sø- & handelsrettens dombog

(1985)p. 253, at: ”the salt form of a drug is known to influence a number of physicochemical properties of the parent compound, including solubility and dissolution rate, stability and hygrosco- picity, which in turn affect the formulation characteristics of the drug. examples of the properties and uses of various pharmaceutical salts are abundant in the literature and have been reviewed elsewhere [18]. in this brief discussion we will focus only on predic- tive relationships between chemical structure within a series of salt-forming species and the thermodynamic properties of their salts with the same drug. quantitative relationships between structure and the physicochemical properties of salts are virtually nonexistent. as we saw in the case of nonelectrolytes, however, various qualitative relationships are recognized.” serajuddin m.fl. anfører i artiklen: “preformulation study of a poorly water-soluble drug, α-pentyl-3-(2-qulnollnylmethoxy)benzenemethanol: selection of the base for dosage form de- sign”

(1986)p.492, at: - 90 - “in consideration of the better stability of the base, the variability in the hydration of the salt, and the absence of a higher dissolution rate of the salt, the base was selected for the dosage form design.” banker og rhodes anfører i bogen ”modern pharmaceutics”, 2. udgave

(1990)p. 508-510: “lyophilization (freeze-drying) […] the advantages of freeze-drying are stabilization of heat- and oxygenlabile drugs, often more rapid solubility, greatly reduced levels of particulate matter, and elegant appear- ance. disadvantages include the difficulty of achieving a product whan a crystalline (ra- ther than amorphous) form is required for stability, limited solvent choices for a given drug, occasionally a reduced solubility rate and longer reconstitution times, an increased haze in the reconstituted soluton with some drugs, and the relatively high expenses of the method.” morris m.fl. anfører i artiklen: “an integrated approach to the selection of optimal salt form for a new drug candidate”

(1994), p. 209-211 og p. 216-217: “the number of tiers necessary to reach a decision on the optimal salt form of a com- pound may depend on the physicochemical properties studied and the number of salts available. this salt selection process can be completed within 4-6 weeks and be easily adopted in the drug development program.” […] development of a salt selection strategy gould

(1986)described a salt selection process based on melting point, solubility, stabil- ity, wettability etc. of various salt forms. however, in the absence of clear go/no go deci- sions at any particular stage of the salt selection process, this approach would lead to the generation of extensive physicochemical data on all salt forms synthesized. gould con- cluded that “the balance required in assessing the correct salt form to progress into drug development makes it a difficult semiempirical exercise. “a more rational approach is, therefore, required to select the appropriate salt form expeditiously during drug devil- ment. in the present method the physicochemical tests were conducted at different tiers and a go/no go decision was made after each tier of testing the salts, thus avoiding gener- ation of extensive data on each salt form synthesized. the studies were planned such that the least time-consuming experiments which could still give a go/no go decision were conducted at tier i. progressively more time-consuming and labor-intensive experiments were conducted at tier 2, tier 3 etc. in this way, many different salt forms could be screened with the minimum of experimental effort. based on the review of literature (berge et al. 1977; hirsch et el, 1978, gould 1986; sera- juddinet al., 1986) and our experience in product development, we identified low hygro- scopicity, integrity of crystal form at different storage conditions, aqueous solubility, and chemical stability as primary criteria for the selection of bms-180431. salts, and set limits for the acceptability of these criteria. all salt forms of the compound which were found to be crystalline were tested at tier i for their hygroscopicity. - 91 - […] “the salts which were considered to have acceptable hygroscopicity were then screened in tier 2 for changes in crystal structure under extremes of humidity conditions by using combinations of powder x-ray diffraction and thermal analysis techniques.” […] “at this stage, the salts were also screened for their aqueous solubilities to determine if there is any potential dissolution and bioavailability problems and whether the formula- tion of a solution dosage form, if required, is feasible.” […] “finally, at tier 3, the selected salts were subjected to accelerated thermal stability and photostability screening. since the stability testing of salts required much time and effort, placing this at tier 3 limited the number of salts on which such tests were conducted and avoided generation of unnecessary data with other salt forms. compatibility screening with selected excipients may also be conducted at this stage. in the above scheme, the number of salt forms available and the physicochemical proper- ties considered important for the bulk drug substance as well for the expected dosage forms will dictate how many tiers would be necessary to select a salt form. there may al- so be rare situations where all salts progressed form a lower tier to a higher one are unac- ceptable for development. for example, the solubility of all salts at tier 2 may be unac- ceptable or chemical stability of all the salts at tier 3 may be poor. if this happens, addi- tional salt forms or free acids/bases should be considered prior to reevaluating any salt that was dropped at an earlier tier. also, the criteria of profession form a lower tier to the next higher one may depend on the physicochemical properties of the available salts. if, for example, all salts are found to be highly hygroscopic, it might be necessary to pro- gress some of them to a higher tier, keeping in mind that, if selected, they might require special manufacturing and storage conditions.” […] summary a systematic three-tier approach was applied to the selection of the optimum salt form of bms 180431 (sodium, calcium, zinc, magnesium, potassium, lysine and arginine) were screened for their hygroscopicity and the nature of moisture present. four salts (sodium, potassium, calcium and zinc) were eliminated at this stage due to their excessive hygro- scopicity over the expected ambient humidity range of pharmaceutical manufacturing plants. the remaning three salts were clevated to tier 2 for the evaluation of any change in their crystal structures under extremes of relative humidity conditions and the deter- mination of aqueous solubility. no change in crystal structures of arginine and lysine salts was observed when thay were exposed to 6 and 75% relative humidity conditions. the two salts were also freely soluble in water. on the contrary, the magnesium salt ex- hibited humiditydependt change in crystal structure and it was only slightly soluble in water. the magnesium salt was, therefore, dropped from further consideration, and the amino acid salts were elevated to the next tier. at tier 3, the solid-state thermal and light stabilities and the drug-excipient compatibilities of arginine and lysine salts were shown - 92 - to be equivalent. it was concluded that arginine and lysine salts of bms-180431 have comparable physicochemical properties and that both salts are superior to the others with respect to their suitability for pharmaceutic dosage form design. after careful evaluation of other factors such as ease of synthesis, ease of analysis, marketing preference, etc., the arginine salt was recommended for development. the hygroscopicity studies at tier i were completed in 2-3 days and the tier 2-studies took one week. the most time-consuming part of the process was the stability testing at tier 3, which required four weeks of time; this could be completed in less time if the develop- ment schedule was tighter. thus, the entire salt selection process may take approx.. 4-6 weeks. since the preparation of salt form is the last step in a chemical synthesis process, it has been our general experience that such a salt selection study can be completed while the chemists are still involved in scaling up the chemical synthesis process, thus avoiding any delay in the developmental program.” parterne har under sagen været enige om, at bogen af stahl og wermuth: ”handbook of pharmaceutical salts, properties, selection, and use”

