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sø- & handelsrettens dombog

- lab udskrift af sø- & handelsrettens dombog ____________ kendelse afsagt den

  1. juli 2018 a-4-18 1) astrazeneca ab (advokat sture rygaard) 2) astrazeneca a/s (advokat sture rygaard) mod sandoz a/s (advokat klaus ewald madsen) sagens baggrund og parternes påstande denne sag om midlertidigt forbud, som er anlagt den
  2. januar 2018, vedrører gyldigheden af to af astrazeneca ab og astrazeneca a/s’ patenter for lægemidler indeholdende fulve- strant, der anvendes til behandling af brystkræft. sandoz a/s har erkendt, at selskabets produkt ”fulvestrant sandoz” krænker de to patenter, hvis patenterne kan anses for at være gyldige. -2- astrazeneca ab og astrazeneca a/s har nedlagt følgende påstande: 1: det forbydes sandoz a/s at udbyde, bringe i omsætning eller anvende farmaceutiske formuleringer til behandling af en benign eller malign sygdom i brystet eller forplant- ningskanalen ved intramuskulær indgivelse, hvor formuleringen omfatter fulvestrant i et ricinoleatvehikel, et farmaceutisk acceptabelt ikke-vandigt ester-opløsningsmiddel og en farmaceutisk acceptabel alkohol, og hvor formuleringen er tilpasset til opnåelse af en fulvestrant-blodplasma-koncentration på mindst 2,5 ngml-1 i mindst 2 uger, eller importere eller besidde de pågældende formuleringer med et sådant formål, så længe patent nr. dk/ep 1250138 er i kraft. 2: det forbydes sandoz a/s at udbyde, bringe i omsætning eller anvende farmaceutiske formuleringer til brug ved behandling af brystcancer ved intramuskulær indgivelse, hvor den farmaceutiske formulering omfatter fulvestrant, en farmaceutisk acceptabel alkohol, der er en blanding af 10 vægt-% ethanol pr. formuleringsvolumen og 10 vægt- % benzylalkohol pr. formuleringsvolumen, og hvor formuleringen indeholder 15 vægt- % benzylbenzoat pr. formuleringsvolumen og en tilstrækkelig mængde af et ricinolea- tvehikel til fremstilling af en formulering indeholdende mindst 45 mgml-1 af fulve- strant, hvor ricinoleatvehiklet er ricinusolie, og hvor den totale formuleringsvolumen er 6 ml eller mindre, eller importere eller besidde de pågældende formuleringer med et sådant formål, så længe patent nr. dk/ep 1250138 eller dk/ep 2266573 er i kraft. 3: principal påstand 3: udgået subsidiær påstand 3: det forbydes sandoz a/s at udbyde, bringe i omsætning eller anvende farmaceutiske formuleringer, der indeholder fulvestrant, som er omfattet af sandoz a/s' markedsfø- ringstilladelse med d.sp.nr. 29420, eller importere eller besidde de pågældende for- -3- muleringer med et sådant formål, så længe patent nr. dk/ep 1250138 eller dk/ep 2266573 er i kraft. 4: principal påstand 4: udgået subsidiær påstand 4: det forbydes sandoz a/s at udbyde, bringe i omsætning eller anvende lægemidlet fulvestrant "sandoz", der er omfattet af sandoz a/s' markedsføringstilladelse nr. 56584, eller at besidde de pågældende formuleringer med et sådant formål, så længe patent nr. dk/ep 1250138 eller dk/ep 2266573 er i kraft. 5: udgået 6: udgået 7: det påbydes sandoz a/s at omgående tilbagekalde allerede skete leverancer af læge- midlet fulvestrant "sandoz" solgt i henhold til markedsføringstilladelse nr. 56584 fra alle, hvortil levering er foretaget af sandoz a/s, og at anmode købere og modtagere af de pågældende leverancer om at tilbagekalde og returnere leverancerne af det pågæl- dende lægemiddel til sandoz a/s. i henvendelsen om tilbagekaldelse skal modtageren gøres opmærksom på sø- og han- delsrettens kendelse, og henvendelsen skal omfatte følgende ordlyd: "sø- og handelsretten i københavn har ved kendelse af [dato] i en sag om midlertidigt forbud truffet afgørelse om, at lægemidlet fulve- strant "sandoz" (markedsføringstilladelse nr. 56584) krænker patentret- tigheder, og sø- og handelsretten har derfor nedlagt forbud mod blandt andet salg, anvendelse og besiddelse af det pågældende læge- middel. -4- vi skal derfor anmode om, at alle eksemplarer af det pågældende pr o- dukt, som måtte være i deres besiddelse, omgående returneres til san- doz a/s for sandoz a/s' regning. sandoz a/s vil refundere de return e- rede produkter. vi anmoder dem endvidere venligst om, at de tager kontakt til alle, som har fået leveret fulvestrant "sandoz" via dem, herunder de rele- vante hospitalsenheder, og anmoder disse om at returnere alle eksem- plarer af fulvestrant "sandoz" til sandoz a/s for sandoz a/s' regning, og at de fremsender en kopi af nærværende brev til de pågældende modtagere." der skal fremsendes kopi af alle henvendelserne om tilbagekaldelse til astrazeneca ab og astrazeneca a/s' advokater. 8: det påbydes sandoz a/s straks at afregistere dets pris for lægemidlet fulvestrant "sandoz" i henhold til markedsføringstilladelse nr. 56584 i det danske prisregister (www.medicinpriser.dk). forbud og påbud i henhold til ovenstående påstande påstås nedlagt uden sikkerhedsstillelse, subsidiært skal forbud nedlægges på betingelse af, at astrazeneca stiller sikkerhed for det tab, som sandoz a/s evt. måtte lide som følge af forbuddet. sandoz a/s har nedlagt påstand om, at begæringen om nedlæggelse af forbud og påbud nægtes fremme, subsidiært at begæringen om forbud og påbud fremmes mod tilvejebringel- se af en af sø- og handelsretten fastsat sikkerhed. oplysningerne i sagen sagens parter -5- astrazeneca ab og astrazeneca a/s (herefter astrazeneca) tilhører begge astrazeneca- koncernen, der beskæftiger sig med forskning og udvikling af originale lægemidler og driver forretning i mere end 100 lande. astrazeneca ab ejer de to patenter, patent nr. dk/ep 1250138 og dk/ep 2266573 (herefter 138- og 573-patenterne), som sagen vedrører. astrazeneca a/s er ansvarlig for markedsfø- ring af koncernens produkter i danmark. sandoz a/s (herefter sandoz) er en del af sandoz-koncernen, som er en del af den multinati- onale schweiziske novartis-koncern. selskabet beskæftiger sig med kommercialisering og salg af generiske lægemidler. sagens oplysninger sagen vedrører alene 138- og 573-patenterne, idet parterne den
  3. maj 2018 blev enige om under nærmere bestemte vilkår at lade patent nr. dk/ep-1272195, der oprindelig var omfat- tet af sagen, udgå. af patentkravene i 138-patentet, hvoraf krav 1, 2, 4, 18, 19, 23 og 24 er uafhængige, fremgår bl.a. følgende: ”…
  4. anvendelse af fulvestrant ved fremstilling af en farmaceutisk formulering til behand- ling af en benign eller malign sygdom i brystet eller forplantningskanalen ved intramu- skulær indgivelse, hvor formuleringen omfatter fulvestrant i et ricinoleatvehikel, et far- maceutisk acceptabelt ikke-vandigt ester-opløsningsmiddel og en farmaceutisk accepta- bel alkohol, og hvor formuleringen er tilpasset til opnåelse af en terapeutisk signifikant blodplasmafulvestrantkoncentration i mindst 2 uger. …
  5. anvendelse af fulvestrant ved fremstilling af en farmaceutisk formulering til behand- ling af en benign eller malign sygdom i brystet eller forplantningskanalen ved intramu- skulær indgivelse, hvor formuleringen omfatter fulvestrant, 17-23 vægt-% af en farma- ceutisk acceptabel alkohol pr. formuleringsvolumen, 12-18 vægt-% benzylbenzoat i et ri- -6- cinoleatvehikel pr. formuleringsvolumen og en tilstrækkelig mængde af et ricinoleatve- hikel til fremstilling af en formulering med mindst 45 mgml-1 af fulvestrant. …
  6. anvendelsen ifølge et hvilket som helst krav fra 1 til 26, hvor det totale formulerings- volumen er 6 ml eller mindre, og koncentrationen af fulvestrant er mindst 45 mgml-
  7. …
  8. anvendelsen ifølge krav 28, hvor den totale mængde af fulvestrant i formuleringen er 250 mg, og det totale formuleringsvolumen er 5 til 5,25 ml.
  9. anvendelsen ifølge et hvilket som helst af kravene 1-29, hvor den farmaceutisk accep- table alkohol er en blanding af 10 vægt-% ethanol pr. formuleringsvolumen, 10 vægt-% benzylalkohol pr. formuleringsvolumen, og hvor formuleringen indeholder 15 vægt-% benzylbenzoat pr. formuleringsvolumen, og hvor ricinoleatvehiklet er ricinusolie. …” i 573-patentet genfindes bl.a. ikke det i ovennævnte krav 1 anførte om ”terapeutisk signifikant blodplasmafulvestrantkoncentration i mindst 2 uger”. af patentkravene til 573-patentet fremgår bl.a. følgende: ”…
  10. farmaceutisk formulering til anvendelse ved behandling af brystkræft ved intramu- skulær injektion, hvor den farmaceutiske formulering omfatter fulvestrant, en farmaceu- tisk acceptabel alkohol, der er en blanding af 10 vægtprocent ethanol pr. volumen formu- lering og 10 vægtprocent benzylalkohol pr. volumen formulering, og formuleringen in- deholder 15 vægtprocent benzylbenzoat pr. volumen formulering og en tilstrækkelig mængde af en ricinoleatvehikel til fremstilling af en formulering med mindst 45 mgml -1 fulvestrant, hvor ricinoleatvehiklen er en ricinusolie, og hvor det samlede volumen af formuleringen er 6 ml eller mindre.
  11. farmaceutisk formulering ifølge krav 2, hvor den samlede mængde fulvestrant i for- muleringen er 250 mg, eller mere, og det samlede volumen af formuleringen er 6 ml, eller mindre.
