fold higher than the value for free factor Xa. i k Therefore, the offset of action can be accurately described by the elimination of rivaroxaban from the plasma which based on elimination half-lives of 11 - 13 h can be assumed between 48 - 72 h after the last intake of rivaroxaban 10 mg rapid-release tablet. This supports the once-daily dosing regimen for rivaroxaban. The data mentioned on page 13 table 1-1 and page 13 line 2 to 5 clearly demonstrate the efficacy of od administration of rivaroxaban, namely fewer occurrence of composite endpoint events, i.e. fewer cases of DVT, PE or death compared to untreated conditions, and in the range of standard therapy (see 30 mg dose od and bid). Furthermore, the od administration is surprisingly perfect in line with twice daily (bid) ad-ministration. By comparing the total daily doses administered it could also be demonstrated that after once daily administration efficacy on one hand and major bleeding, an expected side effect on the other hand, match well the expected effects after twice daily administration (page 4 line 20 to 22). The data mentioned on page 14 table 1-2 and page 14 line 3 to 5 clearly demonstrate the safety of od administration of rivaroxaban (see 28 30 mg dose od and bid). The occurrence of any major bleeding events is low, approximately in the range of standard therapy and again perfect-ly in line with results from bid administration. The dose form and the use mentioned in the present application are not mentioned in detail in the prior art, i.e. D2 and D
  9. Furthermore, look-ing at the half life of rivaroxaban it is surprising that administration of rivaroxaban as rapid-release tablet once daily is sufficient for the thera-py. Therefore, the present application shows novelty and an inventive step. … We claim [rettelsesmarkeringer udeladt]
  10. The use of a rapid-release tablet of 5-Chloro-N-({(5S)-2-oxo-3-[4(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2thiophenecarboxamide for the manufacture of a medicament for the treatment of a thromboembolic disorder administered no more than once daily for at least five consecutive days, wherein said inhibitor has a plasma concentration half life of 10 hours or less when orally administered to a human patient.
  11. The use as claimed in Claim 1, wherein the thromboembolic disorder is ST Segment Elevation Myocardial Infarction (STEMI), Non ST Segment Elevation Myocardial Infarction (NSTEMI), unstable angina, reocclusion after angioplasty or aortocoronary bypass, pulmonary embolisms, deep vein thromboses or stroke.” Examining Division svarede den
  12. april 2012 Bayer som følger: “1 Present claims 1 and 2 are in agreement with Art. 123
(2)EPC and also overcome the objections as to lack of novelty raised in the previous communication (Art. 54 EPC). In particular, D2 discloses oral doses of rivaroxaban for 5 days with food. However, the document does not disclose administration in the form of tablets. 2 The amended claims are also considered to involve an inventive step (Art. 56 EPC) and could provide the basis for the grant of a patent. It is however noted that present claim 1 does no longer relate to direct factor Xa inhibitors, whereby the feature referring to "said inhibitor", namely "wherein said inhibitor has a plasma concentration half life of..." introduces some obscurity as concerns the scope of the claim (Art. 84 EPC). In order to remove the above deficiency the following formulation is suggested for claim 1: 29 "The use of a rapid-release tablet of the compound 5-Chloro-N({(5S)-2-oxo-3-[4- (3- oxo-4- morpholinyl) phenyl]-1,3- oxazolidin-5- yl} methyl)-2-thiophenecarboxamide for the manufac-ture of a medicament for the treatment of a thromboembolic disorder administered no more than once daily for at least five consecutive days, wherein said compound has a plasma con-centration half life of 10 hours or less when orally administered to a human patient".” Bayer accepterede Examining Divisions forslag, jf. Bayers brev af
  1. september 2012, og ændrede kravsættet i overensstemmelse hermed. Patentet blev herefter udstedt med det ændrede kravsæt. Bayer har for landsretten indleveret en skriftlig erklæring af
  2. juli 2024 fra Dr. Person 8, som på Bayers vegne besvarede Examing Divisions indsigelser og underskrev de ovennævnte breve. I erklæringen er anført blandt andet: ”
  3. I understand from Bayer's attorneys in Sweden that the counterparties in the legal proceedings in Sweden concerning the infringement and validity of the Patent argue that the claim amendment insofar as it concerns the inclusion of "rapid-release tablet" (original claim 5) into the new claim 1 was made to meet the requirements of novelty (Art. 54 EPC) and inventive step (Art. 56 EPC). That is incorrect.
  4. The feature "rapid-release tablet" consists of two parts, namely "rapid-release" and "tablet". As seen in the section under the heading "Novelty and Inventive step" in Bayer's reply to the communication from the Examining Division (Annex 4), the rapid release of rivaroxaban (first paragraph of said section), together with rivaroxaban's short half-life (second paragraph of said section), was relied on by Bayer to support novelty (Art. 54 EPC) and inventive step (Art. 56 EPC). The same is clear from the other paragraphs of said section.