(2002), er udtryk for kendt viden på prioritetstidspunktet, selvom udgivelsesdatoen af bogen ligger efter prioritetstids- punktet. eli lilly har til brug for sagen kontoroversat forskellige afsnit af ovenstående bog. der fremgår i uddrag heraf p.20, p.35 og p.105: ”2. opløselighedsadfærd af syrer, base og deres salte (side20) 2.1 måling af vandig opløselighed opløseligheden af en ioniserbar forbindelse som en funktion af ph, kendt som ph- opløselighedsprofilen, kan bestemmes ved hjælp af faseopløselighedsteknikker [10] [11]. mættede opløsninger af en fri syre, base eller salt fremstilles ved at ryste en overskuds- mængde af faststoffet med en passende volumen af deioniseret vand ved en kontrolleret temperatur. opløseligheder ved forskellige ph-værdier bestemmes ved trinvis titrering af disse suspensioner med en forholdsvis stærk syre eller base. efter hver tilsætning gen- etableres ligevægt ved omrøring. suspensionens ph måles, og supernatantopløsningsfa- sen analyseres for den samlede opløste koncentration. processen fortsættes, indtil hele ph-opløselighedsprofilen er opnået. systemets ionstyrke kontrolleres ikke i denne meto- de. 4. relevansen af ph-forhold mellem opløselighed og opløsning og saltudvælgelse og - formulering (side 35) 4.1. opløsningsformuleringer til formulering af en stabil opløsningsdoseringsform (oral eller parenteral) er ligevægts- opløseligheden mere vigtig end opløsningshastigheden. ’in-situ’-saltdannelse med den frie form og en egnet modion til justering af ph kan give samme fordel, som hvis der an- vendes et salt. - 93 - en foreløbig undersøgelse af ph-opl’selighedsprofilen med forskellige modioner giver en indikation af, hvilken modion der er bedst egnet til at maksimere opløseligheden (eller optimere

