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sø- & handelsrettens dombog

- iiw udskrift af sø- & handelsrettens dombog ____________ kendelse afsagt den 15. juni 2018 a-49-17 1) eli lilly and company (advokat mikkel vittrup) 2) icos corporation (advokat mikkel vittrup) 3) eli lilly danmark a/s (advokat mikkel vittrup) mod sandoz a/s (advokat klaus ewald madsen) sagens baggrund og parternes påstande denne sag om midlertidigt forbud i henhold til retsplejelovens kapitel 40 vedrører, hvorvidt sandoz a/s ved fremstilling, udbud, salg og anvendelse af det generiske lægemiddel ”tada- lafil sandoz” i tabletter med styrkerne 2,5 mg, 5 mg og 10 mg tadalafil krænker eli lilly and company, icos corporation og eli lilly danmark a/s´ rettigheder i henhold til det danske patent nr. dk/ep 1173 181 (herefter benævnt stridspatentet). -2- sagens tvist angår gyldigheden af ovennævnte patent. sandoz a/s gør gældende, at patentet er ugyldigt på grund af manglende opfindelseshøjde. det er ubestridt, at ”tadalafil sandoz” med styrkerne 2,5 mg og 5 mg udgør en krænkelse, såfremt patentet er gyldigt. eli lilly and company, icos corporation og eli lilly danmark a/s har nedlagt følgende på- stande: påstand 1: det forbydes sandoz a/s i danmark at fremstille, udbyde, bringe i omsætning, markedsføre eller anvende lægemidlet tadalafil "sandoz" i tabletter med styrkerne 2,5 mg tadalafil og 5 mg tadalafil, jf. dansk specialitetsnummer 30004, eller importere eller besidde det med et så- dant formål, så længe dansk patent nr. dk/ep 1 173 181 er i kraft. påstand 2: det påbydes sandoz a/s at tilbagekalde allerede skete leverancer af lægemidlet tadalafil "sandoz" i tabletter med styrkerne 2,5 mg tadalafil og 5 mg tadalafil, jf. dansk specialitets- nummer 30004, fra samtlige grossister og apoteker, hvortil levering er foretaget af sandoz a/s. påstand 3: det påbydes sandoz a/s straks at afregistere priserne for tadalafil "sandoz" i tabletter med styrkerne 2,5 mg tadalafil og 5 mg tadalafil i det danske prisregister (www.medicinpriser.dk). påstand 4: det forbydes sandoz a/s i danmark at levere eller tilbyde lægemidlet tadalafil "sandoz" i tabletter med styrken 10 mg tadalafil, jf. dansk specialitetsnummer 30004, når det markeds- -3- føres med en indlægsseddel indeholdende oplysning om anvendelse af tadalafil i enhedsdo- sering på 2,5 mg og/eller 5 mg, så længe dansk patent nr. dk/ep 1 173 181 er i kraft. påstand 5: det påbydes sandoz a/s at tilbagekalde allerede skete leverancer af lægemidlet tadalafil "sandoz" i tabletter med styrken 10 mg tadalafil, jf. dansk specialitetsnummer 30004, fra samtlige grossister og apoteker, hvortil levering er foretaget af sandoz a/s, når disse læge- midler markedsføres med en indlægsseddel indeholdende oplysning om anvendelse af tada- lafil i enhedsdosering på 2,5 mg og/eller 5 mg. forbud og påbud påstås principalt nedlagt uden sikkerhedsstillelse, subsidiært mod en af retten fastsat sikkerhed. sandoz a/s har nedlagt følgende påstande: principalt: at begæringen om nedlæggelse af forbud og påbud (påstand 1-5) nægtes fremme. subsidiært: at begæringen om nedlæggelse af forbud og påbud (påstand 4 og 5) nægtes fremme. mere subsidiært: at begæringen om forbud og påbud fremmes mod tilvejebringelse af en af sø- og handelsrettens fastsat sikkerhed. oplysningerne i sagen sagens parter og de omhandlede lægemidler icos corporation og eli lilly denmark a/s er begge datterselskaber af eli lilly and com- pany, der er en amerikansk farmaceutisk virksomhed. icos corporation er registreret inde- haver af stridspatentet. det danske datterselskab eli lilly denmark a/s står for -4- markedsføringen og salget af lægemidlet cialis i danmark. selskaberne benævnes herefter samlet (eli lilly) sandoz a/s (herefter benævnt sandoz) er producent af generiske lægemidler og indgår som datterselskab i den multinationale schweiziske novartis-koncern. sandoz opnåede den 9. de- cember 2016 markedsføringstilladelse for lægemidlet ”tadalafil sandoz”. tadalafil er et aktivstof, som er blevet godkendt til behandling af blandt andet erektil dys- funktion. stoffet tilhører en gruppe af lægemidler, som kaldes phosphordiesterase type- hæmmere (pde 5-hæmmere). stoffet blev oprindeligt udviklet af lægemiddelkoncernen gla- xo group limited, men udviklingen blev senere overtaget af icos og eli lilly. tadalafil var beskyttet som en ny kemisk forbindelse ved patent nr. ep 0740 668 (daugan i). patentskriftet beskriver en række sygdomme, men det var ikke rettet mod behandling af erektil dysfunkti- on. patentet udløb den 18. januar 2015, og det supplerende beskyttelsescertifikat nr. cr 2003 00008 for ”tadalafil og fysiologiske acceptable salte deraf”, udløb den 14. november 2017. lægemidlet ”cialis” indeholder aktivstoffet tadalafil. lægemidlet markedsføres i fire tablets- tyrker hhv. 2,5 mg, 5 mg, 10 mg og 20 mg. af et produktresumé for ”cialis” fremgår blandt andet, at lægemidlet anvendes til behandling af erektil dysfunktion hos voksne mænd, og at seksuel stimulation er nødvendig for, at tadalafil kan virke. om dosering og administration fremgår blandt andet: ”den anbefalede dosis af cialis er generelt 10 mg, som tages før forventet seksuel akti- vitet, enten med eller uden mad. hos de patienter, hvor tadalafil 10 mg ikke giver til- strækkelig effekt, kan 20 mg forsøges. tabletten tages mindst 30 minutter før seksuel ak- tivitet. den maksimale doseringshyppighed er en gang daglig. tadalafil 10 og 20 mg er tiltænkt brug før forventet seksuel aktivitet og anbefales ikke til vedvarende daglig brug. hos patienter, som forventer et hyppigt brug af cialis (mindst 2 gange ugentligt), kan en én gang daglig dosering med de laveste cialis-doser anses for at være hensigtsmæs- sig, baseret på patientens og lægens vurdering. den anbefalede dosis til disse patienter er 5 mg dagligt, indtaget på ca. samme tidspunkt hver dag…” hver tabletstyrke har sin egen indlægsseddel, som også har været fremlagt under sagen. -5- lægemidlet ”tadalafil sandoz” er en generisk version af ”cialis”. lægemidlet indeholder ak- tivstoffet tadalafil og markedsføres i styrkerne 2,5 mg, 5, mg, 10 mg og 20 mg. der har under sagen været fremlagt et produktresumé for ”tadalafil sandoz” indeholdende tilsvarende op- lysninger som ovenfor nævnt vedrørende ”cialis”. endvidere har der under sagen været fremlagt en fælles indlægsseddel for de fire tabletstyrker. det er oplyst, at ”viagra” på stridspatentets prioritetsdato var et velkendt lægemiddel til be- handling af erektil dysfunktion hos mænd. lægemidlet indeholder aktivstoffet sildenafil, som også er en pde 5-hæmmer. ”viagra” markedsføres i styrkerne 25 mg, 50 mg og 100 mg, og dette var også tilfældet på prioritetstidspunktet. der har under sagen været fremlagt et pro- duktresumé for ”viagra”. stridspatentet ep 1173 181 b1 blev udstedt den 15. oktober 2003 med prioritet fra den 30. april 1999. den danske udgave blev første gang offentliggjort den 16. februar 2014 som dk/ep 1173 181 t3 (herefter dk/ep 181). efter anmodning fra eli lilly blev kravene den 27. april 2015 begrænset, således at enheds- dosen blev reduceret fra 1 til 20 mg tadalafil til 1 til 5 mg tadalafil. på den baggrund blev en ændret version offentliggjort som dk/ep 1173181 t6. følgende fremgår bl.a. af dk/ep 181: ”… -6- -7- -8- -9- - 10 - - 11 - - 12 - - 13 - - 14 - - 15 - - 16 - - 17 - - 18 - - 19 - - 20 - - 21 - - 22 - - 23 - - 24 - - 25 - - 26 - - 27 - - 28 - - 29 - - 30 - - 31 - - 32 - - 33 - - 34 - punkt 85 - 87 i dk/ep 1173181 t6 har følgende indhold: ”… - 35 - …” - 36 - de begrænsede patentkrav i stridspantet fremgår af dk/ep 1173181 t6 og har følgende ord- lyd: ”… - 37 - kendt viden daugan ii - 38 - sandoz gør overordnet gældende, at stridspatentet er ugyldigt på grund af manglende op- findelseshøjde i forhold til pct patentansøgningen wo 97/03675 (herefter benævnt daugan ii). parterne er enige om, at daugan ii er den nærmeste kendte teknik. patentskriftet blev publiceret internationalt den 6. februar 1997 med prioritet fra den 14. juli 1995 og har blandt andet følgende indhold: ”… - 39 - - 40 - - 41 - - 42 - - 43 - - 44 - - 45 - - 46 - - 47 - - 48 - - 49 - - 50 - - 51 - - 52 - - 53 - - 54 - - 55 - - 56 - - 57 - - 58 - - 59 - dokumenter vedrørende fagmandens viden om sildenafil til illustration af fagmandens viden om sildenafil på prioritetstidspunktet er der fremlagt en række artikler vedrørende sildenafil, der blev publiceret forud for prioritetsdagen for eli lil- lys patent. af en international artikel om impotens fra 1996 af blandt andre mitradev boolell: ”sildenafil: an orally active type 5 cyclic gmp-specific phosphodiesterase inhibitor for the treatment of peniel erec- tile dysfunction” fremgår blandt andet: ”… clinical study - 60 - the efficacy of sildenafil on penile erectile activity was evaluated in 12 patients who had a history of penile erectile dysfunction of at least six months duration. on clinical evaluation there was no obvious organic cause for penile erectile dys- function. patients were excluded from the study if tbore was evidence of neuro- vascular disease on aical evaluation, diabetes, drug or alcohol se, or other estab- lished causes for their penile erectile dysfunction. the study was a double-blind, placebocontrolled, randomised, four-way crosso- ver design. a period of at least three days was allowed between consecutive treatment periods to ensure that there was adequate clearance of sildenafil from the circulation. on each dosing period, patients were admitted to a hospital bed with complete privacy. they received a single dose of sildenafil (10, 25 or 50

  1. mg)or placebo. each dose was followed by visual sexual stimulation (vss) starting 30min post-dose and lasting for two hours. vss was provided by viewing of sex- ually explicit material chosen from a selection of videos and magazines. drug ef- ficacy on penile erectile activity was evaluated by measurement of penile rigidity at the base and tip of the penis by penile plethysmography (rigiscan, dacomed corporaion). the study was approved by the local ethics committee. … pharmacokinetics of sildenafil in human volunteers the results from the single-blind escalating single oral dose (studies [i] and [ii] under pharmacokinetic method) demonstrate that sildenaål is rapidly absorbed with maximum observed plasma concentrations occurring within one hour after oral dosing. plasma concentrations decline in a biexponential manner with a mean terminal half life of 3 to 5 h. pharmacokinetic simulations predict signifi- cant accumulation of the drug after repeated once-daily dosing. … … - 61 - … sildenafil demonstrates ideal pharmacokinetics for an oral agent to be taken, as required, prior to sexual activity for the treatment of penile erectile dysfunction. it is rapidly absorbed when administered orally, and has an onset of action of less
  2. c)than one hour. furthermore, the drug has a relatively short plasma half life of approximately 4 h and is not expected to accumulate on repeated single daily administration. in the dose range studied, sildenafil is generally well tolerated and has no significant effects on pulse rate and blood pressure...” en artikel af goldstein og feldman omhandlende et forsøg med sildenafil: ”oral sildenafil (viagra) for the treatment of erectile dysfunction” (goldsteins abstract) er udgivet i british jour- nal of urology i 1997 som abstract 356. af forsøget fremgår blandt andet: ”… - 62 - - 63 - artiklen “the effect of the specific phosphordiesterase (pde) inhibitors on human and rabbit cavern- ous tissue in vitro and in vivo” af blandt andre christian g. stief, blev udgivet i april 1998 i the journal of urology. af denne artikel fremgår blandt andet: ” … conclusion our in vitro and in vivo studies showed a dose-related relaxant response of selective pde-inhibitors on cavernous tissue from men and rabbits. in both approaches, however, a significant species difference was observed regarding the relaxant response of the cav- ernous tissue to the pde-iii inhibitor milrinone. the data presented provide a rationale for the concept of using selective pde inhibitors in the treatment of human erectile dys- function.” artiklen “oral sildenafil in the treatment of erectile dysfunction” af blandt andre dr. irwin gold- stein blev udgivet den 14. maj 1998 i the new england journal of medicine (hereafter gold- stein 1998). af artiklen fremgår blandt andet: “… in two sequential studies, we studied a total of 861 men 18 years of age or older with a clinical diagnosis of erectile dysfunction (as defined previously 1) of six months’ duration or longer at 37 centers in the united states. each man had to be in a stable relationship with a female partner that had begun at least six months earlier. the cause of erectile dys- function was determined from the medical history, physical examination, and other di- agnostic procedures, including a test involving the intracavernosal injection of a vasoac- tive drug (done in 31 percent of the men), a rigiscan test of nocturnal penile tumescence (26 percent), penile duplex ultrasonography (21 percent), and endocrine testing (21 per- cent). on the basis of these evaluations, the men were classified as having organic, psy- chogenic, or mixed erectile dysfunction. of the 861 men studied, 605 (70 percent) were judged to have organic erectile dysfunction, 99 (11 percent) to have psychogenic erectile dysfunction, and 157 (18 percent) to have mixed erectile dysfunction. men were excluded if they had penile anatomical defects, a primary diagnosis of another sexual disorder (e.g., premature ejaculation), spinal cord injury, any major psychiatric disorder not well controlled with treatment, poorly controlled diabetes mellitus, active peptic ulcer disease, a history of alcohol or substance abuse, major hematologic, renal, or hepatic abnormali- ties, or a recent (within the previous six months) stroke or myocardial infarction or if they were receiving nitrate therapy. … after 12 weeks of treatment in the dose-escalation study, the proportions of men taking 25, 50, or 100 mg of sildenafil were 2 percent (4 men), 23 percent (38 men), and 74 percent (121 men), respectively. for the men taking placebo, the corresponding proportions were 0 percent, 5 percent (8 men), and 95 percent (158 men). two hundred twenty-five men who completed the 12-week study were enrolled to receive open-label sildenafil for an additional 32 weeks. - 64 - efficacy in the dose–response study, increasing doses of sildenafil were associated with higher mean scores for the questions of the international index of erectile function assessing frequency of penetration (question 3) and maintenance of erections after sexual penetra- tion (question 4) (p,0.001) (table 2). the mean scores for these questions did not vary ac- cording to the cause of erectile dysfunction. for question 3, the percentage increases in mean score from base line to the end of treatment were 60, 84, and 100 percent for the men who received 25, 50, and 100 mg of sildenafil, respectively, as compared with an in- crease of 5 percent for the men who received placebo. for question 4, the corresponding values were 121, 133, and 130 percent for the men who received 25, 50, and 100 mg of sildenafil, respectively, as compared with 24 percent for those who received placebo. in the dose-escalation study, the mean scores for questions 3 and 4 of the international index were significantly higher after treatment for the sildenafil group than for the place- bo group (p,0.001) (table 2). the percent increase from base line was 95 percent for ques- tion 3 and 140 percent for question 4 for the men taking sildenafil, as compared with 10 percent and 13 percent, respectively, for those taking placebo… - 65 - dokumenter vedrørende fagmandens generelle viden om lægemiddeludvikling der har under sagen været fremlagt følgende publikationer om fagmandens generelle viden om lægemiddeludvikling: - en engelsk oversættelse af et uddrag af lærebogen ”lehrbuch der klinischen pharmazie” af bl.a. ulrich jaehde fra 1998. - 66 - - eds. holdford ngh, hale m, ko hc, steimer j-l, sheiner lb and peck cc