  12. farmaceutisk formulering ifølge krav 2, hvor den samlede mængde fulvestrant i for- muleringen er 250 mg, og det samlede volumen af formuleringen er 5 til 5,25 ml. …” prioritetsdatoen for 138-patentet er den
  13. januar
  14. der var europæisk indleveringsdato den
  15. januar 2001, hvilket betyder, at patentet vil udløbe den
  16. januar
  17. -7- patentansøgningen for 138-patentet blev offentliggjort som pct-ansøgning. det europæiske patent (138-patentet) blev udstedt den
  18. oktober
  19. krav 24, 27 og 30 svarer til de nuvæ- rende krav. krav 1 havde denne ordlyd: “…
  20. a pharmaceutical formulation comprising fulvestrant in a ricinoleate vehicle, a pharmaceutically acceptable nonaqueous ester solvent, and a pharmaceutically ac- ceptable alcohol wherein the formulation is adapted for intramuscular administration and attaining a therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. …” efter udstedelsen var der en indsigelsessag for epo vedrørende 138-patentet, hvor patentet endte med at blive opretholdt med ændrede krav. kravene blev således ændret til formålsbestemte fremgangsmådekrav, hvor man indskrev, hvilken sygdom der skulle behandles, nemlig benign eller malign sygdom i brystet. krav 1 havde herefter følgende ordlyd: “…
  21. use of fulvestrant in the preparation of a pharmaceutical formulation for the treatment of a benign or malignant disease of the breast or reproductive tract by in- tra-muscular administration, wherein the formulation comprises fulvestrant in a ric- inoleate vehicle, a pharmaceutically acceptable non-aqueous ester solvent, and a pharmaceutically acceptable alcohol, and wherein the formulation is adapted for at- taining a therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. …” ansøgningen for 573-patentet blev indgivet den
  22. september 2010 og har samme indgivel- sesdag og udløbsdag som 138-patentet. det europæiske patent for 573-patentet blev udstedt den
  23. juni
  24. epo fandt den
  25. juli 2017 ved en indsigelsessag 573-patentet ugyldigt. afgørelsen er appelleret, og efter det oplyste er der berammet mundtlig forhandling i appel- sagen den
  26. januar
  27. -8- parterne er enige om, at den eneste forskel mellem patentbeskirivelserne for 138- og 573-patenterne er, at afsnit 57 og 58 i beskrivelsen af 573-patentet ikke genfindes i be- skrivelsen af 138-patentet. af det europæiske patentskrift for 573-patentet fremgår nogle fremdragne publikatio- ner, herunder af riffkin, mcleskey og howell. af patentbeskrivelsen for 573-patentet fremgår bl.a. følgende “… [0001] the invention relates to a novel sustained release pharmaceutical formulation adapted for administration by intra-muscular injection containing the compound 7a-[9- (4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5

(10)-triene-3,17β-diol ifl solution in a ricinoleate vehicie which additionally comprises at least one alcohol and a non- aqueous ester solvent which is miscible in the ricinoleate vehicle, for use in the treatment ot breast cancer. [0002] oestrogen deprivation is fundamental to the treatment of many benign and malig- nant diseases of the breast and reproductive tract. in premenopausal women, this is achieved by the ablation of ovarian function through surgical, radiotherapeutic, or medi- cal means, and, in postmenopausal women, by the use of aromatase inhibitors. [0003] an alternative approach to oestrogen wthdrawal is to antagonise oestrogens with antioestrogens. these are drugs that bind to and compete for oestrogen receptors (er) present in the nuclei of oestrogen-responsive tissue. conventional nonsteroidal anti- oestrogens, such as tarnoxifen, compete efficiently for er binding but their effectiveness is often limited by the partial agonism they display, which results in an incomplete blockade of oestrogen-mediated activity (furr and jordan 1984, may and westley 1987). [0004] the potential for nonsteroidal antioestrogens to display agonistic properties prompted the search for novel compounds that wauld bind er with high affinity without activating any of the normal transcriptional hormone responses and consequent manifes- tations of oestrogens. such molecules would be “pure” antioestrogens, clearly distin- guished from tamoxifen-like ligands and capable of eliciting complete ablation of the trophic effects of oestrogens. such compounds are referred to as estrogen receptor- downregulators (e.r.d.). the rationale for the design and testing of novel, pure anti- oestrogens has been described ifl: bowler et al 1989, wakeling 1990a, 199gb, 1990c. wakeling and bowler 1987, 1988. [0005] steroidal analogues of oestradiol, with an alkylsulphinyl side chain in the 7a posi- tion, provided the first examples of compounds devoid of oestrogeflic activity (bowler et al 1989). one of these, 7α-[9-f4,4,5,5,5-pentafluoropentyl sulphinyl)nonyl]oestra-1 ,3,5-
(10)triene-3,17β-diol was selected for intensive study on the basis of its pure oestrogen afitagonist activity and significantly increased antioestrogenic potency over other availa- ble antioestrogens. in vitro findings and early clinical esperience with 7α-[9-(4,4,5,5,5- pentafluoropentylsulphinyl)nonyl]oestra-l,3-5
(10)-triene-3,17β-diol have promoted inter- -9- est in the development of the drug as a therapeutic agent for oestrogen-dependent indica- tions such as breast cancer and certain benign gynaecotogical conditions. [0006] 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3-5
(10)-triene-3,17β- diol, or ici 182,780, has been allocated the international non proprietary name fulves- trant, which is used hereinafter. when referring to fulvestrant we include pharmaceuti- cally-acceptable salts thereof and any possible solvates of either thereof. [0007] fulvestrant binds to er with an afflnity similar to that of oestradiol and comptetely blocks the growth stimulatory action of oestradiol in human breast cancer cells in vitro; it is more potent and more effective than tamoxifen in this respect. fulves- trant blocks completely the uterotrophic action of oestradiol ifl rats, raice and monkeys, and also btocks the uterotrophic activity of tamoxifen. [0008] because fulvestrant has none et the oestrogen-like stimulatory activity that is char- acteristic of clinically available antioestrogens such as tamoxifen or toremifene, it may of- fer improved therapeutic activity characterised by more rapid, complete, or longer- lasting tumour regression; a lower incidence or rate of devetopment of resistance to treatment; and a reduction of tumour invasiveness. [0009] in intact adult rats, fulvestrant achieves maximum regression et the uterus at a dose which does flot adversely affect bone density or lead to increased gonedotrophin se- cretion. if also true in humans, these findings could be of extreme importance clinically. reduced bone density limits the duration et oestrogen-ablative treatment for en- dornietriosis. futvestrant does not block hypothalamic er. oestrogen ablation atso caus- es or exacerbates hot flushes and other menopausal symptoms; fulvestrant will not cause such effects because it does net cross the blood-brain barrier. 3 [0010] european patent application no. 0 138 504 discloses that certain steroid deriva- tivas are effective antioestroenic agents. the disclosure includes information relating to the preparation of the steroid derivatives. in particular there is the disclosure within ex- ample 35 of the compound 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1,3,5
(10)-triene-3,17β-diol, which compound is specifically named ifl claim 4. it is also disclosed that the compounds of that invention way be provided for use in the form of a pharmaceutical composition comprising a steroid derivative et the invention together with a pharmaceutically-acceptable diluent er carrier. it is stated therein that the compo- sition can be in a form suitable for oral er parenteral administration. [0011] fulvestrant shows, along with other steroidal based compounds, certain physical properties which make formulation of these compounds difficult. fulvestrant is a particu- larly lipophilic molecule, even when compared with other steroidal compounds, and its aqueous solubility is extremely low at around 10 ngml-1 (this is an estimate from a waten/solvent mixture solute since measurements thia low could not be achieved in a water only solute). [0012] currently there are a number of sustained release injectable steroidal formulations which have been commercialised. commonly these formulations use oil as a solvent and wherein additional excipients may be present. below in table i are described a few com- mercialised sustained release injectable formulations. - 10 - [0013] in the formulations within table 1 a number of different oils are used to solubilise the compound and additional excipients such as benzyl benzoate, benzyl alcohol and ethanol have been used. volumes of oil needed to solubilise the steroid active ingredient are low. extended release is achievable for periods from 1 to 8 seeks. table i - oil based long-acting intramuscular injectlons …. [0014] in us 5,183,814 example 3 an oil based injection formulation of fulvestrant is de- scribed which comprises 50mg of fulvestrant. 400mg of benzyl alcohol and sufficient cas- tor oil to bring the solution to a volume at 1 ml. manufacture at a commercial scale of a formulation as described in us 5,183,814 will be complicated by the high alcohol concen- - 11 - tration. therefore, there is a need to lower the alcohol concentration in fulvestrant forrnu- lations whilst preventing precipitation of fulvestrant from the formulation. [0015] table 2 shows the solubility of fulvestrant in a number of different solvents. table 2 – solubility of fulvestrant [0016] as can be seen fulvestrant is significantly more soluble in castor oil than any of the other oils tested. the greater solvating ability of castor oil for steroidal compounds is known and is attributed to the high number of hydro groups of ricinoleic acid, which is the major constituent of the fatty acids within the triglycerides present in castor oil - see (riffkin et.al. j. pharm. sci.,
(1964). 53, 891). [0017] however, even when using the best oil based solvent, castor oil, we have found that it is not possible to dissolve fulvestrant in an oil based solvent alone so as to achieve a high enough concentration to dose a patient in a low volume injection and achieve a therapeutically significant release rate. to achieve a therapeutically significant release rate the amount of fulvestrant needed would require the formulation volume to be large, at least 10 ml. this requires the doctor to inject an excessively large volume of formula- tion to administer a dose significantly high enough for human therapy. [0018] currently guidelines recommend that no more than 5mls of liquid is injected in- tramuscularly in a single injection. pharmacologically active doses required for a 1 month long acting depot formulation of fulvestrant is around 250mg. therefore, when dissolved in just castor oil, fulvestrant would need to be administered in at least l0ml of castor oil. [0019] the addition of organic solvents in which fulvestrant is freely soluble, and whiich are miscible with castor oil, may be used, such as an alcohol. with the addition of high concentrations of an alcohol concentrations of >50mgml-1 of fulvestrant in a castor oil formutation is achievable, thereby giving an injection volumes of <5ml - see table 3 below. we have surprisingly found that the intro- duction at a non-aqueous ester solvent which is miscible in the castor oil and an alcohol surprisingly eases the solubilisatian at fulvestrant into a concentration at at least 50 mgml-1 - see table 3 below. the finding is surprising since the solubility of fulvestrant in non-aqueous ester solvents - sea table 2 above - is significantly lower than the solubility of fulvestrant in an alcohol. the solubility of fulvestrant is also lower in non-aqueous es- ter solvents than is the solubility of fulvestrant nl castor oil. - 12 - [0020] therefore, we present as a feature of the application a pharmaceutical formulation comprising fulvestrant (preterably fulvestrant is preseflt at 3-10%w/v, 4-9%w/v, 4-8%w/v, 4-7%w/v, 4-6%w/v and most preferably at about 5%w/
  1. v)ifl a ricinoleate vehicle, a phar- maceutically acceptable non-aqueous ester solvent, and a pharmaceutically acceptable alcohol wherein the formulation is adapted for intramuscular administration and attaining a therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. [0021] another feature of the application is a pharmaceutical formulation comprising ful- vestrant in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plas- ma fulvestrant concentration for at least 2 weeks. [0022] further features at the application include a pharmaceutical formulation adapted for intra-muscular injection comprising fulvestrant, 30% or less weight of a pharmaceuti- cally-acceptable alcohol per volume of formulation, at least 1% weight at a pharmaceuti- cally-acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per volume of formulation and a sufficient amount ot a ricinoleate vehicle so as to prepare a torniulation which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concontration for at least 2 weeks. [0023] further features at the application include a pharmaceutical formulation adapted for intra-muscular injection comprising fulvestrant; 35% (preferably 30% and ideally 25%) or less weight of a pharmaceutically-acceptable alcohol per volume of formulation, at least 1% (preferably at least 5% or ideally 10%) weight of a pharmaceutically-acceptable non-aqueous ester solvent miscible within a ricinoleate vehicie per volume of formulation and a sufficient amount of a ricino- leate vehicle so as to prepare a formulation ot at least 45mgml-1 of fulvestrant. [0024] for the avoidance of any doubt when using the term % weight per volume of for- mulation for the constituents of the formulation we mean that within a unit volume at the formulation a certain percentage of the canstituent by weight will be present, for example a 1% weight per volume formulation will contain within a 100ml volume of formulation 1g of the constituent. by way of further illustration … [0028] the pharmaceutically-acceptable alcohol may consist of one alcohol or a mixture at two or more alcohols, preferably a mixture of two alcohols. preferred pharmaceutically- acceptable alcohols for parenteral administration are ethanot, benzyl alcohol ar a mixture at both ethanol and benzyl atcohol, preferably the ethanol and benzyl alcohol are present in the formulation in the same w/v amounts. preferably the formulation alcohol contains 10% w/v ethanol and 10% w/v benzyl atcohol. - 13 - [0029] the pharmaceuticatty-acceptable non-aqueous ester solvent may consist of one or a mixture of two or more pharmaceutically-acceptabte non-aqueous ester solvents, pref- erably just one. a preferred pharmaceutically-acceptable non-aqueous ester solvent for parenteral administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate,isopropyl palmitate or a mixcture of any thereof. … [0032] preferred concentrations at the pharmaceutically-acceptabte non-aqueous ester solvent present in any at the above formulations are; at teast 5% w/v, at least 8% w/v, at least 10% w/v, at least 11% w/v, at least 12% w/v, at least 13% w/v, at least 15% w/v, at least 16% w/v, at least 17% w/v, at least 18% w/v, at least 19% w/v and at least 20% w/v. preferred maximal concentrations of the pharmaceuticatly-acceptable non-aqueous ester solvent are; 60% w/v or less, 50%w/v or less, 45% w/v or less, 40% w/v or less, 35% w/v or less, 30% w/v or less and 25% w/v or less. a preferred concentration is 15% w/v. preferred ranges at pharmaceutically- acceptable non-aqueous ester solvent present in any at the above tormulatians are select- ed from any minimum or maximum value described above and preferably are; 5- 60%w/v, 7-55%w/v, 8-50%w/v, 10-50%w/v, 10-45%w/v, 10-40%w/v, 10-35%w/v, 10- 30%w/v, 10-25%w/v, 12-25%w/v, 12-22%w/v, 12-20%w/v, 12-18%w/v, 13-17%w/v and ideally 14-16%w/v. preferably the ester solvent is benzyl benzoate, most preferably at about 15%w/v. … [0034] preferred combinations of pharmaceutically-acceptabte alcohol and phamaceuti- cally-acceptable non-aqueous ester sotvent in the formulation are set out below [0035] by the use ot the term ricinoleate vehicle we mean an oil which has as a proportion (at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ar 95% w/