  5. The inclusion of "tablet" in the new claim 1 was a consequence of the claim amendments made to ensure support in the appli-cation as filed (cf. Art. 123
(2)EPC). As "rapid-release" was only disclosed clearly and unambiguously with "tablet" in the origi-nal claim 5 and in the application as filed (see e.g. page 10 rows 6-9 in the application as filed), the amendments were made by simply merging the claims. Based on my experience as a Euro-pean Patent Attorney, this is a common and straightforward way of amending claims to ensure support in the application as filed. The inclusion of "tablet" in the new claim 1 was thus made to ensure support in the application as file pursuant to Art. 123
(2)EPC when amending the claims by including the "rapid-release" feature in combination with the short half-life in the new claim 1.” 30 Den efterfølgende indsigelsessag ved Den Europæiske Patentmyndighed I Bayers indlæg af 16. november 2016 i indsigelsessagen for Opposition Division ved EPO fremgår af pkt. 120: “Regarding the calculation of the half life, the Opposed Patent in para. [0009] refers to p. 27 of the 7th edition
(1985)of the standard pharmacology textbook Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, which in its penultimate para. defines the usually reported half life as the "terminal log-linear rate of elimination " (see D9a, p. 27, right col., penultimate para., last 4 lines). In general, the skilled person has no difficulties in determining plasma concentrations and calculating the half life of chemical compounds such as rivaroxa-ban. Methods employed to this end, such as HPLC and MS, were rou-tine for the skilled person and formed part of his common general knowledge. The opponents have not substantiated why plasma concen-tration determination should not have been possible at the effective fil-ing date of the Opposed Patent. Patentee submits that this clearly was the case.” Opposition Division fandt ved afgørelse af
  1. april 2018, at patentet skulle ophæves som følge af manglende opfindelseshøjde, jf. Den Europæiske Patentkonventions artikel
  2. Ved afgørelse af
  3. oktober 2021 (T 1732/18) tilsidesatte EPO’s Technical Board of Appeal Opposition Divisions afgørelse af
  4. april 2018 og opretholdt patentet i dets helhed. Appelkammeret fandt i den forbindelse, at der ikke var tale om utilladelig udvidelse, jf. patentkonventionens artikel 100, litra c, og artikel 123, stk. 2, og at betingelserne om nyhed, jf. artikel 100, litra a, artikel 52, stk. 1, og artikel 54, beskrivelse, jf. artikel 100, litra b, samt opfindelseshøjde, jf. artikel 100, litra a, artikel 52, stk. 1, og artikel 56, var opfyldt. Af afgørelsen af
  5. oktober 2021 fremgår blandt andet: ”Reasons for the Decision …
  6. Patent in suit 2.1 The patent in suit (see paragraph [0001]) relates to the field of blood coagulation, in particular to a medicament and dosage reg-imen for treating thromboembolic disorders by administering a direct factor Xa inhibitor. Factor Xa plays an important part in blood coagulation. The activated serine protease Xa cleaves prothrombin to thrombin. The resulting thrombin cleaves fibrinogen to the coagulant fibrin. Thrombin is also a potent effector of platelet aggregation (see the patent in suit, paragraph [0002]). 2.2 31 2.3 According to claim 1 as granted, the envisaged treatment is oncedaily administration (see point 3.1 below), for at least five consecutive days, of a rapid-release tablet of the direct factor Xa inhibitor rivaroxaban. 2.4 This dosage regimen is backed up by data from a clinical phase II dose guiding study with 642 patients undergoing elective primary total hip replacement (see the patent in suit, paragraphs [0035] to [0045]) . The objective of the study was the assessment of safety, tolerability and efficacy of rivaroxaban at different oral doses (od and bid) compared with subcutaneously administered enoxaparin in the prevention of venous thromboembolism (VTE).
  7. Claim construction 3.1 Dosage regimen 3.1.1 According to claim 1 as granted, the medicament is to be administered for at least five consecutive days. This can only mean that the medicament is to be administered on consecutive days, and therefore at least once daily. Since the claim also requires that the medicament is to be administered no more than once daily, the dosage regimen defined in claim 1 is once-daily administration. 3.1.2 Once-daily administration as conventionally understood includes the administration, once a day, either of just one dosage form or of two or more dosage forms simultaneously or consecutively within a short time period. This is also how the term is understood in the application as filed (see page 10, lines 18 to 20) and the patent in suit (see paragraph [0033]) . 3.2 Plasma concentration half-life 3.2.1 It was a subject of dispute whether the claim feature "wherein said compound has a plasma concentration half life of 10 hours or less when orally administered to a human patient" is redundant or has a delim-iting effect. 3.2.2 In claim 1 of the application as filed, the definition of the drug compound had a broader scope ("a direct factor Xa inhibitor, wherein said inhibitor has a plasma concentration half life of 10 hours or less when orally administered to a human patient"). The application states that rivaroxaban is a preferred embodiment of such compounds (see page 3, lines 19 to 30 and claim 6 as filed). While claim 1 as granted is restricted to the preferred embodiment rivaroxaban, it still recites the feature in question relating to plas-ma concentration half-life. 3.2.3 The respondents argued that this feature must be regarded as limiting since it was not inherent to the compound and the half-life requirement would not inevitably be met by all patients, in particular not by elderly patients (see D8, page 2: "After procedure"; 32 D23: page 413, column 1, paragraph 2 and D108: page 413, column 2, lines 2-7; all reporting that the half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in the elderly). This mattered all the more because the thromboem-bolic disorders to be treated were especially relevant in the elder-ly. 3.2.4 The appellant submitted that the half-life parameter merely served to characterise the class of drug compounds under consideration. Thus, it was redundant in granted claim 1, which had been re-stricted to one specific compound (rivaroxaban). The only half-lives known for rivaroxaban in humans at the effective date of the patent had been reported to be well below ten hours. 3.2.5 For a skilled person considering the wording of claim 1, the question of what would be required to comply with the claim feature defining a plasma concentration half-life of ten hours or less would indeed arise. In these circumstances, it would be logical to consult the description to establish the context in which this fea-ture occurs. 