(1999)“simulation in drug development: good practices”. - holly kimko & josé pinheiro
(2014)“model-based clinical drug development in the past present and future: a commentary”. bjcp dokumenter vedrørende godkendelsen af tadalafil ved kommissionens beslutning af
  1. november 2002 om tilladelse til markedsføring af det humanmedicinske lægemiddel ”cialis – tadalafil” fik eli lilly tilladelse til at markedsføre 10 mg og 20 mg til brug for ”on demand”. det europæiske lægemiddelagentur (emea) udarbejdede en vurderingsrapport for cialis i 2005 (”european public assessment report for cialis”). af denne vurderingsrapport fremgår, at man har testet doser fra 2 mg til 100 mg i fase ii forsøg. emea kom med følgende anbefaling: ”… the agreed posology recommends that tadalafil “can be taken up to 12 hours and as early as 30 minutes prior to sexual activity”. the maximum recommended dosing frequency is once per day and daily use of tadalafil is strongly discour- aged” eli lilly ansøgte den
  2. maj 2006 om udvidelse af markedsføringstilladelsen til godkendelse af tabletstyrkerne 2,5 mg og 5 mg til et doseringsregime ”en gang om dagen”. eli lilly opnå- ede denne tilladelse ved kommissionens beslutning af
  3. juni
  4. emea´s vurderingsrapport af
  5. april 2007 (epar scientific discussion cialis) har været fremlagt i sagen. publikationer efter prioritetsdagen der er under sagen fremlagt følgende publikationer dateret efter prioritetsdatoen: - 67 - tomlinson j and wright d
(2004):”impact of erectile dysfunction and its subsequent treatment with sildenafil: qualitative study”. bmj 328:1037, rosen rc, allen kr, ni x and araujo ab
(2011):”minimal clinically important differences in the erectile function domain of the international index of erectile function scale”. eur. urol; 60:1010-6. erklæringer der er både til denne og til tidligere sager mellem parterne i udlandet afgivet en række ek- sperterklæringer. dr. irwin goldstein har den 8. august 2017 afgivet følgende eksperterklæring: - 68 - - 69 - - 70 - - 71 - - 72 - professor adam f. cohen har til brug for en lignende sag i holland afgivet en eksperterklæ- ring af 5. maj 2017. af denne fremgår: - 73 - - 74 - - 75 - - 76 - - 77 - - 78 - - 79 - - 80 - - 81 - - 82 - - 83 - - 84 - den 24. oktober 2017 har professor cohen afgivet en supplerende eksperterklæring, hvoraf følgende fremgår: - 85 - - 86 - - 87 - - 88 - - 89 - - 90 - - 91 - - 92 - - 93 - - 94 - - 95 - af en eksperterklæring af afgivet den 31. januar 2018 fra dr. gerald brock fremgår blandt andet følgende: 3.9 the work that i do on behalf of various pharmaceutical companies repre- sents about 15% of my work. eli lilly represents around 30% of this work… 3.13 over the past two decades since completing my research fellowship, i have been involved in clinical and basic research investigations. i have served on research steering committees for the pharmaceutical industry providing advice in design and implementation of phase ii & iii trials for pfizer, lilly, astellas, gsk and bayer. additionally i served as the inde- pendent drug monitoring committee chair for a large multi-centre trial for johnson & johnson pharmaceuticals evaluating the safety and efficacy of a short acting ssri for premature ejaculation, involving almost 800 pa- tients in nearly 100 research sites. 3.14 i was a principal investigator in a ten site multi-centre trial in canada looking at doses of 2-25mg of what we referred to as ic351 (later given the non-proprietary name of tadalafil) compared to placebo. this study ran from april 1999 through august 1999. in addition, i served on the advisory board for lilly (beginning in the period 1997-1998), focussing on the study design for tadalafil trials. 3.15 after the priority date, my involvement with tadalafil has continued to the present day, through my role as an investigator in various clinical tri- als as well as in my practice as a clinical urologist. 4. the skilled team 4.1 the concept of the ‘skilled team’ has been explained to me. i understand that the skilled team would consist of a person (or persons) who, as at the priority date, would have had a practical interest in putting into effect the technical subject matter of the 181 patent (the “skilled team”). 4.2 given that the subject matter of the 181 patent pertains to dosing, efficacy, tolerability and side effects of tadalafil for the treatment of erectile dys- function, i believe that the skilled team would be a team led by a clinical urologist with a special interest in research into erectile dysfunction (here- inafter referred to as the “skilled clinician”). 4.3 the development of tadalafil will have proceeded through various stages at which various disciplines will have been involved in addition to that of - 96 - the skilled clinician who would have determined the clinical need to be met in the first place. 4.4 initially the molecule will have been discovered by the medicinal chemist who will have screened its chemical selectivity and potency and com- pared it to the known pde inhibitors in the clinic. if found to have prop- erties making it suitable for development, the new drug will be selected for progression into preclinical (animal) development at which time the team would include input from: (
  1. a)a formulation expert (to formulate suitable dosage forms) the “skilled formulator"; (
  2. b)a toxicologist to assess its safety the “skilled toxicologist"; and (
  3. c)a pharmacokineticist to assess the preclinical animal data the “skilled pharmacokineticist". 4.5 if the preclinical data proved satisfactory, the drug would then proceed into human trials. the medicinal chemist will have dropped out of the team by this stage but the skilled clinician, skilled toxicologist, skilled formulator and skilled pharmacokineticist would remain involved and play their part. if the drug is found to be found to be safe and effective the skilled team would also include a person with experience in regulato- ry affairs. 4.6 given the significance of the dosing regimen in the 181 patent, i believe that in making decisions as regards the dosing of tadalafil, the skilled cli- nician would take the lead in the skilled team. as i have described above, different individuals would play a part in the development process, but given that the driver is the safe and effective therapeutic use and the treatment of patients, it is the skilled clinician who would put all the in- formation together and drive the process forward. 4.7 in relation to the issue of “priority” addressed in section 8 below, the skilled team would have included a chemist (hereinafter referred to as the “skilled chemist”). 4.8 the evidence that i give below is from the perspective of the skilled clini- cian and it has been made clear to me that what is important are not my own personal views on the issues addressed in this report but those of the ‘average’ skilled clinician. i believe that the views expressed in this report would have been representative of the views of the average skilled clini- cian as at the priority date. … 5.17 it was also recognised and understood that pde5 inhibitors may affect other biological pathways as a result of the inhibition of pde5. for exam- ple, clinicians involved in research recognised that "cross-talk" may play a role in regulating cgmp/camp levels. in other words, when an intact in- dividual is exposed to an agent that alters levels of one cyclic nucleotide (for example cgmp) levels of another cyclic nucleotide (for example - 97 - camp) may be altered indirectly. this effect was noted in boolell et al1, which highlights the concept of synergistic action between cgmp and camp (cross-talk). stief et al2, similarly explained that inhibiting pde5 and increasing intracellular cgmp also inhibits pde3. pde3 inactivates the signalling molecule camp. accordingly, even though pde5 does not regulate intracellular camp directly, inhibiting pde5 could increase camp levels, potentially causing side effects associated with higher con- centrations of camp. causes of erectile dysfunction 5.18 erectile dysfunction is a medical condition appropriately described as the inability of a man to obtain and maintain an erection sufficiently hard for penetration of their partner and sexual satisfaction. erectile dysfunction is a common medical condition, and is believed to affect upwards of 50% of men aged 40-70. 5.19 the cause of erectile dysfunction may be physiological, psychological or both. physiological causes tend to be those that affect: (
  4. a)blood flow, such as hypertension, smoking, diabetes, drugs (both pre- scription and recreational), venous leakage and dyslipidemia (abnormal lipid levels); (
  5. b)signalling pathways, such as hormonal disorders and neurological conditions; © or organ damage such as corporal fibrosis, peyronie’s disease or physi- cal trauma (for example pelvic surgery). 5.20 as an erection requires some form of sexual stimulation, psychological conditions such as depression, guilt, stress, anxiety, lack of confidence and discord in the patient's relationship with their partner can also lead to erectile dysfunction. there are often multiple factors involved in an indi- vidual's erectile dysfunction. physiological factors can induce psychologi- cal factors. for example, a post-prostatectomy patient who has had cav- ernous nerve injury from his surgery has lost a portion of his ability to signal vascular dilation and as such may have higher stress levels when attempting intercourse. psychological factors can also induce physiologi- cal factors, such as by causing the release of stress hormones and neuro- 1 boolell m, allen mj, ballard sa, gepi-attee s, muirhead gj, naylor am, osterloh, ih, gingell c
(1996)sildenafil: an orally active type 5 cyclic gmp-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. international journal of impotence research 8:47-52; see exhibit gbb- 2. 2 stief cg, uckert s, becker aj, truss mc and jonas u
(1998)the effect of the specific phosphodiesterase (pde) inhibitors on human and rabbit cavernous tissue in vitro and in vivo. journal urology 159
(4):1390-1393; see exhibit gbb-
  1. - 98 - transmitters that interfere with the physiological pathways associated with an erection. existing treatments - sildenafil 5.21 at the priority date there were surgical treatments that were largely re- served for salvage approaches and for those men who did not respond to injection therapy or could not tolerate it. for patients who were respon- sive to medical management, it was recognised that the goal of research in the field was to achieve an oral agent (preferably in solid form) with a rapid onset of action (no more than 2 hours). 5.22 viagra® (sildenafil), marketed by pfizer, first obtained regulatory ap- proval from the fda on 27 march
  2. it became the first, and was the only, oral pde5 inhibitor available on the market for treatment of erectile dysfunction at the priority date. prior to and immediately following vi- agra®’s launch pfizer published, and also presented in seminars and conferences, a great deal of information on sildenafil. following the launch of viagra®, the skilled clinician would have known the loca- tions and substrate selectivities of pdes 1 to
  3. at the time, it was known that there was likely to be other putative pdes beyond those identified which had not been fully elucidated or described. 5.23 it was well known that viagra® was a pde5 inhibitor. it was available only through prescription, and was prescribed on demand (and based on my clinical experience reached peak plasma concentration (cmax) after about 60 minutes, which would be the best time after ingestion to attempt intercourse) with a typical starting dose (for erectile dysfunction) of 50mg, with the most common dose being 100mg and in rare exceptions (approximately 3% of patients) a dose as low as 25mg (which was and is only used in patients with metabolic issues leading to poor metabolism of the drug). while there was data showing some efficacy at lower doses, the marketed viagra® doses at the priority date of 25mg, 50mg and 100mg and their relative use and commercial success speak to the “best” dose in clinical practice. 5.24 the key publication on sildenafil was the goldstein