  2. v)at its composition as tri- glycerides of ricinoleic acid. the ricinoleate vehicle may be a synthetic oil ar conveniently is castor oil, ideally of pharmacopoeial standards, as described above. [0036] we have surprisingly found that the above formulations of the application pro- vide, after intra-muscular injection, satistactory release at fulvestrant over an extended period at time. [0037] this finding is indeed surprising for the following reasons. 1. 1. previously tested by the applicants have been intra-muscular injections of fulvestrant in the form of an aqueous suspension. we have found extensive - 14 - local tissue irritation at the injection site as woll as a poor release profile. 8 is believed that the tissue irritation/infiammation was due to the presence of fulvestrant in the form of solid particles. the release profile appeared to be determined by the extent of inflammation/irritation present at the injection site and this was variable and difficult to control. also the fulvestrant release rate was not sufficiently high to be clinically significant. 2. 2. our findings from studies using 14c labelled benzyl alcohol show that it dissipates rapidly from the injection site and is removed from the body with- in 24 hours of administration. [0038] it would be expected that ethanol will dissipate at least as quickly, if not more rap- idly, from the injaction site. [0039] it is known that benzyl benzoate is metabolised by conjugation to glycine to form hippuric acid by the human hver and excreted into the urine - martindale: the extra pharmacopoeia 32nd edition psge 1103, and, therefore, it is unlikely that benzyl benzoate, when used, is present at the injection site during the whole of the extended relaase period. [0040] we have found that despite the rapid eliminstion of the additional solubhlising ex- cipients, i.e. the alcohol and pharmaceutically-acceptable non-aqueous ester solvent, from the formulation vehicle and the site of injection efter injection of the formulation, extend- ed release at therapeutically significant levels of fulvestrsnt over an extended period can still achieved by the formulation of the invention. [0041] by use of the term “therapeutically significant levels” we mean that blood plasma concentrations of at least 2.5 ngml-1 ideally at least 3 ngml-1 at least 8.5 ngml-1, and up to 12 ngml-1 of fulvestrant are achieved in the patient. preferably blood plasma levels should be less than 15 ngml-1. … [0044] simply solubilising fulvestrant in an oil based hiquid formulation is not predictive of a good release profile or lack of precipitation of drug efter injection at the injection site. [0045] table 3 shows the solubility of fulvestrant in a castor oil vehicle additionally con- taining alcohols ethanol and benzyl alcohol with or without benzyl benzoate. the results clearly show the positive effect of benzyl benzoate an fulvestrant sohubility ifl castor oil, despite fulvestrant having a lower solubility in benzyl benzoate than in either alcohol ar castor oil. table 3 [0046] table 3 – effect of benzyl benzoate on fulvestrant solubility in castor oil at 250c - 15 - [0047] the following table 4 shows the solubility of fulvestraant in a range of oil based formulations which contain the same ammounts og alcohol and benzyl benzoate but in which the oil is changed. the data also shows solubility of fulvestrant after removal of the alcohols. table 4 [0048] precipitation of fulvestrant and the release profile was determined wth the above formulations in an in vivo rabbit study. [0049] figure 1 shows the release profile in vivo of the four formulations from the second part of table 4 and shows the effect of the fixed oil component on fulvestrant plasma pro- file over five days foliowing intramuscular administration in rabbits (data normalised to 50mg per 3kg; mean given; number of animals per timepoint = 8, plasma samples assayed for fulvestrant content using lc-ms/ms detection following solvent extraction). as can be sean the castor oil formulation showed a particularly even release profile with no evi- dence of precipitation of fulvestrant at the injection site. …” for så vidt angår den ovenfor viste tabel 3 (table 3) er parterne enige om, at det nok er en fejl, at der står 45 mg/ml ud for fulvestrants opløselighed ved en formulering med 10 % ethanol og 10 % benzylalcohol. - 16 - derudover er der enighed om, at der i den ovenfor viste tabel 1 (table 1) er en fejl vedrørende de sidste to formuleringer, idet tallene i de sidste tre kolonner skal rykkes én kolonne til ven- stre. under sagen er der fremlagt tegninger, der er udfærdiget af astrazeneca, som viser, hvad der sker, når et oliedepot sprøjtes gennem et subkutant fedtlag og overhud ind i musklen. parterne er enige om, at man ikke kan se i hvilken rækkefølge, at de forskellige excipienter forsvinder. af tegningerne fremgår følgende: - 17 - - 18 - figur 1 i patentbeskrivelsen viser ”releaseprofilen” for tre af formuleringerne, hvor det ses, at formuleringen f1 med castorolie har et ret jævnt optag i kroppen. - 19 - modhold – prior art – kendt teknik: sandoz gør gældende, at stridspatenterne er ugyldige, fordi de savner op- findelseshøjde på baggrund af indholdet i en artikel af anthony howell m.fl.: ”pharma- cokinetics, pharmacological and anfi-tumour effects of the specific anti-oestrogen ici 182780 in women with advanced breast cancer”, british journal of cancer, 1996, 74, s.300-308, og en artikel af sandra w. mcleskey: “tamoxifen-resistant fibroblast growth factor-transfected mcf-7 cells are cross-resistant in vivo to the antiestrogen ici 182,780 and two aromatase inhibitors”, clinical cancer research, 1998, vol. 4, s.697-711, der er uenighed om, hvorvidt howell-artiklen er ”closest prior art”, idet astrazeneca gør gældende, at artiklen ikke udgør en ”enabling disclosure”, fordi stofformuleringen, der an- vendes i howell-artiklen, ikke oplyses. der er enighed mellem parterne om, at man ikke af howell-artiklen kan se den præcise sammensætning af den anvendte stofformulering. artiklen beskriver det første forsøg på mennesker med metastaserende brystcancerpatienter, der var resistente over for tamoxifen, som er et andet antiøstrogen. forud for howell-artiklen var fulvestrant alene blevet givet til mennesker, der skulle opereres for brystkræft for at få tumoren til at mindskes. af howell-artiklen fremgår bl.a. følgende: - 20 - ”… pharmacokinetics, pharmacological and anfi-tumour effects of the specific anti-oestrogen ici 182780 in women with advanced breast cancer a howell1, dj defriend2, jfr robertson3, rw blamey3, i, anderson1, e anderson4, fa sutcliffe5 and p walton5 1crc department of medical oncology, university of manchester, christie hospital, wilmslow road, manchester m20 43x; 2department of surgery, university hospital of south manchester, nell lane, west didsbury, manchester m20 8lr; 3department of surgery, city hospital, not- tingham ng5 1pb 4tumour biochemistry laboratory, christie hospital, wilrnslow road, man- chester m20 43x; 5zeneca pharmaceuticals. alderley park, macclesfield, cheshire sk10 4tg, uk. summary we have assessed the pharmacokinetics, pharmacological and anti-tumour ef- fects of the specific steroidal anti-oestrogen ici 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. the agent was administered as a monthly depot in- tramuscular injection. peak levels of ici 182780 occurred a median of 8-9 days efter dos- ing and then declined but were above the projected therapeutic threshold at day 28. cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. the aucs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respective- ly, suggesting some drug accumulation. luteinising hormone (
  3. lh)and follicle- stimulating hormone (fsh) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ici 182780 on the pituitary—hypothalamic axis. there were no significant changes in serum levels of prolaetin, sex hormone-binding globulin (shbg) or lipids. sideeffects were infrequent. hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. thirteen (69%) pa- tients responded (seven had partial responses and six showed ‘no change’ responses) to ici 182780, after progression on tamoxifen, for a median duration of 25 months. thus ici 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer. … a new class of specific anti-oestrogens has been developed that produce more complete suppression of the proliferative effects of oestrogen upon tumours. substitution of a long side-chain at the 7 alpha position of the oestradiol molecule has produced compounds that appear more active as anti oestrogens than the triphenylethylene derivatives such as tamoxifen (wakeling and bowler, 1987, 1988). the structure of the prototype specific anti- oestrogen, ici 164384, is shown in figure 1 together with that of ici 182780, {7a- [9(4,4,5,5,pentafluoropentyl-stilphinyl)nonyl]oestra- i ,3,5,
(10)-triene-3,17β-diol} the com- pound selected for clinical evaluation because of its greater potency and affinity for the er (wakeling et at., 1991). … ici 164384 and ici 182780 are up to two orders ot magnitude more potent than tamoxifen as inhibitors of cell growth in vitro. - 21 - … … we report that although some drug accumulation occurred at the dose level used in this study, administration of ici 182780 was associated with a lower than expected incidence of side-effects (such as hot flushes and vaginal problems) together with a high response rate and long response duration in women previously treated with tamoxifen. a prelimi- nary report of the early clinical result of this study has been published (howell et al., 1995). patients and methods patients nineteen patients with advanced breast cancer resistant to tamoxifen were treated with ici 182780. the study was approved by the ethics committees of each clinical centre. patients were eligible for the study if they were post menopausal and age less than 81 years, with histologically verified breast cancer. patients were included if they had been treated with tamoxifen as an adjuvant to surgery for more than 2 years and then relapsed, or if they had been treated with tamoxifen for advanced disease, had a complete or partial remission or disease stabilisation (‘no change’) for at least 6 months, and subse- quently progressed while taking tamoxifen. … one patient had adjuvant therapy for only 9 months and progressed and was thus a pro- tocol violation, but is included in the analysis. she had progressive disease when treated with ici 182780. - 22 - … ici 182780 was administered as a long acting formulation contained in a castor oil-based vehicle by monthly im. injection (5
  1. ml)into the buttock. for appraisal of drug safety, the first four patients received escalating doses of ici 132780, starting with 100 mg in the first month and increasing to 250 mg i.m. from the second month onwards, following confir- mation of lack of local or systemic drug toxicity at the 100 mg dose. patients 5-19 received 250 mg month-1 i.m. from the outset. treatment with ici 182780 was continued until ob- jective tumour progression occurred. patients were seen at intervals of 3—7 days during the first month after commencing treatment with ici 182780 in order to monitor local and systemic drug tolerability and to collect blood samples for pharmacokinetic studies. thereafter, patients were reviewed at monthly intervals in order to evaluate objective tumour response to ici 182780 and to further monitor local and systemic drug tolerabil- ity. … results pharmacokinetics serum concentrations of ici 182780 were measured during the first month of treatment in 15 patients who started treatment at the 250 mg dase level and in 11 patients who re- mained on treatment with ici 182780 during the sixth month. in the majority of patients, the measured cmax was reached 8 or 9 days after the start of the drug administration. however, samples were not available between day 2 and day 8. the profile was quite flat between days 2 and 8, supported by preclinical data in dogs where the cmax was seen on day 1 or 2. following both the 100 mg and 250 mg doses, continuous release of drug from the ici 182780 slow release formulatien was shown throughout the one month dosing interval. the profiles af the serum concentration of ici 182780 are shown in figure 2. comparison of data after the first and sixth monthly 250 mg doses of ici 182780 showed that the mean exposure to the drug increased slightly after multiple dosing. mean cmax (which occurred an day 7) increased from 10.5 ng ml-1 to 12.8 ng ml-1, accompanied by increases in mean end-of-month concentrations from 3.1 ng ml-1 to 5.6 ng ml-1 and auc values from 140.5 ng day ml-1 to 206.3 ng day ml-1 for the first and sixth months respec- tively in the 11 patients studied. multiple dosing produced a 1,2-fold increase in cmax and a 1.5-fold increase jo auc, indicating a degree of accumulation at the 250 mg dose level. this greater exposure was not associated with any inereased side-effects or irritancy (see below). there was no significant difference in the median cmax and auc between re- sponders and non-responders to treatment (table ii). after 6 months of treatment there was no significant difference between cmax and auc for patients who had a partial re- ponse (