3.2.6 According to paragraph [0001] of the patent in suit, the active compounds envisaged for treating thromboembolic disorders are direct factor Xa inhibitors which have "a plasma concentration halflife indicative of a bid or tid administration interval, e.g. of 10 hours or less", but, nevertheless, these compounds are to be ad-ministered once daily. Thus, it is apparent to the reader that the patent uses the half-life parameter to describe a group of drug compounds envisaged for the invention. It is also mentioned that the plasma concentration half-life of rivaroxaban was found to be four to six hours in the participants of a multiple-dose escalation study (see paragraphs [0014] and [0017] of the patent specification, referencing document D2). According to the context given in the patent, rivaroxaban therefore meets the half-life criterion. Based on its presentation in the patent in suit, it cannot be inferred that the half-life parameter is supposed to be an absolute criterion (i.e. that the half-life is required to be ten hours or less in all hu-mans or in all patients with thromboembolic disorder under any circumstance). Nor can it be inferred that the plasma concentration half-life has any relevance for the implementation of the treatment in individual patients. 3.2.7 Since claim 1 is restricted to rivaroxaban, characterised in the description as having a half-life of four to six hours, and no other intended meaning of the feature is apparent from the context given in the patent, the feature "wherein said compound has a plasma con- 33 centration half life of 10 hours or less when orally administered to a hu-man patient " is redundant. … Novelty in relation to D1 5.6 Document D1 discloses compounds of a "general formula (I)" and envisages their use as anticoagulants, for the prophylaxis and/or therapy of thromboembolic disorders (D1: claims 1 and 10). Rivaroxaban is a preferred compound (D1: claim 7, paragraph [0145]). According to D1 (paragraph [0367]), all customary admin-istration forms are suitable, including tablets. 5.7 While some of the relevant features are thus disclosed in different passages of the document, the respondents failed to identify direct and unambiguous specific disclosure in D1 of all the mandatory technical features of claim 1 of the patent in suit in combination (i.e. rapid-release tablets of rivaroxaban, administered no more than once daily for at least five consecutive days and showing a clinical benefit in a thromboembolic disorder). 5.8 The further passages of D1 relied on by the respondents either do not add any information (paragraph [0355] is about "compounds of the general formula (a)"[sic] and the treatment of "disorders" in general) or merely state that it may be advisable to divide large amounts of the medicament into several administrations over the course of one day (paragraphs [0368] and [0372]). This does nothing to remedy the lack of specific disclosure of the required combination of features. Novelty in relation to D2 and D11 5.9 The content of documents D2 and D11 is largely identical. Both relate to the same phase I clinical study of rivaroxaban carried out with healthy male volunteers. Neither document discloses tablets (let alone rapidrelease tablets or a clinical benefit of a once-daily dosage regimen of rapid-release rivaroxaban in the therapy or prophylaxis of thromboem-bolic disorders. Accordingly, the subject-matter of claim 1 differs from the disclosure of D2 and D11 in features defining the composition and in features defining the therapeutic application. 5.9.1 The mere assumption that tablets may well have been used in the study of D2/D11 does not meet the standard of direct and unambiguous disclosure in the prior art. 5.9.2 The clinical study described in D2/D11 was a preliminary phase I study carried out with healthy subjects. It was not designed to test 34 the efficacy and safety of a specific dosage regimen in subjects requiring prophylactic or therapeutic anticoagulant treatment. The board concurs with the appellant that the group of candidates eligible for prophylactic treatment with anticoagulants does not include healthy subjects. There has to be a reason, i.e. some risk factor for thromboembolism, to justify prophylactic treatment with a medicament which may potentially cause major bleeding as a severe adverse effect. Hence, claim 1 of the patent in suit, even where it relates to prophylactic treatment, does not encompass the treatment of healthy subjects. Clinical efficacy is only determined in phase II and phase III studies. A phase I study limited to the initial testing of a range of doses on healthy subjects to obtain certain base parameters cannot establish the clinical efficacy of a dosage regimen for treating patients with pathology. Also, the established absence of bleeding complications in healthy subjects treated with the drug (as reported in D2/D11) is not sufficient by itself to justify the conclusion that the same treatment is safe for patients with pathology. As credibly set out by the appel-lant, susceptibility to bleeding or potential causes of bleeding are exclusion criteria for a phase I anticoagulant trial (see the state-ment setting out the grounds of appeal, page 41, point
(119); D110: page 14, second paragraph and D122: point 55). As a consequence, the absence of bleeding in the subjects of a phase I trial would be expected but would not necessarily be indicative of clinical safety in patients. On the other hand, if bleeding nevertheless occurred, this would indicate a serious safety problem. Conclusion on novelty 5.10 … For these reasons, the subject-matter of claim 1 as granted is novel relative to the disclosure of documents D1, D2 and D11. The same conclusion applies to dependent claim 2. 8. Sufficiency of disclosure (Article 100(
  1. b)EPC) 8.1 The respondents' objections regarding insufficiency of disclosure cannot succeed for the following reasons. 8.2 Objections regarding the scope of the terms used in claim 1 8.2.1 The respondents' objections concerning the skilled person's (lack
  2. of)understanding of the terms "rapid-release tablet" and "thromboembolic disorder" come down to an alleged lack of clarity (Article 84 EPC) rather than insufficiency of disclosure since, at most, the boundaries of these terms might be in doubt. As both terms appear in claim 1 as granted, this ground for objection cannot be dealt with in opposition appeal proceedings (see Enlarged Board of Appeal decision G3/14, OJ EPO 2015, A102). 35 8.2.2 Both terms are, in any case, readily understood. The widely used and accepted term "thromboembolic disorder" in claim 1 is understood, without any need for consulting the de-scription, as any condition that promotes or increases the risk of intravascular thrombus formation, which may lead to throm-boembolic events (as a piece of a thrombus can detach as an embo-lus, which can travel through the circulation and lodge some-where else as an embolism). "Rapidrelease tablet" (also referred to as "immediate-release tablet") is a well-known term of art. 8.3 Objections regarding lack of guidance 8.3.1 Preparation of rapid-release tablets Indeed, rapid-release (or immediate-release) tablets are one of the most common dosage forms in the field of pharmacy (see also D4: page 410, right column). There is no reason to doubt that a person of ordinary skill in the art would be able to prepare rapid-release tablets on the basis of common general knowledge and routine measures. Specific instructions in the application/patent are not required. 