(1998)publication, on the front page of an issue of the prestigious new england journal of med- icine3. the authors describe results from over 500 men treated with oral sildenafil at doses of 25mg, 50mg and 100mg compared to placebo. they reported using the international iief as their primary endpoint. im- portantly, a dose response escalation study is reported, as well as a flexi- ble long term extension study. 5.25 using the iief they reported 60%, 84% and 100% improvement over base- line for question 3 amongst men receiving 25mg, 50mg and 100mg of sildenafil respectively. these are percentage increases in mean score from baseline after treatment. in the dose response portion of this paper, after 3 goldstein i, lue t, padma-nathan h, rosen r, steers w and wicker a
(1998)oral sildenafil in the treatment of erectile dysfunction. nejm 338:1397-1404; see exhibit gbb-4. - 99 - 12 weeks only 2% of men were using 25mg, 23% were using 50mg and 74% had selected 100mg as their best dose. the main adverse events were headache, flushing and visual disturbances. this report documents safety and efficacy of sildenafil in a broad population of men. it provides de- tailed information on dosing, demonstrating clear superiority of and a preference for 100mg for roughly three quarters of those studied. 5.26 in my own clinical practice before the priority date, i observed that the 100mg dose was selected as the preferred dose by approximately three quarters of my patients, with the 50mg dose selected by the other quarter of patients. almost no patients selected 25mg as their preferred dose. the majority patient preference for the 100mg dose was known at the pri- ority date. 5.27 when sildenafil was first authorised for the treatment of erectile dysfunc- tion, regulators recommended a starting dose of 50mg of sildenafil. they still do today. however, in my practice, and in my assessment in the general practice in the field, 100mg has been the most commonly pre- scribed (around 75%) dose since the release of viagra (included at the priority date, and up to today). about a quarter of patients are pre- scribed 50mg doses. in practice, only a very small proportion of patients are prescribed doses of 25mg and this was typically reserved for special populations, including those with metabolic issues (such as renal or he- patic impairment) and those patients taking protease inhibitors (which af- fects the metabolic pathway) for hiv. 5.28 despite most regulatory authorities recommending a 50mg starting dose, at the priority date, and now, most clinicians (including myself) start pa- tients with the 100mg dose, even though it may be associated with in- creased severity and incidence of some side effects in some patients. this is for four reasons. first, it is widely reported that when given the choice, most patients prefer the 100mg dose of sildenafil. it makes sense to start patients on the dose they are most likely to ultimately prefer. 5.29 second, at the priority date and since i have had a real concern, based on my clinical experience and the scientific literature, that if i prescribe a 50mg dose to a new patient, and the patient does not experience a clini- cally meaningful improvement in their ability to have intercourse, the pa- tient will assume that sildenafil is not an effective therapy for them. this will most likely mean that their erectile dysfunction remains untreated. the patient may also feel like a failure, which can lead to or exacerbate depression in some patients. accordingly, there is a higher chance that prescribing a 50mg dose of sildenafil to a new patient will turn out to be ineffective, or not provide enough improvement. in some patients, not experiencing a sufficient improvement may make the problem worse. in comparison, if i prescribe a 100mg dose and the patient experiences effi- cacy but has concerns about side effects, they are more likely to continue their therapy. i can prescribe a lower dose, such as the 50mg dose, to see if the lower doses reduces their side effect while still maintaining suffi- - 100 - cient efficacy. in my experience, most of my patients are able to tolerate the side effects associated with a 100mg dose. 5.30 my clinical experience at and since the priority date is consistent with the findings reported in tomlinson & wright.4 in this study, patients were interviewed to determine the “impact that erectile dysfunction had on participants’ self-esteem, relationships, and welfare, as well as exploring their expectations of sildenafil as a treatment and the impact its success or failure had on their morale” (page 1, column 2). the study confirmed that erectile dysfunction can significantly affect a patient’s confidence, morale and relationship with their partner (page 2, column 2 to page 3, column 1). 5.31 the authors found (see page 3, columns 1 and 2) that participants often had high expectations of sildenafil before taking it, often resulting from media reporting. their perception of failure was related to their high ex- pectation that they had to take only one pill to achieve excellent efficacy. after failing with the drug, most patients tried again but a second failure attempt confirmed their negative feelings. the authors conclude at page 3, column 2 that: “[f]or some, sildenafil did not work the first time and the blow was severe. although it is now known that with help and advice, the patient can often succeed eventually, a proportion were so disappointed that they did not try again. many thought that they had failed yet again in their life, add- ing to their already existing feeling of worthlessness.” 5.32 third, when treating erectile dysfunction there is limited clinical benefit to obtaining partial efficacy. there is limited benefit to cause a slight im- provement in erectile function if the patient is still unable to engage in in- tercourse. the best dose of sildenafil is the dose that is most likely to produce an improvement that is of sufficient magnitude that it will pro- vide a clinical benefit to the patient. for most men, this will be a 100mg. 5.33 in 1999, the iief was widely used to measure erectile function and as a means to document a change in erectile function and sexual function. us- ing the iief, you could understand that if you gave someone a drug they would go from point a to point b. however, it had never been quantified what difference in their iief score was needed to have a clinically rele- vant effect (rather than a statistically significant effect). as a clinician, you would have patients who would use the iief and it would be diffi- cult to determine how much of an improvement they needed for it to be meaningful to them. 5.34 the first time that a clinically important difference was defined was in a study published by dr raymond rosen in 2011.5 prior to this publica- tion, although there were the tools to judge sexual function in many dif- 4 tomlinson j and wright d
(2004)impact of erectile dysfunction and its subsequent treatment with sildenafil: qualitative study. bmj 328:1037; see exhibit gbb-5. 5 rosen rc, allen kr, ni x and araujo ab
(2011)minimal clinically important differences in the erectile func- tion domain of the international index of erectile function scale. eur urol; 60:1010-6; see exhibit gbb-
  1. - 101 - ferent domains, clinicians did not actually know if it was a clinically meaningful difference. the rosen publication defined, for the first time, that a man who has mild erectile dysfunction may need less of an im- provement than a man with moderate erectile function or a man with severe erectile dysfunction. the improvement needed will vary based on what the patient’s baseline function is. for example, if you improve erectile function just a little bit in a man who has severe erectile dysfunc- tion, he still has erectile dysfunction. however, if you have a man with mild erectile dysfunction, even a small improvement is meaningful to him. 5.35 fourth, while the 100mg doses of sildenafil might cause more transitory side effects than 50mg and 25mg doses, those side effects pose no addi- tional danger to the patient. 5.36 the skilled clinician would have known the potency of sildenafil for pde5 as compared to the other known pdes and its selectivity for pde5 over other pdes as these characteristics were used by pfizer to emphasise its safety, particularly the absence of cardiovascular effects which were considered to be a consequence of inhibiting pde1 and pde3 found in cardiovascular smooth muscle. the skilled clinician would have known that the exception to this was sildenafil’s selectivity as between pde5:pde6 which was only 10:1 and that as a consequence vision ab- normalities were observed particularly at the higher recommended doses of sildenafil
  2. 5.37 at the priority date, which was following a year’s experience prescribing it, the side effect profile of sildenafil was also well known. the most commonly observed side effects observed at all doses were headache, flushing and dyspepsia. as mentioned above, vision abnormalities were observed more commonly at higher doses. these were recorded in vi- agra®’s label approved on 27 march 1998 as follows7: 6 ballard, s.a. et al
(1998)j urol pp 2164-2171 7 obtainable from the fda website at: http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/viagralabel2.pdf - 102 - 5.38 apart from allergic reactions to the active drug or carrier molecules in the tablet, the mechanisms underlying the side effects were considered to fall into two categories: (
  1. a)effect on other pdes: the vision abnormalities were widely believed to be caused by sildenafil’s inhibition of pde6, which is present in the retina. it was believed that inhibition of pde1 and pde3 by sildenafil would cause cardiovascular side effects, although this was not proven, and it was not known what physiological effects would be seen through unintended inhi- bition of other pdes (cross-talk). (
  2. b)inherent to pde5 inhibition: the remaining side effects were believed to be inherent to pde5 inhibition and therefore inextricably linked with sildenafil’s mechanism of action in erectile dysfunction. pde5 was known to exist in a number of peripheral sites other than the corpus cavernosum, including skeletal and visceral and vascular smooth muscle. in smooth muscle cells, sildenafil prevents the hydrolysis of cgmp to the inactive gmp, with the result that levels of cgmp remain elevated, thereby promot- ing smooth muscle relaxation. when smooth muscles in the walls of a blood vessel relax, this increases the diameter of the vessel in a process termed vasodilation. headaches, facial flushing and non-allergic rhinitis caused by pde5 inhibition all have vasodilation as their root cause. dys- pepsia is caused by stomach acid flowing up into the oesophagus due to re- laxation of the smooth muscle of the lower oesophageal sphincter. for this reason the belief was that if a pde5 inhibitor was given at a dose which was effective to improve erectile function, it would by default also vasodilate other vascular beds in the body through the pde5 mechanism causing the side effects inherent to pde5 inhibition described above. - 103 - 5.39 the majority of patients taking sildenafil do not suffer side effects. for some of the patients that do, the impact of the side effects (such as head- ache, flushing, dyspepsia and vision abnormalities) is significant. patients who would otherwise benefit from pde5 inhibition may be prevented from taking this medication or being able to escalate their dose to an effective therapeutic level. it must also be borne in mind that the level of side effects which are tolerable to patients in this therapeutic area (erectile dysfunction being a quality of life issue), is different than in treatment of a life threaten- ing condition. 5.40 for a small proportion of patients, the onset of certain side effects, while tolerable, reduces their ability to successfully engage in intercourse, essen- tially negating any clinical effect that may otherwise have been produced by sildenafil. for example, facial flushing is associated with an increase in heart rate, and a feeling of warmth and redness over the neck and face. dyspepsia can cause pains in the chest. some erectile dysfunction patients have cardiovascular disease and may associate these side effects with a cardiovascular event. consequently, while both of these side effects are transitory and do not pose any long term threat, for a small proportion of patients it feels like they are having a heart attack (or experiencing the symptoms of some other ominous episode), and can be a source of concern and anxiety. as erectile dysfunction has a psychogenic aspect to it, anxiety can affect a patient’s ability to engage in intercourse, negating the therapeu- tic efficacy of sildenafil. similarly, experiencing a headache may reduce the efficacy of the treatment in some patients, even if they know that the head- ache is not dangerous and is tolerable over short duration of time. 5.41 for the desired patient population, it is a matter of ensuring that the doses are highly efficacious (to ensure that the majority of that patient population will experience a sufficient improvement in their erectile function to mean- ingfully and consistently improve their ability to engage in sexual activity) while at the same time not causing side effects that the majority of that pa- tient population do not tolerate and not causing side effects that will reduce the efficacy of the drug in the majority of the patient population. 5.42 nitrates have always been contraindicated with sildenafil. nitroglycerin is a cardiac medication prescribed for treatment of angina. it produces a rapid increase in no, which diffuses throughout the body and through its effects on guanylate cyclase increases cgmp levels dramatically, causing vasodila- tion of the coronaries and other vascular beds. pde5 inhibition prevents the metabolism of cgmp. for this reason, exposure to high levels of no caused by nitroglycerin intake in conjunction with pde5 inhibition, can result in profound vasodilation and hypotension, owing to sustained high levels of cgmp. - 104 - other oral drugs used for erectile dysfunction 5.43 oral phentolamine (vasomax®), an alpha-adrenergic antagonist, was approved in some markets. however it was minimally effective and fraught with side effects. 5.44 apomorphine, a centrally acting agent approved for use in parkinson’s disease, was occasionally prescribed for use in erectile dysfunction. how- ever it had minimal efficacy and a very unfavourable side effect profile which limited its use. similarly, trental® (pentoxifylline) was not ap- proved for erectile dysfunction, was rarely used but did have limited litera- ture reports of efficacy in erectile dysfunction. 5.45 there had been studies on melanotan and melanotan-ii, however this never received regulatory approval. 5.46 additionally, there were some off-label herbal agents such as yohimbine, which were available but not approved for use in erectile dysfunction. by the priority date there was some recognition that it had some pde5 inhibi- tory effect in addition to its alpha-2 adrenergic effects. animal models used in erectile dysfunction research 5.47 at the priority date, there were a number of animal models used in re- search to study erectile dysfunction. these studies tended to be designed to assess the impact of various diseases (and the aging process) on erectile function and mechanisms. these were models of diseases which, in hu- mans, predisposed the individual to a higher incidence of erectile dysfunc- tion, for example models of diabetes, androgen deficiency, renal failure, high cholesterol levels or hypertension. 5.48 one common model was streptozotocin-treated rats, which act as a model of juvenile-onset diabetes (crowe