  2. pr)compared with those with a no change tnc) response. effects on hormones and lipids the serum levels of fsh, lh, prolactin and shbg, before and during treatment with ici 182780, are shown in figure 3. … - 23 - … side-effects no serious drug-related adverse events occurred in any of the 19 patients treated with ici 182780. minor systemic adverse events were reported by two patients and comprised a transient bloodstained vaginal discharge and a subjective feeling of living in a ‘dream- like state’ (similar to one she had while taking tamoxifen) in one patient and alteration of body odour (noticed by her husband for a 1 month period), possibly associated with in- creased hair greasiness, in the other. administration of the pure anti-oestregen was not associated with any atleration in the frequency of night sweats or hot flushes, if already present, and none were initiated. none of the patients reported vaginal dryness or altered libido despite direct questioning at each monthly out-patient attendence. the long-acting formulation of ici 182780 used in this study appeared well tolerated locally at the site of injection despite the relatively large volume (5
  3. ml)administered. one patient developed bruising over the buttock and a second developed tenderness at the injection site follow- ing drug administration on one occasion each, and a third patient had local erythema at the injection site on one occasion. … - 24 - … discussion this study represents the irst investigation of long-term administration of the specific an- ti-oestrogen, ici 182780, to patients with breast cancer and demonstrates that predicted therapeutic levels of ici 182780, as judged from animal experiments (wakeling et al., 1991; dukes et al., 1993) and our previous short phase 1 study (defriend et al., 1994b) can bc achieved and maintained for 1 month following a single i.m. injection of the long- acting formulation used. treatment with ici 182780 was associated with minor effects on serum hormones and lipid levels, produced few side-effects and resulted in a high re- sponse rate after tamoxifen failure, together with a median reponse duration of 25 months. … however, there was evidence of drug accumulation after multiple dosing, such that after 6 months treatment there was an 80% increase in mean end of month drug levels and a 50% increase in the auc compared with data from month 1. these data suggest that lower doses of the drug may be effective in maintaining therapeutic serum drug levels, although further clinical studies are required to confirm this hypothesis. … all but four patients in the present study were treated with tamoxifen up until treatment with ici 182780 was initiated. … the lack of apparent adverse effects of ici 182780 seen in the present study would, if con- firmed in future larger trials, give the specific anti-oestrogen potential advantages over currently available second-line endocrine agents. … the most troublesome side-effects of tamoxifen, the current first-line endocrine therapy of choice, are the inception or exacerbation of hot flushes and sweats and the initiation of vaginal discharge. as already stated, ici 182780 did not induce or exacerbate hot flushes er sweats in the present study and furthermore did not cause symptoms of vaginal dry- ness or altered libido. … in the highly selected group of patients reported here, there appeared to be no cross- resistence between ici 182780 and taxomifen in 69% of patients and the median duration of reponse was 25 months. … - 25 - ici 18780 is thought to act exvclusively as an anti-oestrogen via er (wakeling et al., 1991). responses to treatment with ici 18780 after progression on tamoxifen in such patients suggests that tamoxifen failure may be because of the intrinsic agonist activity of tamoxi- fen or one of its oestrogenic metabolites (simon et al., 1984; gottardis et al., 1989; osborne et al., 1991, howell et al., 1992; defriend et al., 1994a) or because tamoxifen is, in some way, sequestered from the er (pavlick et al., 1992; wolfe et al., 1993) allowing endoge- nous oestradiol to recommence tumour stimulation. … in addition, we and others have demonstrated so-called withdrawal responses in breast cancer patients after stopping treatment with tamoxifen at the time of tumour progres- sion, further suggesting tumour stimulation by tamoxifen as a possible cause of treatment failure (howell et al., 1992). however, in most studies withdrawal responses occur in on- ly one-third or less of patients and thus tamoxifen withdrawal responses are unlikely to account for ali the responses seen after treatment with ici 182780 in the current study. … although these very low levels of oestrogen may be insufficient to produce any signifi- cant directiy mitogenic effects in breast cancer cells, recent experimental studies have shown that small concentrations of oestradiol can act synergistically to amplify the effects of other growth promoting pathways such as epidermal growth factor/transforming growth factor alpha (egf/tgf-α), insulin-like growth factor (igf)-l and the fibroblast growth factor family (stewart et al., 1990; westley and may, 1991). … we conclude from the results of this preliminary study that the pure anti-oestrogen, ici 182780, is well tolerated during long-term treatment and is active as an anti-tumour agent in patients with advanced breast cancer who have previously relapsed on tamoxifen. at the dose used, there was accumulation of the drug over time and thus lower doses than those administered in this study may be as effective. …” af en artikel af marco m. gottardis m.fl.: ”inhibition of tamoxifen-stimulated growth of an mcf-7 tumor variant in athymic mice by novel steroidal antiestrogens”, cancer research 49,4090-4093, au- gust 1, 1989, fremgår bl.a. følgende: “… inhibition of tamoxifen-stimulated growth of an mcf-7 tumor variant in athymic mice by novel steroidal antiestrogens abstract this investigation examines the tamoxifen (tam)-dependent growth in vivo of an mcf-7 tumor variant, mck-7tam, previously reported in this journal (m. m. gottardis and v. c. jordan, cancer res., 48: 5183-5187,1988). ovariectomized athymic mice were implanted with 1-mm3 - 26 - pieces of mcf-7tam and were treated with silastic capsules of varying sizes containing tam to demonstrate dose-dependent growth over a 10-wk experiment. … tumor areas were significantly different (p < 0.03) at wk 20. the growth of tam-stimulated tumor, mcf-7tam, was inhibited by the novel steroidal antiestrogens, ici 164,384 and ru 39,411. tam-stimulated growth (0.5-cm silastic capsule) was maintained at control levels by 8 wk of treatment with ici 164,384 (1 mg s.c. every other day). ici 164,384 alone had no stimula- tory activity. at the same dose, ru 39,411 inhibited tam-stimulated growth of mcf-7tam, although not to control levels. … materials and methods … where indicated, ru 39,411 and ici 164,384 (provided by roussel uclaf) were injected in a 0.1- ml volume s.c. as a fine suspension. this suspension was made by dissolving the compounds in ethanol, mixing in tween 80 (sigma chemical) (1:1 dilution), and adding a 1:10 dilution of iso- tonic saline to precipitate the compound. …” af en artikel af alan e. wakeling m.fl.:”a potent specific pure antiestrogen with clinical potential”, cancer research 51,3867-3873, august 1, 1991, fremgår bl.a. følgende: “… a potent specific pure antiestrogen with clinical potential alan e. wakeling, michael dukes, and jean bowler … abstract … sustained antiestrogenic effects, following a single parenteral dose of ici 182,780 in oil suspension, were apparent both rats and pigtail monkeys. in vivo, antitumor activity of ici 182,780 was demonstrated with xenografts af mcf-7 and br10 human breast cancers in nude mice. a single injection of ici 182,780 provided antitumor efficacy equivalent to that og daily tamoxifen treatment for at least 4 weeks. … materials and methods - 27 - … tumor growth inhibition assays. mcf-7 cells were suspended in culture medium (no serum) and inoculated s.c. into the flank of adult female mice (0.1 ml/approximately 5 x 106 cells). … tamoxifen was administered once daily p.o. at a dose of 10 mg/kg (1 ml/100 g body weight of aqueous dispersion in 0.5 % tween 80) and ici 182,780 as a single s.c. injection of 5 mg/mouse (50 mg/ml in arachis oil) tumor size was assessed weekly as the product of caliper measurements of the largest diameter and the axis perpendicular to it. … results … breast cancer growth inhibition … human breast tumors in vivo. the effects of ici 182,780 were compared with those of tamoxifen in two models of human breast cancer grown in nude mice. the growth of xenografts of mcf-7 human breast cancer cells, supported by continuous treatment with ethynyl estradiol, was blocked completely for at least 4 weeks by a single s.c. injection of 5 mg of ici 182,780 in oil suspension (fig. 9). the magnitude of this effect was campara- ble with that in animals treated continuously with a high dose of tamoxifen (10 mg/kg/day p.o.). the growth of transplants of the br10 human breast tumor was also suppressed effective- ly by ici 182,780. mice implanted with 1-2 mm3 tumor mass were given a single 5-mg s.c. injection of ici 182,780 on the day of implantation or daily treatment for 8 weeks with tamoxifen (10 mg/kg/day p.o.). tumor measurements (fig. 10) showed a substantial and sustained reduction of tumor growth in ici 182,780-treated mice similar to that of high- dose tamoxifen treatment. … - 28 - …” af en artikel af david j. defriend m.fl.: ”investigation of a new pure antiestrogen (ici 182780) in women with primary breast cancer”, cancer research 54, 408-414, january 15, 1994, vedrørende det første forsøg på mennesker med fulvestrant i en formulering baseret på propylenglycol, der er en alkohol, fremgår bl.a. følgende: - 29 - “… investigation of a new pure antiestrogen (ici 182780) in women with primary breast cancer … abstract … in conclusion, ici 182780 was well tolerated after short term administration and pro- duced demonstrable antiestrogenic effects in human breast tumors in vivo, without show- ing evidence of agonist activity. these properties identify ici 182780 as a candidate agent with which to evaluate whether a pure estrogen antagonist offers any additional benefit in the treatment of human breast cancer over conventional nonsteroidal antiestrogens, typified by tamoxifen, which exhibit variable degrees of agonist activity. … study design… … all patients randomized to receive ici 182780 were visited on each treatment day by an investigator, who administered the trial medication and monitored local and systemic tolerance. ici 182780 was administered by i.m. injection into the buttock as a short-acting formulation, containing 20 mg/ml drug in a propylene glycol-based vehicle. blood sam- ples were taken before and after the study period for measurement of complete blood count, prothrombin time, clinical biochemistry, and serum levels of gonadotropins and shbg. during the study period additional blood samples were taken, immediately prior to drug administration, from patients receiving treatment with ici 182780, for measure- ment of serum drug levels. … drug tolerability. treatment with ici 182780 caused no serious drug-related adverse events, and no patients were withdrawn from the study because of drug toxicity. …” af den ovenfor nævnte artikel af sandra w. mcleskey: “tamoxifen-resistant fibroblast growth fac- tor-transfected mcf-7 cells are cross-resistant in vivo to the antiestrogen ici 182,780 and two aromatase inhibitors”, clinical cancer research, 1998, vol. 4, s.697-711, som sandoz mener, at man skal kombinere howell-artiklen med, fremgår bl.a. følgende: “… tamoxifen-resistant fibroblast growth factor-transfected mcf-7 cells are cross- resistant in vivo to the antiestrogen ici 182,780 and two aromatase inhibitors 1 - 30 - … abstract although the antiestrogen tamoxifen has been the mainstay of therapy for estrogen re- ceptor (er)-positive breast cancer, successful treatment of responsive tumors is often followed by the acquisition of tamoxifen resistance. subsequently, only 30—41% of patients have a positive response to second hormonal therapies. this lack of response might be explained by mechanisms for tamoxifen resistance that sensitize er path- ways to small amounts of estrogenic activity present to tamoxifen or that bypass er pathways completely. to elucidate one possible mechanism of tamoxifen resistance, we treated ovariectomized tumor-bearing mice injected with fibroblast growth factor (fgf) transfected mcf-7 breast carcinoma cells with the steroidal antiestrogen ici 182,780 or one of two aromatase inhibitors, 4-oha or letrozole. these treatments did not slow estrogen independent growth or prevent metastasis of tumors produced by fgf-transfected mcf-7 cells in ovaricctonized nude mice. fgf-transfected cells had diminished responses to ici 182,780 in vitro, suggesting that autocrine acthity of the transfected fgf may be replacing estrogen as a mitogenic stimulus for tumor growth. er levels to fgf transfectants were not down-regulated, and banal levels of transcripts for estrogen-induced genes or of er-mediated transcription of entrogen response ele- ment (ere) luciferase reporter constructs in the fgf expressing cells were not higher than parental cells, implying that altered hormonal responses are not due to down- regulation of er or to fgf mediated activation of er. these studies indicate that es- trogen independence may be achieved through fgf signaling pathways independent of er pathways. if so, therapies directed at the operative mechanism might produce a therapeutic response or allow a response to a second course of afitiestrogen treatment. … although the mechantsms of tamoxifen resistance described above should be amenable to alternative hormonal therapy, early results for small numbers of tamoxifen-resistant patients have shown that only about 30-40% of such patients have a positive response to subsequent ici 182780 or aromatase inhihitor therapy (13-20). these data imply alterna- tive mechanisms for tamoxifen resistance. … fgfs and their recepters have been shown to be present with high frequency in breast cancer specimens (41-50). evidence for a possible role for fgf signaling in the estrogen- independent growth at breast tumors is gained from study of clonal and polyclonal fgf- transfected mcf-7 cell lines, which are capable of forming large, progressively growing tumors in ovariectomized or tamoxifen-treated nude mice. moreover, the fgf- transfected cells are metastatic, forming micrometastases in lymph nodes, lungs, and oth- er organs (21, 22, 5l). the etrogen-independent and tamoxifen-resistant growth of fgf- transfected mcf-7 cells suggests an interaction betweenfgf signaling pathways and er- activated pathways that could occur at the level of the er itself or at the end point of both pathways, where they impinge on growth mechanisms. if fgf-mediated growth path- ways bypass the er pathway to affect growth directly, we would expect that growth would be unaffected by hormonal treatments devoid of agonist activity. we therefore sought to determine the sensitivity of the estrogen-independent tumor growth of fgf- transfected mcf-7 cells to ici 182.780 or aromatase inhibitors. in contrast to what was - 31 - seen with erb-b signaling pathways, we report that fgf-mediated pathways appear to provide an alternative growth stimulatery signal that is not dependent on er activation. … drugs. ici 182,780 was kindly donated by dr. alan wakeling of zeneca pharmaceuticals (macclesfield. england), and was administered s.c at a dose et 5 mg in 0,1 ml of vehicle every week. for the experiment depicted in fig. 1., powdered drug was first dissolved in 100% ethanol and spiked into warmed peanut oil (eastman kodak, rochester,
