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ECLI:DK:SHR:2023:BS0000004187 Sag om, hvorvidt Sagsøgte er berettiget til at indlede en sag om midlertidigt forbud og påbud i medfør af retsplejeloven

SØ-OG HANDELSRETTEN KENDELSE afsagt den 28. februar 2023 Sag BS-12527/2022-SHR Novartis AG (advokat Mikkel Vittrup) og Novartis Pharma AG (advokat Mikkel Vittrup) og NOVARTIS HEALTHCARE A/S (advokat Mikkel Vittrup) mod Zentiva Denmark ApS (advokat Anders Valentin) Denne afgørelse er truffet af dommer Peter Juul Agergaard sammen med de sagkyndige medlemmer Karin Verland og Søren Valdgård Boye. Sagens baggrund og parternes påstande Sagen, der blev modtaget den 23. marts 2022, drejer sig om, hvorvidt der i henhold til retsplejelovens kapitel 40 er grundlag for at nedlægge midlertidigt forbud og påbud over for sagsøgte, Zentiva Denmark ApS, baseret på patentrettigheder tilhørende sagsøgerne, Novartis AG, Novartis Pharma AG og Novartis Healthcare A/S. 2 Sagen rejser navnlig spørgsmål om gyldigheden af disse rettigheder. Sø- og Handelsretten afsagde den 17. juni 2022, på hvilket tidspunkt patentet Patent nr. 1 (Stridspatentet), jf. nedenfor, endnu ikke var udstedt, kendelse mellem parterne under samme sagsnummer vedrørende et spørgsmål om, hvorvidt der skulle ske afvisning af Novartis’ påstand 1 grundet manglende retlig interesse, da påstanden på daværende tidspunkt ikke havde den fornødne aktualitet. Af Sø- og Handelsrettens kendelse fremgår, at Novartis’ påstand 1 afvises, og at afgørelsen om sagsomkostninger vedrørende Zentiva Denmark ApS udskydes til sagens endelige afgørelse. Ved kendelse af 6. oktober 2022 stadfæstede Østre Landsret Sø- og Handelsrettens kendelse om afvisning af Novartis’ påstand 1. Novartis AG, Novartis Pharma AG og Novartis Healthcare A/S (herefter Novartis) har nedlagt følgende påstande: Påstand 1: Zentiva Denmark ApS forbydes i Danmark at udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet Fingolimod "Zentiva", jf. dansk specialitetsnummer 31752, eller importere eller besidde det med et sådant formål, så længe dansk Patent nr. 1 er i kraft. Påstand 3: Zentiva Denmark ApS påbydes at tilbagekalde allerede skete leverancer af lægemidlet Fingolimod "Zentiva", jf. dansk specialitetsnummer 31752, fra samtlige kommercielle aftagere, herunder hospitaler, grossister, apoteker og sygehusapoteker, hvortil levering er foretaget af Zentiva Denmark ApS. Påstand 4: Zentiva Denmark ApS påbydes omgående at meddele over for Amgros I/S og alle hospitaler, hvortil leverancer af lægemidlet Fingolimod "Zentiva", jf. dansk specialitetsnummer 31752, er sket, at det ikke er muligt at indkøbe lægemidlet Fingolimod "Zentiva", jf. dansk specialitetsnummer 31752, så længe der er nedlagt midlertidigt forbud herimod. Påstand 5: Zentiva Denmark ApS påbydes omgående at afregistrere den indmeldte pris for Fingolimod "Zentiva", jf. dansk specialitetsnummer 31752, i det danske prisregister (www.medicinpriser.dk). Novartis har udeladt påstand 2 som følge af, at begæringen om midlertidigt forbud og påbud baseret på Patent nr. 2 i sagen er sat i bero på afgørelse fra EPO's Indsigelsesafdeling i den verserende indsigelsessag vedrørende det nævnte patent. 3 Forbud og påbud påstås principalt nedlagt uden sikkerhedsstillelse, subsidiært mod en af retten fastsat sikkerhed. Zentiva Denmark ApS (herefter Zentiva) har nedlagt principal påstand om frifindelse og subsidiær påstand om nedlæggelse af forbud og påbud med en sikkerhedsstillelse på ikke under 20 mio. kr. Oplysningerne i sagen Sagens Parter Novartis er en global lægemiddelvirksomhed med hovedsæde i Basel, Schweiz, og er blandt verdens største internationale producenter af lægemidler. Novartis-koncernen driver primært virksomhed inden for forskning og udvikling af nye originale lægemidler. Novartis-koncernen markedsfører blandt andet lægemidlet Gilenya, der indeholder fingolimod som aktivstof, og som anvendes til behandling af multipel sklerose. Zentiva er en tjekkisk medicinalkoncern, der primært specialiserer sig i generiske lægemidler. Stridspatentet Sagen vedrører patentet Patent nr. 1, som er indehavet af Novartis AG (herefter Stridspatentet), og som har benævnelsen ”Titel” . Patentet blev udstedt Dato 2. Stridspatentet har prioritet fra 27. juni 2006 afledt af Patent nr. 4. Af patentets beskrivelse fremgår følgende blandt andet: [ Udeladt ] 4 [ Udeladt ] 5 [ Udeladt ] 6 Beskrivelsens punkt 14, 15, 16 og 17 har samme ordlyd som patentansøgningens (herefter Stridspatentansøgningen) punkt 30, 31, 32 og 33. Patentet indeholder følgende patentkrav: [ Udeladt ] Lægemidler Af et produktresume for lægemidlet Gilenya fremgår, at lægemidlet udbydes med en sammensætning indeholdende 0,5 mg fingolimod, og at Novartis Healthcare A/S er repræsentant for indehaveren af markedsføringstilladelsen, Novartis Pharma GmbH. Det fremgår af et produktresume for lægemidlet Fingolimod ”Zentiva” , at dette lægemiddel ligeledes udbydes med en sammensætning indeholdende 0,5 mg fingolimod, og at Zentiva er repræsentant for indehaveren af markedsføringstilladelsen, Zentiva k.s., og at markedsføringstilladelsen er udstedt den 9. december 2020. Tilstrækkelig beskrivelse Af en intern forsøgsrapport af 12. maj 2009 fra Novartis fremgår følgende blandt andet: ”… Effects of FTY720 on experimental autoimmune encephalomyelitis-induced angiogenesis (acute and relapsing) … Summary Experimental autoimmune encephalomyelitis (EAE) in Lewis rats is a well characterized model of multiple sclerosis (MS). Our clinical and histopathological findings from the current experiments are in agreement with the literature, with a prodromol phase (acute), remission and relapse phase. Histological analysis shows less inflammation in the relapse phase compared to the remission. Axonal damage is present during relapse but there is little demyelination. 7 FTYY720 (a well described sphingosine-1-phosphate receptor agonist) is well known to ameliorate EAE, both clinically and pathologically, when given daily. However, for the first time we demonstrate that FTY720 re-duces clinical scores of the acute phase of EAE at a dose of 0.3 mg/kg p.o. given either daily, every other day or even every third day. No effect of FTY720 was seen using a once a week treatment schedule. Additionally, FTY720 blocked relapse formation when given at a dose of 0.3 mg/kg p.o. either daily, every other day, every 3rd day or even when given only once a week. FTY720 when given daily suppresses inflammation and axonal dam-age. … 2 Methods … 2.1 Acute EAE … 2.2 Chronic relapsing EAE [Method Report RD-2004-03393] To induce chronic-relapsing EAE, Lewis rats were injected in the hind paws with an emulsion of guinea pig spinal cord in complete Freund's ad-juvant. Usually 80-100% of the sensitised rats showed clinical relapses dur-ing the first 40 days. Treatment with the test compound started on day 16 (after first disease bout) and continued until day 31, unless stated other-wise. In both acute and chronicrelapsing forms, clinical grades of EAE were assessed using a clinical scale from 0 to 3. The number of diseased an-imals and time of EAE onset were recorded for each experimental group (6-10 rats). Clinical grades: 1 = loss of tail tonicity 2 = weakness of one or both hind legs, or mild ataxia 3 = severe ataxia or paralysis accompanied by urinary incontinence … 3 Results 3.1 Effects on different FTY720 treatment regimes on EAE symptoms Figure 3-1 FTY720 reduces clinical EAE symptoms in both the acute and relapse phases of disease. 8 FTY720 prevents the development of the acute EAE (left pane of Figure 3-1) when given daily starting at the day of immunization similar to cyclosporin A p.o.. After cessation of treatment disease re-occurs with both compounds. If either FTY720 or cyclosporine A treatment was initiated during remis-sion, the relapse phase was prevented (Figure 3-1). If cyclosporin A admin-istration was halted after 9 days of treatment (day16-25) EAE symptoms were observed beginning after day 30. However, in the same treatment par-adigm no EAE symptoms were observed in the FTY720 treated group. Figure 3-2 Effects of various treatment schedules of FTY720 on the acute and relapse phase EAE in the Lewis rat. Treatment of the acute phase of EAE in Lewis rats is successful when FTY720 at a dose of 0.3 mg/kg p.o. is administered daily, every other day or even every 3rd day. If FTY720 is given weekly, e.g. on days 0, 6 and 13, the acute phase is unaffected. Continuation of any of the treatment schedules, results in complete (daily, every 2nd and every 3rd day) or almost complete (three doses only – day 0, day 6, and day 13) abrogation of the relapse phase. … 9 Figure 3-5 FTY720 reduces the increased vascular density during EAE relapse. All treatment schedules with FTY720 result in pronounced, almost com-plete inhibition of disease-induced neo-angiogenesis. The most striking re-sults were obtained using a FTY720 treatment every 3 days rather than a daily delivery. Figure 3-6 Quantitation of μCT from thoracic and lumbar spinal cord demonstrates the efficacy of FTY720 in suppressing angiogenesis during EAE relapse. There were no significant changes in blood vessel density observed in the acute phase of EAE as compared to healthy control rats (left pane of Figure 3-6). No effect of FTY720 treatment was seen. In contrast there was a signifi-cant and prominent increase in new blood vessel formation in rats going through the relapse phase of EAE (right pane of Figure 3-6). This increase in blood vessel density by close to 100 % was completely prevented by ei-ther treatment with FTY720 (daily or even once/week). … 5 Source data location Location of original data used in this report 10 [ Billede udeladt pga. personfølsomme oplysninger ] …” Angivelsen ”FTY720” er synonym med fingolimod. Af en erklæring af 10. november 2017 udarbejdet af Person 3 til brug for en amerikansk sag om Stridspatentet fremgår følgende blandt an-det: ”… I, Person 3, declare as follows: 1. I am an inventor listed on U.S. Patent nr. 5, the subject of these inter-partes review (IPR) proceedings. I am currently employed by Novartis Pharma AG, a subsidiary of Patent Owner Novartis AG in these proceedings. I submit this declaration to authenticate Exhibits 2057, a May 12, 2009 internal Novartis report that describes research underlying my in-vention; and 2070, a two-page signature sheet that confirms the report’s completion. 2. Exhibit 2057 is an internal report I prepared with my co-inventor Person 4, plus two other scientists—Person 5 and Person 6. While prepared in 2009, the report summarizes our experi-mental results from late 2005, as reflected in the chart on page 22. That chart shows the November 2005 dates for the experiments Person 4 and I per-formed that underlie the ’Patent nr. 5. We prepared the report in 2009 in an-ticipation of publishing some of our research in a scientific paper, which we did in 2010. …” Det omtalte Exhibit 2057 udgør den ovenfor omtalte interne forsøgsrapport fra Novartis. Opfindelseshøjde Det er et stridspunkt i sagen, hvad der udgør nærmeste kendte teknik. Der er fremlagt følgende præsentation af 21. juni 2005 udarbejdet af Novartis, hvoraf følgende fremgår blandt andet: [ Billede udeladt ] [ Billede udeladt pga. personfølsomme oplysninger ] [ Billede udeladt ] [ Billede udeladt ] [ Billede udeladt ] [ Billede udeladt ] [ Billede udeladt pga. personfølsomme oplysninger ] [ Billede udeladt ] [ Billede udeladt pga. personfølsomme oplysninger ] [ Billede udeladt ] 16 [ Billede udeladt ] [ Billede udeladt ] Præsentationen blev offentlig tilgængelig på Novartis’ hjemmeside den 16. marts 2006. 17 Af en pressemeddelelse af 6. april 2006 fra Novartis fremgår følgende blandt andet (fodnoter udeladt): ”… Phase II data for FTY720 shows sustained efficacy and good tolerability over 18 months in patients with relapsing multiple sclerosis (MS) MS is the leading cause of neurological disability in young adults -high unmet need for effective and convenient therapies Basel, April 6, 2006 - Data from the extension of a Phase II study to 18 months support the significant effects of FTY720 (fingolimod), a novel once-daily oral compound in development for treatment of relapsing-remit-ting multiple sclerosis (MS). More than two million people worldwide are estimated to suffer from MS, which is the leading cause of neurological dis-ability in young adults and affects twice as many women as men. The data, presented at the American Association of Neurology (AAN) meeting, showed that both patient groups taking FTY720 (1.25 mg and 5