(1983)8; abdelbaky
(1998)9). a rabbit hypertension model was used as a model of impotence resulting from ath- erosclerotic vascular disease (azadoi
(1992)11; azadoi
(1998)12). the spon- taneous hypertensive rat model, which is a model of hypertension, was al- so used as it exhibits erectile dysfunction as a result of hypertension (clark
(1995)10). additionally, as aging brings morphological changes which of- ten result in erectile dysfunction, some research focused on aging animal models, such as the chacma baboon (bornman
(1985)11). 5.49 the animal models of erectile dysfunction were typically used for under- standing of the disease process by academic centres doing research in erec- tile dysfunction, and how one disease would impact on erectile dysfunc- tion. for example, animal models were commonly used for assessment of vascular insufficiency inducing erection. 8 crowe, r. et al. diabetes. 1983 nov; 32
(11): 1075-7 9 abdelbaky, t.m. et al. endocrinology. 1998 jul;139
(7):3143-7 11 azadzoi, k.m. and goldstein, i. j urol. 1992 jun;147
(6):1675-81 12 azadzoi, k.m. et al. j urol. 1998 dec;160(6 pt 1):2216-22. 10 clark, j.t. neurosci biobehav rev. 1995 summer;19
(2):279-302 11 bornman, n.s. et al. j med primatol. 1985;14
(1):13-8 - 105 - 5.50 animal models of erectile dysfunction were not typically used in pharma- ceutical development because of the limitations of assessment tools. in par- ticular, it was difficult in animals to simulate human sexual stimulation and assess the corresponding response. in order for these drugs to work (pde5 inhibitors) there needs to be sexual arousal causing the release of nitric ox- ide, this would be hard to achieve in a free-living animal in a natural way. similarly, the efficacy assessment tools available, most notably the iief scale, are subjective and cannot be applied to animals. therefore, once a drug is established as safe, assessment of efficacy is only really possible in humans. dose selection during pharmaceutical research 5.51 in vitro and animal studies are conducted prior to commencing human clinical trials. the in vitro studies would provide information on the poten- cy (ic50 and ec50 measurements) and selectivity (ratio of potency for the target pde against others) of the compound of interest. the animal studies are used to assess safety and toxicity (typically in two or three different species). it was not necessary for these to be animal models of erectile dys- function, and in fact they were not, for the reasons i have described above. they allowed an assessment of general biological activity (i.e. that pde in- hibition causes drop in blood pressure for example), toxicity effects and pharmacokinetics in animals. 5.52 phase i trials in healthy volunteers would follow the animal studies. these determine whether the drug may be administered without significant ad- verse effects. 5.53 in some therapeutic areas, a signal of efficacy can be obtained from phase i studies, (as an example a hypertension drug) however in the case of erectile dysfunction trials of pde5 inhibitors this is not feasible or possible. the re- quirement for careful monitoring of healthy subjects in a clinical environ- ment precludes the opportunity for sexual stimulation (an absolute necessi- ty to induce activity of the pde5 inhibitors) given the need for blood test- ing at intervals, pk and pd studies. additionally, as the tools used to measure efficacy are based on vaginal intercourse, this clinical laboratory setting in which phase i trials are conducted would make that possibility unlikely. 5.54 in selecting the dose to be tested in the efficacy (phase ii and phase iii) tri- als, the skilled team would be guided by many factors including tolerabil- ity, potency, selectivity, absorption/distribution, elimination and experi- ence with any comparable products (i.e. those working through the same mechanism, for the same therapeutic indication). 5. tolerability is a drug characteristic such that after ingestion the patient is willing to continue using it. for any given individual, tolerability is the bal- ance between any benefits the patient derives from the drug, as against any adverse physiological effects they experience. this varies from patient to patient and between different therapeutic areas, and can only be deter- mined by testing the drug in humans. characteristics that may make a - 106 - drug intolerable, which can only be determined after testing, would in- clude gastrointestinal side effects, headaches, rashes, myalgia and potential interaction with other agents. in selecting a dose for phase ii and iii trials the skilled team would not yet have efficacy data, so tolerability in the true sense cannot yet be assessed, but the side effect profile would be taken into account. 5.56 the potency of the agent (ic50) describes what concentration of the com- pound achieves a predetermined level of inhibition of the target enzyme. however it alone would not allow prediction of dosing. for example, if in vitro testing demonstrates a very potent agent in vitro, but it is an agent that cannot achieve adequate concentrations in the organ of interest, or it has effects on other pdes in the organ of interest which impact on efficacy, then the ic50 may not be a good measure of its likely effect in vivo. 5.57 selectivity is a critical aspect of this therapeutic area, and although these drugs are called “pde5 inhibitors” they have activity against other pdes. in addition to adverse events (such as concomitant inhibition of pde6 by sildenafil causing vision abnormalities), selectivity may also directly effect a drug’s efficacy at a given dose. for example, an effect on pdes other than pde5 in the vasculature, may increase capacitance (the capacity for vol- ume), cause vasodilation in specific vascular beds or organs, and result in either reduced or enhanced efficacy for erectile dysfunction. at the time, as explained at paragraph 5.22 above, it was known that there was likely to be other putative pdes beyond those already identified which had not been fully elucidated or described. even if the selectivity of a drug against the known pdes was established, its binding on other unidentified pdes was unknown and the effects of any such binding on the drug’s efficacy and side effects could not be predicted until human studies had been per- formed using that compound. the impact on efficacy would be particularly relevant if such unidentified pdes were present in the corpus cavernosum. 5.58 we have now identified a pde that was not known at the priority date, namely pde11. pde11 is present, in addition to other places, in the corpus cavernosum tissue and tadalafil has a higher degree of selectivity for pde11 than does sildenafil. though this specific pde had not been identi- fied at the priority date, the potential for as yet unidentified pdes having an impact on a drug’s efficacy and side effects was known. 5.59 the degree of absorption/distribution of the drug into the blood circulation and into the target tissue is also relevant. this is particularly relevant with respect to pde physiology and erectile dysfunction. at the time it was be- ing recognised that these pde enzymes had specific distributions and con- centrations in various organs. for erectile dysfunction, it would not be enough for the drug to reach the circulation, it had to relax the cavernous smooth muscle directly, which required it to be absorbed from the blood- stream into the surrounding penile smooth muscle. 5.60 in order for the drug to be effective its duration of activity must be ade- quate prior to elimination from the tissue to allow for achievement and maintenance of erection for an adequate period of time to allow patient sat- - 107 - isfaction. therefore, the degree of elimination of the drug not only from the blood but also from the target tissue is an important factor in trying to pre- dict the effective dose. 5.61 the effective dose of any other comparable products would also be an im- portant contributing factor in dose selection, although understanding that a different molecule may have different tolerability, potency, selectivity, ab- sorption/distribution and elimination characteristics, all of which may im- pact on dose selection. as i have explained above, at the priority date the only oral pde5 inhibitor used to treat erectile dysfunction was sildenafil. this would have been a helpful point of reference when selecting a dose to use in phase ii trials. however, differences in those properties listed above (which will vary between two compounds) would need to be taken into ac- count when selecting doses. most significantly, it cannot be assumed that two drugs’ absorption, distribution and elimination characteristics will be the same, so the same dose of each may produce different concentrations in the target tissue. 5.62 in selecting which dose(
  1. s)to use during clinical development, the clinician would advise the skilled team, based on their clinical experience and judgment, in relation to matters such as: (
  2. a)what therapeutic effect would be adequate or preferred by patients; (
  3. b)the nature, severity and frequency of side effects that patients would toler- ate; (
  4. c)where the best balance lies between therapeutic effect and side effects (which is relevant to dose selection); (
  5. d)the duration of therapeutic effect that patients would desire; (
  6. e)the routes of administration that patients would prefer and find acceptable; (
  7. f)the appropriate measures of erectile function and the interpretation of their relevance; (
  8. g)the characteristics of a clinically meaningful improvement in erectile func- tion; (
  9. h)the doses that best balance efficacy and side effects; (
  10. i)the selection of targeted patients to be studied (efficacy in different patient populations would be expected in this therapeutic area); (
  11. j)whether the results of clinical trials are acceptable; and (
  12. k)any other matters regarding the properties that patients and clinicians de- sire from an erectile dysfunction treatment. - 108 - 5.63 given that the driver is the safe and effective therapeutic use and the treatment of patients, the information provided by the clinician would be critical to the success of the drug development program. 6.the disclosure of the prior art wo 97/0367 - “daugan” 6.1 i first read daugan in 2013 as part of my involvement in the canadian pro- ceedings described in paragraph 2.5 above. 6.2 daugan describes the invention as the use of potent and selective inhibitors of cgmp-specific phosphodiesterase for the treatment of male erectile dysfunc- tion (impotence) (page 1, lines 3-5). it describes a general structural formula, termed “formula (i)”, and lists the different substituents followed by a list of thirteen chemical names described as “suitable individual compounds of the invention” (page 2). it then names two of these thirteen as “specific com- pounds of the invention” referring to them as “compound a” and “com- pound b” (lines 24-28, page 3). the skilled clinician would not have the exper- tise to identify the difference between these compounds. i have been told that compound a is tadalafil. 6.3 daugan states that oral is the preferred route of administration (page 4, line 29), and in patients that have a swallowing disorder or impairment of drug absorption it may be administered parenterally. daugan goes on to provide dosing information applicable to both compound a and compound b (page 5, lines 1-14). it states that oral dosages for an average adult patient weighing 70kg “will generally be in the range of from 0.5-800mg daily” and the indi- vidual tablet or capsule contains “from 0.2-400mg of active compound …. for administration in single or multiple doses, once or several times per day” (page 5, lines 3-7). the skilled clinician would understand the 0.5-800mg range to be referring to the daily dose and the 0.2-400mg range referring to the unit dosage forms that make up the daily dose. 6.4 however, the document makes clear that the above information is only a guide, stating that “in practice the physician will determine the actual dosing regimen” based on a number of factors and that the cited ranges are “exem- plary of the average case but there can be individual instances in which high- er or lower dosage ranges may be merited.” 6.5 there then follows a description of chemical processes for synthesising com- pounds a and b (as well as a third compound) (pages 6 to 12) followed by a number of formulations (pages 12 to 16) of compounds a and b. as a skilled clinician, i would note that a range of formulations are described, including many different carrier agents in varying amounts but that all the formulations selected 50mg of active ingredient from the broad ranges of doses described earlier in the document. 6.6 the ic50 and ec50 values against recombinant pde5 of 2nm and 0.2µm re- spectively are provided for compounds a (example 1, page 10) and b (ex- ample 2, page 11). - 109 - 6.7 i see also that the claims cover a number of compounds including com- pounds a and b (claims 2, 4, 6 and 8, as well as in combination with an un- specified additional active agent in claim 11), however i do not believe that the skilled clinician would have paid much attention to this. these claims are expressed in different ways, but directed to use in the treatment of erectile dysfunction. claim 9 refers to treating a male animal with an effective amount of a pharmaceutical composition according to claim 5 or 6. the skilled clinician would understand this to mean an amount that works, but the document gives no guidance as to what this amount would be. putting tadalafil into development from daugan 6.8 plesner asked me whether there is enough information in daugan to deter- mine whether one or both of compounds a and b will be tolerable and effec- tive in treating erectile dysfunction. daugan discloses no clinical bioavailabil- ity or pharmacokinetic data and i cannot determine based on the potency da- ta alone whether compounds a and b will be tolerable and effective. 6.9 plesner next asked me what i would do if asked to develop a treatment for erectile dysfunction in light of: (