1. ph)som vist på fig. 4. yderligere anvendelse af dette princip blev omtalt af marra-feil og anderson [56]. forfatterne påviste, at flere modioner, som blev tilsat i for- ud fastlagte mængder, således at de ikke oversted opløselighedsproduktet (ksp) af noget salt, gav en betydelig højere opløselighed end en hvilken som helst anden enkelt modion. der er redegjort for relevansen af ph-max. for opløsningsformuleringer med acceptable ph til intravenøs indgivelse [20]. hvis ph-justeringen alene ikke giver en tilstrækkelig forbedring af opløseligheden, kan der anvendes kombinationsmetoder såsom tilsætning af en co-solvent sammen med ph-justering [20] [57]. ligevægtsopløseligheden af et salt og dets frie form forventes at være den samme under identiske betingelser for ph, modion og ionstyrke. saltformen kan imidlertid stadig komme i betragtning til flydende formuleringer af procesbekvemmelighed, såsom hurtig opløsning. yderligere faktorer, som kan have indflydelse på valget af den endelige form, indbefatter krystallinitet og stabilitet i fast tilstand og vil blive beskrevet detaljeret i kapi- tel 6. 5. parenterale indgivelsesveje (side 105) opløseligheden af et lægemiddelstof i vandige systemer er den mest afgørende faktor ved fremstilling af lægemiddelprodukter til parenteral indgivelse, fordi lægemiddelstof- fet skal indgives i opløsning. der skal hyppigt gøres en usædvanlig indsats for at nå frem til en terapeutisk virksomdosis i en volumen, som ville muliggøre en injektion eller infu- sion. der er derfor et incitament til at søge efter salte, som har en trilstrækkeligt høj vandopløselighed. […] beslutningen om, hvilken form af lægemiddelstof der skal tilvejebringes for at fremstille parenterale opløsninger, forenkles hyppigt ved muligheden for in-situ-opløsning af den pågældende frie base, syre eller zwitterionforbindelse og justering af den ønskede ph ved hjælp af en egnet syre eller base. modionen udvælges på basis af opløselighedsek- sperimenter som beskrevet i kapitel 2 - 94 - salt trometamol, tromethamin, tris. anvendelser og eksempler carboprost, desglugastrin, fosfomycin, ketorolac, lodoxamid, prostaglandin f 2α. bemærkninger tromethaminsalte er de relativt bedste h2o-opl’selige. hidtil har man ikke observeret nogen hydratdannelse i mange tromethaminsalte [39]. selv om de finder anvendelse i andre lande, blev tro- metaminsalte ikke godkendt før 1974 affda. dets an- vendelse inden for farmaceutisk praksis har imidlertid på det seneste fået øget opmærksomhed [40] [41]. det første tromethaminsalt, der blev godkendt af fda (i juli 1981) er tromethaminsaltet af prostaglandin f 2α (ny dyremedicin dinoprosttromethamin, intramuskulær injektion) til abort af feedlot-kvæg [42]. tromethaminsal- tet af analgesisk ketorolac blev godkendt af fda i 1989 (intravenøst) og 1991 (oralt) [43].” herudover har parterne dokumenteret enkelte afsnit i den engelske udgave af bogen p.137 og p.149: ”2.1 feasibility assessment for salt formation no predictive procedure to determine whether a particular acidic or basic drug would form a salt with a particular counter-ion has been reported in the literature. 2.5 effect of counter-ions on salt solubility - 95 - it has been reported extensively in the literature that aqueous solubilities of different salt forms of a compound may vary depending on counter-ions used [9] [16] [17] [22 – 25]. streng et al. [16] attributed the difference in aqueous solubilities of lactic acid, me- thanesulfonic acid, hci, and h3po4 salts of terfenadine on the difference in their ksp val- ues with different counter-ions. anderson and flora [4] reviewed the literature for this as- pect of salt formation; however, no predictive relationship emerged. it is often difficult to predict a priori how solubilities of different salt forms of a particular drug will differ for each other. 6. summary and conclusions in this chapter, a systematic strategy for the selection optimal salt forms for acidic and basic drugs has been described. the selection of an optimal salt form for a drug involves the selection of both chemical and physical forms. at the end of a study, it might also be concluded that a salt form is not suitable for a particular drug, and the free acid or base form is preferred. based on physicochemical principles described in this chapter, it is hoped that some of the ‘trials and erroers’ usually associated with salt selection can be avoided, this saving valuable time and resources in a drug-development program.” eli lillys lægemiddel ”alimta®” eli lilly opnåede den 20. september 2004 markedsføringstilladelse til alimta, der findes i 2 forskellige udgaver indeholdende henholdsvis 100 mg pemetrexed(som pemetrexeddinatri-