  1. mg)who had experienced more than a 50% reduction in their annualized relapse rate during the study's first six months compared to placebo main-tained this low relapse rate during the subsequent 12-month extension. Currently marketed MS therapies afford an average reduction in relapse rates of only 30% in two-year studies and require frequent injections rang-ing from daily to weekly. In patients who switched from placebo to either the 1.25 mg or 5 mg dosing of FTY720 after six months, the annualized relapse rate was reduced to a similar extent during the subsequent twelve-month extension phase of the study compared to the first six months on placebo. At month 18, Magnetic Resonance Imaging (MRI) scans were performed in a subgroup of patients. Consistent with what was seen in MRI scans at month six, the vast majority of patients were free from lesions showing active inflammation at month 18. "We are very encouraged to see that the effects of fingolimod in signifi-cantly reducing both clinical relapses and inflammatory disease activity are maintained over 18 months," said Dr. Person 7, MD, St. Michael's In-stitute, Toronto, Canada. "We hope that the magnitude of benefits shown in the Phase II study can be confirmed in the larger-scale Phase III study pro-gram, which is currently being initiated." 18 The most frequently reported adverse events in patients treated up to 18 months were non-serious infections (colds, influenza) and headache. Effects initially seen in the first six months of treatment (i.e. first dose heart rate re-duction, increase in blood pressure, alteration in liver function, mild in-crease in airway resistance) did not appear to progress with continued dos-ing beyond six months. There were also no unexpected safety findings dur-ing the extension phase compared to the six-month placebo-controlled phase. All patients in the extension study are now continuing with the 1.25 mg dose since both the 5 mg dose, which had a higher rate of adverse events, and 1.25 mg doses were equally effective in reducing disease activ-ity. … Phase III study program Novartis has initiated its first Phase III pivotal study called "FREEDOMS" (F ingolimod R esearch E valuating E ffects of D aily O ral therapy in M ultiple S clerosis). The 24-month, randomized, doubleblind, placebo-controlled FREEDOMS study will include more than 1,000 patients with relapsin-gremitting MS between age 18-55. Study participants will be equally ran-domized to either receive either 1.25 mg or 0.5 mg ofFTY720 or placebo once daily for up to 24 months. This study has begun enrolling patients in several European countries. No-vartis is currently in discussions with the US Food and Drug Administra-tion (FDA) on Phase III initiation in the US. "Oral fingolimod has a novel mode of action different from all available MS therapies. If the Phase III clinical program confirms the promise of the Phase II results, oral fingolimod could represent a major improvement in the way MS will be treated in the future," said chief investigator Professor Ludwig Kappos, MD, Department of Neurology at the University Hospital in Basel, Switzerland. … About Multiple Sclerosis … This release contains certain forward-looking statements relating to Novar-tis' business, which can be identified by the use of forward-looking termi-nology such as "encouraged", "hope", "expected", "will", "could", or similar expressions, or by express or implied statements regarding the potential long-term impact of a patient's use of fingolimod, the potential commence-ment of Phase III studies of fingolimod in the US, the potential regulatory approval of fingolimod in any jurisdiction, or potential future revenue from 19 fingolimod. Such forward-looking statements reflect the current views of Novartis regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with fin-golimod to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Phase III studies of fingolimod will be permitted to com-mence in the US, or that fingolimod will be approved for any indications or labeling in any market. … …” Kendt teknik Der er fremlagt en række artikler inden for forskellige emner til belysning af kendt teknik på Stridspatentets prioritetstidspunkt. Kendt teknik vedrørende kliniske studier Af en artikel fra november 1983 af John F. Kurtzke fremgå følgende blandt andet: ”… Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDDS) … Appendix B. Expanded Disability Status Scale (EDDS) 0 = Normal neurologic exam (all grade 0 in Functional Systems [FS]; Cerebral grade 1 acceptable). 1.0 = No disability, minimal signs in one FS (ie, grade 1 excluding Cerebral grade 1). 1.5 = No disability minimal signs in more than one FS (more than one grade 1 excluding Cerebral grade 1). 2.0 = Minimal disability in one FS (one FS grade 2, others 0 or 1). 2.5. = Minimal disability in two FS (two FS grade 2, others 0 or 1). 3.0 = Moderate disability in one FS (one FS grade 3, other 0 or 1), or mild disabil-ity in three or four FS (three/four FS grade 2, others 0 or 1) though fully ambula-tory. 3.5 = Fully ambulatory but with moderate disability in one FS (on grade 3) and one or two FS grade 2; or two FS grade 3; or five FS grade 2 (others 0 or 1). 20 4.0 = Fully ambulatory without aid, self-sufficient up and about some 12 hours a day despite relatively severe disability consisting of one FS grade 4 (other 0 or 1), or combination of lesser grade exceeding limits of previous steps. Able to walk without aid or rest some 500 meters 4.5 = Fully ambulatory without aid, up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance; characterized by relatively severe disability, usually consisting of one FS grade 4 (others 0 or 1) or combination of lesser grades exceeding limits of pre-vious steps. Able to walk without aid or rest for some 300 meters. 5.0 = Ambulatory without aid or rest for about 200 meters; disability severe enough to impair full daily activities (eg, to work a full day without special provisions). (Usual FS equivalents are one grad 5 alone, others 0 or 1; or combinations of lesser grades usually exceeding specifications for step 4.0.) 5.5 = Ambulatory without aid or rest for about 100 meters; disability severe enough to preclude full daily activities. (Usual FS equivalents are one grade 5 alone, other 0 or 1; or combinations of lesser grades usually exceeding those for step 4.0.) 6.0 = Intermittent or unilateral constant assistance (cane, crutch, or brace) required to walk about 100 meters with or without resting. (Usual FS equivalents are combinations with more than two FS grade 3+.) 6.5 = Constant bilateral assistance (canes, crutches, or braces) required to walk about 20 meters without resting, (Usual FS equivalents are combinations with more than two FS grade 3+.) 7.0 = Unable to walk beyond about 5 meters even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about in w/c some 12 hours a day. (Usual FS equivalents are combinations with more than one FS grade 4+; very rarely, pyramidal grade 5 alone.) 7.5 = Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels self but cannot carry on in standard wheelchair a full day; may require motorized wheelchair. (Usual FS equivalents are combinations with more than one grade FS 4+.) 8.0 = Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed itself much of the day; retains many self-care functions; generally has effective use of arms. (Usual FS equivalents are combinations, generally grade 4+ in several systems.) 21 8.5 = Essentially restricted to bed much of the day; has some effective use of arm(s); retains some self-care functions. (Usual FS equivalents are combinations, generally 4+ in several systems.) 9.0 = Helpless bed patient; can communicate and eat (Usual FS equivalents are combinations, mostly grade 4+.) 9.5 = Totally helpless bed patient; unable to communicate effectively or eat/swallow. (Usual FS equivalents are combinations, almost all grade 4+.) 10. = Death due to MS. …” Af en artikel fra april 1993, der er udarbejdet af ”The IFNB Multiple Sclerosis Study Group” fremgår følgende blandt andet: ”… Article abstract - … One-third of the patients received placebo, one-third 1.6 million international units (MIU) of IFNB, and one-third 8 MIU of IFNB, selfadministered by subcutaneous injections every other day. … Discussions. … Because study end points had been reached, the External Advisory Committee recommended that placebo and 1.6 MIU group patients be of-fered option of changing to 8 MIU dosage in an orderly and expeditious manner. While the data indicate a definite dose effect in favor of the 8 MIU treatment group, further clinical experience with IFNB will be necessary to determine whether different dosing schedules might produce more benefit. In an early pilot trial 16 MIU three times weekly produced unacceptable toxic-ity (including chills, fever and injection site reactions). There is no experi-ence with a daily dosing schedule in MS patients. …” Af ICH-E4 Guideline for Industry om Dose-Response Information to Support Drug Registration fra November 1994 fremgår følgende blandt andet: ”… II. OBTAINING DOSE-RESPONSE INFORMATION … 22 C. Regulatory Considerations When Dose-Response Data Are Imperfect Even well-laid plans are not invariably successful. An otherwise well-de-signed dose-response study may have utilized doses that were too high, or too close together, so that all appear equivalent (albeit superior to placebo). In that case, there is the possibility that the lowest dose studied is still greater than needed to exert the drug's maximum effect. Nonetheless, an acceptable balance of observed undesired effects and beneficial effects and beneficial effects might make marketing at one of the doses studied reason-able. This decision would be easiest, of course, if the drug had special value, but even if it did not, in light of the studies that partly defined the proper dose range, further dose-finding might be pursued in the postmar-keting period. Similarly, although seeking dose response data should be a goal of every development program, approval based on data from studies using a fixed single dose or a defined dose range (but without valid dose response information) might be appropriate where benefit from a new therapy in treating or preventing a serious disease is clear. … III. STUDY DESIGNS FOR ASSESSING DOSE RESPONSE … B. Specific Trial Designs … 1. Parallel Dose-Response … It is all too common to discover, at the end of a parallel dose-response study, that all doses were too high (on the plateau of the dose-response curve), or that doses did not go high enough. A formally planned interim analysis (or other multi-stage design) might detect such a problem and al-low study of the proper dose range. …” Følgende fremgår blandt andet af en meddelelse fra december 1997 fra Food and Drug Administration (herefter FDA): ”… 23 … 3.1.3.3 Phase III (Most typical kind of study: Therapeutic confirmatory). … Studies in Phase III may also further explore the dose-response relationship or explore the drug’s use in wider populations, in different stages of disease, or in combination with another drug. …” Følgende fremgår blandt andet af en artikel fra 2005 af Person 8: ”… ”… Af ”The Textbook of Pharmaceutical Medicine, Fifth Edition” fra 2006 fremgår følgende blandt andet: “… 6 Purpose and design of clinical studies … 6.2 Basic Ethical Considerations … 24 Clinical trials can be divided into those that may result in some benefit to the participant, and those trials where no benefit can conceivably be ex-pected. The most obvious example of the latter is the trial involving healthy non-patient subjects. Such trials are frequently called non-therapeutic. Therapeutic studies are those from which the subject may derive benefit from exposure to the study drug. This is an oversimplification. For exam-ple, a Phase IIa dose-ranging study in study subjects with the target disease will include some doses which may be ineffective, or which prove to be too high. The design of the trial (e.g. crossover design) limits a therapeutic response within the confines of the study. Thus, therapeutic trials tend to occur in the later stages of clinical development at Phases III and IV. … 6.2.4 The use of placebo … … At least one government agency (the FDA) believes that the placebo comparison is preferable to an active agent because it is a fixed and reliable reference point. … … 6.6.7.10 Dose selection In clinical practice, the optimal dose is the smallest that will result in the desired therapeutic response. Inherent within that statement is the concept of individualisation of dose for each given study subject, as it would not be unreasonable to expect considerable variation in response, depending on many factors such as body size, efficiency of the metabolising and excretory pathways, race, age, state of disease and so on (see Section 6.5). In practice, it is not possible for a sponsor to investigate more than a few doses, and frequently only one or two doses for registration of a given indication. It is often in clinical practice that adjustment (most frequently, downwards) to final regimens occur. The impact of pharmacogenetics on individual dose has yet to be shown. 6.6.7.10.1 Dose-response relationships, potency and efficacy An understanding of the dose – response relationship is fundamental to successful clinical drug development and to therapeutic practice. The pharmacological effect of a drug is related to the concentration of the drug at its site of action – within certain limits, the higher the concentration, the greater the pharmacological effect. The relationship between the concentra-tion of a drug at its site of action and the intensity of the pharmacological effect is called its doseresponse curve. It often takes the shape illustrated in 25 Figure 6.2, in which (by convention) the intensity of the response is plotted against the logarithm of the dose, giving a sigmoid curve. … Fig. 6.2 The shape of most dose-(or concentration-) response curves is sigmoid in which the rate of rise of the response eventually flattens off despite increasing concentrations. … The application of the principles of dose-response relations to Phase II and III clinical trials focuses on the practical aspect of determining which doses will be selected for these trials and which will be taken forward to registra-tion (see below). … 6.6.7.10.3 Dose schedules Dose selection for exploratory studies requires knowledge of the pharma-cology, toxicology, metabolism and kinetics in animals and man. This is discussed in detail in Chapter 4. Dose selection for Phase II and III studies depends on a number of factors. These include: 1. The duration of action against the primary efficacy endpoint. 2. the pharmacokinetic characteristics of the parent compound and any ac-tive metabolites: in particular, the area under the concentration-time curve, clearance, plasma half-life and bioavailability of the formulation. On the ba-sis of these data, it should be possible to decide on the dosing frequency for the study and the range of doses to be used. It is also possible to establish a relationship between the dynamic response and the plasma concentration of the drug (or metabolite). 3. The chances of detecting differences between intermediate doses based on the primary endpoint responses. 4. The number of study subjects (and centres) available for inclusion. 26 5. Whether a therapeutic or a surrogate endpoint is chosen as primary re-sponse measure. By the end of a dose-ranging programme of studies, the sponsor should be able to define the following: • The therapeutic dose range in the core population who will most fre-quently receive the drug • • • • The dose that is tolerated in the majority of the defined population The minimum effective dose(
  2. s)The maintenance dose range (when relevant) The therapeutic dose range in ‘ at-risk’-groups, for example, the elderly, the hepatically impaired, etc. … 6.6.7.11 Study subject compliance, tolerability and acceptability … Assessment of compliance in a trial leads to the question as to whether the data generated from those who fail to comply should be included or ex-cluded from analysis. The general principles that apply are that they should be excluded from Phase II (explanatory trial approach), but not from Phase III or IV trials. The reason for exclusion from Phase II is that these studies are designed to determine efficacy under well defined eligibil-ity criteria, and so non-compliers will dilute the efficacy response. …” Kendt teknik angående anvendelse af fingolimod i forhold til nyretransplantationer Af en artikel af blandt andre Budde fra 2002 fremgår følgende blandt andet: ”… First Human Trial of FTY720, a Novel Immunomodulator, in Stable Re-nal Transplant Patients … Abstract. FTY720 is a novel immunomodulator to be developed for use in organ transplantation. The primary objective of this study was to measure safety, singledose pharmacokinetics, and pharmacodynamics in stable re-nal transplant patients – the first human use of FTY720 from 0.25 to 3.5 mg in 20 stable renal transplant patients on a cyclosporine-based regimen. … … … The half-life of FTY720 in animals varies: 12 h in rats, 29 h in dogs, and 36 h in baboons