  13. a)daugan; and (
  14. b)the common general knowledge. 6.10 there is not enough information in daugan to allow me to predict which of compounds a and b is more likely to be an effective treatment for erectile dysfunction. they have the same ic50 and ec50 data, and no other data or information that would allow me to predict which of these two compounds might be more effective. given the total absence of clinical information and lack of bioavailability or pharmacokinetic data, or tolerability, selection of compound a or b would be a complete guess. if the skilled team were asked to develop a treatment for erectile dysfunction in light of daugan, they would first have to test the bioavailability, toxicology and safety of both compounds in preclinical studies using animal models. as i have said above, there were no predictive efficacy animal models for erectile dysfunc- tion available for oral drug development at the priority date. 6.11 if one or both of compounds a and b were shown to be tolerable and bio- available (in terms of being well absorbed and displaying a favourable me- tabolism profile) in preclinical studies, the compound that showed the most promise might be taken forward into phase i trials to test its safety and bio- availability in humans. assuming that it was shown to have acceptable safety and bioavailability properties, the compound might be taken for- ward into a phase ii trial. 6.12 based on the information in daugan, i cannot predict which dose(
  15. s)of compounds a and b would be effective and tolerable in animal models or - 110 - humans, or predict whether one is more likely to be preferred over the oth- er. 6.13 at this stage the clinician would have no information on an efficacious dose for compound a and b because there were no predictive efficacy animal models used for oral drug development available at the priority date, and the phase i studies are designed to assess safety, and therefore report on adverse events, together with a number of pharmacokinetic properties in the absence of any efficacy data (which would not be available during an erectile dysfunction drug development process). phase i studies are con- ducted in healthy volunteers, in this case without erectile dysfunction, in a clinical setting in the absence of any sexual stimulation (if anything sexual stimulation would be suppressed compared with normal day to day life), and as such would not be expected to be able to report on any efficacy pa- rameters. as a result, the clinician can only rely on the adverse events and bioavailability observed with different doses, when recommending the dose for phase ii. 6.14 tolerability is important when treating erectile dysfunction. for an erectile dysfunction drug, severe, permanent and/or dangerous side effects may af- fect its viability as an effective therapy. the clinician would accordingly not recommend testing a dose in phase ii doses that had an unacceptable side effect profile. 6.15 however, this does not mean that the doses that cause the least side effects would be selected for phase ii studies. higher doses would be expected to produce a greater improvement in erectile function, while lower doses may not produce any improvement at all. as phase ii studies are intended to determine whether the drug is an effective treatment, in the absence of any prior efficacy data, the clinician would be inclined to recommend starting with the highest dose or range of doses found to be tolerable or produce ac- ceptable side effects. this is because a higher dose is more likely to achieve higher plasma concentrations in the blood and target tissue (cmax) and produce a clinical effect. that said, the clinician would understand that cmax is an imperfect surrogate of efficacy in that other biological factors may result in poor efficacy, despite perceived adequate drug concentra- tions being achieved in the target tissue. 6.16 therefore, starting from daugan, the skilled person would see that the ex- amples disclose a unit dosage form of 50mg and the dose range goes up to 800mg. without any other information, the skilled person would be in- clined to think that the effective doses would be at the higher end of the dose range (50mg and above). … - 111 - 7. the disclosure of the 181 patent 7.1 in the section entitled “background of the invention” at [0003], the 181 patent briefly explains the mechanism of action of pde5 inhibitors and goes on, at [0004] to [0006], to provide some details of sildenafil, including the marketed unit doses and some potency information. it also explains the side effects recorded with sildenafil treatment, explaining that colour vision abnormali- ties are theorised to be due to sildenafil’s lack of selectivity for pde5 over pde6, and that it is contraindicated for patients taking organic nitrates. this information was all known at the priority date. 7.2 the 181 patent explains that a compound has been identified, to which it re- fers as “compound (i)”, which “can be administered in a unit dose that pro- vides an effective treatment without the side effects associated with…sildenafil” ([0008]). it states that “prior to the present invention such side effects were considered inherent to the inhibition of pde5” (page 2, lines 53-54) and as set out at paragraph 5.38 above, with the exception of the colour vision abnormalities recorded for sildenafil, the skilled clinician would agree that this was indeed the case. 7.3 it states specifically at [0009] that there is a significant reduction in flushing and that the compound may be “administered with clinically insignificant side effects associated with the combined effects of a pde5 inhibitor and an organic nitrate.” flushing is defined at [0022] as “an episodic redness of the face and neck attributed to vasodilation caused by ingestion of a drug, usual- ly accompanied by a feeling of warmth over the face and neck and sometimes accompanied by perspiration.” 7.4 compound (
  16. i)is identified by two chemical names at page 2, lines 49-51, and a structural formula is provided at [0014] and [0032]. i have been told that compound (
  17. i)is tadalafil. 7.5 there are references to dosing and dosage forms of tadalafil throughout the 181 patent. paragraph [0014] states that “the present invention provides a pharmaceutical unit dosage composition comprising 1 to 5mg of [tadala- fil]…suitable for oral administration up to a maximum total dose of 5mg per day” and [0015] states that this may be used for “the manufacture of a medic- ament” at these unit and daily dose levels for treatment of sexual dysfunc- tion. the skilled clinician reading this at the priority date, would understand that the key therapeutic potential of tadalafil in this context is treatment of male erectile dysfunction. 7.6 the 181 patent discusses side effects in the section headed “detailed descrip- tion”. it explains in [0031] that administration of tadalafil is able to remove or reduce to clinically insignificant levels, side effects previously believed to be inherent in pde5 inhibition. these side effects are listed as including facial flushing, vision abnormalities and significant decreases in blood pressure when administered with organic nitrates. this is supported by the provision - 112 - in [0034] and [0035] of potency data, in the form of ic50 figures against pde5 and pde6. it shows high potency (2.5nm) for pde5 and relatively low poten- cy (3,400nm) for pde6, with a ratio of pde6/pde5 of 1360. the skilled clini- cian would understand that this high selectivity for pde5 over pde6 (com- pared to the “10-fold” figure provided for sildenafil on page 2, line 28) is like- ly the reason that tadalafil does not cause the colour vision abnormalities ex- perienced with sildenafil. 7.7 moreover, in the context of tadalafil’s greater selectivity for pde5 over pde6, the skilled clinician would note that it states (page 4, lines 55-57) that “the minimal effect of compound (i), administered in about 1 to about 5 mg unit dosage forms, on pde6 also allows the administration of a selective pde5 in- hibitor to patients suffering from a retinal disease, like diabetic retinopathy or retinitis pigmentosa.” the skilled clinician would understand that tadalafil’s better selectivity therefore opens up a patient population previously unable to receive pde5 inhibitor therapy. 7.8 examples 1 to 4 give exemplary formulations and their method of manufac- ture, containing dosage forms with 1mg, 2.5mg, 5mg and 10mg of tadalafil in various forms. 7.9 example 5 describes a clinical study which evaluated the hemodynamic ef- fects of concomitant administration of tadalafil and short-acting nitrates on healthy male volunteers. the patients were administered sublingual nitro- glycerin, along with a daily dose of placebo or 10mg of tadalafil for seven days. the study found that there was “minimal, if any, effect on mean systolic blood pressure” (page 10, lines 51-52) and that the most common side effects recorded were headache, dyspepsia and back-pain. 7.10 example 6 describes two studies, stating that both daily dosing and on de- mand therapy with tadalafil were used. it reports that doses from 5mg to 20mg were found to be efficacious and demonstrated “less than 1% flushing” and no reports of vision abnormalities. it states that a “10 mg dose of [tadala- fil] was fully efficacious and demonstrated minimal side effects” and that it “significantly improved the percentage of successful intercourse attempts, in- cluding the ability to attain and maintain an erection in both “on demand” and daily dosing regimens” (page 11, lines 1-6). 7.11 as at the priority date, the concept of daily dosing of pde5 inhibitors was not widely discussed, as sildenafil (with a half-life of 4 hours) does not accu- mulate sufficiently to allow blood plasma and tissue levels of the drug to be maintained at a constant therapeutically effective level when taken at inter- vals of 24 hours. there was therefore no real advantage envisaged of daily dosing over on demand therapy with sildenafil. 7.12 additionally, having a long half-life does not automatically render a drug suitable for chronic dosing. whether chronic dosing is pursued is primarily dependent on the indication in question and i set out below the factors which - 113 - i believe the skilled clinician would have considered when deciding whether to recommend chronic dosing of tadalafil for erectile dysfunction. 7.13 i recall that as a member of the advisory board on tadalafil’s development, we were asked in an advisory board meeting that i attended in around 1999- 2000 whether lilly should investigate a daily dosing regimen for tadalafil and we advised against it (although ultimately they did decide to do so). i recall that everyone agreed that viagra would have a huge effect on what pa- tients wanted and expected. we thought that it would make no sense, and indeed patients would be unwilling, to take a drug every day when it had been reported and we knew from experience that on average couples had sex five to six times per month (as i explain in paragraph 7.15(
  18. b)below). the cost of daily treatment when the therapeutic benefit was needed infrequently was another factor which i recall we considered when advising lilly against in- vestigating daily dosing. 7.14 at that time we didn’t have any data on the fact that daily dosing could pro- vide the benefit of reduced side effects and although we did appreciate the spontaneity point, none of us thought that that was enough to make it a via- ble dosing option in light of the objections related to drug cost and potential exposure to chronic side effects. dr. william pullman of lilly-icos, who gave evidence in the uk proceedings, asked us this question and said that they had drawn up a daily dosing protocol that he was going to show to us. when we unanimously recommended against it, he thanked us for saving the company millions of dollars, as the intended clinical trials needed to examine the daily dosing regimen would have been costly. 7.15 in considering whether chronic dosing was appropriate, i believe that the skilled clinician would have taken into account the following key considera- tions: (
  19. a)sildenafil: with a second in class drug such as tadalafil, the paradigm for treatment established by an existing drug, particularly one like sildenafil which was a huge clinical and commercial success, has a strong bearing on the focus of the newer drug’s development. the skilled clinician’s experience of treating patients with the only other approved pde5 inhibitor, sildenafil, would be an important factor when assessing the viability of chronic dosing of tadalafil. viagra® had already established the paradigm of on demand dosing, and this is what patients were used to and expected. (
  20. b)frequency of sexual attempts: the average coital frequency for married and co-habiting couples (from the general population) is approximately seven times per month12, although from my clinical experience for erectile dysfunc- tion patients this is typically lower (between 4 and 5 times per month). the skilled clinician would not believe that patients would want to take a drug 12 rao, k.v. and demaris, a.