8.3.2 Dosage frequency As set out above (see point 3.1), claim 1 requires that the tablets be administered once daily. Hence, it is not necessary that the patent and the underlying application provide data in support of dosage regimens that involve less frequent dosing. 8.3.3 Dosage range The respondents' arguments that claim 1 ought to indicate a dosage range and that efficacy may be lacking at low doses cannot succeed either. The dosage regimen in claim 1 is characterised by once-daily administration (implicitly of an adequate dose, see also point 8.4.1 below) of rivaroxaban in rapid-release form. While claim 1 does not specify a dosage range, the person skilled in the art would be well aware that there must be, in practice, a lower dosage limit to ensure efficacy and an upper limit to ensure safety, and that these can be determined by appropriate clinical studies within the ordi-nary scope of ability of a skilled person. Hypothetical "literal" em-bodiments involving doses clearly outside the scope of practical application would not be regarded as being covered by the claims. The description of the patent in suit also provides some reference points with regard to dosing (see paragraph [0032] and example 1). This situation is different from the situation examined in decision T 1038/14 (cited by respondent 14). … 36 The conclusions drawn in case T 1038/14 on the basis of a different situation are not pertinent to the current case. Firstly, it is implicit that only safe and effective doses can provide clinical treatment. Secondly, the respondents did not provide evidence to doubt that the favourable dose range can be determined by usual means without undue burden. 8.3.4 Plasma concentration half-life As established in section 3.2 above, the treatment defined in claim 1 does not include any mandatory step of verifying the plasma concentration half-life of rivaroxaban in the individual patient be-ing treated and/or adjusting this parameter to keep within certain limits. Hence, there is no basis for an objection of insufficient dis-closure in this regard. 8.4 … Objections regarding lack of support for the therapeutic indication 8.5 For these reasons, the ground for opposition under Article 100(
  3. b)EPC does not prejudice maintenance of the patent as granted. 9. Inventive step (Articles 100(a), 52
(1)and 56 EPC) 9.1 The technical background and content of the patent in suit are summarised in section 2. above. Starting point in the prior art 9.2 At the priority date, the entirety of published clinical data on rivaroxaban was phase I data. It was common ground that the conference abstracts D2 and D11 represented the closest prior art. 9.3 The content of D2 and D11 is largely identical. Both relate to the same clinical study, namely the appellant's own placebo-controlled phase I clinical trial of rivaroxaban (BAY 597939) in healthy male subjects. This was a multiple-dose escalation study investigating the pharmacodynamics, safety and pharmacokinetics of rivaroxaban, in development for the prevention and treatment of thromboembolic diseases. The oral doses given were 5 mg once daily, twice daily or three times daily; or 10 mg, 20 mg or 30 mg twice daily for five days. Distinguishing technical features and alleged technical effects 9.4 Both D2 and D11 mention the investigated drug compound only by its internal project code name "BAY 59-7939". The appellant's argument that D2/D11 do not provide enabling disclosure of the active compound does not succeed since the person skilled in the 37 art would have found no difficulty in looking up the chemical identity and preparation of "BAY 59-7939" in the appellant's fur-ther publications on this compound. As this was a recent development, only a limited number of publications would have had to be viewed. D16 (entitled: "In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 - an oral direct factor Xa inhibitor") indicates the chemical name and structure of "BAY 59-7939" (see D16: page 515, left column, first paragraph and Figure 1). D1 is the ba-sic patent application disclosing its synthesis (see D1: claim 7 and example 44). Thus, the specific choice of the factor Xa inhibitor is not a technical feature distinguishing the claimed subject-matter from the disclosure of D2/D11. 9.5 As already determined in the context of novelty assessment (see point 5.9 above), D2/D11 neither disclose the use of tablets nor do they establish the clinical benefit of any specific dosage regimen of rivaroxaban in the therapy or prophylaxis of thromboembolic disorders. The release properties of the dosage form and the dosing frequency are functionally linked and together constitute the dosage regimen. 9.6 Thus, the features distinguishing the subject-matter of claim 1 from the disclosure of D2/D11 are the use of tablets and the medi-cal use achieved with a specified dosage regimen (namely, once-daily dosing of rapid-release rivaroxaban for at least five consecu-tive days). 9.7 Tablets are a conventional dosage form. The appellant did not base its reasoning in favour of inventive step on the choice of tablets over other dosage forms (e.g. capsules). 9.8 The proposed dosage regimen involving once-daily administra-tion of rapid-release rivaroxaban has the alleged benefits of pro-viding safe and effective treatment as well as patient convenience (patent in suit: paragraphs [0009] and [0012] and example 1). Objective technical problem and solution 9.9 The objective technical problem may thus be defined as providing a safe, effective and convenient oral dosage regimen of "BAY 597939" (i.e. rivaroxaban) for the prophylactic and therapeutic treatment of thromboembolic disorders. 9.10 The views of the parties diverged on the question of which of the above-named technical effects should be included in the formulation of the objective technical problem. 9.11 Some respondents contested that efficacy and safety should form part of the technical problem: 38 - According to respondents 7 and 10, claim 1 did not indicate a limiting dosage range that ensured the safety and efficacy of the treatment across the scope claimed. - According to respondent 6, example 1 of the patent in suit did not credibly demonstrate the safety of the treatment in light of the disclosure of D110d (relating to a phase II study of razaxaban). 9.12 As mentioned above, the medical indication "for the treatment of a thromboembolic disorder" in claim 1 implies that the treatment provided by the medicament and dosage regimen fulfils its pur-pose, i.e. that it is safe and effective. Embodiments that do not achieve this are not encompassed by the claim. The respondents' concerns under point 9.11 are thus an issue under sufficiency of disclosure rather than inventive step, and are dealt with in points 8.3.3 and 8.4 above. 