(18). Maximal blood concentrations were reached after 7 to 27 8 h and 2 to 24 h in dogs and baboons, respectively. A near linear relation-ship between FTY dose and concentration was observed in these studies. FTY is metabolized to produce carboxylic acid derivates that are devoid of immunosuppressive activity and ultimately excreted in urine and feces
(19). … Pharmacodynamics … All treated groups, 0.25 to 3.5 mg of FTY720, consistently manifested a more pronounced decrease in lymphocyte counts compared with the placebo group; the mean nadir range approximately 0.5 to 1.0 X 109 /L lower, than the measured in the placebo group (Table 3; figure 2). The ma-jority of FTY-treated subjects (83 %) had a nadir below 1.5 X 109 /L, with a mean nadir of 42 ± 14 % compared with baseline (range, 17 to 77 %). All FTY-randomized groups manifested a temporal pattern of relative lym-phopenia, detected at the latest by 6 h postdose. Similar to placebo-treated patients, most patients (71 %) throughout the different dosing cohorts had the lymphocyte nadir after 6 h (mean, 6.9 ± 2.9; range, 2 to 12 h). … Figure 2. Lymphocytes as percent baseline (mean for different dosing co-horts) versus hours postdose. … Discussion … 28 Although FTY exhibits very predictable pharmacokinetics with a linear dose response relationship, the pharmacodynamic effect was not linear over the dose range tested in this study. … Single oral doses of FTY in doses ranging from 0.5 mg to 3.5 mg caused a dosedependent, reversible lymphopenia. Together, these data support fur-ther clinical trial-based investigations of the capacity of FTY to provide safe, potent and synergistic immunomodulatory activity in organ trans-plantation. …” Af en anden artikel af blandt andre Budde fra 2003 fremgår følgende blandt andet: ”… Pharmacodynamics of Single Doses of the Novel Immunosuppressant FTY720 in Stable Renal Transplant Patients … Introduction … In a previous report
(22)we described the safety, pharmacokinetics and reversible lymphopenia after single oral doses of FTY in stable renal trans-plant patients. … Results … As described in our initial report
(22), all treatment groups exhibited a tem-poral reversible lymphopenia. The mean lymphocyte counts for each treat-ment group are plotted in Figure
  1. … Exploratory examination of the data suggested that the doses 0.25-1.0 mg were not markedly different in terms of lymphocyte response. … 29 Figure
  2. Lymphocytes as percent baseline (mean ± standard error for different dosing cohorts) vs. hours post dose, with pharmacokinetic/pharmacodynamic model fit superimposed. … … The lower dosing cohorts (0.25-1.0 mg FTY) had interchangeable curves with lowest values between 6 and 12 h and a slow recovery over time. The nadir of these groups was very similar and approximated 60 % of placebo (range 57-60 %). After 24 h, relative lymphopenia had recovered to 81 ± 16 % of placebo, reaching baseline after 72 h (96 ± 12 % of placebo) in these dose groups. The more rapid onset, the higher degree and the sustained ef-fect of 3.5 mg FTY on lymphocyte numbers is clearly documented in the Figure
  3. The curve for the 2.0 mg dosing cohort is between the highest and the lower dosing cohort with an exceptionally high value after 12 h as a re-sult of an outlier. … 30 Figure
  4. Effect of FTY on the ratio of treated to placebo lymphocyte count as a function of time post FTY dose. … Discussion … … In this first human study of the use of FTY720 ranging from 0.25 to 3.5 mg were administered to stable renal transplant subjects on a CsA-based immunosuppression regimen. As FTY induces a dose-dependent lym-phopenia in animals (12-15, 18-20), the anticipated pharmacodynamic re-sponse in this Phase I study was a reduction in lymphocyte counts. … … While the lymphopenic effect of FTY is seen with multiple lymphocyte sub-sets, monocyte and granulocyte counts are unaffected by single doses of FTY. However, it is of note that repeated administration of FTY may have different effects, as seen in the present single-dose study. … … Although FTY exhibits very predictable pharmacokinetics with a linear doseresponse relationship
(22), the pharmacodynamic effect was not linear over the dose range tested in this study. … … For nonhuman primates, the lymphopenic effect of FTY has no linear doseresponse relationship
(14). In baboons, the response onset was faster and the duration was longer at higher doses, but the maximal lymphodepletion was similar within the large dose range (0.03-0.3 mg/kg) administered. The 31 results of the present study support this observation: higher doses caused a more rapid and more sustained lymphopenia; however, the degree of lym-phopenia showed only minor differences. … …” Af en artikel fra oktober 2003 af bl.a. Kahan fremgår følgende blandt andet: ”… PHARMACODYNAMICS, PHARMACOKINETICSM AND SAFETY OF MULTIPLE DOSES OF FTY720 IN STABLE RENAL TRANSPLANT PATIENTS: A MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED PHASE I STUDY … Methods. … Patients received once-daily doses of 0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28 days. … Results. FTY720 doses greater than or equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte count by up to 85 %, which reversed within 3 days after discontinuation of study medication. … Conclusions. At doses up to 5.0 mg/day for 28 days, stable renal trans-plant patients treated with FTY720 in combination with CsA and pred-nisone displayed a dose-dependent, reversible decline in peripheral blood lymphocytes without an enhanced incidence of collateral toxici-ties, except possibly bradycardia. … … At clinically relevant concentrations, FTY720 appears to reduce the circulating peripheral blood lymphocyte pool not because of apoptosis ( 6-9 ), but rather by preferentially increasing cellular chemotaxis responses to homing more than inflammatory chemokines. … Administration of single oral dose of FTY720, ranging from 0.25 to 3.5 mg, to stable renal transplant patients maintained on a regimen of CsA and prednisone caused a dose-dependent, although transient, reduction in pe-ripheral blood CD4+ and CD8+ T and B cells
(23). At doses greater than 1.0 mg, the mean nadir counts were 30 % to 60 % below the baseline values. … PATIENTS AND METHODS 32 … Patient Population … Administration of azathioprine, mycophenolate mofetil, or cyclophos-phamide was mandated to be discontinued at least 14 days before the first dose of study medication. … … RESULTS … Pharmacodynamics During day 1, alle patients showed a decrease in the absolute lymphocyte count from the baseline value. During the first 24 r, subjects treated with 0.125 or 0.25 mg FTY720 showed changes similar to patients treated with placebo. Although recipients administered 0.5 mg or 1.0 mg FTY720 showed more profound changes, they displayed recovery to the baseline value at 20 hr. However, members of the 2.5- and 5.0-mg FTY720 groups showed reductions in peripheral blood lymphocyte counts by 60 % of base-line that persisted to the end of the day (data not shown). Figure 1 reveals that throughout the 28-day treatment period, the morning absolute lymphocyte counts showed a dose-dependent decrease from baseline in alle treatment groups compared with the increase in the placebo group. Lymphocyte counts were reduced by up to 85 % in the 5.0 mg/day group, with sustained mean lymphocyte counts of 300 to 400 cells/mm3 . … Figure 1. Impact of dose on the kinetics of percent change from baseline of the absolute lymphocyte count by study day during FTY720 treatment 33 (28 days) and posttreatment (days 28-56) periods. ( open squares ) Placebo; ( filled squares ) 0.125 mg; ( filled circles ) 0.25 mg; ( open triangles ) 0.5 mg; ( open diamonds ) 1.0 mg; ( asterisks ) 2.5 mg; ( filled triangles ) 5.0 mg. … DISCUSSION Multiple oral doses of FTY720 ranging from 0.125 to 5.0 mg produced a dosedependent decrease in peripheral blood lymphocyte count during and delay in recovery over 31/2days after discontinuation of FTY720 therapy de-spite its long t . At daily doses of 1.0 mg or higher, FTY720 produced approximately an 85 % reduction in peripheral blood lymphocytes. … … Af en artikel fra 2005 af blandt andre Park fremgår følgende blandt andet: ”… Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients … Abstract … We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to re-ceive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. … The Effect of PD was calcu-lated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg). 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5
  1. mg)between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r2 = 0.98) and showed low inter- and intraindividual variability. FTY720 produced a dosedependent increase in mean percent reduction of peripheral lymphocyte counts max (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple E model [E = (E max * C)/(C + EC50 )] was the max best-fit PK/PD modeling for FTY720 dose (E = 78.3 ± 2.9 % and EC50 = 0.59 ± 0.09 ng/ml, r2 = 0.89) vs effect (% reduction in peripheral lympho-cytes). FTY720 PK/PD is dose dependent and follows an E max model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80 %) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection. … 34 Material and Methods … Pharmacokinetics/pharmacodynamics … Pharmacodynamics study. The surrogate marker of the pharmacodynamic ef-fect of FTY720 used in this study was the peripheral lymphocyte count in the blood compartment. … The pharmacodynamic effect of FTY720 was de-termined either as absolute reduction in peripheral lymphocyte counts or as percent reduction compared to the lymphocyte count obtained pre-trans-plant and before the administration of the first dose of FTY720 or MMF. … … PK/PD modeling was used to find the best-fit model of the correlation between absolute or percent reduction in peripheral lymphocyte count and increasing doses or blood concentrations of FTY720. … Pharmacodynamics … … The reduction in the number of lymphocytes was observed as early as week 1, reached its peak at about week 4, and was fully reversed 4 to 8 weeks after treatment interruption. The extent of lymphopenia and the time to return to baseline values appear to depend on the magnitude of the FTY720 dose. 35 Figure 4. Time curse of FTY720-induced lymphopenia during the 12-week treatment phase and return to baseline values upon drug discontinuation. MMF = mofetil mycophenolate. … Figure 5. Linear regression analysis correlating mean FTY720-induced re-duction of peripheral lymphocyte counts and drug dose (A) or concentra-tions (B) 36 Figure 6. Pharmacokinetic and pharmacodynamic inhibitory E max model correlating FTY720 dose (A) og blood concentration (B) with absolute lymphocyte counts in peripheral blood. 37 Figure 7. Pharmacokinetic and pharmacodynamic simple E max model correlating FTY720 dose (A) or blood concentration (B) with percent reduction in lymphocyte counts in peripheral blood. … PK/PD analysis The observed linear correlation between FTY720 dose and steady-state blood concentrations did not translate into linear correlations between dose or blood concentrations and lymphopenia. In the 10-fod dose range studied in this trial (0.25 to 2.5 mg/day) FTY720 pharmacodynamics was not dose-linear (r2 = 0.57 and 0.53), as can be observed in Figure 5A and B. Searching for a best-fit model we identified the inhibitory E max model as the one with the best prediction of the relationship between both FTY720 dose or blood concentrations and absolute peripheral lymphocyte count. … For FTY720 dose 0 and concentration relations, E and E max were very similar, with EC50 38 ofmax 0.08 mg or 0.13 ng/ml, respectively (Figure 6A,B). Conversely, the simple E model was the one that best predicted the relationship between either FTY720 dose or blood concentration and percent reduction in peripheral lymphocyte count. … Again, using this model, the correlation between individual FTY720 doses or steady-state blood concentrations and percent reduction in peripheral lymphocyte counts produced coefficients of determi-nation of r2 = 0.94 and r2 = 0.89, respectively. For FTY720 dose and concen-tration max correlations, E was 87,8% and 78.3%, with EC50 of 0.48 mg or 0.59 ng/ml respectively (Figure 7A,B). … … For the absolute lymphocyte count, the inhibitory E max model was selected since there was a decrease (inhibition) in the number of lymphocytes in peripheral blood with increasing drug dose or concentration, showing high coefficients of determinations (Figure 6). … For the percent reduction in lymphocyte counts, the simple E maxmodel was selected since there was an increase in percent reduction of the number of lymphocytes in periph-eral blood with increasing drug dose or concentration, also showing high coefficients of determination (Figure 7). There was an evident difference in EC 50 between the two PK/PD models for both FTY720 dose (0.08 vs 0.48
  2. mg)and blood concentration (0.13 vs 0.59 ng/ml). A simple explanation for this finding is the large but frequently observed variability of the peripheral lymphocyte counts when drug dose or concentrations were equal to zero (E 0 term), suggesting that the use of percent reduction, which naturally corrects for baseline differences, is more appropriate as a surrogate marker of the pharmacodynamic effect of FTY720 in the blood compartment. … In a phase II clinical trial, the 2.5-dose of FTY720 showed good efficacy for the prevention of acute rejection after kidney transplantation. This dose produced a reduction of about max 80 % in lymphocyte count, close to the maxi-mum effect (E ). … Af et abstrakt af blandt andre Park fra 2003 fremgår følgende blandt andet: ”… PERIPHERAL BLOOD FTY720 PHARMAKOKINETIC/PHARMACODYNAMIC (PK/PD) MODELING IN RENAL TRANSPLANTED RECIPIENTS … … CONCLUSION. According to the PK/PD model, EC 50 was achieved at FTY720 doses of 0.5 mg and blood concentrations of 0.6 ng/mL. Since 39 FTY720 PK are dose-linear and effective doses of FTY720 are 2.5 and 5 mg/day, the immunosuppressive effect of FTY720 may depend upon induc-tion of high degree lymphopenia (~80%) and/or be associated with other FTY720 effects out of the blood compartment, perhaps in secondary lym-phoid tissue were lymphocyte home.” Kendt teknik angående fingolimod til behandling i forhold til EAEdyremodeller Af en artikel vedrørende anvendelse af EAE på Lewis rotter fra 1990 fremgår føl-gende blandt andet: ”… The neuropathology of chronic relapsing experimental allergic en- cephalomyelitis induced in the Lewis rat by inoculation with who spinal cord and treatment with cyclosporin A* … Summary. … Recently Polman et al. [28] have induced chronic relapsing EAE in the Lewis rat by inoculation with guineapig spinal cord and treatment with low-dose cyclosporin A (CsA). The present study was undertaken to investigate the neuropathology in this model. A brief preliminary report of this work has been published [26]. … Følgende fremgår af en artikel af blandt andre Gijbels fra 2000: ”… EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS: AN ANIMAL MODEL FOR MULTIPLE SCLEROSIS … SUMMARY The first section reviews the current knowledge about the neuropathology, pathophysiology, clinical symptomatology, diagnosis and treatment of multiple sclerosis (MS). Where possible, the text will refer to animal models of MS with a special emphasis on experimental autoimmune en-cephalomyelitis (EAE). EAE serves as an animal model for the human inflammatory demyelinating diseases of the central nervous system (CNS): acute disseminated encephalomyelitis (ADEM) and MS. Both the histopathological characteris-tics and the clinical picture of EAE are very similar to MS. Taken together with the fact that the generic background of the animals determines suscep- 40 tibility for EAE, it demonstrates that this model is in many aspects very reminiscent of MS. However, EAE is an induced disease with a known autoantigen, whereas the autoimmune nature of MS and the causative autoantigen(