(1995)j biosoc sci. apr; 27
(2);135-50 - 114 - every day when the therapeutic effect was only required approximately once per week maximum. there was seen to be an issue of patient compliance, caused by having to remember to take a pill every day. (
  1. c)tolerability: chronic dosing does not necessarily imply a reduction in the administered dose and as a result a reduction in adverse effects and a better tolerated drug. in fact, the flip-side of maintaining a constant therapeutic lev- el of pde5 inhibition, where efficacy was thought to be intrinsically linked to many commonly-occurring side effects (as explained at paragraph 5.38 above), is that it would theoretically expose these patients to near continuous levels of adverse events. for a quality of life drug such as tadalafil, based on their clinical experience the skilled clinician would have required a very low side effect profile such that a constant occurrence would not outweigh the fact that the therapeutic benefit was only required typically once per week. at the priority date, the skilled clinician would not have expected this to be possible because the commonly-reported side effects were thought to be inherently linked to pde5 inhibition. (
  2. d)tachyphylaxis: chronic dosing of any drug runs the risk of causing tachy- phylaxis in the patient. this is where, due to long term administration of the drug, there is a diminishing response to successive doses over time. this can be an effect of chronic dosing where insensitivity to the drug or down regula- tion of the response to a drug is seen over time. the clinical implications are significant in that the patient would need to increase the dose over time to achieve the same or even lower efficacy. (
  3. e)cost implications: the skilled clinician would question whether patients would accept daily dosing, with its cost implications13 given that they would only need the therapeutic effect a maximum of once per week and even less regularly for single individuals. in my clinical experience this is a key reason for patients refusing daily dosing therapy. 7.16 if the skilled clinician were asked for his views on chronic dosing of tadala- fil, i believe the skilled clinician would have counseled against it for the rea- sons given in paragraph 7.15 above. 7.17 therefore skilled clinician would have been surprised to see this dosing regimen being tested in example 6 of the 181 patent and being shown to be effective at the doses discussed, with minimal side effects. the expectation would have been that daily dosing would exacerbate or prolong side effects. 7.18 one of the shortcomings of sildenafil therapy as reported by patients was the need to take a pill a certain time in advance of sexual activity. this was also recognised as a common reason for treatment failure – patients did not 13 the generally cited figure is that daily dosing treatment with tadalafil costs approximately usd4 per day, which equates to usd 1461 per year. - 115 - wait an adequate time between ingestion of the medication and attempting sexual activity. the skilled clinician would understand that daily dosing of tadalafil would allow for spontaneity, rather than requiring the patient to take a tablet in advance of a particular sexual activity. therefore the skilled clini- cian would recognise from the patent the advantages of tadalafil in allowing daily dosing: spontaneity and the removal of a common cause of treatment failure. 7.19 the ability to prescribe tadalafil as a daily dose has turned out to be very valuable to patients, as it provides them with “normal” function not tempo- rally linked to a tablet, and for this reason there is a strong preference amongst patients for tadalafil over sildenafil which does not have the daily dosing advantage. it is the half-life and selectivity for pde5 over other pdes which allows for the maintenance of constant therapeutically effective pde5 inhibition at very low doses, and its favourable side effect profile at these doses which makes it tolerable. 7.20 example 7 describes a clinical study in which two hundred and twelve men with mild to severe erectile dysfunction received on demand therapy with tadalafil, at doses of 2mg, 5mg, 10mg, 25mg and placebo. this is the study discussed at paragraph 3.14 above, for which i was principal investigator. it states specifically, at page 11, lines 17 -18 that these doses were administered no more than once per twenty four hours. the primary efficacy variables were rec- orded by iief questions 3 and 4, and the secondary efficacy variables were scores across the iief domains and responses to the sep and gaq. statistically signifi- cant increases over placebo were recorded at all doses for iief question 3 (ability to penetrate). for question 4, only the 5mg, 10mg and 25mg doses provided sta- tistically significant increases over placebo. it is usual to see a lower score for question 4 than for question 3, so the fact that the 5mg dose achieved statistical- ly significant increases over placebo in both questions would make 5mg stand out to the skilled clinician as a promising dose. 7.21 example 7 also notes that the most commonly recorded side effects were headache, dyspepsia and back-pain and states that the “incidence of treatment- emergent adverse events appeared related to dose” (page 11, lines 44-45). exam- ple 7 concludes that the results, when combined with the secondary efficacy vari- ables, show that all four tested doses exhibit significant improvement relative to placebo. 7.22 the table below, (at [0085]), summarises the changes from baseline in erec- tile dysfunction domain scores across the range of studies recorded in the 181 pa- tent. it shows an increase between 2mg, 5mg and 10mg, with a plateau develop- ing between 10mg and 25mg, and flattening off between 25mg and 100mg. - 116 - 7.23 a second table (at [0086]), reproduced below, summarises the percentage of treatment-emergent adverse effects recorded across the dose range. 7.24.1 it shows similar levels of adverse effects at the 2mg and 5mg doses as com- pared to placebo, for headache, back pain, myalgia and flushing. the lev- el of side effects which are tolerable to patients in this therapeutic area (erectile dysfunction being a quality of life issue), is different than in the case of life threatening conditions. side effects such as headache, back- ache, myalgia and flushing have a significant impact on patient tolerabil- ity, and therefore the lower incidence of these effects at the claimed doses of 2mg and 5mg would be seen as a real advantage of the lower dose. - 117 - 7.25 at the higher doses of 25mg and above, the incidence of these side effects (i.e. headache, back pain, myalgia and flushing) increase which is con- sistent with the statement beneath the table that an increase in adverse events was recorded at 25mg through 100mg doses. 7.26 the incidence of these side effects at a 10mg dose lies between the 2mg and 5mg dose on the one hand and 25mg and higher on the other. 7.27 claim 1 of the 181 patent states as follows: “a pharmaceutical unit dosage composition comprising 1 to 5 mg of a compound having the structural formula: said unit dosage form suitable for oral administration up to a maximum total dose of 5 mg per day.” 7.28 claims 2 and 3 of the 181 patent state as follows: 2. the dosage form of claim 1 comprising 2.5mg of the compound in unit dosage form. 3. the dosage form of claim 1 comprising 5mg of the compound in unit dosage form. 7.29 claims 6 to 9 of the 181 patent state as follows: “6. the dosage form of any of claims 1 through 3 for use in treating a condition where in- hibition of pde5 is desirable. 7. the dosage form of claim 6 wherein the condition is sexual dysfunction. 8. the dosage form of claim 7 wherein the sexual dysfunction is male erectile dysfunction. 9. the dosage form of claim 7 wherein the sexual dysfunction is female arousal disorder.” … - 118 - 1 11. obviousness 11.1 i understand that the 181 patent will lack inventive step if the differences be- tween its claimed subject matter and that of the prior art (the ‘inventive concept’), particularly daugan, would have been obvious to the skilled clinician at the rele- vant date. i understand that the relevant date for daugan is the priority date, i.e. 30 april 1999. 11.2 the skilled clinician would understand that the inventive concept is what is set out in the claims, namely a pharmaceutical composition comprising a unit dosage form of tadalafil of 1 to 5 mg for oral administration up to a maximum daily dose of 5mg, and with respect to a number of the claims, for use in the treatment of erectile dysfunction. the skilled clinician would understand that, whether taken on demand or daily, this low dose has the benefit of reducing the side effects previously believed to be an intrinsic part of pde5 inhibition to clini- cally insignificant levels, whilst maintaining efficacy. daugan 11.3 i have been asked to consider (
  4. a)what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim based on daugan alone; and (
  5. b)whether those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention, assuming the skilled team had the results of the phase i clinical trials, having put tadalafil into development from daugan. 11.4 as regards scenario (a), daugan describes a broad range of maximum daily doses between 0.5800mg comprised of dosage forms in the range of 0.2-400mg per single dose, although this is by way of guidance only (leaving the actual dos- ing regimen to the discretion of the physician). for every formulation described, daugan gives a dose of 50mg per tablet/capsule. the skilled clinician would as- sume there was some reason for having selected 50mg as the dose for formula- tion. 11.5 the skilled clinician would not have predicted or expected a dose of 5mg or even lower to be effective and the invention as defined in paragraph 11.2 would not be obvious. 11.6 as regards scenario (b), for the reasons given above in paragraphs 6.8 to 6.16error! reference source not found., the skilled clinician would have coun- selled the skilled team that a 50mg dose would be the best dose to assess safety, tolerability and efficacy in a phase iia clinical trial. therefore the invention as de- fined in paragraph 11.2 would not be obvious. 11.7 plesner has asked me, should the 50mg dose be effective in phase iia, which doses would i recommend to take forward into a phase iib dose ranging study. - 119 - 11.8 as the skilled clinician on the team, i would consider the doses of 25, 50 and 100 mg (i.e. a dose 2fold lower and 2-fold higher than 50
  6. mg)as the doses to take forward for the dose ranging study. for the reasons given in above at para- graphs 7.12 to 7.16, i do not believe the skilled team would have conducted this study at both on demand and daily dosing. it would only be an on demand study of placebo, 25, 50 and 100mg. 12.professor cohen’s expert declaration 12.1 plesner provided me with a copy of the expert declaration of professor ad- am cohen and asked me to comment on the matters set out in professor cohen’s declaration. where i do not comment on a statement in professor cohen’s dec- laration, this does not mean that i necessarily agree with that statement. 12.2 at paragraph 13, professor cohen sets out selected pharmacokinetic data for tadalafil and sildenafil and states that these parameters would be compared be- tween the two compounds. i disagree with professor cohen that sildenafil and tadalafil would be compared on this level for the reasons i set out at paragraphs 5.51 to 5.63 above and address each of the parameters that professor cohen has selected below: (
  7. a)at paragraph 13a, professor cohen gives the reported ic50 values for sildenafil and tadalafil and notes that the ic50 would be determined in- house. i would note that ic50 measurements provide variable results de- pendent on the assay type and conditions, and direct comparisons will be fraught with inaccuracies if not done in the same lab in the same run under the same conditions; (
  8. b)at paragraph 13b, professor cohen sets out the molecular weight of the two compounds, which i note would have very different chemical struc- tures and as such, the skilled clinician would know that the two com- pounds would have different pharmacokinetics and pharmacodynamics (even if they both inhibited pde5); (
  9. c)at paragraph 13c, professor cohen provides the protein binding for sildenafil and tadalafil. however, the extent of protein binding would not have been available nor could it have been calculated at the priority date without doing the experiments with tadalafil directly; (
  10. d)in paragraph 13d, professor cohen refers to certain blood values for sildenafil and tadalafil (plasma concentration, cmax, tmax and half-life) that appear in nichols et al 2002 (“nichols”, for sildenafil) and forgue et al 2005 (“forgue”, for tadalafil). i observe that both nichols and forgue were published after the priority date, and in particular, the forgue reference from 2005 was published more than five years after the priority date. ad- ditionally, nichols provides the absolute bioavailability for sildenafil, while forgue provides only the relative bioavailability for tadalafil. - 120 - (
  11. e)thought of in the most basic terms, the bioavailability of a drug is that per- centage of the active agent that is available for biologic activity. absolute bioavailability is typically determined by comparing the blood (plasma) concentration-time-curves of a drug after oral administration to that after intravenous (i.v.) application of the identical compound. so, i.v. application is used as the reference form of application, as with i.v. 100% is bioavaila- ble. in stark contrast, relative bioavailability is determined by comparing the plasma concentrationtime-curves after administration of two different formulations or drugs. however, as tadalafil cannot be administered i.v., only the relative bioavailability between different formulations can be measured. thus a true comparison cannot be made between the bioavail- ability for two different compounds. 12.3 professor cohen then states at paragraph 14 that the above parameters would be used in a computer model to obtain dose-response curves. he sets out in figure 1 a simulated profile of the sildenafil concentration in blood plasma at a daily dose of 50mg. he provides the reason for selecting the dose of 50mg for the simulation because “50 mg is one of the standard doses of sildenafil”. as i set out in paragraphs 5.23 to 5.41 above, the most effective and most commonly prescribed dose of sildenafil was 100mg. the skilled person would know that in developing tadalafil, it would have to be at least as effective as sildenafil in order to compete with it as a second in class. additionally, professor cohen does not provide any reasons why the skilled person would assume that both sildenafil and tadalafil would be dosed daily when the dosing paradigm at the priority date was firmly es- tablished as on demand. i set out at paragraphs 7.13 to 7.16 above why the skilled clinician would have counseled against daily dosing at the priority date. 12.4 the simulated graphs of sildenafil blood concentration (figure 1) and sildenafil’s inhibition of pde5 activity (figure 2) use poetic license and do not reflect what actually happens in the body. looking at figure 1, it ap- pears from professor cohen’s stylized graph that there is an almost instan- taneous effect whereas we know food and other factors delay absorption and effect, and in an ideal situation sildenafil reaches tmax at 60 minutes. additionally, the skilled person would expect there to be some concentra- tion-inhibition relationship, however, the shape of the curves in figure 1 and figure 2 appear different, for which there is no explanation provided. 12.5 it is unclear how the pde5 activity in figure 2 was generated or which da- ta/parameters were used to obtain this result. if it is based on those param- eters that professor cohen lists at paragraph 13 for sildenafil, this simula- tion does not provide the complete picture of the pk/pd of sildenafil be- cause it does not take into account