  4. ny)to give a final concentration of 50 mg/ml. for the experiments depicted in fig. 1. b and c, 50 mg/ml preformulated drug in a vehicle of 10% ethanol, 15% benzyl benzoate, 15% benzyl alcohol, brought to volume with castor oil, was supplied by b. m. vose (zeneca pharma- ceuticals). 4-oha was donated by angela brodie (university of maryland, baltimore,
  5. md)and was administered s.c. at a dose og 1 mg/mouse/day 6 days of the week in a ve- hicle of 0,3% hydroxypropylcelluose. letrozole was donated by dr. ajay bhatnagar (no- vartis, ltd., basil. switzerland) and was administered via gavage at a dose of 1 mg/mouse/day 6 days ot the week in a vehiele of 0.3% hydroxypropylcellulose. sus- tained-release (60 day) pellets containing 5 mg of tamoxifen were obtained from lnnova- tive research of america (sarasota,
  6. fl)and implanted s.c. in the interscapular area at the time of tumor cell injection. … results estrogen-independent growth of tumors produced by fgf-transfectcd mcf-7 cells is not inhibited by treatment with a pure antiestrogen or with aromatase inhibitors. we have previously shown that both fgf-l - and fgf-4-transfeeted mcf-7 cells form progressively growing tumors in ovariectomized nude mice, as well as in similar mice treated with tamoxifen (21, 22, 53). although ovariectomized mice could be expected to have substantially lower levels of estrogenic compounds than reproductively intact mice, some estrogens are synthesized at extraovarian sites, such as adrenal gland, liver, fat, or possibly the tumor itself. the transteced cells evidently still possess ers, because they re- spond to estrogen and tamoxifen administered to the mice, as well as to these com- pounds used in tissue culture (21, 22). to test the hypothesis that growth of the fgf- transfected cells in ovariectomized or tamoxifen-treated nude mice is due to increased sensitivity to the small amounts of estrogens still present in ovariectomized nude mice, we tested the ability of a pure antiestrogen, ici 182.780, and two aromatase inhibitors, 4- oha and letrozole, to inhibit the estrogen-independent tumor growth produced by these fgf-transfected cell lines. … treatment with ici 182,780 did not inhibit tumor growth below that achieved in vehicle- treated mice (p=0,675). thus, the failure of ici 182,780 to inhibit the estrogen-independent growth exhibited by this cell line supports the hypothesis that such growth does not re- sult from small amounts of estrogenic growth stimulation achieved by extraovarian es- trogen production. … - 32 - … thus, the continued progressive in vivo growth of fgf-transfected cells in ovariectomized animals treated with either a pure antiestrogen or aromatase inhibitors demonstrates that the estroen-independent growth of these cells in untreated ovariectomiized nude mice is not due to estrogenic activity produced at exlraovarian sites. because ici 182,780, 4-oha, and letrozole were without effect in the experiments de- scribed above, we injected reproductively intact female mice for 2 weeks with these com- pounds at the same doses used in the above experiments to observe for activity in pre- venting effects of endogenous estrogen on the endometrium. uteri harvested from mice injected with either ici 182,760, 4-oha, and letrozole weighed less than those from con- trol mice and exhibited a complete lack of endometrial glandular structures (data not shown). thus, these compounds retained activity, although they had no effect on tumor growth in our experiments. … thus, taken together, our results indicate that the transfected fgfs are stimulating growth by a mechanism that bypasses the er-mediated growth-stimulatory pathway. discussion in this report, we have shown that the estrogen-independent in vivo growth of fgf- transfected mcf-7 cells is not affected by ici 182.780 or by either of two aromatase inhib- itors. this treatment failure cannot be attributed to an estrogen-, tamoxifen-, or fgf- induced decrease in the immunocompetence remaining in nude mice. the persistence of estrogen-independent growth despite pharmacological strategies to abrogate all estro- genic activity supports the hypothesis that the effect of fgf transfection in promoting such growth is due to a direct effect of the transfected fgf. these findings are supported bu our data showing normal numbers of ers present in the fgf transfectants, which are - 33 - able to direct expression of known estrogen induced genes and interact with an ere- containing promoter in a reporter piasmid but which are not constitutively activated in the fgf-transfected cell lines. the direct effect of fgf tranfection on tumor growth may be to promote mitogenesis of the transfected cells by autocrine or intracrine fgf receptor activation. this viewpoint is supported by the generally increased proliferation rate and colony-forming ability af the fgf transfectants under estrogent-depleted tissue culture conditions. however, in addition to having a mitogenic effect on tumor cells, the trans- fected fgf may also stimulate tumor growth via effects on stromal components of the tumor, such as fibroblasts or endothelial cells. … the mecanism(
  7. s)determining whether a given clinical case of antiestrogen resistance will be responsive to a second hormonal manipulation has not been elucidated and may be multifactorial. because only 30-40% of patients with acquired tamoxifen reststance have a positive response to a second hormonal therapy, with an additional 30% showing no im- mediate disease progression after switching therapies (13, 14, 19, 20). … ln summmy, our studies implicate direct action by fgfs in the estrogen-independent growth produced by transfection of either fgf-4 or fgf-1 into mcf-7 cells, and they rule out effects resulting from increases sensitivity of the transfectancs to small amounts of ex- traovarian estrogen production. … acknowledgements the auhtors are indebted to a. brodie, a. bhatnagar, and a. wakeling for providing 4- oha. letrozole and ici 182.780, respectively. (…) … references … 19. howell, a. (…) …” der er i sagen deuden fremlagt en erklæring, der er udarbejdet af kemikeren paul richard gellert til brug for en lignende retssag i holland. af erklæringen, som vedrører samme peri- ode som de nævnte artikler, fremgår følgende: ”… - 34 - - 35 - - 36 - - 37 - - 38 - - 39 - - 40 - - 41 - - 42 - - 43 - - 44 - - 45 - - 46 - - 47 - …” generelle formuleringstekniske forhold af artikel fra 1964 af c. riffkin m.fl. ”castor oil as a vehicle for parenteral administration of steroid hormones”, journal of pharmaceutical sciences, vol. 53, no. 8, august 1964, s. 891-895 fremgår følgende: - 48 - - 49 - - 50 - - 51 - - 52 - af bogen ”pharmazeutische technologie” fra 1978 af fuchs m.fl. fremgår bl.a. følgende (dansk oversættelse): ”… farmaceutisk teknologi udgivet af heinz sucker, peter fuchs og peter speiser […] udvikling af parenterale depotlægemiddelformer parenterale depotlægemiddelpræparater indgives intramuskulært eller subkutant; her- ved dannes der et depot i vævet ved injektionsstedet, hvorfra lægemiddelstoffet frigives langsomt327. den foretrukne injektionsform i den forbindelse er intramuskulær injektion dybt i gluteal- eller lumbalmuskulaturen. disse væv har generelt en god tolerance i for- hold til både hydrofile og lipofile depotpræparater, mens subkutan indgift i fedtvævet under huden i reglen kun anvendes ved vandige præparater med en sammensætning, der giver en god tolerance. fordelen ved intramuskulær eller subkutan indgift af depot- lægemiddelpræparater er, at de skal gives mindre hyppigt og at der er mulighed for selvmedicinering (som ved diabetes), og sikkerheden er større end ved intravenøs ind- gift. mulige negative effekter er sensibilisering eller irritation samt forstyrrelse af bioryt- men. …” - 53 - af bogen ”lehrbuch der pharmazeutischen technologie” fra 1987 af voigt fremgår bl.a. følgende (dansk oversættelse): ”… rudolf voigt lærebog i farmaceutisk teknologi 6. udgave […] 19.5.1.2. ikke-vandige opløsninger organiske opløsningsmidler bruges som grundlag for injektionsopløsninger, hvis - lægemiddelstoffet har en utilstrækkelig opløselighed i vand - lægemiddelstoffet dekomponerer let i vand - der ønskes en depotvirkning. 19.5.1.2.l. fede olier et større antal lægemidler forarbejdes som olieopløsninger eller oliesuspensioner til in- jektionsformål. de enkelte farmakopeer foreskriver forskellige vegetabilske olier hertil. de vigtigste er jordnøddeolie, olivenolie, mandelolie, solsikkeolie, sojabønneolie og se- samolie. ricinusolie har ofte en opløselighed, der er særligt gunstig for lægemidler. olierne er fysiologisk indifferente og har en god tolerance. en forudsætning herfor er, at de er særligt renset og har lave syre- og peroxidtal. frie fedtsyrer udrystes i givet fald med ethanol og fjernes. da intravenøs anvendelse ikke er mulig på grund af manglende blandbarhed med blodserummet og kan forårsage lungeemboli, kan der udelukkende ske anvendelse til intramuskulære og subkutane injektionspræparater. olieopløsninger eller -suspensioner forbliver på applikationsstedet i relativt lang tid (ofte op til 1 måned) og frigiver aktivstofferne over en længere periode. … på grund af de fede oliers høje viskositet er der smerter ved indgiften. en tilsætning på 5% benzylalkohol virker lokalbedøvende. …” af bogen ”pharmaceutical dosage forms: parenteral medications”, volume 1, fra 1992 af kenneth e. avis m.fl. fremgår bl.a. følgende: ”… - 54 - - 55 - - 56 - …” af bogen ”pharmazeutische technologie für studium und beruf” fra 1993 af voigt fremgår bl.a. følgende (dansk oversættelse): ”… rudolf voigt farmaceutisk teknologi til studie og erhverv under medvirken af manfred bornschein syvende, reviderede udgave 20.7 parenterale depotlægemiddelformer - 57 - parenteralt applicerbare præparater med forlænget virkning har været tilgængelige i længere tid, men har efterhånden fået langt større betydning. de indgives intramusku- lært, sjældent subkutant. problemerne med fremstilling af depotlægemiddelformer er i disse tilfælde ikke lige så komplicerede og mangeartede som ved lægemiddelformer til peroral administration. ved anvendelse af forskellige principper, enten enkeltstående el- ler i kombination, opnås det ønskede resultat (tabel 63). andre mulige farmakologiske metoder er omtalt tidligere under 12.2. i det følgende behandles de vigtigste kemiske og farmaceutisk-teknologiske principper. …” af ”handbook of pharmaceutical excipients” af wade og wellers fremgår bl.a. følgende: “… 7. applications in pharmaceutical formulation or technology benzyl benzoate is used as a solubilizing agent and nonaqueous solvent in intramuscular injections at concentrations between 0,01-46,0% v/v.
(1)it is also used as a solvent and plasticizer for cellulose and nitrocellulose. however, the most widespread pharceutical use af benzyl benzoate is as a topical therapeutic agent in a treatment of scabies. bezyl benzoate is also used therapeutically as a parasiticide in veterinary medicine.
(2)other applications of benzyl benzoate include its use as a solvent and fixative for flavors and parfumes in cosmetics and food products. …” af en artikel: “administration of medications via the intramuscular route: an integra- tive review of the literature and research-based protocol for the procedure”af suzanne c beyea og leslie h. nicoll fra 1995 fremgår bl.a. følgende: “… administration of medications via the intramuscular route: an integrative review of the literature and research-based protocol for the procedure … volume the precise volume that can be safely administered via the im route is unclear. the only consistent recommendation that could be found in the literature is that the maximum volume not exceed 5 ml for an adult. …” af banker og rhodes’ bog: ”modern pharmaceutics” fra 1996 fremgår bl. a. følgende: “…
  1. the intramuscular route - 58 - the im route of administration is second only to the iv route in rapidity of onset of sys- temic action. injections are made into the striated muscle fibers that lie beneath the sub- cutaneous layer. the principal sites of injection are the gluteal (buttocks), deltoid (upper arm), and vastus lateralis (lateral thigh) muscles. the usual volumes injected range from 1.0 to 3.0 ml. with volumes up to 10.0 ml sometimes being given (in divided doses) in the gluteal or thigh areas (see table i). again, it is important to aspirate before injecting to ensure that the drug will not be administered intravenously. needles used in administer- ing im injections range from 1 to 1½ in. and 19 to 22 gauge, the most common being 1½ in. and 22 gauge. the major clinical problem arising from im injections is muscle or neural damage, the in- jury normally resulting from faulty technique, rather than the medication. … intramuscularly administered products typically form a “depot” in the muscle mass from which the drug is slowly absorbed. the peak drug concentration is usually seen within 1- 2 hr. factors affecting the drug-release rate from an im depot include the compactness of the depot (the less compact and more diffuse, the faster the release) the rheology of the product (affects compactness), concentration and particle size of drug in the vehicle, na- ture of the solvent or vehicle, volume of the injection, tonicity of the product and the physical form of the product. …” af ”good practice guidelines” fra 1998, som er fra en publikation vedrørende forskellige me- todikker til administration af lægemidler i forsøgsdyr, fremgår bl.a. følgende: ”… c) intramuscular dosing intramuscular injection in small laboratory species can be difficult because of the lack of big muscles. it is a route which is not recommended unless there are good scientific reasons for using it. key points include:
  2. use very small volumes in small laboratory species (see table).
  3. make certain the substance is not irritant.