  3. s)are still a matter of debate. Extrapolation of findings in EAE to MS should be done cautiously, especially when immune-specific mecha-nisms are involved. … INTRODUCTION A major goal in MS research is to understand the pathogenesis of this humane-mediated chronic neurological disease. A second, more practical goal is to develop new targeted therapies to slow down or even halt the causative pathological process. There are no ideal animal models for MS, but models such as EAE mimic this human disease in key features and offer a useful approach to study some aspects of the pathogenesis of MS and to improve therapies. … … Table I. Comparison of MS with the EAE model. 41 … Use of the EAE model EAE can be used to study immunologic and inflammatory mechanisms in general (e.g. autoimmune tissue-specific inflammation), as well as a disease model for MS in particular. We already mentioned the potential problems of extrapolating findings on antigen/immune-specific mechanisms and in-terventions in EAE to the human situation in MS. When using EAE as a model to study therapeutic interventions intended for MS, one should first demonstrate that the affected disease mechanism is indeed operative both in EAE and in MS. … CONCLUSIONS Taking the caveats already mentioned into account, EAE still is the best ani-mal model available to study some of the key mechanisms in MS pathogen-esis, as well as therapeutic interventions aimed at these mechanisms. Fur-ther developments in MRI and their application to the EAE model will un-doubtedly help us to better understand how the pathophysiological mecha-nisms in EAE and MS correlate, and how findings in the animal model can be extrapolated to the human disease. …” Følgende fremgår blandt andet af en artikel fra marts 2004 af blandt andre Webb: 42 ”… Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice … 1. Introduction … … It now appears that at least one of the mechanisms by which FTY720 achieves its effects in vivo is by a sequestration of circulating lymphocytes in peripheral lymph nodes (Pinschewer et al., 2000; Brinkmann et al., 2000, 2001a,b; Mandala et al., 2002, Xie et al., 2003). … Two papers have appeared indicating that FTY720 is active in rodent mod-els of experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis. … … While these data are impressive, the efficacy of FTY720 when given at the onset of clinical symptoms or on established EAE is unknown. In the present investigation, we have examined the efficacy of FTY720 and its phosphate ester on an established disease state in the relapsing-remitting EAE model in SJL mouse (SJL rr-EAE), a model which mimics several fea-tures of human MS. … In this study, we characterise the effects of FTY720 and its phosphorylated derivate on the clinical state, and levels of circulating lymphocytes in the SJL mouse rr-EAE model. Initiating dosing just prior to the onset of clinical signs delays and blunts the first phase of the disease as previously reported in the rat models. More significantly for the clinical setting, if treatment with these compounds is delayed until the peak of the first phase of dis-ease, there is an immediate and rapid improvement of the clinical status of the animals which is maintained for as long as dosing is continued. … We also show that there is a correlation between a magnitude of clinical im-provement and the levels of lymphopoenia achieved at any given dose of FTY-P, but this correlation is incomplete, indicating that nonselective S1P receptor agonism may exert its effects in this model by additional mecha-nisms. FTY-P is also effective in an adoptive transfer version of the disease. … 2.2 Lymphopoenia assays … 43 Whole blood from EAE animals was collected by retroorbital bleeding, us-ing EDTA as an anticoagulant. The blood was used within 4 h at room tem-perature for cell counting. Lymphopoenia was defined in or assay as the re-duction of lymphocyte, cell density (cells/µl) as compared to PLP control vehicle. Data were expressed by plotting cell density as a function of time (days in vivo) and analysed using software PrismTM 3.0 (San Diego, CA) All values are expressed as mean ± standard error of mean (S.E.M.). … 3.4. Lymphopoenia in FTY-treated mice … … As has been reported previously (Sewell and Andrews, 1989), treating mice with pertussis toxin, as was done routinely in the EAE induction pro-tocol, results in a large increase in the levels of circulating peripheral lym-phocytes, probably because these cells are unable to home to the peripheral lymphoid organs. Densities of circulating lymphocytes were approximately 7000/mm 3 in naїve animals. … 4. Discussion FTY720 has been reported previously to be effective in ameliorating several autoimmune diseases, including EAE (Chiba et al., 1996; Suzuki et al., 1996a, 1998; Masubichi et al., 1996; Matsuura et al., 2000). … As has been reported previously, we saw a dose-dependent and reversible lymphopoenia on treatment with FTY720 or FTY-P. This reached a maxi-mum of about 70-80 % depletion at the highest doses used. This level of lymphopoenia was established over several days after the initiation of dos-ing, and we were able to show that cumulative clinical scores over the dos-ing period correlated with the plateau levels of lymphopoenia achieved for each specific dose. This would be expected if, as has been claimed, the lym-phopoenia is a manifestation of the mechanism of action of FTY720, a re-versible sequestration of autoagressor T lymphocytes in peripheral lymph nodes (Xie et al., 2003). Because EAE is known to be a T cell-dependent dis-ease, such sequestration, by preventing the entry of T cells with specificity for myelin components into the CNS, would account for the therapeutic ef-ficacy. … … 44 In dose response experiments, we found that a threshold of about 70 % de-pletion of peripheral lymphocytes was required to see any efficacy, and thereafter, the dose-response relationship between clinical benefit and lym-phopoenia was very steep. In spite of these observations, we did observe disconnection between lymphopoenia and clinical scores. This was particu-larly seen at the initiation and termination of dosing. At initiation of dosing in sick animals, we saw a rapid onset of clinical improvement which was evident prior to the establishment of substantial levels of lymphopoenia. On withdrawal of compound, there was a delay of 1-2 days before the clini-cal signs began to increase. Nevertheless, animals were seen to have re-lapsed to clinical scores of 2 or above while levels of lymphopoenia re-mained the same as they were when the animals had scores little above baseline (0.5). The correlation between lymphopoenia and clinical efficacy is this imperfect, and although the lymphopoenia is a biomarker correlated with clinical efficacy and may be a contributory mechanism to this efficacy, additional mechanisms may also be involved in producing the overall ther-apeutic benefit seen in models of transplant and autoimmune disease. … Kendt teknik om fingolimod i forhold til raske mennesker Af en artikel af blandt andre Kovarik fra 2004, der vedrører forsøg med fingolimod med en enkeltdosis, fremgår følgende blandt andet: ”… Single-dose FTY72O pharmacokinetics, food effect, and pharmacological responses in healthy subjects … Methods In this randomized, two-period, crossover study, 14 healthy subjects re-ceived placebo on day – 1 of each period with baseline circadian measurements of lympho-cyte count and heart rate. Subjects subsequently received a single 1 mg oral dose of FTY720 on day l under fasting conditions and after a high fat meal. Blood FTY720 concentrations, lymphocyte count, and supine heart rate were as-sessed over an 8 day period after each FTY720 dose. The effect of food on FTY720 pharmacokinetics was assessed by standard bioequivalence testing. … Conclusions Single l mg doses of FTY720 were well tolerated in healthy subjects and elicited a moderate decrease in peripheral blood lymphocyte count and a 45 transient decrease in heart rate consistent with its pharmacological mode of action. … … Discussion This study provides the first pharmacodynamic and pharmacokinetic data for FTY720 in healthy subjects. A single 1 mg dose of FTY720 was well tol-erated and the only notable effects were on lymphocytes and heart rate. … A nearly full recovery of lymphocyte count was observed after 1 week. This is similar to the effect of FTY720 in renal transplant patients in whom the decrease in blood lymphocyte count was not associated with an increased risk of infections [6]. …” Fodnote nummer 6 i citatet ovenfor refererer til artiklen af blandt andre Budde fra 2002. Af en anden artikel af blandt andre Kovarik fra 2004, der vedrører forsøg med fingolimod med flere doser, fremgår følgende blandt andet: ”… Multiple-Dose FTY720: Tolerability, Pharmacokinetics, and Lymphocyte Responses in Healthy Subjects … … Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure-response modeling provided evidence that 5 mg/day FTY720 resulted in a near-maximal dynamic effect of this drug on lymphocytes. … … We chose a subtherapeutic and a therapeutic dose of FTY720 to span a broad range of exposures and responses. … DISCUSSION … … In FTY720-treated subjects, lymphocyte counts decreased from baseline by about 60% in the low-dose group and by about 75% in the high-dose group by the morning after drug administration. The absolute nadir lym-phocyte counts occurred between days 3 and 7, averaging 0.4 and 0.2 x 109 /L in the low- and high-dose groups. An inhibitory E max model reason- 46 ably described the relationship between the cumulative exposure to FTY720 over the weeklong treatment phase versus the nadir lymphocyte count. …” Review-artikler om fingolimod Af en review-artikel af Dumont fra 2005 fremgår følgende blandt andet: ”… Fingolimod Mitsubishi Pharma/Novartis Francis J Dumont … Metabolism and Pharmacokinetics … Pharmacokinetic and pharmacodynamic modeling in renal transplant pa-tients revealed that the EC 50 value for lymphopenia was achieved at a 0.5mg dose of fingolimod and blood concentrations of 0.6 ng/ml. Since effec-tive doses of fingolimod were reported at 2.5 to 5 mg/day, this suggested that the immunosuppressive effect of fingolimod may depend upon the in-duction of a high degree of lymphopenia (~80%) [579948]. Furthermore, analysis of the effects of single dose of ≤ 40 mg in healthy volunteers indi-cated that the duration of lymphopenia correlated with the extent of drug exposure, therefore, high-dose regimens of fingolimod may have clinical potential [579944]. …“ Henvisningen “579948” i citatet ovenfor refererer til artiklen fra Park, og henvisningen ”579944” refererer til artiklen fra Kovarik, der vedrører enkeltdoser med fingolimod. Følgende fremgår blandt andet af en artikel af Thomson fra 2006: ”… FTY720 in multiple sclerosis: the emerging evidence of its therapeutic value … Core emerge evidence summary for FTY720 in multiple sclerosis 47 … Evidence of activity in animal models of multiple sclerosis Orally administered FTY720 is effective in a number of preclinical models of transplant rejection and autoimmune disease. The experimental autoim-mune encephalomyelitis (EAE) model is one of the most widely used ani-mal models of multiple sclerosis mimicking a number of pathologic charac-teristics of the disease. In a rat model, orally administered FTY720 0.3 mg/kg per day prevented the development of EAE, as assessed by clinical disease score (Brinkmann et al. 2002). … Outcomes achieved with FTY720 Pharmacokinetic and pharmacodynamic outcomes following single- or multipledose administration of FTY720 have been determined in both healthy subjects and transplantation patients (Table 3). These data are in-cluded here as these outcomes are not affected by disease status and may be extrapolated to include those patients with multiple sclerosis. Pharmacodynamic outcomes Results from a number of clinical studies have shown that FTY720 pro-duces profound and reversible immunomodulation following oral adminis-tration. The mechanism of action of FTY720 leads to a reversible redistribu-tion of lymphocytes from the circulation to secondary lymphatic tissue. The resulting lymphocyte sequestration is a convenient surrogate marker of the pharmacodynamic effect of FTY720 and may be a useful parameter for monitoring the immunomodulatory effect of the drug in the clinic. There is substantial evidence that lymphocyte sequestration develops in healthy volunteers and renal transplant patients treated with FTY720 (Ta-ble 3). Administration of a single oral dose of FTY720 1 mg to 14 healthy volunteers resulted in a 38% reduction in the number of peripheral blood lymphocytes 2 days postdose (Kovarik et al. 2004b). In another study, the 48 same dose led to a 44% reduction in the number of blood lymphocytes in 32 subjects with or without hepatic impairment (Kovarik et al. 2005). A similar effect was also seen in a phase I study after single-dose administration of FTY720 (0.25-3.5