9.13 According to the appellant, it was not justified to include patient convenience in the formulation of the objective technical problem. Since no patient had been known to have taken rivaroxaban in any dosage regimen, there was no baseline patient convenience mea-sure at the priority date, and it would have been too early to have patient convenience as a goal at the priority date of the patent. 9.14 The board takes the view that it is appropriate to include patient convenience in the formulation of the objective technical problem since this is an evident benefit obtained by the claimed subjectmatter. As acknowledged in the patent in suit (see paragraph [0009]), a oncedaily dosage regimen is favourable in terms of the generally desirable goal of patient convenience and the resulting improved compliance. The technical problem as defined in point 9.9 above does not translate into a requirement that patient convenience be improved over an implied existing dosage regimen or that the aspect of convenience be prioritised over efficacy and safety. Mentioning convenience in the objective technical problem is not a pointer to the solution, either, since different measures contributing to convenience might have been considered. 9.15 According to respondent 13, the objective technical problem should in addition to convenience include the requirement that a sustainedrelease form be avoided, as this was a further advantage mentioned by the appellant in its statement setting out the grounds of appeal. 9.16 This suggestion would, however, introduce a pointer to the solu-tion (the subject-matter of claim 1) by implying that an immediaterelease form should be used. 39 9.17 For these reasons, the board considers the objective technical problem defined in point 9.9 above to be correct. 9.18 In view of the known clinical data, the board also considers that the objective technical problem is credibly solved by the subject-matter as defined in claim 1 (see the comments made in section 8 above in the context of sufficiency of disclosure). Obviousness of the solution 9.19 Based on D2/D11 stating that rivaroxaban was a direct factor Xa inhibitor and in development for the prevention and treatment of thromboembolic diseases, the person skilled in the art would have had a general expectation that this drug could provide clinical efficacy for this indication. D2/D11 also reports preliminary favourable results regarding safety in healthy subjects. Thus, there was agreement among the parties that the skilled person would have made the transition from phase I to phase II clinical testing. 9.20 The issue to be decided under obviousness is whether the skilled person would have had an incentive and reasonable expectation of clinical success regarding the specific regimen defined in claim 1, i.e. once-daily dosing of rapid-release rivaroxaban for at least five consecutive days, in patients, i.e. subjects at heightened risk for thromboembolism. No pointer in D2/D11 9.21 The respondents argued that the disclosure of D2/D11 was consistent with rapid-release dosing. Abstracts D2/D11 also taught that pharmacodynamic effects were still present after 12 hours. While half-life was usually a guiding factor for determining dos-ing frequency, the importance of using pharmacodynamic data obtained in phase I trials was also generally recognised. After the phase I study described in D2/D11, the skilled person would not have ruled out once-daily dosing (in any case a desirable goal in terms of patient convenience and compliance) as a viable regimen since no discouraging results had been observed. In addition, it was known from the pre-published review article D6 that short-term direct inhibition of factor Xa could lead to a sustained downstream biological action and that the therapeutic window of direct factor Xa inhibitors was expected to be relatively large in comparison to other anticoagulants (see D6: page 153, left column, last paragraph and page 154, left column, second para-graph). 9.22 The board considers that the disclosure of D2/D11 by itself, or in light of common general knowledge, would not have provided motivation to the person skilled in the art to pursue clinical testing of a once-daily regimen of rapid-release rivaroxaban in patients, for the following reasons. 40 9.22.1 The abstracts D2/D11 relate to a phase I study in healthy volunteers. This was a multiple dose escalation study following up on a phase I single dose escalation study with healthy volunteers (in turn described in abstracts D3 and D12, both relating to the same single dose study). At the effective date of the patent in suit, it had not been shown that rivaroxaban was safe and effective in patients, i.e. subjects re-quiring therapeutic or prophylactic anticoagulant treatment (see also point 5.9.2 above). Neither had this been shown for the class of directacting oral factor Xa inhibitors in general. Solving the objective technical problem thus involved providing a dosage regimen for rivaroxaban's first medical use in patients. The current case differs in this aspect from the typical situation in oth-er "dosage regimen cases", where development is based on estab-lished therapeutic uses of the drugs concerned. 9.22.2 Due to ethical and safety concerns, the person skilled in the art would have adopted a cautious attitude regarding the set-up of firsttime dose-ranging clinical studies of a novel anticoagulant in patients since the risk of both bleeding and thrombosis was ex-pected to be high. Participants in phase I anticoagulant studies are selected to ex-clude susceptibilities to and potential causes of bleeding. The fact that no bleeding complications had been observed with rivaroxa-ban in healthy volunteers did not permit drawing the conclusion that the drug would be safe in patients with pathology. It was known, for instance, that the phase II trial for the direct fac-tor Xa inhibitor razaxaban had revealed serious safety concerns despite positive phase I results (see D110d and D77: page 69, first paragraph). Before the publication of phase II data, nothing was known about the therapeutic window of rivaroxaban. The therapeutic window of anticoagulants can be narrow, since the same mechanism is responsible for the therapeutic effect (anticoagulation) and the potentially lethal side effect of bleeding. There would have been legitimate concerns that fluctuations in drug concentration might result in either excessive bleeding (due to overdosing) or thromboembolism (due to underdosing). 9.22.3 The skilled person would, therefore, have pursued an approach that minimises such fluctuations. To avoid over- or underdosing, they would have considered the half-life of the drug, as this was, in common general knowledge, the fundamental factor in deter-mining dosing frequency (see also paragraph [0010] of the patent in suit citing D14; D14: page 89, final paragraph; and D9, page 26, paragraph bridging left and right columns). 