  4. be certain about the local anatomy: avoid veins, arteries and nerves. …” af bogen “recepteerkunde” af g.k. bolhuis m.fl. fra 1999 fremgår bl.a. følgende “… 27.2.6 choice of physical form and solvent by far, most parenteral administrations that are being used are in the form of aqueous so- lutions. rinsing liquids are without exception solutions. - 59 - in case the drug that is to be administered is poorly water soluble, a cosolvent can be added. cosolvents that can be used are: ethanol, benzylacohol, glycerol and propylene glycol. (see also 5.1.2 and 8.3.3). a well known combination of cosolvents is ethanol, pro- pyleneglycol and water. phenytoin sodium and phenobarbital sodium are examples which can be formulated to an injection in this way. products that contain one or more cosolvent can exhibit precipitation upon intravenous injection, which is caused by dilu- tion of the injected formulation [7]. another phenomenon is that the cosolvents can cause a considerable shift in the pka of weak acids and bases [8]. upon dilution, the bufferca- pacity at a certain ph changes which may give rise to precipitations. precipitation in the central circulation can lead to obstructions of the vessel; in tissue this effect can lead to a (unintentional) depot-effect. the use of benzylalcohol can have a threefold function; sol- ubility enhancement, local anaestetic activity, and preservation. a combination of ben- zylalcohol with ethanol and propyleneglycol is used in e.g. the diazepam-injection. in case of epidural administration the use of ethanol or propyleneglycol is not allowed. gly- cerol can be an alternative then [9]. … oilly vehicles are usually applied in subcutaneous or intramuscular injections. in contrast to water, an oil resides relatively long on the injection-spot, which can last even upto three months after administration [2]. wrongly, it is often assumed that an oilly injection is per definition an extended releasing injection. whether this is indeed the case depends on the way the pharmacon has been formulated (suspension or solution) and on the oil- water partition coefficient of the pharmacon. vegetable oils like olive oil, ricinus oil, sunflower oil and soy oil can be used. … to enhance the solubility of steroids in oil, benzylbenzoate is used. …” af henning gjelstrup kristensens bog ”almen farmaci” fra 2000 fremgår bl.a. følgende: ”… kapitel 7 – lipofile hjælpestoffer … vegetabilske olier omfatter en række triglycerider, bl.a. ricinusolie, majsolie, bomuldsfrøolie, oli- venolie, sesamolie, sojabønneolie og jordnøddeolie. de nævnte olier anvendes som opløsningsmid- ler i formuleringer til forskellige administrationsveje inkl. intramusculær administration med henblik på at opnå depoteffekt (kap. 8.3). flere markedsførte injektionsvæsker indeholder desuden benzybenzoat, der har en opløselighedsfremmende effekt i olievehiklerne. de nævnte vegetabilske olier indeholder fedtsyrer, der kan give anledning til dannelse af fri radika- ler. olierne er derfor normalt tilsat antioxidant. fraktioneret kokosnødolie, der har et højt ind- hold af mættede c8 og c10 fedtsyrer, er stabil mod oxidation. - 60 - … jordnødolie er en klar, gullig væske, der er næsten uden lugt og med en mild smag. olien udskil- ler ved 0 °c hvi de, krystallinske bestanddele og størkncr til en salvcagtig masse ved lavere temperaturer. jordnødolie er det her i landet almindeligst anvendte lipofile opløsningsmiddel. til magistrelle læ- gemidler, der er ordineret som opløsninger i olie. anvendes ifølge dls jordnødolie. olien hører til de mindst viskøse blandt de vegetabilske olier (ca. 40 cp ved 20 °c; til sammenligning er viskosite- ten af olivenolie ca. 100 cp ved 20 °c ). jordnødolie varmebehandles ved 140 °c i tre timer. … kapitel 8 – flydende formuleringer … ethanol anvendes i lægemiddelfremstillingen altid i blanding med vand, f.eks. som stærk sprit (ca. 93 %) eller fortyndet sprit (ca. 62 %) … ethanol anvendes i injektionsvæsker i blanding med vand med henblik på forøgelse at lægemiddel- stoffets opløselighed og/eller stabilitet; i koncentrationer over ca. 15% i vand opnås en konserve- rende virkning. koncentrationen i injektionsvæsker er normalt højst 25%. … kapitel 10 – lægemidlers mikrobielle renhed … benzylkohol virker i koncentrationen 1-3% baktericidt, men kun i ringe grad fungicidt. det sorbe- res kun i ringe grad i gummilukker – jf. fordelingskoefficienten, tabel 10.8 —og anvendes derfor til konservering af flere injektionsvæsker. vandige opløsninger virker lokallrriterende ved inddryp- ning i konjuntivalsækken, hvorfor benzylalkohol ikke bør anvendes i lægemidler til øjnene. benzylalkohol anvendes normalt i koncentrationen 1-1,5%. benzylalkohol anvendes foruden som konserveringsstof også som opløsningsfremmende middel i olieholdige opløsninger, f.eks. i koncen- trationen 5% i olieholdige injektionsvæsker; hensigten hermed er primært at hindre udkrystallisa- tion af lægemiddelstof ved kold opbevaring af lægemidlet. …” afgørelserne fra epo vedrørende 138- og 573-patenterne af en afgørelse af
  5. marts 2014 fra epo’s tekniske appelkammer vedrørende 138-patentet fremgår bl.a. følgende: - 61 - “… d13 s. mcleskey et al., “tamoxifen—resistant fibroblast growth factor— transfected mcf-7 ceils are cross—resistant in vivo to the antiestrogen ici 182,780 and two aromatase inhibitors”, clinical cancer research 4, 1998, 697—711 … d15 a. howell et al., “pharmacokinetics, pharmacological and anti—tumour ef- fects of thespecific anti-oestrogen ici 182780 in women with advanced breast cancer”, british journal of cancer 74, 1996, 300—308 … reasons for the decision …
  6. admissibility of documents d13 and d15 to d24 3.1 documents 1313 and d15 to 1324 have either been fiied by the appellant himself or adopted by him from anonymous third parties submissions ali of which were made after the date of the filing of the statement of grounds of appeal. therefore, all these documents are to be considered as late filed documents of the appeliant. the juris- prudence of the boards of appeal dealing with the problem of anonymously filed third party observations is of no relevance. 3.2 document d13, in view of the arguments submitted with document d16, in particu- lar point 2.1, is found highly relevant with regard to the question of novelty of the subject-matter of claim i of the main reguest. this is because of the disclosure in doc- ument 013 at the right column of page
  7. due to this finding, the factual framework of the case has substantially changed. one of the results of this is that the disclosure of the further documents d15 and d17 to d24 becomes of relevance. therefore, the board admits all these documents (d13 and d15 to 024) into the pro- ceedings. …” af indsigelsesafdelingens afgørelse af
  8. januar 2015 i sagen vedrørende 138-patentet frem- går bl.a. følgende: “… the opposition division has decided: account being taken of the amendments made by the patent proprietor during the oppo- sition proceedings, the patent ep-b-1 250 138 and the invention to which it relates are found to meet the requirements of the convention. - 62 - …
  9. with letter at 30.12.14, the appellant withdrew the opposition.
  10. with letter at 2.01.15, the patentee filed a new main request and auxiliary requests 1-
  11. … d7 riffkin et al., j. pharm. sci. 1964, 53
(8), 891 -895 … d13 s. mcleskey et al., “tamoxifen-resistant fibroblast growth factor-transfected mcf-7 ceils are cross-resistant in vivo to the antiestrogen 101182,780 and two aromatase inhibitors’, olinical cancer research 4, 1998, 697-711 … d15 a. howell et al., pharrnacokinetics, pharmacological and anti-tumour effects at the specific anti-oestrogen cl 182780 ifl women with advanced breast cancer, british journal at cancer 74, 1996, 300-308 … ii. decision … 2.2 the change of category of the claims from subject-matter directed to a formulation to a use of a formulation for the manufacture of a medicament entails a narrowing of the scope of protection and does therefore flot contravene the requirements of art. 123
(3)epc. … 4. novelty (art. 54 epc) 4.1 novelty in the light af d13 … the opposition division is at the opinion that d13 does flot disciose the use at the formu- lation for the treatment at a benign or malignant disease at the breast or reproductive tract by intra-muscular injection. the subject-matter at the present claims is therefore cansidered novel in the light at d13. … 5. inventive step (art. 56 epc) - 63 - … the objective technical problem to be solved by the present application can therefore be formulated as how to ncrease the solubility of fulvestrant in an intramuscular formula- tion. the solution presented by the patent resides in the addition of a non-aqueous ester solvent. … d13 discloses such a formulation as detined the present patent. however, the document is a scientific article reporting on a study that almed at determining the sensitivity of par- ticular tamoxifen-resistant breast cancer cells to i.a. fulvestrant. the formulation was ad- ministered to the mice subcutaneously. the opposition division is therefore of the opinion that the skilled person would not have had any incentive to look at d13 when seeking for a solution to increase the solubili- ty of fulvestrant in an intramuscular formulation (c.f. 5.2, d13 as the closest prior art). the claimed solution is also flot obvious from d7… … 5.2 d13 as the closest prior art d13 is considered a less suitable closest prior art document: the document a priori does not relate to the treatment of individuals but reports on a study to investigate the sensi- tivity of fgf-transfected mcf-7 breast cancer cells to i.a. ici-182,780 (fulvestrant). the subject-matter is therefore flot disclosed for the same purpose and does flot aim at the same objective as the claimed invention. the document uiscloses the same composition as that one claimed, and in addition a sec- ond one comprising ici-182,780; the administration to mice is subcutaneously. 5.3 d15 as the closest prior art on top of col. i on p. 301 of d15 it is disclosed that ‘ici-182780 was administered as a long-acting formulation contained in a castor-oil based vehicle by monthly im. injection (5ml) into the buttock. d15 differs from claim 1 in that it does not disclose a formulation comprising a pharmaceutically acceptable non-aqueous ester solvent and pharmaceuti- cally acceptable alcohol. the problem can be formulated as an alternative formulation of fulvestrant for im. ad- ministration. the opposition division is of the opinion that the skilled person would not have had any incentive to combine the teaching of d15 with the disclosure of 013 in order to find an al- ternative composition to that disclosed in d15 due to the following reasoning: the doc- ument a priori does not relate to the treatment of individuals but reports on a study to in- vestigate the sensitivity of fgf-transfected mcf-7 breast cancer cells to i.a. ici -182,780 (fulvestrant). - 64 - furthermore, the document does flot only disclose the composition that is defined in the present claim 1, but also another one. the solution of the patent-in-suit is therefore not considered obvious from a combination of d15 with d13. …” af indsigelsesafdelingens afgørelse af 20. juli 2017 vedrørende 573-patentet fremgår bl.a. føl- gende: ”… … … - 65 - … … … - 66 - - 67 - … - 68 - - 69 - 1 - 70 - - 71 - - 72 - - 73 - - 74 - - 75 - - 76 - - 77 - - 78 - - 79 - - 80 - - 81 - - 82 - - 83 - - 84 - - 85 - - 86 - - 87 - - 88 - - 89 - - 90 - - 91 - - 92 - … …” artikel efter prioritetstidspunktet i januar 2000 af artiklen “spatial distribution of oil depots monitored in human muscle using mri” af r.w. kalicharan m.fl. fra 2016 fremgår bl.a. følgende: - 93 - “… although many i.m. oil depots for sustained drug delivery have been marketed the rate and extent of drug release is often difficult to predict. the drug-release and absorption rate from the oil solution is controlled by the drug partitioning between the oil vehicle and the tissue fluid (kalicharan et al., 2016b). however, several other factors such as the injection site (minto et al., 1997; shaik et al., 2015; soni et al., 1988), injection volume (minto et al., 1997), the rate of bioconversion of the prodrug into the parent drug, the ab- sorption and distribution of the oil vehicle and the extent of spreading of the depot at the injection site might affect the overall pharmacokinetic profile of the drug (larsen et al., 2009; weng larsen and larsen, 2009). …” udbudsmateriale af udbudsbekendtgørelse fra de fem regioners fælles udbudsorganisation amgros vedrø- rende fulvestrant fremgår bl.a., at dispenseringsformen er injektionsvæske, og at styrken er 50 mg/ml. den anslåede værdi af udbuddet er 60.600.000 kr., og varigheden af kontrakten er fra 1. april 2018 til 31. marts 2019 med mulighed for forlængelse. amgros har i brev af 12. december 2017 til astrazeneca meddelt, at leverancen tildeles san- doz, og har anført bl.a. følgende: ”… orienteringsskrivelse om tilbudsvurdering vedrørende eu-udbud af lægemidler 2018 - udbudsgruppe 1.704.a amgros takker for jeres tilbud angående ovennævnte udbudsgruppe. i henhold til ud- budsmaterialet for denne udbudsgruppe tildeles ordren det økonomisk mest fordelagtige tilbud vurderet efter tildelingskriteriet "pris", og der indgås rammeaftale med én leve- randør pr. udbudsnummer. … til orientering vedlægges endvidere oversigter over samtlige udbudsnumre omfattet af udbudsgruppen med angivelse af, hvilke firmaer amgros agter at indgå aftale med for hvert af de enkelte udbudsnumre (bilag
  1. a)og med angivelse af, hvilke firmaer (i vilkårlig rækkefølge) der har afgivet konditionsmæssigt tilbud under hvert af de enkelte udbuds- numre (bilag b). - 94 - …” af hjemmesiden www.medicinpriser.dk fremgår, at sandoz markedsfører produktet, hvor- om der er anført følgende: af et udskrift af 27. marts 2017 af hjemmesiden for ”clinical cancer research”, som er det tids- skrift, hvor mcleskey-artiklen blev offentliggjort, fremgår bl.a. følgende: “… clinical cancer research publishes innovative clinical and translational cancer research studies that bridge the laborafory and the clinic. the journal is especially interested in clinical trials evaluating new treatments, accompanied by research on pharmacology, and molecular alterations or biomarkers that predict response or resistance to treatment. the journal also prioritizes laboratory and animal studies of new drugs and molecule- targeted agents with the potential to lead to clinical trials, and studies of targetable mech- anisms of oncogenesis, progression of the malignant phenotype, and metastatic disease. specific areas of interest include clinical and translational research in targeted therapies; mechanisms of drug sensitivity and resistance; pharmacogenetics and phar- macogenomics; personalized medicine; novel applications of bioinformatics and biosta- - 95 - tistics; immunotherapy and clinical immunology; gene therapy; radiobiology and radia- tion oncology; large-scale molecular characterization of human tumors; diagnostic bi- omarkers; innovative imaging and other novel methods with potential applicability fo clinical investigation; clinical genetics; and detection of minimal disease. …” vedrørende spørgsmålet eventuel sikkerhedsstillelse har sandoz fremlagt følgende tabsop- gørelse: eksperterklæringer - 96 - under sagen er der fremlagt erklæringer af professor daniel j.a. crommelin, europæisk pa- tentagent ulla klinge, professor sven frøkjær, professor herman vromans og professor thomas rades. af professor daniel j.a. crommelins første erklæring fremgår bl.a. følgende: “… 4. mcleskey tries to unravel in her research aspects of the mechanism of the growth of tumor cells. as such, it has nothing to do with the development of a therapeutic against breast cancer. 5. for this research, mcleskey deploys as a tool a number of well-known active sub- stances (such as fulvestrant) in order to block the estrogenic activity. hereby these substances are administered in such a high dosage so that one can be sure that the estrogenic activity would not have any effect on the study of the estrogen- independent growth of fgf tumors. the formulations described by mcleskey are (at least partially) specific formulations for animal experiments (see e.g. the formu- lation of tamoxifen). 6. two fulvestrant formulations are described here which are applied subcutaneous- ly, once per week. the relative amount of administered fulvestrant is extremely high; much higher than the amount that is now being applied in the treatment of breast cancer. i understand that the main purpose of mcleskey has been a certain obstruction of estrogen receptors of the tested mice. 7. however, a subcutaneous formulation for application in a mouse model is not simply extrapolated to a human intramuscular application. things like e.g. tissue irritation, mechanism and kinetics of release, dosing interval (a month instead of a week) and dosage level should be subjected to extensive examination. 8. in addition, the following matters caught my attention concerning the formulation with 5% fulvestrant in 10% benzylaclohol, 10% ethanol, 15% benzyl benzoate and castor oil:
  2. a)the formulation contains four components in addition to the active agent (castor oil, ethanol, benzyl alcohol and benzylbezoaat). this is quite unusual, because normally an attempt is made to have a formulation with as few components as possible. i see that prof. vromans refers to table 1 of the pa- tent in order to suggest that such a combination of excipients is well-known in castor oil. however, i also understand (from the statement of dr. gellert 2008) that this information is clearly incorrect. i have checked the underlying reference (riffkin3) from which it is apparent that the information from ta- ble 1 is indeed incorrect.