  4. mg)to 20 stable renal transplant patients receiving a cy-closporinebased regimen (Budde et al. 2002). Although the higher doses of FTY720 produced a more rapid and sustained lymphocyte sequestration, the actual degree of this property was similar across the range of doses used in the study and no clear dose-response relationship was detected. … … The profound lymphocyte sequestration observed with multiple doses of FTY720 has also been shown to be reversible after cessation of drug treat-ment. For example, in a placebo-controlled study lymphocyte counts de-creased by 80 and 88% in healthy subjects receiving orally administered FTY720 1.25 or 5 mg/day, respectively (Kovarik et al. 2004a). … Similar out-comes were also seen in a study with patients treated with FTY720 0.25-2.5 mg/day for 12 weeks following renal transplantation (Park et al. 2005). … Clinical outcomes … In this phase II international multicenter trial, 281 patients with active relaps-ing multiple sclerosis were randomized to receive FTY720 1.25 mg (n=94), or 5 mg (n=94), or placebo (n=93) once daily for 6 months (Table 4; Kappos et al. 2005). The primary outcome was inflammatory disease activity as as-sessed by the mean total number of gadolinium (Gd)-enhancing lesions in monthly postbaseline MRI scans. Compared with placebo, FTY720 1.25 and 5 mg/day significantly reduced inflammatory disease activity by 43 and 61 %, respectively (P≤ 0.006). Similarly, new disease activity (as measured by MRI) was also reduced by FTY720 (actual data not provided). In addition, when compared with placebo treatment the annual relapse rate was signifi-cantly reduced by 55 and 53% with FTY720 1.25 and 5 mg/day, respectively (P values not provided in the ab-stract). A total of 86% of patients in both FTY720-treated groups were relapse-free compared with 70% of placebo-treated patients (P≤ 0.008) after 6 months. … Drug profile … FTY720 has shown promising results in preclinical models of EAE, which in part has led to its clinical evaluation in multiple sclerosis. There is moderate evidence from two meeting abstracts of a phase II study that FTY720 (admin- 49 istered orally once daily for up to 12 months) improved the patient-oriented outcomes of relapse rate and the likelihood of remaining relapse-free. In addition, there is moderate evidence that disease-oriented outcomes were also improved by FTY720 in that inflammatory disease activity (both new and existing) was reduced as determined by MRI. …” Af en review-artikel af blandt andre Chiba fra februar 2006 fremgår følgende blandt andet: ”… Role of Sphingosine 1-Phosphate Receptor Type 1 in Lymphocyte Egress from Secondary Lymphoid Tissues and Thymus … Mechanism of action of FTY720, S1P receptor modulator FTY720 induces lymphocyte sequestration into secondary lymphoid tissues and thymys … A striking feature of FTY720 is the induction of a marked decrease in the number of peripheral blood lymphocytes (lymphopenia) at doses that dis-play an immunomodulating activity in these disease models. In rats, the number of lymphocytes (T cells and B cells) in peripheral blood decreased dramatically within 6 hours after oral administration of FTY720 at 0.1 to 1 mg/kg (8, 18, 19). In particular, the reduction in T cell numbers is remark-able. In mice, dogs, and cynomolgus monkeys, marked lymphopenia is also induced by FTY720 administration (11, 14, 28, 29). In the phase la study, ad-ministration of single oral doses of FTY720, ranging from 0.25 to 3.5 mg/kg, to stable renal transplant patients maintained on a regimen of CsA and corticosteroid, causes a dose-dependent reduction in peripheral blood T cells and B cells
(30). At doses greater than 1.0 mg, the mean nadir counts are 30% to 60% below the baseline values. In the phase lb study on pharma-codynamics, pharmacokinetics, and the safety of multiple FTY720 doses in stable renal transplant patients, FTY720 at 1.0 mg/day or greater signifi-cantly reduces the number of peripheral blood lymphocytes by up to 85%, which reverses within 3 days after discontinuation of the study medication (31, 32). … Effects of FTY720 on experimental autoimmune disease models FTY720 at 0.1 mg/kg p.o. or higher doses almost completely prevents paral-ysis in experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein in LEW rats (11, 27, 46, 47). Therapeutic treatment 50 with FTY720 inhibits EAE relapse induced by myelin proteolipid protein immunization in SJL mice (48-50). …” Kendt teknik om fingolimod til behandling af multipel sklerose Af et abstract vedrørende en studie af blandt andre Kappos fra 2005 fremgår følgende blandt andet: ”… FTY720 in relapsing MS: results of a double-blind placebo-controlled trial with a novel oral immunomodulator … … There was no compelling dose-related difference in efficacy on MRI or clinical endpoints. Treatment was generally well tolerated with 255 (91%) of patients completing study and 249 (89%) electing to continue into the ex-tension phase where PL patients were rerandomized to one of the active drug dose groups. Adverse events were more common in the 5mg group, with the most frequently reported (> 15% patients) being mild headaches and nasopharyngitis. Conclusion: This proof of concept study demonstrates efficacy of FTY720 on both MRI and relapse-related endpoints. Both the efficacy and safety evaluations strongly suggest that FTY720 has the potential to be an effica-cious disease modifying treatment for relapsing forms of MS with the addi-tional benefit of once daily oral administration. …” Af et andet abstract vedrørende et studie af blandt andre Kovarik fra 2005 fremgår følgende blandt andet: ”… FTY720 exposure/efficacy relationship in a 6-month phase 2 study in patients with relapsing MS … … Results: FTY720 Css averaged 7.3 ± 4.3 ng/ml at 1.25 mg/day and 30.2 ± 19.1 ng/ml at 5 mg/day. Within the observed FTY720 exposure range, relationships to the efficacy variables appeared relatively flat. For example, in exposure quintiles of < 5, 5 – 9, 9 – 15, 15 – 28, > 28 ng/ml, freedom from relapse was 96%, 76%, 92%, 80%, 85% (placebo, 70%). With regard to covari-ates, patients with more relapses in the past had a higher likelihood of ex-periencing a relapse in the 6-month study period (p = 0.005). Patients with a higher number of T1 lesions at baseline (p = 0.002) and younger patients (p 51 = 0.06) tended to have a worse MRI outcome. Conclusion: In line with the comparable efficacy achieved at both the 1.25 and 5.0 mg FTY720 dose lev-els (e.g. reduction of annualized relapse rate by 55% and 53% vs placebo, p = 0.009 and 0.014, respectively), pharmacokinetic/dynamic modeling showed a flat exposure-relationship, suggesting near-maximal responses were achieved at the two dose levels tested. These data support exploring potentially lower doses of FTY720 in future MS studies. Study supported by Novartis Pharma AG Basel. …” Kendt teknik vedrørende andre behandlinger Af en udskrift fra bogen ”Videnskabelige tabeller” af Konrad Diem og Cornelius Lentner, 1975, fremgår, at et voksent menneske i gennemsnit har et lymfocyttal på 2185, og at området normalt er i intervallet 1029-
  1. Af en artikel af blandt andre Cook af 1987 fremgår følgende blandt andet: ”… Total Lymphoid Irradiation in Multiple Sclerosis: Blood Lymphocytes and Clinical Course … We have found a significant relationship between blood lymphocyte count and prognosis in 45 patients receiving either total lymphoid irradiation or sham irradiation for chronic progressive multiple sclerosis. Patients with sustained lymphocyte counts less than 900 mm-3 for prolonged periods af-ter treatment showed less rapid progression over the ensuing 3 years than did patients with multiple sclerosis who had lymphocyte counts above this level (p < 0.01). Our results suggest that a simple laboratory test, the abso-lute blood lymphocyte count, may serve as a valuable barometer for moni-toring the amount of immunosuppressive therapy needed to prevent pro-gression in patients with multiple sclerosis, and possibly other autoim-mune diseases. … Methods Patient Selection Patients were considered for the study if they met the folllowing criteria: were aged 20 to 60 years; had clinically definite MS [9] for at least 3 years; had progressive neurological disability (as documented by a neurologist or confirmed by the patient and a family member) for at least the previous year; had a score of 4 to 8 on a disability scale [8] modified from the Kurtzke disability status scale; and would remain available for at least 2 52 years of follow-up. Most patients had previously received steroids or ACTH. Reasons for exclusion were severe psychiatric or medical disease, dementia, prior immunosuppression, active infection, or pregnancy [8]. Radiotherapy and Clinical Evaluation TLI, 1,980 rad, or sham TLI was administered over 29 to 64 days (mean, 40 days) to all patients at the Clara Maass Medical Center, Belleville, NJ. De-tails of this therapy have been published elsewhere [8]. … Results Relationship of Blood Lymphocyte Count to Clinical Score When clinical results were analyzed by comparing the relationship be-tween mean absolute blood lymphocyte count and functional scale, signifi-cant differences between patients were noted in Kaplan-Meier curves (Fig 1) and in progression at fixedtime intervals after thetapy (Tables 2, 3). Patients whose mean abso-lute lymphocyte count was less than 900 over the first 3 months after treat-ment (all TLI patients) predictably did significantly better at all time inter-vals than those whose lymphocyte count was above this level (TLI patients plus sham patients) (see Fig 1 and Table 2). … … Significant differences were also seen in the clinical course when patients with sustained lymphocytopenia (< 900 mm-3 ) over the first 12 months after therapy who received TLI were compared to patients who received sham TLI only (lymphocyte levels > 900 mm-3 ) (p < 0.01). … Discussion In this study we found a significant relationship between absolute blood lymphocyte count and prognosis in patients with chronic progressive MS. … … Finally, although TLI appears to have potential value in lowering blood lymphocyte levels and possibly in the therapy of chronic progressive MS, it should be considered an experimental therapy until its efficacy is con-firmed in larger studies. Until that time, its use should be limited to MS study groups. …” Vedrørende stoffet azathioprin fremgår følgende af en oversat udgave af bogen ”Multiple Sclerosis” af Schmidt og Hoffmann fra 2006: 53 ”… 16.4 Immunosuppression 16.4.1 Azathioprine … Active principle Azathioprine (Imurek®) is a weak cytostatic drug that can be administered orally in tablet form. It interferes with the purine nucleotide metabolism, and as 6mercaptopurine it also enters the CNS. It is able to suppress acute and chronic experimental encephalomyelitis in the animal model of MS (Mertin 1987). … Effectiveness … The effect of azathioprine on immunological parameters has also been studied on a large scale. Azathioprine suppresses the proliferation of T and B lymphocytes (Bach and Bach 1972), lead to a decrease in the number of cells in the cerebrospinal fluid (Wurster 1988, Gopel 1972) and reduces in-trathecal IgG synthesis (Wurster 1992). … Side effects and risks Reduction in blood count and lcbcr enzymes. Under an immunosuppressive therapy with Azathioprine, a desired decrease of leucocyte counts based on lymphopenia is frequently observed. (Haas 1982). This lymphope-nia usually does not entail therapeutic consequences and are in a certain manner considered to be desirable in the sense of an intended anti-inflam-matory and immunosuppressive therapeutic effect. …” Dokumenter efter prioritetstidspunktet Af en artikel af blandt andre Cohen af
  2. januar 2010 fremgår følgende blandt andet: ”… Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis … 54 RESULTS A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod — 0.20 (95% confidence interval [Cl] , 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% Cl, 0.12 to 0.21) in the 0.5-mg group — than in the interferon group (0.33; 95% Cl, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the pri-mary results. No significant differences were seen among the study groups with respect to progression of disability. … …” Sagsbehandlingen af Stridspatentet ved EPO EPO’s Examining Division afgav den
  3. januar 2020 en foreløbig udtalelse om Stridspatentansøgningen og indkaldte samtidig til mundtlig forhandling. Af brevet fremgår følgende blandt andet: ”… Documents cited by third parties under Article 115 EPC: … D10 … Novartis press release of the 6th of April 2006 (TM1) 4 Amendments under Articles 123
(2)& 76
(1)EPC 4.1 Basis for the subject matter of this claim is present in the application documents as originally filed at the end of page 9 of the description (last 3 lines); the basis for the dosage of 0.5 mg p.o. is to be found at page 13 under C. Clinical trial (at line 23). The subject matter of the main request thus meets the requirements of Article 123
(2)EPC. 4.2 This file is a divisional application, the parent applicant being Patent nr. 6. Basis is to be found in the parent applicant at the same places as in the parent (pages 9 and 13). The subject matter of the main request thus also meets the requirements of Article 76
(1)EPC. 5 Novelty (Article 54 EPC) 5.1 Document TM 1, now renamed D10, (Novartis media release of the 6th April 2006) that has been mentioned repeatedly by the third parties dis-closes the use of 0.5 mg of FTY 720 (Fingolimod) for the treatment of MS (see the second page under "Phase III study programme"). 55 5.2 This is considered to encompass the subject matter of present claim 1 and, as such, document TM 1 / D10 is novelty destroying for the subject matter of the present claim
  1. … 7 Sufficiency of disclosure (Article 83 EPC) 7.1 As mentioned above under inventive step, no data showing that the compound and dosage that are presently claimed carry out the claimed effect are currently on file. This objection has been raised previously in the telephone conversation of the 6th November 2019 as well as in sev-eral of the third party observations. 7.2 Given the fact that the present claim 1 concerns a purpose limited composition claim, such data is essential to recognising the effective thera-peutic nature of the claimed subject matter. 7.3 As such, the present application does not meet the requirements for sufficiency of disclosure under Article 83 EPC. …” Som svar på Examining Divisions foreløbige udtalelse fremsendte Novartis ved brev af
  2. oktober 2020 bemærkninger hertil, hvor der blandt andet argumente-res for, hvorfor Stridspatentansøgningen opfylder kravene om nyhed og til-strækkelig beskrivelse i patentkonventionen. Af brevet fremgår følgende blandt andet: “… II. Documents … In reply to the preliminary opinion of the Examining Division and to the observations of third parties, the following documents are submitted: … D24 Expert Report of Person 8, Dato 3 2020 … D31 Novartis experimental report, Effects of FTY720 on experimental autoimmune encephalomyelitis-induced angiogenesis (acute and relapsing),