(1)the metabolites of sildenafil or
(2)the off target interactions of sildenafil and its metabolites that will affect effica- cy, side effects and tolerability. - 121 - 12.6 as an example, the major circulating metabolite for sildenafil has an in vitro potency for pde5 that is approximately 40% of sildenafil (as set out in the viagra label). the viagra label also states that plasma concentrations of sildenafil’s major metabolite are approximately 40% of those seen for sildenafil. this tells the skilled clinician that the metabolite of sildenafil makes a significant contribution to the inhibition of pde5, and thus the ef- ficacy, produced by sildenafil. in comparison, the major circulating metab- olite of tadalafil is not expected to be clinically active at observed metabolic concentrations, or in other words, is not expected to contribute to the effi- cacy of tadalafil (however, this information about tadalafil would not be known by the skilled person at the priority date). this represents an ap- proximately 15% increase in efficacy of sildenafil compared with tadalafil that was not incorporated into professor cohen’s simulation. 12.7 at paragraph 20, professor cohen compares the cmax for a 50 mg dose of sildenafil (nichols) to a 20 mg dose of tadalafil (forgue) and that “to obtain the same cmax, about 3 times less tadalafil than sildenafil is required”. it is unclear why professor cohen is relating a 20 mg dose of tadalafil with 50 mg of sildenafil – the cmax of the two compounds alone cannot be directly compared as it will not predict the clinical effect; the skilled person would need information on potency, distribution, elimination, tolerability, side ef- fects and the binding strength of the active ingredient to the receptor, amongst other factors. 12.8 in paragraph 21, professor cohen states that “various other properties also lead to a reduced required dosage of tadalafil as compared to sildenafil” and refers to the ic50 (paragraph 21a), molecular weight (paragraph 21b) and protein binding (paragraph 21c) of sildenafil and tadalafil, and at par- agraph 22, he states that “all these factors also result in a lower dose of tadalafil being required to obtain the same effect.” i’ve set out my reasons at paragraphs 5.51 to 5.63 why i disagree with this approach; the pharma- cokinetic data for tadalafil and sildenafil are distinctly different and cannot be directly compared. 12.9 at paragraph 23, professor cohen states that computer modeling supports his analysis and in figure 3, includes a simulated profile of tadalafil blood plasma concentration at a daily dose of 5mg. however, it is not entirely clear how professor cohen has reached a dose of 5 mg tadalafil on which to base this simulated profile. 12.10 at paragraph 25, professor cohen then states that “figure 4 shows how a 5 mg daily dose of tadalafil affects the pde5 activity. as can be seen from figure 2, the pde% activity reduces sharply to a value of about 18% of the 100% baseline after the first intake of tadalafil.” it is unclear where profes- sor cohen derives the 18% pde5 activity data from, or exactly which pa- rameters he has used in the simulation to reach this result. as discussed above for sildenafil, the skilled person would not know whether the me- - 122 - tabolites of tadalafil would have activity on pde5 or cause side effects by interacting with other pde and non-pde enzymes in the body. when one is evaluating the clinical effects of a drug, the predominant active agent and all of its metabolites need to be considered to fully understand the clinical effects of the drug on the patient. the enzymes responsible for many of the side effects of tadalafil (including myalgia, back pain, transient amnesia, and sudden hearing loss) continue to remain unknown today. it is also un- known what effect, if any, the inhibition of pde11 by tadalafil has on ad- verse events. 12.11 i explain the importance of cross-talk in the regulation of cgmp/camp lev- els at paragraph 5.17 above. as a result of tadalafil and sildenafil having different chemical structures and therefore affinities for the various pde enzymes, it is possible that they will produce different levels of camp. while cgmp is the primary signaling molecule that causes smooth muscle relaxation in penile tissue, at the priority date, camp levels in the body were also known to affect the relaxation of smooth muscle and contribute to tumescence. in fact, modulation of camp levels was used by prosta- glandin e1 (caverject), an erectile dysfunction drug that had regulatory approval at the priority date. again, although tadalafil and sildenafil are both pde5 inhibitors, as a result of crosstalk it is possible that their efficacy and safety profiles may not be similar. even today, the attributable causes of many of the side effects associated with pde5 inhibitors, including sildenafil and tadalafil, are not well defined. 12.12 overall, i disagree that the skilled team would take the approach set out by professor cohen at the priority date. rather, the simulation is dependent on knowledge that would not have available to the skilled team, 18 years after the priority date and long after the release and widespread use of tadalafil 5mg for daily dosing. 13. conclusions 13.1 as i set out at paragraph 11.6 and 11.8 above, i believe that the skilled team would have selected a dose of 50mg for a phase iia clinical trial and, should 50mg be effective, would have conducted an on demand study of 25, 50 and 100mg in phase iib. furthermore, i believe that lilly’s choice of dosing regimen and lowering the dose to doses as low as 5mg and below would not have been obvious to the skilled team…” - 123 - dr. gerald brocks cv er fremlagt i sagen, og af dette fremgår blandt andet, at han i 1999 del- tog i eli lillys advisory board, og at en række af ham modtagne stipendier er finansieret af eli lilly. af en supplerende eksperterklæring af 15. marts 2018 fra dr. gerald brock fremgår blandt andet: ”… 1. i am the same gerald brock who provided a first expert declaration in this action on 31 janu- ary 2018 (my “first declaration”). i have read the second expert opinion of professor ad- am f. cohen dated 24 october 2017, along with annex a and b thereto. i have sought to re- ply to those points which appear to be of most significance to the matters on which i am giv- ing evidence in this case. i have not responded to all of the matters set out in the opinion of professor cohen and, simply because i do not address them in this declaration, it should not be assumed that i agree with all of the statements made in that opinion. 2. in this declaration, the relevant sections and paragraphs i refer to below are those contained in the opinion of professor cohen, unless otherwise stated. i use the same terminology (and de- fined terms) in this declaration as i used in my first declaration. skilled team 3. at paragraph 3, professor cohen states, “a case in point is the pde5 inhibitors used in pulmo- nary hypertension and in sexual dysfunction. the claim that a team of drug developers of a drug like tadalafil is always led by a urologist is a misrepresentation, of course without di- minishing the importance of clinical expertise” (emphasis added). in my first declaration, i describe the skilled team by reference to the 181 patent, rather than by reference to a team of drug developers developing tadalafil for any indication, and state at paragraph 4.2, “given that the subject matter of the 181 patent pertains to dosing, efficacy, tolerability and side effects of tadalafil for the treatment of erectile dysfunction, i believe that the skilled team would be a team led by a clinical urologist with a special interest in research into erectile dysfunction.” at paragraph 4.4 of my first declaration, i also set out the other members that would be in- volved in the skilled team. 4. at paragraph 4, professor cohen then recognises that a clinician specialising in urology would be a member of the skilled team. he states, “the clinician, as the team member with experi- ence of treating patients, has particular importance when assessing the clinical significance of an effect – whether it is a desired effect or a side effect. additionally, the clinician will advise on the importance of certain endpoint measurements for the patient.” i agree with this state- ment and would add the following. for many indications, the therapeutic effect level can be clearly measured. one such example would be the development of a drug that lowers blood pressure - there are clear and established methods used to measure a change in a patient’s blood pressure. the clinicians’ role in developing a new drug to lower blood pressure would be more limited, given there are reliable tools and measurements of efficacy. 5. however, for an indication like erectile dysfunction, the role of the clinician is critical, particu- larly with regards to assessing the clinical level of efficacy and the effect of any side effects on that efficacy. i describe in my first declaration at paragraphs 5.33-5.34 that, at the priority date, the improvement in erectile function that was needed to be considered clinically relevant - 124 - was not well-established; as such, the skilled team would have heavily relied upon the clini- cian’s expertise and experience in treating patients with erectile dysfunction. i also described in my first declaration at paragraphs 5.37-5.41, the side effects that were known to be inti- mately associated with pde5 inhibition at the priority date. patients are sensitive to side ef- fects such as headache and flushing to the extent that they reduce the efficacy they would oth- erwise experience. after all, erectile dysfunction is a quality of life issue, and there can be a significant psychological component to it. 6. i do not wholly agree with professor cohen when he states in paragraph 4, “quantification of doses and the dose response is a matter primarily for the clinical pharmacologist, working with all members of the team, including the clinician”, and in paragraph 5, “in my view, the clinical pharmacologist will take the lead in selecting doses to be tried in the dose ranging study or studies, albeit with input from the clinician.” i do not believe the clinical pharmacol- ogist would take the lead in dose selection as it is the clinician who would be able to deter- mine the importance of the side effects and interpret efficacy, as i have discussed above. daugan 7. at paragraph 10, professor cohen states, “from the information in daugan, it would be obvious for a skilled team to take tadalafil forward into a routine pre-clinical and clinical trial pro- gramme as an oral treatment for male erectile dysfunction at the priority date. no inventive effort would be required for the research programme to succeed in establishing tadalafil as a safe, tolerable and effective treatment for male erectile dysfunction.” 8. i do not agree that it would be obvious from daugan to take tadalafil forward for development; indeed, despite glaxo originally performing phase i clinical trials with tadalafil (as seen the phase i clinical trial reports included in my first declaration), they did not develop it further; rather it was icos that took it forward for development. daugan only discloses a two-fold difference in potency as compared with sildenafil, no selectivity data, no further pk infor- mation and no clinical data (such as efficacy or tolerability). as such, i do not believe it would have been obvious to move forward to develop tadalafil based on daugan alone. 9. furthermore, professor cohen characterises pre-clinical and clinical trials as “routine”. while clinical studies follow a general step-wise path of testing pk and safety in phase i, efficacy and tolerability in phase ii, and confirm findings in larger populations in phase iii, i disagree that there is anything routine about the individual clinical trials and the results that come out of them. the planning of each clinical trial requires a significant amount of input, considera- tion and value judgments as to the population that is selected (severity of the disease, the age of the patients, etc), the measurements that will be used to assess efficacy, the endpoints that are selected, etc. the decisions and value judgments made are even less routine when you don’t have established ways to evaluate the results, as was the case for treating erectile dys- function. 10. at paragraph 12, professor cohen states, “because of prior knowledge of the side effects of sildenafil, it was known which effects would limit the tolerability. these were reductions in blood pressure and effects on vision.” changes in blood pressure and effects on vision were not the main issues of tolerability for sildenafil. i believe this statement illustrates why it is so important that a skilled clinician with experience of treating erectile dysfunction leads the skilled team, particularly for the reasons i give above at paragraph 5. a clinical pharmacolo- gist would not have the necessary level of understanding of how sensitive the efficacy would be in relation to side effects in this therapeutic area. in my experience headache and facial flushing associated with sildenafil use are much more likely to be a source of noncompliance - 125 - and intolerability, limiting its commercial utility, than blood pressure changes or blue-green colour vision alterations. 11. at paragraph 13, professor cohen states, “in the phase i study, a number of unknowns would be resolved, firstly the pharmacokinetics of the drug which would indicate duration of action.” this is incorrect. while the pk results from phase i studies would give the skilled team the blood concentration levels and the halflife of the drug, efficacy would not be tested and there- fore the skilled team would not have any indication of the blood concentration level needed to achieve efficacy or the duration of action for therapeutic efficacy. in fact, efficacy cannot be tested in phase i studies. pde5 inhibitors do not induce an erection, rather they interact in a complex biological pathway (including other pdes that were not yet known at the priority date) which results in the ability of a man to have an erection when he is appropriately stimu- lated. phase i studies take place in healthy volunteers, in a clinic, without a sexual partner. to measure efficacy, it must be in a patient with erectile dysfunction, where that patient is in a comfortable setting with a sexual partner he feels comfortable with. 12. professor cohen also states at paragraph 13, “secondly, the dose would be determined as a po- tentially pharmacologically active dose (pad). again we know that overall those tests would be expected to produce favourable results based upon animal and laboratory experiments per- formed before these trials were performed.” as discussed at paragraphs 5.47-5.50 of my first declaration, at the priori- ty date, there were no useful animal models of erectile dysfunction and the efficacy of a drug could only be assessed in humans. 13. at paragraph 14, professor cohen states, “the skilled team would have information on (