  3. b)fulvestrant formulation in mcleskey contains a lot of alcohol (20%). a per- son skilled in the art knows that these alcohols rapidly disappear after ad- ministration in human beings, usually within a day. since the amount of ful- vestrant in the remaining oil is above the solubility limit, a skilled person can reasonably expect that fulvestrant will crystallize and thus cause irrita- tion. 9. based on these considerations, i would assume that a skilled person would not just use the formulation concerned for the treatment of breast cancer. in my point of - 97 - view, he would rather set up an extensive research program in order to find an ef- fective formulation for intramuscular administration (1 month). normally, such an examination starts with the determination of the solubility of the active substance in various excipients based on which the skilled person – if he would consider the usage of benzyl benzoate – would discover that fulvestrant has a poor solubility in benzyl benzoate (see table 2 of ep138). in such a case, in my view, the usage of benzyl benzoate for the cumbersome fulvestrant is not obvious. 10. i do not see on the basis of which technical information in mcleskey a skilled per- son can have an expectation that the castor oil formulation described therein would be the golden opportunity for the intramuscular treatment of women with breast cancer. …” af professor daniel j.a. crommelins anden erklæring fremgår bl.a. følgende: “… the patent … 10. professor vromans refers to some other medicines that can indeed be administered as suspension (very small solid particles in a fluid), due to which the skilled person would think that presence of solid particles in muscular tissue would not be a problem. i think that this argument is incorrect. in the first place: local irritation at the injection site by medicinal particles is very strongly dependent on the active substance, the formulation and injection circumstances, and must be tested in ani- mal models. secondly: one of the medicinal products that professor vromans spe- cifically refers to concerns a progesteron variant that has already been formulated as a solid substance. precipitation at the site of injection as could occur in fulves- trant formulations, is therefore not up for discussion. the reference to insulin is in so far incorrect that insulin is administered subcutaneously, and possible irritation is then completely different because the medicine is not injected in the muscles. solid particles are already formed there as well before administration. 11. the point is therefore that the answer to the question whether in situ precipitation (that is, after administration) can lead to an unacceptable irritation at the injection site, depends on the active ingredient. in fulvestrant this is apparently a cause for concern and also dependent of the used formulation. … 16. the patent therefore teaches that a specific formulation has been developed, with specific properties due to which the formulation is suitable as an intra-muscular depot formulation in the treatment of breast cancer. blood plasma concentrations are in the desired range during 2-4 weeks. i am therefore of the opinion that the pa- tent makes this plausible, also on the basis of the animal tests that were conducted. … mcleskey - 98 - 18. as also indicated in my first declaration, mcleskey only tries to unravel aspects of the mechanism of the oestrogen independent growth of tumor cells in her study. as such this has got nothing to do with the development of an effective and safe sustained release formulation against breast cancer. 19. mcleskey used an oestrogen receptor blocker (such as fulvestrant) as aid, together with aromatase inhibitors (a substance that inhibits aromatase, an enzyme that produces oestrogen) to prevent oestrogen production and activity completely. on account hereof mcleskey knows for sure that there was no ‘hidden’ oestrogen, which could disturb the research design. … 21. the formulations of fulvestrant were subcutaneously administered in a mice mod- el (and therefore not intramuscularly). also, those substances were administered in a very high dose (a lot higher than a human dose). mcleskey administered the an- ti-oestrogen substances on a weekly basis (and therefore not once every two or four weeks like in the patent), and did not measure any blood plasma levels at all. there is therefore no knowledge of this. the conclusion that professor vromans draws in paragraph 27 of his third declaration, that mcleskey teaches the skilled person that the blood plasma concentration of the preformulated fulvestrant for- mulation lasts for at least a week in mice, is therefore unfounded. 22. as already clarified in my first declaration, a formulation that is used (subcutane- ously) for animals cannot be extrapolated just like that to a human intramuscular application. matters such as tissue irritation, mechanism and kinetics of release, dosing interval (one month instead of one week) and dosing amount must be ex- amined in detail. 23. professor vromans puts a lot of emphasis on the word ‘preformulated’ in mcles- key. he gives this word one specific interpretation (namely, a therapeutic formula- tion that has already been developed and clinically tested, and that is used to treat patients), which in my view is a lot less probable than the other possible interpreta- tions. it seems to me that it is much more obvious that the formulation was called 'preformulated' because it concerned an instant formulation (in contrast to the oth- er, peanut oil fulvestrant formulation that mcleskey had to prepare herself)… … 25. in my first declaration i indicated that the fulvestrant formulation of mcleskey comprises a lot of alcohol (20%). a skilled person knows that these alcohols diffuse quickly from the oil after administration in the human muscle, usually already in one day. because the concentration of fulvestrant in the remaining oil is above the solubility boundary, a skilled person could reasonably expect that fulvestrant pre- cipitates, therefore causes unacceptably much irritation and offers an uncontrolled and unpredictable blood plasma concentration. … 27. such toxicological study is however always required to establish that a new formu- lation is safe. the point however is that practice shows that an alcohol concentra- - 99 - tion of 20% is most uncommon and could lead to precipitation and unacceptable pain at the injection site. i refer in this respect to paragraphs 31-32 of the declara- tion of dr schaupp, in which it is referred to more than 10 handbooks and articles showing this to be the case. there is therefore no ground for the argument of pro- fessor vromans that an alcohol concentration of 20% would be “not extremely high” (he does not put any example forward to substantiate his argument). there- fore the skilled person would not expect that this formulation could be successfully applied to treat breast cancer, and would not even get round to the toxicological research mentioned by professor vromans. …” af professor daniel j.a. crommelins tredje erklæring fremgår bl.a. følgende: “… howell and the opposition division’s approach … 10. the opposition division also refers to riffkin (d9 in the opposition proceedings) to support its view that a skilled person would simply use benzyl alcohol and ben- zyl benzoate to obtain a 50 mg/ml fulvestrant formulation, and speculates that this would result in an ‘effective’ formulation (i.e., a formulation to effectively treat breast cancer). 11. i believe that the opposition division’s opinion is not only speculative, but is also incorrect. riffkin’s publication, which i studied again to prepare for this opinion1, describes formulations without benzyl alcohol, or with 2% or 5% benzyl alcohol. a maximum of 5% of benzyl alcohol is not sufficient to dissolve the required amount of 50 mg of fulvestrant per ml2. so even if a skilled person were to try all of the variants described in riffkin, the mere fact of insufficient solubility alone would prevent that person from obtaining an effective formulation. i say “the mere fact alone” because sufficient solubility in itself usually does not result in a formulation that can be used to replicate howell (i.e., the release profile will not generally be such that a single injection is effective for at least two weeks and without unac- ceptable irritation and pain occurring at the injection site). 12. the fact that solubility in itself is not sufficient for obtaining an acceptable formula- tion becomes apparent from riffkin itself, for example. a comparison of tables v and vi clearly shows that the same formulation can be either accepted or rejected, depending on the effective steroid. i refer to the castor oil-based formulation (58%) with 40% benzyl benzoate and 2% benzyl alcohol. this formulation is acceptable for estradiol valerate, but rejected for 17-hydroxyprogesterone. this, too, clearly shows that there is no way of predicting whether a certain formulation will be ac- ceptable or not.3 13. the patent, too, shows that solubility is not the only requirement for obtaining the desired product. table 4 lists two formulations (f2 and f3), both of which contain a solution of a sufficient amount of fulvestrant, but neither formulation is suitable - 100 - because fulvestrant precipitates. precipitation at the injection site causes irritation and inflammation at the injection site (as described in paragraph [0037] under 1). taking a realistic approach for finding a suitable formulation … 21. gellert 2016, at paragraph 41, clearly shows that all other 50 mg/ml fulvestrant for- mulations that were tested by astrazeneca caused precipitation problems and/or unacceptable irritation at the injection site. sensitivity to small adaptations to the excipients (or the quantity thereof) are also shown by the fact that, once astra- zeneca had found the claimed formulation, an addition of only 2% of a well- known surfactant (lecithin) once more caused necrosis (see gellert 2016, paragraph 41, final sentence in quote). 22. the literature and astrazeneca’s experiments (gellert 2016) therefore show that a fulvestrant formulation that would work in the clinical trials carried out by howell (good tolerability and good release profile) would not have been discovered with- out extensive research and a certain amount of luck.7 … conclusion 27. it is my opinion that cannot serve as a starting point for finding a suitable and ef- fective fulvestrant formulation which can be used to treat breast cancer patients by means of an intramuscular injection that would be effective for at least two weeks, since essential information about such a formulation is lacking, meaning that the skilled person would not be able to replicate the clinical studies described in how- ell without first having to set up a research programme themselves. 28. the information that is lacking in howell (an unusually high concentration of al- cohols and an unusual number of excipients, namely a four-component system) cannot be found in handbooks or review articles. such a combination is unique in the field of oil-based parenteral formulations, and i am therefore firmly convinced that such a combination was not self-evident. 29. additionally, i mention that the skilled person cannot find any indication in mcleskey that such a four-component formulation would be suitable for breast cancer treatment using intramuscular injections that are administered no more than once every two weeks. this has already been discussed extensively in the my earlier opinions and the declaration of dr. schaupp. …” af professor daniel j.a. crommelins fjerde erklæring fremgår bl.a. følgende: “… the publication of kalicharan and vromans - 101 - 3. the relevant passage from the article of kalicharan and vromans is the following: although many i.m. oil depots for sustained drug delivery have been marketed, the rate and extent of drug release is often difficult to predict.(…) … 4. of these factors, as far as i know, it was only known that fulvestrant was not a prodrug, and that metabolites do not play a significant role. of all other possible factors, the effect was not known on the priority day. these are: a. the drug partitioning between the oil vehicle and the tissue fluid; b. injection site; c. injection volume; d. the absorption and distribution of the oil vehicle; e. the extent of spreading of the depot at the injection site. … 7. in my view, however, this information does not affect the expectations of the per- son skilled in the art: … b. i am greatly surprised by the statement under point (b). professor vromans made this statement in his very first declaration, and i explicitly disputed that submission in my first declaration1. the combination of ethanol, benzyl alcohol and benzyl benzoate had never been used in an oil-based formula- tion. professor vromans has (rightly) never returned to this in his further statements in the preliminary injunction proceedings. the opposite state- ment of professor vromans in paragraph 6b of his last declaration is there- fore misleading and incorrect. i want to emphasise that riffkin indeed shows that apparently small changes in i.m. preparations can have a large effect (the difference between acceptable and unacceptable). c. mcleskey (point
  4. d)does not teach anything about the factors either which professor vromans considers relevant in his article. nothing has been de- scribed therein about the partition coefficient, absorption and distribution, or the distribution of the injected volume in the mouse. even if something was written about it by mcleskey, it is questionable to what extent the sub- cutaneous administration can be translated into intramuscular administra- tion. professor vromans seems again to assume that the mcleskey composi- tion is the same as that used in the howell study. this is clearly hindsight. … necrosis - 102 - 9. professor vromans states that necrosis is very exceptional and therefore would hardly play a role in the development of i.m. depot formulations. 10. in my view this is incorrect. of course, commercial products (as described in treadwell) are such that normally no (or only in exceptional, patient-dependent situations) necrosis occurs. this does not alter the fact that non-commercial depot formulations can actually cause necrosis, and that therefore the tolerability of a re- search formulation is an important aspect of the pre-clinical research phase. riffkin also extensively researched that aspect2. 11. the patent also describes the problems with the development of an i.m. formula- tion, in which ‘extensive local tissue irritation’, and ‘irritation/inflammation’, has been observed (see [0037] of the patent). dr. gellert describes in his declaration3 that the possible occurrence of necrosis has been investigated by astrazeneca, and that a formulation was sought where no necrosis could be seen, see paragraph 36 and 41. …” af professor daniel j.a. crommelins femte erklæring fremgår bl.a. følgende: “… the statement of prof vromans 2. prof. vromans comments on the decision of the court of appeal, specifically the conclusion in paragraph 4.21, which reads that the man skilled in the art does not have a reasonable expectation of success that the fulvestrant-formulation disclosed in mcleskey is suitable for treating breast cancer (as well as that it is tolerable, and that it establishes a therapeutically significant plasma concentration), and will forego further research regarding the efficacy of the formulation for the purpose mentioned. 