  3. May 2009 … 56 1.5 Skepticism among the experts In the present case, there was no evidence or teaching in the prior art that fingolimod at a daily dose of 0.5 mg would lead to a reduction of relapse rates. Rather the opposite is true! Based on the available data from trans-plant patients and animal MS models (see detailed explanations below in section VI.5.1), experts were skeptical that the 0.5 mg dose would actually achieve a treatment of RRMS. This is illustrated in detail by Prof. Person 8 in his expert report (D24). Prof. Person 8 is an attending neurologist at the Mt. Sinai Hospital in New York City and, in 2005, he was a member of Novar-tis's Advisory Board, a collection of MS physicians that helped Novartis to design the Phase III trial that was announced in the second aspect of D10 (D24, p. 11, para 3). …” Den
  4. november 2020 blev der afholdt mundtlig forhandling om Stridspatentansøgningen. Af Examining Divisions referat af forhandlingen fremgår følgende blandt andet: ”… 3 1) Merit of the invention The representative essentially pointed out that there was no evidence that the dose of only 0.5 mg worked to treat rrMS. He referred to the raw data in D31, as well as D32, D29, and subsumed that this achieve-ment went beyond D
  5. … 11 After a break from 12:05 pm to 13:05 pm the representative filed auxil-iary request 3 and asked the chair whether it would be possible to dis-cuss this request before the examining division would announce its opinion with respect to auxiliary request
  6. 12 The Chair agreed to discussing auxiliary request 3 first and informed the applicant of the examining division's opinion that this request ful-fills the requirements of Articles 123
(2), formally 54 and 83 EPC. The Chair then invited the applicant to provide an argumentation with re-spect to Article 56 EPC. …” Examining Division besluttede herefter at nægte at udstede Stridspatentet og afgav i den forbindelse den
  1. november 2020 en skriftlig begrundelse herfor, hvoraf fremgår blandt andet: ”… 57 Decision to refuse a European Patent application The Examining Division - at the oral proceedings dated 02.11.2020 - has decided: European Patent application No. 15 177 166.4 is refused. … 16.2 Novelty (Article 54 EPC) … 16.2.11 Concerning the present case, the examining division is of the opin-ion that any prior art document disclosing the therapeutic effect of 2-amino-2-[2-(4octylphenyl) ethyl]propane-1,3-diol / Fingolimod / FTY720 at 1.25 mg p.o on the treatment of relapsing-remitting multiple sclerosis in one part of that document, and then the use of 0.5 mg p.o explicitly dis-closed (albeit without data) is novelty destroying for a claim directed to a treatment for relapsing-remitting multiple sclerosis using 0.5 mg p.o of 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol. In this respect, the 1.25 mg p.o dose is directly and unambiguously disclosed in D10 and is further deemed to be fully enabling given the positive outcome of that part of the trial. The further mention of the 0.5 mg p.o dose in the phase III trial is thus also deemed to be directly and unambiguously disclosed in D
  2. In the light of the entirety of document D10, particularly the results of phase II, the examining division could not see why the dosage of 0.5 mg p.o. was not enabling. …” Novartis AG appellerede den
  3. december 2020 Examining Divisions beslutning om at nægte at udstede Stridspatentet. Af en anonym tredjepartsindvending med relation til Stridspatentet, hvor der blandt andet argumenteres for, at Stridspatentansøgningen ikke indeholder en tilstrækkelig beskrivelse, og som blev modtaget af EPO den
  4. april 2021, frem-går følgende blandt andet: ”… 3 Lack of sufficiency of disclosure (Art. 83 EPC) In its decision to refuse the application, the Examining Division did not explicitly address the requirements under Art. 83 EPC. Only in passing, it was mentioned that several Third Party Observations had raised this issue, but that the applicant had provided experimental data supporting the case and providing a foundation for sufficiency of disclosure. 58 What the Examining Division did not address was whether the application itself discloses the suitability of the product for the intended use in a plausi-ble way. This, however, is the prerequisite for any additional data to be tak-ing into account at all. 3.1 Taking into account post-filed evidence requires plausibility of the claimed treatment Put differently, the decisive question in the case at hand is not whether post-filed evidence shows that the claimed treatment is indeed effective. Rather, it has to be assessed whether the requirements for considering any post-filed evidence were to be fulfilled already at the filing date. Pending claim 1 is in the form of a second medical use claim. Conse-quently, according to well established case law, obtaining the claimed therapeutic effect is a functional feature of the claim (T 609/02). For second medical use claims, it is required not only that the composition itself is dis-closed in an enabling way but also that its suitability for the claimed treatment is plausibly disclosed in the application (T 1616/09). Accordingly, the application must disclose the suitability of the product for the intended medical use by some kind of data unless the suitability was al-ready clear to the skilled person at the priority date (cf. Case Law of the Boards of Appeal, ll-C, 6.2). If the application only provides a vague indica-tion of a medical use, then post-published data cannot remedy this funda-mental insufficiency (T 609/02). While it is not necessary to undertake clinical trials in order to prove the claimed therapeutic effect (T 1023/03), it is nonetheless necessary that the patent application provides some information to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically in-volved in the disease (T 433/05). Only if evidence for this suitability is available from the patent application, then postpublished expert evidence may be taken into account, but only to back-up the findings in the patent application in relation to the use of sub-stance or composition, and not to establish sufficiency of disclosure on its own (T 699/06). As will be shown next, the application in suit does not provide any data nor information as to the efficacy of the claimed treatment regimen. 3.2 Application does not contain results or novel data, but only hypothetical exam-ples 59 In particular, the outline of the clinical trial as described in [0033] and [0034] of the application is so vague that later published data regarding the claimed treatment regimen and its alleged efficacy cannot remedy the fun-damental insufficiency of the application itself. Under the heading “C. Clinical trial", the application merely gives a very rough description of a clinical trial that may be used for investigating any S1P receptor agonist, but from the wording it is clear that this is purely hy-pothetical and that no clinical trial was actually performed. While the claimed dosage amount recited in feature 4 is mentioned in [0033] along-side dosages of 1.25 and 2.5 mg p.o., the application fails to show any data for the efficacy of this dosage, or in fact, any other dose of fingolimod. Even the data pertaining to the animal experiments are purely hypothetical, as is apparent from the use of present tense and from the lack of detailed results such as the ones presented three years later in D
  5. In addition, said experiment suggests to administer fingolimod at a concentration of 0.1 to 20 mg/kg p.o. It is therefore identical to the ones described in D14, wherein 0.1 mg/kg p.o. fingolimod was administered to a rat model for EAE. How-ever, the applicant himself considers that these experiments were not suffi-cient to suggest efficacy of the claimed treatment (cf. p. 22 of the Grounds of Appeal): … So according to the applicant, these data were actually suggestive for complications, so that based on these data, the person skilled in the art had no reason to believe that a dose of 0.5 mg fingolimod would result in a thera-peutic benefit. In that case, it is obvious that when reading the application as filed, the skilled person’s attitude would not have changed because the application does not contain any data at all. In addition, the hypothetical examples merely reiterate what was already known at the filing date. Since these data were, as appellant himself acknowledges, not suffi-cient to suggest efficacy of the claimed treatment, the application clearly fails to disclose the suitability of the suggested treatment. In summary, the application in suit does not render the efficacy of the claimed treatment regimen credible since it does not contain any data which, for the skilled person, directly and unambiguously reflect the effi-cacy of the treatment regimen covered by pending claim
  6. The application is thus similar to the one in suit in T 609/02, where it was found that … … 60 The BoA in that case further concluded with regards to the admissibility of postfiled evidence that the application itself has to provide evidence for some sort of pharmaceutical effect that would suggest treatment efficacy before post-published evidence can be taken into account: … … Therefore, post-published data cannot be used to remedy the insufficiency of disclosure that is inherent to the application itself. This is line with the principle that a patent shall only be granted for the actual contribution to the art, but not for a mere hypothesis that a claimed treatment could be tried and may be effective. The applicant himself has declared that the evidence prior to the filing data was insufficient to suggest efficacy. The application, however, does not contain any data at all that could remedy this insufficiency. Thus, claim 1 of the Main Request violates Art. 83 EPC in a way that pro-hibits the consideration of post-filed evidence. …” Det omtalte dokument D39 udgør den anonyme tredjepartsindvending af
  7. april 2021, der er omtalt ovenfor. EPO’s Technical Boards of Appeal afgav herefter en foreløbig udtalelse af
  8. ok-tober 2021, hvoraf fremgår blandt andet: ”… Documents and evidence V. The board adheres to the following numbering of documents: … c) D39 filed as "D38" by an anonymous third-party with its letter dated 22 April 2021 (see footer of this letter) … 1.3 Remittal (Article 11 RPBA 2020) 1.3.1 In agreement with the appellant's request, the board is minded not to remit the case to the examining division for further prosecution. Accord-ingly, the appellant should be prepared to discuss any other outstanding issues in relation to the main request, in particular the following points: 61 (a) Does the application as filed disclose the suitability of the claimed dosage regimen for the intended use (see points 7.1 to 7.3 of the examining division's communication annexed to the summons to oral proceedings and points 3, 3.1 and 3.
  9. of the third party observations dated 22 April 2021)? Or was the suitability of the claimed dosage regimen for the in-tended use otherwise known to the skilled person reading the application at the effec-tive date? (b) Does the subject-matter of claim 1 involve an inventive step starting from the disclosure of document D10 concerning the completed phase II trial (see point 4.1 of the statement setting out the grounds of appeal)? …” Novartis AG afgav herefter ved brev af
  10. januar 2022 bemærkninger til den foreløbige udtalelse fra EPO’s Technical Boards of Appeal. Af Novartis AG’s brev fremgår følgende blandt andet: ”…
  11. Requests and procedural Remarks … With regard to the anonymous third-party observations dated December 9, 2021, it is requested that document TPO-D1 not be admitted into the proceedings for the following reasons. … In addition, the disclosure content of TPO-D1 is not prima facie relevant. In essence, TPO-D1 describes the results of the FTY720 Phase II trial and gives an outlook on a planned Phase III trial which includes the 0.5 mg dose. This information is already on file, see e.g. D22 and D
  12. …
  13. Detailed response to the Board’s observations 3.1 Documents and evidence … For a direct response to the Board’s and third party’s observations dated April 22, 2021 applicant kindly requests that the following documents be admitted: - D42: Inventor’s declaration authored by Person 3 - D43: Expert declaration authored by Professor Vidne 1 62 - D44: Gijbels et al.
(2000): “Experimental Autoimmune Encephalomyelitis: An Animal Model for Multiple Sclerosis” … D42 is a direct reply to the allegations raised by a third party in the obser-vations dated April 22, 2021 (see page 10) that the animal examples “were merely hypothetical ones which had yet to be put into practice” . … EPO’s Technical Boards of Appeal traf herefter den
  1. februar 2022 afgørelse i sagen, hvoraf fremgår blandt andet: ”… Minutes of the oral proceedings … The appellant presented its case on the question of whether the claimed invention was sufficiently disclosed in the application within the meaning of Article 83 EPC. In the course of the presentation of arguments, the appel-lant referred to various documents, inter alia document D43 (with reference to paragraphs 50 to 52), and answered to questions asked by the board. After deliberation by the board, the Chair stated that the board was of the opinion that initial plausibility was given, that postpublished documents could therefore be taken into account and that, at least for this point, the outcome of the referral G 2/21 was not relevant. The Chair then invited the appellant to present its case on the issue of in-ventive step under Article 56 EPC, having regard to documents D10, dis-closing the completed Phase II study and the announcement of the Phase III study, and D4 as possible starting points for the assessment in the problem-solution-approach. … … The Chair then closed the debate and gave the following decision of the board:
  2. The decision under appeal is set aside.
  3. The case is remitted to the examining division with the order to grant a patent on the basis of the single claim of the main request filed on 18 November 2019 underlying the impugned decision and resubmitted with the statement of grounds of appeal, and a description to be adapted thereto. 63 … Summary of Facts and Submissions I. The appeal of the applicant ("the appellant") lies from the decision of the examining division refusing European patent application No. 15 177 166.4 ("the application") entitled "S1P receptor modulators for treating multiple sclerosis". This application is a divisional application of earlier European patent application Patent nr.