41 On this basis, the skilled person would have wanted to select a dosage form and frequency that compensated for rivaroxaban's short half-life (four to six hours according to D2/D11 or three to four hours according to D3/D12). Considering the short plasma concentration half-life of rivaroxa-ban known from D2/D11 and D3/D12, the person skilled in the art would have expected that twice- or thrice-daily dosing, or else the use of a sustained-release formulation (with the added advantage of less frequent dosing, i.e. better convenience), would be required for maintained efficacy and safety. 9.22.4 In summary, the serious concerns about safety in the case of a new anticoagulant did not warrant a "try-and-see" attitude for the dosage regimen, and the known, relatively short, half-life of ri-varoxaban would not have supported an expectation of success with regard to once-daily dosing of rapid-release rivaroxaban. 9.22.5 The study design (see point 9.3 above) also suggests that the phase I dose escalation study described in D2/D11 was performed in anticipation of a bid dosage regimen in subsequent phase II studies, as the vast majority of doses tested were bid and the only od dose included was the initially tested lowest starting dose (5 mg). In dose escalation studies, the doses are tested in order of increasing strength. The skilled person would have been aware that the study design followed the usual practice of starting with a very low dose as a safety precaution or subtherapeutic control regimen and would not have regarded the inclusion of a low od dose as an in-dication that this regimen was expected by the authors of the phase I study to have clinical relevance as a therapeutic dose. 9.22.6 As far as the relevance of pharmacodynamic data is concerned, it was not known at the priority date which level of a pharmacodynamic effect in which assay would be required to achieve both clinical efficacy (in preventing thrombosis) and safety (in avoiding bleeding) as these clinical correlations can only be established in trials on patients. At most, the pharmacodynamic effect of factor Xa inhibition, being the direct and selective action of rivaroxaban, might have been taken into consideration. 9.22.7 The statements in D2 and D11 that relevant changes in the pharmacodynamic parameters were still present after 12 hours or (in D11: sentences 12 and 13) that factor Xa inhibition effects were maintained for 8 to 12 hours at the 5 mg od dose, and "-12 hours"at the 10 mg bid, 20 mg bid and 30 mg bid doses cannot change the conclusions based on general safety considerations and half-life. This is because it is not possible to infer from these statements that the effects observed would be maintained for longer than 8 to 12 hours and would also suffice to maintain the required level of an- 42 ticoagulation in a patient at risk of thromboembolism over 24 hours. 9.22.8 Document D6 is a review article (published four years before the priority date of the patent) based on preclinical data of early drug candidates in the class of direct factor Xa inhibitors, not including rivaroxaban. The remarks in document D6 cited by the respon-dents relate to direct factor Xa inhibitors in general and do not in-clude any specific quantitative data for rivaroxaban. On this gen-eral and rather speculative basis, the person skilled in the art could not have formed a reasonable expectation that rivaroxaban would show long-sustained efficacy and have a therapeutic win-dow sufficiently broad to enable once-daily administration of a rapid-release form. No pointer in D15/D17 9.23 The respondents also argued that the disclosure of the complementary documents D15/D17 (especially the statement that a sustained effect of BAY 59-7939 on thrombin generation for up to 24 hours had been observed) would have provided the skilled person seeking to solve the objective technical problem with an expecta-tion of success regarding once-daily dosing of rapid-release ri-varoxaban. 9.24 The board arrives at a different conclusion for the following reasons: 9.24.1 Like D2 and D11, documents D15 and D17 are conference abstracts. Both relate to a further phase I study, in this case a singledose study of rivaroxaban (BAY 59-7939) that examined thrombin generation in healthy subjects. This effect was investigated in a placebo-controlled, randomised crossover study in which twelve healthy volunteers received a single 5 mg or 30 mg dose of rivaroxaban. Several assays relating to thrombin generation were carried out, including endogenous thrombin potential (ETP), plateletinduced thrombin generation time (PITT) and platelet-induced clotting time (PICT). Both D15 and D17 state that a single 30 mg dose exerted a sustained effect "on thrombin generation"(D15: sentence 10) or "in some assays of thrombin generation"(D17: sentence 9) for up to 24 hours. The results observed in the individual assays are shown in D17 (for 2 and 12 hours post dose). 9.24.2 According to the study design of D15 and D17, these parameter values were determined in healthy subjects. No information is provided on their potential correlation with clinical efficacy and safety in patients requiring anticoagulant treatment (whose system may be in a hypercoagulable state dif-ferent from that of healthy subjects) or on relevant threshold val-ues or ranges of these parameters. 43 9.24.3 The respondents did not provide any evidence of known correlations or threshold values which would have permitted the person skilled in the art to conclude from the study results reported in D15/D17 on the clinical efficacy and safety of rivaroxaban doses in patients, let alone decide on a dosage regimen including frequen-cy of administration. The skilled person had no reason to assume that the data and statements in D15/D17 were incorrect. However, owing to a lack of an established correlation of the assay parame-ters with clinically relevant effects (thrombosis and bleeding), it would not have been possible to make any predictions regarding dosing frequency on this basis. 9.24.4 The respondents also relied in their reasoning on several postpublished documents (D91, D103, D106 and D108) for interpretation of D15/D17. D106 is the full paper relating to the study of D15/D17 (published four years after the abstracts). All of these post-published documents contain statements made by their authors with hindsight, after the clinical success of ri-varoxaban had been proven. In this context, it appeared plausible that the thrombin generation data from the study of D15/D17 was consistent with the general concept of once-daily administration. As these documents (and the larger context they were based