  1. i)activi- ty against pde5, (
  2. ii)molecular weight, (iii) protein binding, (
  3. iv)blood values (plasma concen- tration, cmax, tmax and half-life) after the phase i study. the parameters would be used in a computer model to obtain doseresponse curves.” to the best of my knowledge, computer modelling at the priority date was not used in the manner that professor cohen describes. fur- thermore, the skilled team would know that there were further factors to consider. at the pri- ority date, not all the pdes had been identified, and we knew that there were further pdes that had not yet been identified, each with the possibility of having a direct or indirect effect on potency and tolerability. as an example of this, today we know that pde11 (which had not yet been identified at the priority date) is also inhibited by tadalafil, whereas sildenafil does not. additionally, sildenafil has active metabolites that are responsible for about 15% of the drug’s efficacy. in comparison, tadalafil does not have any active metabolites, which the skilled person would not know at the priority date. 14. at paragraph 15, professor cohen states that tadalafil, “could be used with a reasonable expec- tation of success for a longer period after administration than sildenafil” and that, “this would also logically lead to questions about continuous use rather than on demand.” in my first declaration at paragraphs 7.15, i discuss the concerns the skilled clinician would have as re- gards daily dosing and why they would have recommended against it. the skilled clinician would have been equally concerned that a pde5 inhibitor with a long half-life would result in a longer duration of side effects when administered on demand. 15. at paragraph 17, professor cohen states that “in dose ranging studies, a similar ((bio)- equivalent) medicinal product is used as a starting point to find an optimal dose in terms of both effectiveness and in terms of safety and side effects.” i have described in my first decla- ration at paragraph 12.3 that the skilled team would know that in order to compete with sildenafil, they would need to develop something that was at least as effective and ideally, - 126 - more effective. at paragraphs 11.3-11.8 of my first declaration, i also set out the doses the skilled clinician would recommend to the skilled team. 16. at paragraph 18, professor cohen discusses that doses as low as 5mg and 10mg had been tested in the development of sildenafil and that, “thus, the selective pde5 inhibitor sildenafil was known to be effective in doses of 5 to50mg and had been investigated within that dose range.” then, after referencing the ic50 of sildenafil and tadalafil, at paragraph 19, he states, “thus the average skilled person had every reason to carry out dose ranging studies of the active in- gredient tadalafil in a range that is rather below the dosage range at which sildenafil is effec- tive.” however, the skilled clinician would have known that sildenafil was not considered clinically effective at doses lower than 50mg, as the 25mg dose was largely reserved for pa- tients that had a metabolic impairment or on concurrent medication that slowed their metabo- lism. the skilled clinician would know that 75% of patients preferred the dose of 100mg…” en erklæring af 14, februar 2018, der er afgivet af dr. ph.d. annamaria giraldi, har følgende indhold: - 127 - - 128 - - 129 - - 130 - - 131 - - 132 - - 133 - - 134 - - 135 - - 136 - en supplerende erklæring af 19.marts 2018, der er afgivet af dr. ph.d. annamaria giraldi, har følgende indhold: - 137 - dr. ph.d. annamaria giraldis cv er fremlagt i sagen, og af dette fremgår blandt andet, at gi- raldi har deltaget i advisory boards for forskellige lægemiddelvirksomheder, herunder eli lilly. en erklæring af 9. marts 2018 afgivet af dr. stig waldorff har følgende indhold: - 138 - - 139 - - 140 - - 141 - - 142 - - 143 - - 144 - - 145 - - 146 - - 147 - - 148 - dr. stig waldorffs cv er fremlagt i sagen. - 149 - reglerne om substitution lægemiddelstyrelsen udarbejder en liste over lægemidler, der kan substitueres, og herefter er apotekerne efter lægemiddellovgivningen forpligtede til at udlevere det billigste læge- middel i den relevante substitutionsgruppe til patienten, medmindre lægen eller patienten fravælger dette. ”cialis” og ”tadalafil sandoz” er i samme substitutionsgruppe, og uddrag af lægemiddel- styrelsens substitutionsliste har været fremlagt under sagen. endvidere har lægemiddelsty- relsens oversigt over prisudviklingen for ”tadalafil sandoz” 2,5 mg, 5 mg og 10 mg været fremlagt under sagen. sandoz har fremlagt en tabsopgørelse, hvoraf fremgår, at sandoz forventer at ville lide et tab på cirka 17,9 mio. kr., såfremt de bliver udelukket fra markedet ved et forbud. vidnet martin pedersen har under hovedforhandlingen nærmere redegjort for opgørelsen. forklaringer der er under sagen afgivet forklaring af professor dr. gerald brock, professor dr. ph.d. an- namaria giraldi, martin pedersen og dr. stig waldorff. gerald brock har forklaret bl.a., at han er urolog. da han havde færdiggjort sin uddannelse, fortsatte han med et fellowship i neurourologi på university of california i san francisco. han har haft en række akademiske stillinger, men de seneste 10 år har han været professor på kirurgisk afdeling. derudover har han været program director, hvor han har undervist i urologi. han har ledet et grundvidenskabeligt forskningslaboratorium. han har haft et uaf- hængigt laboratorium siden 1993, hvor de ser på dyremodeller for erektil dysfunktion. han har udgivet mere end 200 peer reviewed artikler i medicinsk litteratur. han er pt. president of the canadian urology association og secretary general of the international society for sexual medicine. han har de seneste 25 år været aktivt involveret i kliniske forsøg og udvik- ling og klinisk erfaring indenfor erektil dysfunktion. - 150 - hans arbejde for farmaceutiske virksomheder udgør ca. 15 % af hans samlede arbejde, og heraf udgør arbejdet for eli lilly ca. 30 %. dette har ikke påvirket indholdet af de eksperter- klæringer, som han har afgivet. hans rolle er at optræde som ekspert i retten, hvor han skal bidrage med sin ekspertise på en ærlig måde. dette er og har altid været hans intention. han har aldrig været ansat i en medicinalvirksomhed. fra 1999 og frem til 2014 deltog han i et advisory board hos eli lilly, og han har også i den forbindelse været involveret i nogle rets- sager vedrørende ”cialis”. han modtog ikke løn for sin deltagelse i det pågældende adviso- ry board, men han blev dog kompenseret for selve dagen. han kan vedstå indholdet af sine erklæringer af 31. januar og 15. marts 2018. forud for afgi- velse af erklæringerne havde han gjort sig bekendt med stridspatentet og 036- patentansøgningen. dernæst havde han læst al relevant litteratur, herunder daugan, oren, anderson og stoner, eksperterklæringer samt emea-rapporterne fra 2005 og 2007 (hhv. eu- ropean public assessment report for cialis og epar scientific discussion cialis). som beskrevet i afsnit 4 i hans første erklæring bør fagmanden (the skilled team) i begyndel- sen af processen være et team bestående af en dygtig kemiker, en dygtig formulator, og der- udover har man brug for en, som kan evaluere toksikologien, og en som kan vurdere farma- kokinetikken. efterfølgende vil teamet omfatte en dygtig kliniker. klinikeren vil være nøgle- personen, som kan evaluere de data, som teamet modtager, og klinikeren vil bidrage med kliniske ideer og klinisk viden. på dette særlige terapeutiske område og særligt i 1999 vidste man ikke, hvordan man skulle evaluere patienternes respons. man vidste ikke, hvilken for- bedring man havde brug for at se. af disse grunde var den kliniske ekspertise særligt vigtig. ved erektil dysfunktion skal patienten stimuleres, før medicinen virker. patientens respons kan påvirkes af stimuli, mental tilstand og andre faktorer. lige præcis med stridspatentet og på dette terapeutiske område vil klinikeren spille en stor rolle. klinikeren vil også være den rette til at bestemme den rette dosis. dette hænger sammen med, at man ved erektil dysfunk- tion ofte kan se en statistisk forbedring, men hvis patienten ikke kan trænge ind i sin partner, hjælper det ikke, og man har ikke et effektivt produkt. hans baggrund for at udtale sig om - 151 - teamet er, at han har arbejdet i branchen og behandlet patienter i 25 år. han har derudover siddet i forskellige advisory boards for virksomheder og bidraget i mange fase 2 forsøg. det kan være svært at se på informationerne i dag og samtidigt skrue tiden tilbage til 1999, hvor man forstod nogle aspekter på området, men de vidste også, at de ikke kendte hele hi- storien. de vidste eksempelvis, at der var 7 pde-enzymer, og at 1-6 var velbeskrevet. de vid- ste endvidere, at ”viagra” virkede på pde 5, men de kunne ikke definere de øvrige pde’er. før produktet testes på et menneske, som samtidigt stimuleres seksuelt, kan man ikke vide, om produktet er effektivt. cross-talk kan beskrives således: “even though you are targeting one particular second messenger, it will have impact in other physiological bets”. i slutningen af 1999 vidste de en del om ”viagra”, som blev markedsført af pfizer. de kendte til pde 1-6, til at pde 6 sad i øjet, og til at sildenafil havde omkring 10 % cross-over, hvor det var 10 % så effektivt mod pde 6 sammenlignet med pde 5. det var årsagen til, at de så bi- virkninger ved synet hos ca. 10 % af de mænd, som tog 100 mg ”viagra”. de vidste, at ”vi- agra” blev markedsført på verdensplan i doserne, 25, 50 og 100 mg. de vidste, at 100 mg var den klart mest effektive dosis og også den dosis, som 75 % af patienterne foretrak. de kendte til bivirkningerne, som var velbeskrevet i goldstein-artiklen, og til at 50 mg og 100 mg var de mest anvendte doser. de fandt hurtigt ud af, og det var tillige støttet i litteraturen, at 100 mg var den bedste dosis set i forhold til effektivitet. af denne grund tolererede mange patienter mere hovedpine og rødmen for at opnå en bedre erektion. en mand, der lider af erektil dys- funktion, er ofte depressiv og frustreret. hvis han får en dosis, som ikke er effektiv, vil han føle sig som en fiasko. hvis man ikke opnår en funktionel erektion, har man ikke opnået ret meget. eksperter vil derfor også i dag starte med høj dosis på 100 mg. medicinen er meget sikker, og der er ikke alvorlige bivirkninger herved. den vigtigste publikation på området er efter hans opfattelse goldsteins artikel fra 1998. den var på forsiden af new england journal of medicine. det var på mange måder en god un- dersøgelse, da den omfattede mange patienter, og da den viste dosis, effekt og bivirknings- profil. undersøgelsen viste bl.a., at 73 % af patienterne foretrak 100 mg, 25 % foretrak 50 mg, - 152 - og kun 2-3 % foretrak 25 mg. artiklen er i overensstemmelse med hans egen kliniske erfaring med ”viagra” på dette tidspunkt. boolells artikel om sildenafil fra 1996, som så på penisvæv, indeholder gode fund. man defi- nerede pde 3 og pde 5, og man mente, at pde 5 var den vigtigste. der blev udført farma- kokinetiske undersøgelser på raske mennesker, men de kliniske forsøg involverede kun 12 patienter. dernæst anvendte man testmetoden rigiscan, hvor to ringe presses omkring pe- nis. i en sådan situation kan det være svært at bevare en erektion, og patienten sættes i en meget unaturlig situation. testmetoden anvendes ikke længere. boolells artikel viser ikke, at 10 mg viagra ville virke som et klinisk produkt. goldsteins abstract fra 1997 kommer fra en præsentation, og den er således ikke en udgivet artikel. det er forskning, som er blevet peer reviewed, men hvor data ikke er gennemgået. man så på 400 patienter, som fik tildelt forskellige doser på 5, 25, 50 eller 100 mg sildenafil. disse patienter blev sammenlignet med placebo. man ved ikke ret meget om patienterne, herunder deres udgangspunkt. dette er kritisk, da man ikke kan måle en udvikling, når man ikke kender patientens udgangspunkt. man kan ikke udlede, om patienten kan opnå og be- vare en erektion længe nok til at kunne trænge ind i sin partner. undersøgelsen fortæller derfor ikke ret meget. man kan heller ikke udlede af undersøgelsen, at 5 mg ”viagra” ville have en klinisk effekt. foreholdt, at der deltog omkring 400 patienter i goldsteins undersø- gelse fra 1997, forklarede vidnet, at der til sammenligning deltog mere end 800 patienter i goldsteins undersøgelse fra 1998. han er enig med goldsteins synspunkter i erklæringen fra 8. august 2017. man kan ikke sammenligne goldsteins artikel fra 1998 og goldsteins abstract fra 1997. artik- len fra 1998 er en meget detaljeret artikel indeholdende omfattende studier, robuste data, bi- virkninger m.m. både goldsteins abstract fra 1997 og 1998 artiklen viser dog, at 50 mg er den bedste dosis. - 153 - goldstein 1998 viser de almindelige bivirkninger ved både 50 og 100 mg, og disse svarer til de bivirkninger, som man kendte til på prioritetstidspunktet. han mente dengang og også i dag, at der er en forbindelse mellem pde 5- hæmmere og bivirkningerne. hovedparten af bivirkningerne er vaskulære bivirkninger såsom hovedpine, øget blodtilførsel og rødmen. effektiviteten og bivirkningerne hænger sammen på den måde, at produktet er mest effek- tivt, når bivirkningerne sætter ind. på prioritetstidspunktet fandtes produktet ”phentalomine”, som også skulle indtages oralt. det virkede dog på en helt anden måde end ”viagra” og ”cialis”. hans laboratorium har brugt 25 år på at studere forskellige dyremodeller for at forstå fysio- logien ved erektion. de har bl.a. set på diabetes modeller og hypertension modeller, og deres forskning afspejler, at brug af dyremodeller ved stofudvikling ikke har megen validitet. dy- renes anatomi, fysiologi og metabolisme er ofte meget forskellige fra menneskers. dernæst var der kun dyremodeller relateret til toksikologien, men ikke til effektiviteten. ved udvikling af lægemidler foretager man prækliniske undersøgelser. dette sker forud for fase 1 forsøg. ved de første undersøgelser på mennesker ser man på sikkerhed og tolerance. der er tale om et specielt terapeutisk område, hvor produktet kun virker ved seksuel stimu- lation, og hvor stoffets effektivitet og stoffets potens ikke er det samme. potens viser, hvor ef- fektivt man kan hæmme enzymet. selektivitet viser, hvor effektivt man kan fokusere på det ene enzym pde 5, mens effektivitet viser, at mænd, som ikke tidligere kunne få en erektion, nu har en så forbedret erektion, at de kan gennemføre et samleje med deres partner. ved erektil dysfunktion kan man altså ikke sidestille stoffets potens med dets effektivitet. efter fase 1 har man fået farmakokinetiske data. man har c-max og eventuelt andre sammen- lignelige parametre. herefter indleder man fase 2, hvor man gerne vil se en tolerabel dosis, som også er effektiv. man vil derfor anvende en høj dosis i fase 2. ved valget af dosis har det også betydning, hvordan stoffet absorberes og distribueres i blo- det. han ville gerne vide, hvor høj koncentrationen er i den glatte muskel i penis, men det er - 154 - ikke muligt. man må derfor læne sig op ad blodkoncentrationen, som kan give dem et bille- de af, hvad de mener, der sker inde i penis. dernæst ser man på de fysiologiske data, som kan give dem en ide om, hvorvidt koncentrationen i blodet stemmer med den kliniske effekt. metabolismen har også indflydelse på valget af dosis. et produkt mod erektil dysfunktion kan virke helt fantastisk på patienten, men det vil ikke blive en succes, hvis det først virker efter 5 timer. i daugan ii beskrives en dosis i intervallet 0,5 mg - 800 mg f

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