  4. This earlier application is itself a divisional application of European patent application Patent nr.
  5. … VI. Third-party observations were received on 27 April
  6. VII. In a communication under Article 15
(1)RPBA issued on 8 October 2021, the board drew the appellant's attention to the points to be discussed during the oral proceedings and provided a preliminary opinion acknowl-edging novelty of the single claim of the main request. VIII. Further third-party observations were received on 2 November 2021, 17 November 2021, 9 December 2021, 23 December 2021 and 18 January 2022. IX. By letter dated 7 January 2022, the appellant submitted, inter alia, the following documents: D43: Declaration of Professor Vidne 1 Dato 4 2021 D44: K. Gijbels et al., "EXPERIMENTAL AUTOIMMUNE EN-CEPHALOMYELITIS: AN ANIMAL MODEL FOR MULTIPLE SCLERO-SIS", NEUROSCIENCE RESEARCH COMMUNICATIONS 26
(3), 2000, 193-206 … Reasons for the Decision … Procedural issues 2. Admittance of documents D43, D44 and appellant's submissions, all filed on 7 January 2022, into the appeal proceedings (Article 13
(2)RPBA 2020) … 2.3 The appellant argued that documents D43 and D44 and its submissions dated 7 January 2022 had been filed to resolve the issue of plausibility of 64 the claimed medical use which had been raised by the board for the first time in its communication dated 8 October 2021. 2.4 The board accepts the appellant's arguments as cogent reasons justify-ing exceptional circumstances within the meaning of Article 13
(2)RPBA 2020. As a consequence, the board decided to admit documents D43, D44 and the appellant's submissions dated 7 January 2022 into the proceedings. 3. Admittance of the third-party observations received on 27 April 2021, 2 November 2021, 17 November 2021, 9 December 2021, 23 December 2021 and 18 January 2022 within the meaning of Article 115 EPC 3.1 All of these submissions have been received after the filing of the state-ment of grounds of appeal. 3.2 With this statement, the appellant had requested as the main request that the decision under appeal be set aside and that a patent be granted on the basis of the single claim of the main request underlying the impugned decision. 3.3 The board notes that this claim request had already been filed on 18 November 2019, i.e. almost one year before oral proceedings took place before the examining division. 3.4 In view of the foregoing, the board considers that the third-party observations received on 27 April 2021, 2 November 2021, 17 November 2021, 9 December 2021, 23 December 2021 and 18 January 2022 could and should have been filed during the examination proceedings. As a consequence, the board decided not to take these observations into account. Substantive issues – Main request … 5. Sufficiency of disclosure of the claimed invention (Article 83 EPC) … 5.3 As a consequence, under Article 83 EPC, unless already known to the skilled person at the filing date, the application as filed must disclose the suitability of fingolimod (salt) at an oral daily dose of 0.5 mg for the claimed therapeutic application. Post-published evidence may be taken into account but only to back up the findings in the application as filed and not to establish sufficiency of disclosure on its own. Fingolimod in the context of MS 65 5.4 In the case at hand, the appellant submitted that the following findings on fingolimod were disclosed in the prior art. (
  1. a)The lowest effective dose of fingolimod reported in animal models of EAE was 0.1 mg/kg/day p.o. (see document D14, page 17, left-hand col-umn, last paragraph, first sentence). (
  2. b)From these models, a threshold of about 70% depletion of peripheral lymphocytes was believed to be required to see any efficacy (see docu-ment D28, paragraph bridging pages 118 and 119). (
  3. c)The claimed dose of 0.5 mg of fingolimod had been shown not to meet this threshold in stable transplant patients (see document D27, Figure 1) and acute transplant patients (see document D26, Figure 7A) (
  4. d)Pharmacokinetic and pharmacodynamic outcomes following single- or multiple-dose administration of fingolimod in transplantation patients could be extrapolated to patients with MS (see document D23, page 162, right-hand column, second full paragraph). 5.5 On the basis of these facts, the board concludes that the prior art does not support the suitability of the claimed dosage regimen for the claimed therapeutic application. The disclosure of the invention 5.6 However, in the case at hand the information presented in the applica-tion as filed is sufficient by itself to support the suitability of the claimed dosage regimen of fingolimod for the claimed therapeutic application un-der the aspect of sufficiency of disclosure. In other words, the information provided in the application as filed makes it at least plausible that the dosage regimen of fingolimod (salt) recited in claim 1 constitutes an effec-tive therapy of RRMS. As a consequence, the outcome of referral G 2/21, currently pending before the Enlarged Board of Appeal (see also OJ EPO 2021, A102), is not decisive for the decision in the present case. The board was thus able to decide the present case without having to wait for the out-come of this referral first. 5.7 The reasons for acknowledging initial plausibility of the claimed medi-cal use are as follows. … 66 5.18 As a consequence, the board is satisfied that the EAE model used in the EAE study is suitable for studying the therapeutic benefit of fingolimod in human patients with RRMS. … 5.24 The board does not have any reason to doubt Professor Vidne 1's explanations. The board therefore accepts as plausible that a daily oral dose of about 0.042 mg/kg of fingolimod hydrochloride will give rise to the same technical effects as those reported in the application with a weekly oral dose of 0.3 mg/kg of fingolimod hydrochloride, i.e. full blocking of disease-associated neo-angiogenesis and complete inhibition of the relapse phases. … 5.26 The board finds the appellant's line of reasoning convincing. 5.26.1 As set out in point 4.2 above, document D10 discloses the therapeutic efficacy of fingolimod at a daily oral dose of 1.25 mg in human patients with RRMS. Document D14 (see page 17, left-hand column, last paragraph, first sentence), in turn, teaches that fingolimod at 0.1 mg/kg p.o. or higher doses almost completely prevented paralysis in Lewis rats afflicted with EAE. 5.26.2 The board is not aware of any prior-art teaching that oral doses of fingolimod lower than 1.25 mg/day and lower than 0.1 mg/kg/day are ben-eficial in treating RRMS patients and EAE rats respectively. In the absence of such teaching, the board accepts the appellant's submission that the aforementioned fingolimod doses of 1.25 mg/day and 0.1 mg/kg/day are species equivalents in terms of their technical effects of blocking disease-as-sociated neo-angiogenesis and inhibiting the relapse phases. In light of this equivalence, the board's positive finding on plausibility set out in point 5.24 above in respect of a 58% lower EAE rat dose of about 0.042 mg/kg of fingolimod equally applies to a 60% lower dose of 0.5 mg/day in human RRMS patients. 5.27 As a consequence, the board judges the experimental data reported in the application in the context of the EAE study to be sufficient for establishing the initial plausibility of the therapeutic benefit of the claimed dosage regimen in human RRMS patients. Initial plausibility being given, the out-come of referral G 2/21, currently pending before the Enlarged Board of Appeal, is not decisive for the decision in the present case (see point 5.6 above) … 7. Inventive step (Article 56 EPC) 67 The closest prior art 7.1 In agreement with the appellant, the board considers document D10's disclosure concerning the successful phase II trial on RRMS patients treated with fingolimod at an oral daily dose of 1.25 mg (see point 6.2(
  5. a)above) to be a suitable starting point for assessing inventive step of the claimed sub-ject-matter. 7.2 The subject-matter of claim 1 differs from this disclosure in that fin-golimod is administered at an oral daily dose of 0.5 mg. Objective technical problem and solution 7.3 To formulate the objective technical problem, it is necessary to establish the technical effect(
  6. s)achieved by the aforementioned distinguishing fea-ture. 7.4 For the reasons given above regarding sufficiency of disclosure, the board is satisfied that the claimed fingolimod dosage regimen provides an effective therapeutic treatment of RRMS. 7.5 Hence, starting from the closest prior art defined above, the objective technical problem is the provision of further means to effectively treat RRMS. 7.6 The proposed solution to this problem is the fingolimod dosage regi-men recited in claim 1. 7.7 The appellant defined the objective technical problem differently (see point XI. above, under the heading "Inventive step"). However, in view of the outcome of these proceedings, this point does not need further consid-eration. Obviousness 7.8 As set out in point 6.2 above, document D10's disclosure of the success-ful phase II trial with an oral daily dose of 1.25 mg fingolimod is immedi-ately followed by the announcement of a phase III study using oral daily dose of 0.5 mg and 1.25 mg of fingolimod. 7.9 In the board's judgement, this announcement would have provided the skilled person with a reasonable expectation of solving the objective techni-cal problem with fingolimod at an oral daily dose of 0.5 mg, unless a teach- 68 ing in the prior art would have dissuaded the skilled person from consider-ing this dosage regimen as a solution to the technical problem posed. 7.10 In the case at hand, the board is satisfied that the prior art teaches away from the claimed invention. As set out in point 5.4(
  7. b)above, the skilled person would have inferred from document D28 that a threshold of lymphocyte reduction of at least 70% was required for a therapeutic treat-ment of RRMS. Moreover, the board agrees with the appellant's position that the teachings of documents D26 and D27 taken in combination with the teaching of document D23 would have led the skilled person to con-clude that an oral daily dose of 0.5 mg fingolimod would be insufficient for reaching this threshold and hence would not be therapeutically effective in the treatment of RRMS (see points 5.4(
  8. c)and 5.4(
  9. d)above). 7.11 In light of these particular circumstances, the board finds that the announcement of the phase III trial in document D10 would have given the skilled person hope of success but not a reasonable expectation of it. 7.12 A mere hope of success does not suffice as motivation to render the claimed subject-matter obvious. As a consequence, the subject-matter of claim 1 involves an inventive step starting from D10's disclosure of the successful phase II trial with an oral daily dose of 1.25 mg fingolimod. 7.13 For the sake of completeness, the board observes that the same considerations apply when starting the assessment of inventive step from the announcement of the phase III trial in document D10 taken as the closest prior art (see point 6.2 above). …” Efter at EPO’s Technical Boards of Appeal hjemviste sagen til Examining Division, udstedte Examining Division den 18. august 2022 en ”intention to grant” -meddelelse, hvoraf fremgår blandt andet: “… 1. Intention to grant You are informed that the examining division intends to grant a European patent on the basis of the above application, with the text and drawings and the related bibliographic data as indicated below. … 1.3 Observations by third parties The third-party observations received on 6th November 2017, 8th May 2018, 29th November 2018, 31st July 2019, 14th August 2019, 5th Septem-ber 2019, 29th November 2019,14th January 2020,12th August 2020, 28th 69 October 2020, 3rd November 2020, 27th April 2021, 2nd November 2021, 17th November 2021, 9th December 2021, 23rd December 2021,18th January 2022,14th June 2022, 22nd June 2022; 28th July 2022; 29th July 2022 were examined but found not to be relevant. …” Meddelelsen blev fulgt op af en ”decision to grant” -meddelelse den 15. september 2022. Udbud vedrørende fingolimod Af et udbud af 2. marts 2022 fra Amgros I/S fremgår, at dette vedrører fingolimod med doseringen 0,5 mg, og at varigheden løber fra 1. maj 2022 til 31. august 2022. Den anslåede værdi er opgjort til 93.300.000 kr. ekskl. moms. Eksperterklæringer I sagen er der fremlagt følgende eksperterklæringer: - Erklæring af Dato 3 2020 udarbejdet af professor Person 8 - Erklæring af Dato 5 2020 udarbejdet af professor Vidne 2 (I) - Erklæring af Dato 6 2021 udarbejdet af professor Vidne 1 (I) - Erklæring af Dato 7 2022 udarbejdet af Person 9 - Erklæring af Dato 8 2022 udarbejdet af Person 10 - Erklæring af Dato 8 2022 udarbejdet af professor Vidne 3 - Erklæring af Dato 9 2022 udarbejdet af professor Vidne 1 (II) - Erklæring af Dato 10 2022 udarbejdet af professor emeritus Vidne 4 (I) - Erklæring af Dato 10 2022 udarbejdet af professor Vidne 1 (III) - Erklæring af Dato 10 2022 udarbejdet af professor Vidne 2 (II) - Erklæring af Dato 11 2022 udarbejdet af professor Vidne 1 (IV) - Erklæring af Dato 1 2022 udarbejdet af professor emeritus Vidne 4 (II) - Erklæring af Dato 12 2023 udarbejdet af professor Vidne 1 (V) Forklaringer Vidne 2, Vidne 4, Vidne 1 og Vidne 3 har under hovedforhandlingen afgivet forklaring. Vidne 2 har forklaret blandt andet, at han er professor i neurologi, og at han har arbejdet med multipel sklerose i 30 år. Han bruger 80 % af sin tid med forskning inden for området og de resterende 20 % med behandling af patienter. 70 Han har udarbejdet to erklæringer, der er relevante for sagen, og han kan vedstå indholdet af disse. I hans erklæring af Dato 5 2020, afsnit 65, skal henvisningen til ”Journal of Immunology” rettelig være ”Journal of Neuroimmunology” . Fagmanden i denne sag er en neurolog med ekspertise i multipel sklerose i kliniske studier samt en klinisk farmakolog. Som en del af fagmanden er der også et bredere bagvedliggende team med personer, der har kompetencer inden for udvikling af stoffer. Multipel sklerose er i hovedtræk en autoimmun sygdom, der skaber inflammation og deraf følgende læsioner, som over tid medfører, at patienten bliver handicappet. Der findes forskellige typer af multipel sklerose, blandt andet ”relapsing remitting multiple sclerosis” eller ”RRMS” , hvor der kommer løbende attaks. 