  1. on)were not available to the person skilled in the art before the priori-ty date, it is not permissible to use them to interpret the statements and data provided in the abstracts D15/D17. 9.24.5 For these reasons, the skilled person could not have derived a teaching or expectation of success from the data reported in D15/D17 that would have provided them with the specific motiva-tion to explore once-daily dosing of a rapid-release form of ri-varoxaban in subsequent phase II studies in patients. Phase II testing would not necessarily have led to the invention 9.25 The respondents argued, in one approach, that in the course of phase II testing, routine assessment for determining the therapeu-tic window would have revealed that once-daily dosing was fea-sible. 9.26 This approach does not succeed because: - The relevant state of the art for the assessment of inventive step is the state of the art publicly available at the effective date of the patent rather than the inventors' own subsequent research results. - Once the decision to continue with phase II studies had been tak-en, there was no pre-determined path which would inevitably have led the skilled person to the dosage regimen defined in claim 1. 44 9.26.1 As set out above (see points 9.22, 9.24), it would not have been obvious, based on the publicly available phase I data, to include an od regimen of rapid-release rivaroxaban. 9.26.2 Also, the skilled person setting up a phase II clinical trial of a new anticoagulant was not in a routine "try-and-see" situation. Without a reasonable expectation of success with regard to clinical efficacy and safety, the mere wish for patient convenience would not have been sufficient as an incentive for testing an od regimen of a rapid-release form of the drug. 9.26.3 The information leading to the claimed subject-matter would thus have had to be acquired by the skilled person's own subsequent research. 9.26.4 Even after finding an unexpectedly wide therapeutic window in a study exclusively testing bid or tid regimens, or sustained-release regimens included for patient convenience, the skilled person would not inevitably have taken the decision to switch the dosing frequency. They might just as well have continued clinical development with one of the tested bid, tid or sustained-release regi-mens that looked most promising in terms of safety and efficacy. 9.27 For these reasons, the subject-matter of claim 1 of the main request involves an inventive step within the meaning of Article 56 EPC. The same conclusion applies to the dependent claim.” Kendt teknik Den kendte teknik i relation til EP 961 omfatter blandt andet det, som før prioritetsdagen var offentliggjort, om kliniske fase I-forsøg med rivaroxaban (BAY 597939) udført af D. Kubitza m.fl., bestående af dels et enkeltdosis eskaleringsfor-søg (”Kubitza SD-forsøget”), dels et multidosis eskaleringsforsøg (herefter ”Kubitza MD-forsøget”). Resultaterne af Kubitza-forsøgene blev præsenteret på Congress of the Ameri-can Society of Hematology i 2003 (”ASH-kongressen”) og 8th International Con-gress on Thrombosis i 2004 (”ICT-kongressen”) i form af to posters (”Kubitza SD Poster” og ”Kubitza MD Poster”) og to abstracts, som var dokument D2/D11 og D3/D12 i Technical Board of Appeals afgørelse (”Kubitza MD Abstract” og ”Kubitza SD Abstract”). De Kubitza-abstracts, som blev præsenteret på de to kongresser, var stort set identiske, og der sondres derfor ikke mellem dem i det følgende. Da parterne i de foreliggende sager navnlig har fokuseret på det materiale, som blev præsenteret på ASH-kongressen, er det hovedsageligt dette materiale, som omtales i det følgende. Af Kubitza SD Abstract, der har overskriften “Abstract# 3010, Poster Board #Session: 230-III, Single Dose Escalation Study Investigating the Pharmacody- 45 namics, Safety, and Pharmacokinetics of BAY 59-7939 an Oral, Direct Factor Xa Inhibitor in Healthy Male Subjects” , fremgår blandt andet: ”BAY 59-7939 is an innovative, oral, direct Factor Xa inhibitor in development for the prevention and treatment of thromboembolic diseases. In this single-blind, placebo-controlled, dose escalation trial, 103 healthy men received 1.25 to 80 mg of BAY 59-7939 under fasting conditions as tablet, or a 5 or 10 mg doses as oral solution. Full pharmacodynamic (PD) profiles (Factor Xa inhibition, PT, PTT, HepTest) were determined for 24 hours af-ter drug administration. In addition to standard safety assessments, bleed-ing time and the Rumpel-Leede test were performed. Pharmacokinetics were assessed using standard parameters. All PD profiles were dose-dependent; BAY 59-7939 showed a rapid onset of action with maximal ef-fects being observed after 2 hours. At the highest dose (80 mg), maximal Factor Xa inhibition was 60 %, accompanied by maximal changes of PT up to twice the individual baseline values. Similarly, individual maximal changes from baseline peaked at 2.3 for HepTest and 1.5 for aPTT. Stan-dard safety parameters were unaffected, and there were no signs or symp-toms of bleeding. Bleeding time was not prolonged at any dose. After ad-ministration of the oral solution, maximal plasma concentrations were ob-served after about 0.5 hours, followed by a fairly rapid decline leading to a terminal halflife of 3-4 hours. Lower peak concentrations of approximate-ly 50% were observed 2 hours after administration of the tablet. However, the two formulations were comparable in terms of AUC. Increases in AUC and C max were less than dose-proportionate at higher tablet doses, which is probably due to incomplete absorption as a consequence of low solubility of the drug. Pharmacodynamic and pharmacokinetic time profiles showed a close relationship with a correlation coefficient between 0.6 and 0.9, depending on the parameters used. In this study, BAY 59-7939 was safe and well tolerated across a wide range of oral doses (1.25-80
  2. mg)with predictable dose-dependent pharmacodynamics and pharmacokinetics. These data suggest that BAY 59-7939 offers predictable anticoagulation with and excellent safety profile.” Af Kubitza SD Posteren, der har overskriften “Single Dose Escalation Study Investigating the Pharmacodynamics, Safety, and Pharmacodynamics of BAY 597939 an Oral, Direct Facto Xa Inhibitor in Healthy Male Subjects” , fremgår blandt andet: ”Pharmacokinetics BAY 59-7939 plasma concentration increased dose proportionally after administration of oral solutions and tablet doses of BAY 59-7939 up to 10 46 mg, and was less than dose proportional at higher doses, most likely be-cause of low drug solubility and incomplete absorption (Figure 7). Figure 7: Plasma concentration-time profiles of BAY 59-7939 following administration of 1.2580 mg tablets; linear scale (geometric mean). Plasma concentration-time profiles showed rapid absorption after administration of the solution. Maximal plasma concentrations were achieved af-ter ½ 30 minutes, and t was estimated to be 3-4 hours. Both oral solution and tablet formulations produced similar AUC values, but flatter plasma concentrationtime profiles were observed after tablet administration. max hours. … C of BAY 59-7939 was reached after approximately 2 Conclusions • BAY 59-7939 was safe and well tolerated at all doses (1.2580