3. prof. vromans is of the opinion that, based on howell, a man skilled in the art would research as much literature as possible, and would definitely test a formula- tion described in the literature as not prima facie unsuitable to find a formulation that has therapeutic efficacy. moreover , according to prof. vromans, a man skilled in the art will need to choose to either test the fulvestrant-formulation of mcles- key, or start from scratch to develop a formulation that is completely new. he con- cludes that the man skilled in the art would (logically) choose for the former option rather than the latter, and would consequently automatically discover that the mcleskey formulation provides for the same clinical results as the formulation used by howell. my reply 4. the comments of prof. vromans seem to equate to criticism with regards to a legal point. if i read the decision correctly – and this is the way it has been explained to me by the lawyers of astrazeneca as well – the inventive step assessment in this case depends on the question whether a man skilled in the art would have a rea- sonable expectation of success that the fulvestrant-formulation is an effective for- mulation for humans (the correct sustained-release, and tolerability), and is as such - 103 - suitable for the treatment of breast cancer. for this i refer to paragraph 4.22 of the decision of the court of appeal. 5. the point which prof. vroman seems to defend, namely that the man skilled in the art would prefer to research the mcleskey formulation rather than developing a completely new formulation, is therefore not relevant to the inventive step discus- sion. furthermore, prof. vromans essentially puts forward the argument that the man skilled in the art would adopt, in relation to the mcleskey formulation, a ‘try- and-see’ approach, which is precisely what has been explicitly rejected by the court in second instance (see paragraph 4.23). 6. as i explained extensively in my earlier statements (which other experts, such as prof.robertson on behalf of astrazeneca have done too), the skilled man in the art does not have the expectation of success as aforementioned. this has been summa- rized by the court of appeal in orderly fashion: a. mcleskey has not researched the therapeutical effect of the fulves- trant-formulation, and the uterus-test does not have a forecasting val- ue for the therapeutic efficacy of the fulvestrant-formulation (para. 4.8, 4.9, 4.25 and 4.27 of the decision); b. mcleskey describes other formulations which are clearly used solely for animals, which is why it is quite obvious to conclude that the ful- vestrant-formulation is an animal formulation too (para. 4.26 of the decision); c. mclesley does not provide for any information about the plasma levels of the used formulations (para. 4.28 of the decision); d. the fulvestrant-formulation of mclesley consists of an unusual high amount of excipients and an unusual high percentage (20%) of alco- hols; therefore, it is not a conventional formulation (para. 4.26 of the decision); e. the fulvestrant-formulation of mcleskey is injected s.c. in mice on a weekly basis. any indication that this could be extrapolated to a i.m. injection in humans on a monthly basis (like in howell) is lacking (pa- ra. 4.10 and 4.28 of the decision); f. whether an oil-based i.m. formulation is acceptable (good release, no serious irritation) is very hard to predict (see riffkin for a great num- ber of oil-based formulations, and recently by prof. vromans himself) (para. 4.28 of the decision); g. mcleskey discloses nothing about the tolerability of the fulvestrant- formulation, whilst one would expect that, after quick dissipation of alcohols, fulvestrant would sink down in the oil, causing an unac- ceptable degree of irritation and pain (para. 4.29 of the decision). 7. with regards to the necessary research for the questions posed above, the court of appeal correctly considers that testing is required on both animals and humans. the suggestion of prof. vromans that two routine tests are required, that can be done within the timespan of half a year and together would cost around 100.000 euros, is irrelevant (even if this would be correct, which i doubt). that these tests – which prof. vromans concurs as well – are required, in addition to other research, - 104 - to gain a first impression regarding the suitability of the mcleskey formulation, il- lustrates that the man skilled in the art did not have the required expectation of success on the basis of the information disclosed in mcleskey. …” af europæisk patentagent ulla klinges erklæring vedrørende 573-patentet fremgår bl.a. føl- gende: “… 10) what is the objective technical problem to be solved? the objective technical problem is how to provide a fulvestrant formulation for the treatment of breast cancer which is effective and tolerable and shows therapeutically ef- fective fulvestrant levels over a prolonged period of time after intramuscular injection. 11) starting from howell and the objective technical problem, would the skilled person combine the teachings of mcleskey and howell and have a reasonable expectation of success of being able to solve the objective technical problem? it appears from guidelines for examination in the european patent office (november 2017), part g, chapter vii, 5.3, could-would approach: "in the third stage the question to be answered is whether there is any teaching in the prior art as a whole that would inot simply could, but would) have prompted the skilled person, faced with the objective technical problem, to modify or adapt the closest prior art while taking account of that teaching, thereby arriving at something falling within the terms of the claims, and thus achieving what the invention achieves (see g-vii, 4). in other words, the point is not whether the skilled person could have arrived at the invention by adapting or modifying the closest prior art, but whether he would have done so because the prior art incited him to do so in the hope of solving the objective technical problem or in expectation of some improvement or advantage (see t 2/83)..." in t1126/09 the board pointed out that, in accordance with the "couidwould" approach, the as- sessment of inventive step must involve establishing, in each individual case, to what extent the skilled person had good reason, in the light of the closest state of the art or the objective problem derivable from it, to adduce further prior art and apply its teaching to the process/apparatus of the closest prior art - or, in other words, whether any factor is discernible which points towards a combination of the teachings of the citations addressed." [emphasis added] a person skilled in the art, who would have therapeutic goals in mind, and wishing to provide a fulvestrant formulation for the treatment of breast cancer would not combine the teachings of mcleskey and howell, since as explained above, the formulations used in mcleskey do not relate to breast cancer treatment - or treatment at all but rather uses different formulations of fulvestrant and aromatase inhibitors to totally block any estro- gen dependent activity of the cancer cells for the purpose of conducting basic research in- to mechanisms of tamoxifen resistance. the title of mcleskey already teaches that fulves- trant was unsuccessful in the mcleskey model:"tamoxifen-resistant fibroblast growth fac- - 105 - tor-transfected mcf-7 cells are cross-resistant in vivo to the antiestrogen ici 182,780 and two aromatase inhibitors". mcleskey repeatedly indicates that the mouse model studied is hormone independent, see e.g. page 698, right column, top, and page 706, right column. also it appears that ful- vestrant did not inhibit estrogen independent tumor growth: "treatment with ici 182,780 did not inhibit tumor growth below that achieved in vehicle-treated mice (p=0.675). thus, the fail- ure of ici 182,780 to inhibit the estrogenindependent growth exhibited by this cell line supports the hypothesis that such growth does not result from small amounts of estrogenic growth stimula- tion achieved by extraovarian estrogen production"(page 700, right column, bottom). mcleskey thus relates to something different from the invention asdisclosed in the patent in suit, and a person skilled in the art seeking treatment options would not have any mo- tivation to combine howell with mcleskey. for a number of reasons mcleskey does not point to an effective and tolerable fulvestrant formulation for intramuscular injection for obtaining therapeutically effective levels over a prolonged period of time for the treatment of breast cancer:
  5. i)mcleskey does not relate to the treatment of breast cancer by the use of ful- vestrant. rather mcleskey uses fulvestrant for inhibiting estrogen produc- tion in order to be able to study a possible estrogen-independent mechanism of cancer growth in tamoxifen-resistant breast cancer cells. in the mcleskey study fulvestrant did not inhibit tumor growth and a person skilled in the art would not from mcleskey have found any pointer that any of the two fulvestrant formulations used by mcleskey would be suitable for the treat- ment of breast cancer.
  6. ii)mcleskey administered an extremely high dose of fulvestrant, i.e. 5 mg/week/mouse, corresponding to about 17.5 g per week/human or 70 g/month/human, based on a weight of a mouse of 20 g and a human of 70 kg. such extremely high doses of fulvestrant indicate that mcleskey was not interested in studying efficacy, tolerability, or therapeutic use of the formu- lations used or that such formulations might be suitable for the treatment of breast cancer. iii) mcleskey used subcutaneous administration to mice, whereas the invention according to the patent in suit relates to intramuscular injection. intramus- cular and subcutaneous administration are not equivalent forms of admin- istration, and it is not possible to extrapolate from subcutaneous administra- tion in mice to intramuscular administration in humans.
  7. iv)mcleskey does not point to an effect over a prolonged period of time. thus the mice in mcleskey were injected weekly with the two fulvestrant formu- lations in large doses, see above. this implies that the fulvestrant formula- tions did not result in sufficiently high blood plasma concentrations of ful- vestrant for a prolonged period of time beyond one week, despite the fact that relatively high volumes were administered - 0.1 ml administered to mice (mcleskey, page 698, right column) corresponds to 350 ml weekly in a human of 70 kg. - 106 - for the above reasons a person skilled in the art would not have found a pointer in mcleskey to use any of the fulvestrant formulations disclosed therein for the castor-oil based formulation of howell. consequently, a skilled person would not have used any of the fulvestrant formulations in mcleskey for the castor-oil based formulation of howell in the hope of solving the objective technical problem, i.e. to provide a fulvestrant formu- lation for the treatment of breast cancer which is effective and tolerable and shows thera- peutically effective fulvestrant levels over a prolonged period of time after intramuscular injection. even if a person skilled in the art came across mcleskey, he would not assume that the dosages, administrations or formulations disclosed by mcleskey for use in mouse exper- iments would be suitable for treatment of human breast cancer patients. a person skilled in the art would in my opinion not have a reasonable expectation that any of the fulvestrant formulations used subcutaneously in mice would be suitable for use in the treatment of breast cancer.there was no expectation of success. this can be seen from riffkin (exhibit
  8. j)which shows that it was unpredictable how to prepare for- mulations of steroids acceptable for use. riffkin teaches that castor oil may be used for the administration of steroid hormones in solution in combination with other suitable oilmiscible solvents, cf. abstract. combina- tions of castor oil or sesame oil with co-solvents such as benzyl alcohol and/or benzyl benzoate are disclosed. it appears that the results of the use of co-solvents/combinations of cosolvents are quite unpredictable. thus in table v of riffkin is disclosed a composition comprising 250 mg/ml of 17-hydroxyprogesterone caproate in a vehicle of 58% castor oil, 40% benzyl benzoate and 2% benzyl alcohol. said solution is evaluated as "rejected". conversely, in table vi of riffkin, a composition comprising 40 mg/ml of estradiol valerate in the same vehicle, i.e. 58% castor oil, 40% benzyl benzoate and 2% benzyl alcohol, is considered ac- ceptable. furthermore, in table v of riffkin, a composition comprising 250 mg/ml of 17- hydroxyprogesterone caproate in a vehicle of 52% castor oil, 46% benzyl benzoate and 2% benzyl alcohol is considered acceptable, whereas the similar composition comprising 250 mg/ml of 17-hydroxyprogesterone caproate in a vehicle of 58% castor oil, 40% benzyl benzoate and 2% benzyl alcohol was rejected, cf. above. thus it appears that the effect of individual co-solvents is unpredictable and seems to vary significantly based on the individual active steroid ingredient to be dissolved and the type and relative amount of solvent/co-solvent(
  9. s)used. …” af europæisk patentagent ulla klinges erklæring vedrørende 138-patentet fremgår bl.a. føl- gende: ”… 3) what is the objective technical problem to be solved? - 107 - the objective technical problem to be solved is the use of an alternative fulvestrant formulation for the treatment of benign and malignant diseases of the breast and reproductive tract which is effective and tolerable and shows therapeutically effec- tive fulvestrant levels over at least 2 weeks after intramuscular administration …” af professor sven frøkjærs erklæring fremgår bl.a. følgende: “… 6. does it appear from the howell article whether fulvestrant is in a suspension, solution or emulsion and could different formulations be used for intramuscular for- mulations? based on the information in howell's article, there is no information about the physical form of fulvestrant in the castor oil-based formulation. fulvestrant formulated for in- stance as a suspension, a solution, or as microspheres could potentially work as a long lasting depot formulation. other active ingredients were known before 2000 to have been successfully formulated for instance as suspensions (e.g. insulin, monotard, aqueous sus- pension), solutions (e.g. zuclopenthixol decanoate, cisordinol-depot, oily solu- tion/fractionated coconut oil) or microspheres (e.g. leuprolide acetate, lupron depot). … 9. please give an account of the general considerations the team trying to find a suitable formulation for intramuscular administration of fulvestrant based on the howell article (exhibit 18) would have? in general, it can be a challenge to design a therapeutic efficient and tolerable long-acting depot formulation. based on howell's article which used a castor oil-based depot formulation, the project team would primarily look at two formulation principles, i.e. a solution of fulvestrant in oil (potentially as a prodrug), or a suspension of fulvestrant in oil. how a specific steroid should be formulated depends on the individual steroid. a formu- lation which works for one steroid may not work for another steroid. this is apparent for example from riffkin submitted by sandoz as exhibit j. a formulation which works for one steroid, may not work for the next steroid simply because it has another structure, size, polarity etc., which lead to different solubility and lipid/water partition coefficient. fulvestrant formulated in a castor oil-based vehicle may be adsorbed slowly because a hydrophobic formulation does not spread easily in the hydrophilic tissue environment but tend to stay at the injection side as large "drops/compartments" for a prolonged peri- od of time. the formulation scientist would also know that the part of the dose dissolved in the oil phase at any time will be released from the oily compartments primarily deter- mined by the lipid/water partition coefficient of the

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