85-90 % af patienterne har denne type af sygdommen. Der findes også en progressiv type, som 10-15 % af patienterne lider af. Den medicinske behand-ling afhænger af, hvilken type der er tale om. Til behandling af RRMS var der på prioritetstidspunktet to injicerbare behandlinger. Der var i alt 4 stoffer på markedet. I USA kom der nyt stof, som senere blev trukket tilbage på grund af bivirkninger. Problemet var, at behandlingerne ikke var særligt effektive. De kunne reducere attakkerne med omring én tredjedel. Da der var tale om injicerbar behandling, var der nogle vanskeligheder, blandt andet for patienter med nålefobi. Patienternes vedholdenhed var et stort problem. Derudover var der mange neurologer, som slet ikke troede på virkningen af de eksisterende behandlinger. Fingolimod er en sphingosin-1-fosfat-receptor-modulator. Stoffet binder sig til en klasse af receptorer, som kaldes S1P-receptorer. Når det sker, stimuleres receptorerne, hvilket medfører, at receptoren på cellen bliver internaliseret. Fingolimod indebærer, at lymfocytter bliver holdt tilbage i lymfeknuder, hvilket betyder, at de ikke cirkulerer i blodbanen. Det er en selektiv blokade, da ikke samtlige lymfocytter i kroppen bliver holdt tilbage i lymfeknuderne. Reduktion i lymfocytter er baseret på dette en passende biomarkør for at måle effekten af fingolimod. Fingolimod virker ikke på den progressive del af multipel sklerose. Anvendelsen af EAE-dyremodeller opstod i 1920’erne med udviklingen af vaccinen mod rabies, og sådanne modeller blev også anvendt på prioritetstidspunktet til udvikling af behandlinger mod multipel sklerose. Man giver dyr vacciner, som giver dem en inflammatorisk sygdom i nervesystemet. Det er en 71 standard dyremodel for undersøgelse af inflammation i nervesystemet i kontekst af multipel sklerose. Man kan også lave EAE-modeller, som illustrerer RRMS, altså attakvis multipel sklerose, hvilket man også kan gøre med den såkaldte Lewis rotte. Han er uenig i Vidne 3's udsagn om, at der ikke kan drages endelige konklusioner fra studier i EAE-dyremodeller til behandlingen af multipel sklerose. Artiklen af blandt andre Budde fra 2002 er et fase 1-studie. Der testes forskellige doser FTY720, der er det samme som fingolimod, i mennesker, der er blevet ny-retransplanteret. Der testes en enkeltdosis fra 0,25 til 3,5 mg i 20 patienter. Når der er tale om et studie, hvor der alene gives en enkelt dosis, giver det i virke-ligheden alene nogle indledende data om sikkerheden af stoffet. Det vil blive trumfet af et studie, hvor der gives flere doser. Artiklen af blandt andre Budde 2003 er også et studie med en enkeltdosis. Af fi-gur 1 kan man se, hvilke doser der er testet, og han mener, at man heraf kan ud-lede en dosisresponskurve. Han er derfor ikke enig i det, som Person 9 har an-ført herom i sin erklæring. Artiklen af blandt andre Kahan fra 2003 beskriver et studie, hvor der gives forskellige dosisstørrelser, men hvor de også gives flere gange, nemlig én gang dagligt. Der testes på nyretransplanterede patienter. De har testet i 28 dage og dernæst observeret, hvordan stoffet udskilles af kroppen og altså hvordan lymfocyttallet stiger igen. Figur 1 viser antallet af lymfocytter i procent relativt til en baseline. Årsagen til, at man bruger en baseline, er, at lymfocyttallet blandt mennesker generelt er meget variabelt, og det tages der højde for, hvis denne metode bruges. Hvis man sammenlignede over for placebo-gruppen, ville reduktionen i procent stige en smule. Man kan se, at der er en dosisrespons. Resultaterne for 1,0 mg, 2,5 mg og 5,0 mg skiller sig ud. De lavere doser, 0,125 mg, 0,25 mg og 0,5 mg viser en reduktion på 45-50 %, og de højere doser viser en effekt tæt på 80 %. Variabiliteten på de lavere doser er større, og de højere doser viser mindre variabilitet. Man vil gerne finde en dosis, som en stor del af befolkningen får en effekt af, og det vil man bedre kunne opnå med mindre variabilitet. Placebo-gruppen er i hele perioden over baseline, hvilket kan skyldes placebopræparatet, som dog ikke burde påvirke lymfocyttallet. Dag 28 er ”steady state” . Den procentvise re-duktion viser et gennemsnit. De laveste doser vil ligge i intervallet 35-70 %. Nogle patienter i studiet fik andre præparater, før studiet gik i gang. Det fremgår, at de blandt andet fik azathioprin, som stoppede 14 dage før første dosis. 72 Nogle af disse komponenter påvirker også lymfocyttallet. De stoppede 14 dage før for at få lymfocyttallet til at stige, inden studiet skulle gå i gang. Artiklen af blandt andre Park fra 2005 undersøger også forskellige doser fingoli-mod i nyretransplanterede patienter. Man tester doser fra 0,5 mg til 2 mg. Figur 6 anvender det absolutte lymfocyttal, og man ser, hvad der sker med tallet ved anvendelse af de forskellige doser. Figur 7 viser en procentreduktion. Her viser man således reduktionen relativt til en baseline. Forskellen er ret klar. Der er meget variabilitet i figur 6, men i figur 7 får man en mere ren kurve, da man ta-ger udgangspunkt i en baseline. Han vil ligesom forfatterne af artiklen derfor foretrække at anvende figur 7 i vurderingen af virkningen af fingolimod, da man herved får variabiliteten ud af billedet, hvilket giver et mere præcist billede af, hvilken dosis man bør vælge. Figur 7 viser samtidig en variabilitet i resultaterne, der repræsenteres ved prikkerne ud fra de forskellige doser. Gruppen, der får 0,5 mg, får en reduktion på omkring 40-45 %, og han er derfor ikke enig i Vidne 3's udsagn om, at fagmanden ville forvente, at denne dosis ville give en signifikant reduktion i lymfocyttallet. Artiklen af blandt andre Webb fra 2004 vedrører et studie i en EAE-dyremodel og er ikke en review-artikel. Angivelsen i artiklen af en grænseværdi på 70 % reduktion i lymfocytter vil efter hans opfattelse også være relevant for fagmanden at vide i behandlingen af multipel sklerose, uanset at der er tale om en EAE-dyremodel. Der fremgår et forbehold i konklusionen herom. Reduktionen på 70 % er beregnet i forhold til ”PLP control vehicle” . Artiklen af Thomson fra 2006 er en review-artikel. Ud fra resultaterne af studierne vedrørende nyretransplanterede patienter ville man gå ud fra, at patienter med multipel sklerose ville få samme effekt i forhold til reduktionen af lymfocyttal. Artiklen af blandt andre Chiba fra 2006 beskriver, at den laveste effektive dosis i en EAE-model er 1,0 mg. Det fremgår, at der er en grænse på 0,1 mg pr. kg som skal bruges for at hæmme lammelsen af dyrene. Dette var den laveste kendte effektive dosis i en dyremodel på prioritetstidspunktet. Fagmanden ville også undersøge relevante studier i dyremodeller, selv om der foreligger resultater fra et fase 2-studie, da data fra studierne i de transplanterede patienter skaber forbindelsen mellem dosis og en reduktion i lymfocyttal, og dyreforsøgene giver forbindelsen mellem lymfocyttallet og den kliniske score. Man ville som fagmand inkludere al information. Uanset resultaterne af 1,25 og 5 mg i fase 2-studiet ville man således også kigge på dyremodeller med henblik på at vurdere, hvilken dosis der skulle testes fremadrettet. 73 Angivelsen af datoen 21. juni 2005 i præsentationen, slide 2, fra Novartis er nok en henvisning til det tidspunkt, hvorfra man ikke har taget yderligere data med fra studiet. Slide 11 viser 3 grupper: placebo, 1,25 mg og 5 mg. Placebogruppen vil efter 6 måneder blive omfordelt til enten 1,25 mg eller 5 mg, hvor der vil blive testet i yderligere 6 måneder. Resultaterne i præsentationen vil være interessante for fagmanden, men de vedrører alene de indledende 6 måneder, hvor Novartis’ pressemeddelelsen også omfatter den yderligere fase på 12 måneder. Pressemeddelelsen giver derfor mere information, da den giver indtryk af, hvad der sker med testpersonerne over længere tid. Angivelsen af test af 0,5 mg i fase 3 på slide 26 i præsentationen giver ham ikke nogen indikation af, hvordan fase 3-forsøget ville se ud. Baseret på præsentationen og pressemeddelelse ville han ikke vide, om 0,5 mg ville være lige så effektiv som dosen på 1,25 mg eller i øvrigt ville have en klinisk effekt. Baseret på de øvrige data ville han tro, at en dosis på 0,5 mg ikke ville have en klinisk effekt. Forsøgene med nyretransplanterede patienter viste med en dosis på 0,5 mg en reduktion i lymfocyttallet på 45 %, som ligger under de 70 %, som er nødvendig. Dosen på 0,5 mg tog man formentlig med i fase 3-forsøget, fordi de regulatoriske myndigheder gerne ville have påvist en dosisresponskurve. Det skete derfor nok på baggrund af et forslag fra de regulatoriske myndigheder. Det ville ikke være uetisk at tage en sådan dosis med i et fase 3-forsøg. Man vil gerne finde den laveste effektive dosis, men det er ikke et krav, at man finder den. Man kan godt tage subterapeutiske doser med i fase 3-forsøg, og det har han set før. Abstractet fra Kovarik fra 2005, hvor der sker omtale af eventuelle lavere doser, ændrer ikke på hans opfattelse, da de lavere doser ikke er blevet testet på det pågældende tidspunkt. Vidne 4 har forklaret blandt andet, at han er neurolog, og at han har beskæftiget sig med multipel sklerose siden 1981. Han har været med til at starte Sclerosecentret på Rigshospitalet, og han har været leder heraf indtil 2016, hvorefter han har arbejdet som senior overlæge. Han har været professor siden 1986 og er i dag professor emeritus. Han har udarbejdet to erklæringer med relevans for sagen, og han kan vedstå indholdet af disse. Han ville have besvaret spørgsmålene på samme måde, hvis han var blevet udpeget som skønsmand i sagen. 74 Han er enig i Vidne 2's angivelse af, hvem der er fagmanden. Specia-listen i multipel sklerose er en person, der følger med i, hvad der foregår og dermed også læser videnskabelig litteratur. Udviklingen af lægemidler består typisk af 3 faser. I fase 1 gives lægemidlet til raske frivillige. I fase 2 forsøger man at vise en effekt på en sygdom, man ønsker at behandle, og disse forsøg varer typisk 6 måneder og involverer forskellige doser. I fase 3 vil man ofte have én eller to doser, som gennemprøves, og der vil typisk være tale om et 2-årigt forsøg. I de fase 3-forsøg, som han har været involveret i, har 9 ud af 20 haft et positivt udfald. Før prioritetstidspunktet fandtes der to behandlinger af multipel sklerose, som viste en effekt på ca. 30 %. Fingolimod havde man ikke erfaring med i 2006. Der var et abstract, der indikerede en effekt på ca. 50 %, hvilket var væsentligt bedre end det hidtil kendte. I dag klassificeres fingolimod som en højeffektiv behandling. Det indebærer, at man er villig til at gå på kompromis med bivirkninger som følge af stoffets effekt på behandlingen af sygdommen. Uanset at fingolimod også i 2006 ikke viste særlige bivirkninger, herunder ingen alvorlige bivirkninger, ville man have accepteret en dårligere bivirkningsprofil, da der er tale om en oral og ikke injicerbar behandling. Før 2006 vidste man en del om fingolimods virkningsmekanisme. For at lymfocytterne kan komme fra lymfeknuderne ud i blodet skal lymfocytterne bruge en S1P-receptor. Når fingolimod binder sig til lymfocytten, sker der en degradering af receptoren, og derfor kan lymfocytterne ikke bevæge sig fra knuderne til blodet. Man vidste dog ikke, at der skete en reorganisering af undergrupperne af lymfocytter, når man behandler med fingolimod. Der er en gruppe af lymfocytterne, der ikke tilbageholdes i lymfeknuderne ved anvendelse af fingolimod. Man bevarer dermed en immunrespons uanset lave koncentrationer af lymfocytter i blodet. Før prioritetstidspunktet forelå der dyreforsøg, som viste en reduktion af lymfocyttal ved anvendelse af fingolimod. Man skal fortolke disse dyreforsøg forsigtigt, fordi modellen, der bruges for multipel sklerose, ikke er det samme som multipel sklerose i mennesker. 75 Han mener ikke, at en EAE-dyremodel kan afgøre, om en bestemt dosis vil have en klinisk effekt hos mennesker. Det så dog ud til, at man fik en effekt på EAE, hvis man havde en reduktion af lymfocyttallet på ca. 70 %. For mennesker var der på tidspunktet lavet forsøg med nyretransplanterede patienter, hvor man havde set på både enkeltdoser og vedvarende doser i én til flere måneder. De forsøg viste, at doser på 2,5 mg ville give en reduktion af lymfocyttallet på over 70 %. 1,0 mg gav også i nogle af forsøgene en reduktion i nærheden af 70 %, mens 0,5 og 0,25 mg ikke gav reduktion på mere end 50 %, og i øvrigt med en større spredning, som illustrerer, at ikke alle opnåede denne reduktion, der udgjorde gennemsnittet. Leukocytter er hvide blodlegemer. Lymfocytter er en undergruppe heraf. Tallet er variabelt i mennesker, men ligger mellem 800 og ca. 4400. Hvis man undersøger det absolutte lymfocyttal, tages der udgangspunkt i den faktiske forskel mellem de to tal, f.eks. 3000 og 1500. Den relative forskel ville da udgøre 50 %. De absolutte tal kan man bruge til at se på nogle af bivirkningerne ved behandlingen. Lave lymfocyttal er forbundet med en risiko for at udvikle helvedesild. Den relative reduktion bruges til at beskrive behandlingseffekten. Den behandling, der er beskrevet i artiklen af blandt andre Cook fra 1987, udgør en bestråling af vævet, det vil sige ikke blot lymfeknuderne. Behandlingen interfererer med DNA-syntesen, hvilket indebærer, at lymfocytterne dør. Man kan ikke sammenligne et fald i lymfocyttallet i denne behandling med en behandling, som sker som følge af fingolimod, da fingolimod holder lymfocytterne tilbage i lymfeknuderne. Artiklen vedrører desuden kronisk progressiv multipel sklerose og ikke attakvis multipel sklerose, det vil sige RRMS, og man kan ikke uden videre overføre behandlingerne mellem de to typer. Azathioprin er udviklet til behandling af leukæmi. Virkningsmekanismen er, at der sker et celledrab. Det har aldrig været godkendt til behandling af multipel sklerose, og denne type behandling kan heller ikke sammenlignes med behandlingsmekanismen for fingolimod. Azathioprin reducerer dog lymfocyttallet. Artiklen af blandt andre Budde fra 2003 lægger han ikke så meget vægt på, da der er tale om et studie med en enkeltdosis. Man kan ikke sammenligne effekten ved en enkeltdosis med den effekt, som man opnår over tid med flere doser. Der går et stykke tid, før man har en ”steady state” . Studiet kan derfor alene bruges til at konstatere, at der er en effekt, og at stoffet tilsyneladende kan tåles. I artiklen af blandt andre Kahan fra 2003 kan man af figur 1 se, at behandlingen sker over 28 dage med flere forskellige doser til patienter, der er nyretransplan- 76 teret. Ved en høj dosis fremgår, at der sker en hurtig reduktion i lymfocyttallet i løbet af fire dage, og at der ved de lavere doser sker en langsommere reduktion, som også sker til et mindre niveau. Der er stor fluktuation i behandlingen ved de lavere doser, hvilket formentlig er udtryk for, at ikke alle patienter har det lymfocyttal, som gennemsnittet reflekterer. De lavere doser viser ikke en reduktion på 70 %. Artiklen fra blandt andre Park fra 2005 kigger både på farmakokinetik og farmakodynamik. Figur 4 er bygget op på lidt samme måde som den førnævnte fra Kahan. De højere doser viser en hurtigere effekt og lavere doser en større fluktuation. Figur 6 viser de absolutte lymfocyttal. Plateauet nås ved ca. 1,0 mg. Af figur 7 fremgår, at hvis man vil have en reduktion på omkring 70 %, kræves der en dosis på ca. 1,7 mg. Spredningen er desuden mindre ved den større dosis på 2,5 mg i forhold til de mindre. For at være sikker ville fagmanden anvende dosen på 2,5 mg for at få en tilstrækkelig effekt. Muligvis ville han også anvende 1,0 mg. Før prioritetstidspunktet blev EAE-dyremodellen anvendt, og den blev brugt sådan, at hvis man havde et stof, som havde effekt i dyremodellen, så gik man ud fra, at der var en chance for

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