  3. mg)and formulations (oral tablet or solution) in this study of healthy male volunteers. No clinically relevant signs or symptoms of bleeding were observed. • BAY 59-7939 was shown to selectively inhibit FXa without affecting FIIa or antithrombin III. Dose-dependent and predictable effect-time profiles were observed for the pharmacodynamic parameters FXa inhibition, PT, aPTT, and HepTest. A close correlation was observed between the pharmacodynamic effects and plasma concentrations of BAY 59-7939. • The good safety profile, selective inhibition of FXa, and promising pharmacokinetic and pharmacodynamic profiles indicate that further investigation of BAY 59-7939 is warranted.” Af Kubitza MD Abstract, der har overskriften “Abstract# 3004 Poster Board #Session: 224-III Multiple Dose Escalation Study Investigating the Pharmacodynamics, Safety, and Pharmacokinetics of BAY 59-7939 an Oral, Direct Factor Xa Inhibitor in Healthy Male Subjects” , fremgår blandt andet: “BAY 59-7939 is an innovative, oral, direct Factor Xa inhibitor in development for the prevention and treatment of thromboembolic diseases. In this parallel-group, randomized, single-blind, placebo-controlled tri-al, 64 subjects received multiple oral doses of BAY 59-7939: 5 mg once daily, twice daily, or three-times daily, or 10 mg, 20 mg, or 30 mg twice daily for 5 days with food. Full profiles of all pharmacodynamics (PD) parameters (Factor Xa inhibition, PT, PTT, HepTest) were performed on days 1 and 7. In addition to standard safety assessments, bleeding time was also measured. Pharmacokinetics were assessed using standard pa-rameters. At steady state of the highest dose, maximum Factor Xa inhi-bition was 70%, with maximal changes of PT up to 2.6 times the indi-vidual baseline value. Similarly, maximal changes from baseline peaked at 2.7 for HepTest and 1.7 for aPTT. There were no differences between 47 the PD effects on day 1 versus day 7 at any dose step. Comparable profiles were observed for all PD parameters. Relevant changes in the PD parameters were still present after 12 hours. Standard safety parameters were unaffected and no signs or symptoms of bleeding were observed across the dose range. In addition, BAY 59-7939 did not affect bleeding time at any dose. A dose-proportional increase in AUC was seen after the was reached after 2.5 - 4 hours: first dose and at steady state. C max the terminal half-life was 4-6 hours. There was no indication of undue accumulation of drug beyond steady state for all six dose regimens. This study demonstrated that BAY 59-7939 has predictable dose-dependent pharmacodynamics and pharmacokinetics without signs or symptoms of bleeding. In conclusion, oral administration of BAY 59-7939 was safe and well tolerated in doses up to 30 mg bid. " Af Kubitza MD Posteren, der har overskriften “Multiple Dose Escalation Study Investigating the Pharmacodynamics, Safety, and Pharmacokinetics of BAY 597939 an Oral, Direct Factor Xa Inhibitor in Healthy Male Subjects,” fremgår blandt andet: ”Conclusions • BAY 59-7939 was safe and well tolerated after multipledose administration at alle the doses tested without signs or symptoms of bleeding. BAY 59-7939 inhibited FXa activity and dosedependently affected the pharmacodynamic parameters PT, aPTT, and HepTest. • Predictable dose-dependent pharmacodynamics and pharmacokinetics were demonstrated, and indicated that BAY 597939 is suitable for twice-daily administration up to 30 mg. • Close correlation existed between the prolongation of the PT and plasma concentrations. • The good safety profile, selective inhibition of FXa, and promising pharmacokinetic and pharmacodynamic profiles indicate that further investigation of BAY 59-7939 is warranted.” Posteren indeholder 7 figurer, som illustrerer de farmakodynamiske og farmakokinetiske fund. Den kendte teknik omfatter endvidere det, som før prioritetsdagen var offentliggjort, om et klinisk fase I-forsøg udført af Vidne 1 m.fl. i et samarbejde med Bayer.. Vidne 1-forsøget blev præsenteret på ASH-kongressen i 2003 (og på ICTkongressen i 2004) i form et Abstract, benævnt D17 i TBA’s afgørelse (”Vidne 1 Abstract”). Der er mellem parterne uenighed om, hvorvidt forsøget også blev præsenteret ved en poster (”Vidne 1 Poster”) på ASH-kongressen og således er en del af kendte teknik, mens der er enighed om, at en anden poster ”Vidne 1 ICT Poster” , som ikke indeholder fuldstændig samme oplysninger, blev vist på ICTkongressen. Der er enighed om, at Vidne 1 Abstract og Vidne 1 ICT Poster 48 er en del af den kendte teknik, mens det er omstridt om Vidne 1 Posteren er en del heraf. Af Vidne 1 Abstract fra ASH-kongressen, der har overskriften “Abstract# 3003 Poster Board #-Session 223-III Effects of BAY 59-7939, an Oral, Direct Factor Xa Inhibitor, on Thrombin Generation in Healthy Volunteers” , fremgår: “BAY 59-7939 is an innovative, oral, direct Factor Xa inhibitor in development for the prevention and treatment of thromboembolic diseases. Factor Xa inhibitors exert their antithrombotic effects through inhibition of thrombin generation. The effect of BAY 59-7939 on thrombin genera-tion was investigated in this placebo-controlled, randomized, crossover study in which 12 healthy volunteers received a single 5mg or 30mg dose of BAY 59-7939. Several assays measured thrombin generation, in-cluding endogenous thrombin potential (ETP), platelet-induced throm-bingeneration time (PITT), and platelet-induced clotting-time (PICT). ETP is based on the cleavage of a chromogenic substrate by thrombin after ex vivo stimulation of platelet rich plasma (PRP) by tissue factor (TF) [1.4 nmol] or collagen (5 µg/ml). In contrast to ETP, no activator is used in the PITT assay, in which aggregation and coagulation of PRP are photometrically recorded in a rotating plastic cuvette in the pres-ence of low concentrations (0,1 µg.mlL) of hirudin. The PICT assay in plateletpoor plasma uses Russell's viper venom to activate thrombin generation via the Factor Xa pathway. … BAY 59-7939 exhibited dose-dependent inhibition of thrombin genera-tion both in platelets and plasma, using either extrinsic (TF) or intrinsic (collagen) stimuli for platelet activation. A single 30 mg dose exerted a sustained effect in some assays of thrombin generation for up to 24 hours. Factor Xa was inhibited dose dependently after administration of BAY 597939. Maximum inhibition, observed 2 hours following drug administration, was 28% and 56% for the 5 mg and 30 mg doses, respectively. There was close correlation between BAY 59-7939 plasma concentrations and inhibition or Factor Xa activity as well as with decreases in ETP; the correlation was modest with PITT. BAY 59 -7939 had no ef-fect on the actual thrombin content of the plasma. In conclusion, these data suggest that BAY 59-7939 effectively inhibits thrombin generation via both intrinsic and extrinsic pathways.” Af den omstridte Vidne 1 Poster, der har overskriften “Effect of BAY 59-7939, an Oral, Direct Factor Xa Inhibitor, on Thrombin Generation in Healthy Volun-teers” , fremgår blandt andet: ”Introduction BAY 59-7939 is a selective, highly potent, direct Factor Xa (FXa) inhibitor that is being developed for the prevention and treatment of thromboembolic disease. It has been shown to be well tolerated at sin-gle and multiple doses up to 30 mg, and is rapidly absorbed after oral administration, with a terminal half-life of 9-12 hours. ... 49 Results ETP (peak or AUC) was reduced significantly (compared with placebo profiles) by both the 5 mg and 30 mg doses of BAY 59-7939, with maximum effects at 2-4 hours. Inhibition of ETP-peak and ETP-A

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