2. um)eller 500 mg pemetrexed (som pemetrexeddinatrium). af produktresuméet fremgår: - 96 - - 97 - - 98 - - 99 - - 100 - - 101 - fresenius kabis lægemiddel ”pemetrexed fresenius kabi” - 102 - fresenius kabi fik den 26. maj 2016 udarbejdet en ”assessment report” af det europæiske lægemiddelagentur til brug for markedsføringstilladelse til ”pemetrexed fresenius kabi”. det fremgår heraf følgende p. 1: ”international non-proprietary name: pemetrexed”. af rapporten fremgår endvidere følgende: - 103 - - 104 - - 105 - - 106 - - 107 - - 108 - - 109 - - 110 - - 111 - - 112 - - 113 - - 114 - herudover har det europæiske lægemiddelagentur udarbejdet en såkaldt ”summary of opinion (initial authorisation)”, hvoraf det bl.a. fremgår: - 115 - ”pemetrexed fresenius kabi is a generic of alimta, which has been authorized in the eu since 20 september 2004. studies have demonstrated the satisfactory quality of pemetrexed fresenius kabi. since pemetrexed fresenius kabi is administered intrave- nously and is 100% bioavailable, a bioequivalence study versus the reference product al- imta was not required. a question and answer document on generic medicines can be found here.” offentligt udbud både eli lilly og fresenius kabi deltog i offentlig udbud om levering af pemetrexed til det danske sundhedsvæsen. den anslåede værdi af kontrakten, der løber fra 1. juli 2017 til 30. juni 2018 med mulighed for forlængelse, er 180.000.000 kr. leverancen blev tildelt fresenius kabi og eli lilly med fresenius kabi som førsteleverandør. eksperterklæringer parterne har under sagen indhentet eksperterklæringer fra hver deres eksperter. erklæringer fra professor sven frøkjær og professor jesper østergaard eli lilly indhentede den 7. juni 2017 erklæring fra professor sven frøkjær og professor jesper østergaard: “expert report of professors sven frøkjær and jesper østergaard sven frøkjær, of solvej 6, dk-2840 holte and jesper østergaard, of nordtoftevej 52, dk- 3520 farum hereby want to state the following: 1. introduction 1.1 we have been asked by peter-ulrik plesner and mikkel vittrup of advokatfirmaet plesner (“plesner”), who represent eli lilly and company (”lilly”) in a dispute against fresenius kabi, fresenius kabi ab and fresenius kabi oncology plc. (here- after jointly referred to as “fresenius kabi”) to provide this opinion. as regards the dispute between lilly and fresenius kabi, we are informed that fresenius kabi intends to market a pemetrexed product called pemetrexed fresenius kabi, which lilly alleges infringes lilly’s patent rights. 1.2 the background of the undersigned professors appears from our cv’s. sven frøkjær’s cv is shown in exhibit 1. i, sven frøkjær am a professor of drug formulation. i am also a member of the medicinal product committee at the danish medicines agency (“lægemiddelnævnet under lægemiddelstyrelsen”). i have an in-depth knowledge about the documentation required for approval of drugs for marketing. jesper østergaard’s cv is shown in exhibit 2. i, jesper østergaard, am an associate professor at department of pharmacy, lecturing in pharmaceutical physical chemistry and preformu- - 116 - lation. i have an in-depth knowledge about physical chemical characterisation of drug substances. 1.3 we are independent from the parties and their legal and technical advisors. lilly has through its counsels’ asked us to opine on certain aspects relating to the patent ep 1 313 508. the views expressed in the declaration are based on our professional knowledge within pharmaceutics including drug formulation and physical chemistry/physical pharmacy. plesner has helped us to prepare this report but the opinions expressed within it are our own. sections 2-8 below reflects our joint opinion of the relevant questions. un- der section 7, jesper østergaard has elaborated on certain aspects that fall within his spe- cific competence. 2. material instructions 2.1 the substance of the material instructions on the basis of which this report has been writ- ten are as follows:
3. a)we were asked to consider lilly’s patent danish patent no dk/ep 1 313 508 (the “pa- tent” or “the ‘508-patent”) and our view of the technical problem underlying the pa- tent and its solution; and
4. b)we were also asked to consider the medicinal product containing pemetrexed (as pemetrexed diacid with tromethamine) offered for sale by fresenius kabi (“fresenius kabis product”) in view of the patent. 2.2 in preparing this report we have read the following:
5. a)the patent;
6. b)the summary of product characteristic (“smpc”) for fresenius kabis product pemetrexed fresenius kabi and for lilly's product alimta®;
7. c)the assessment report issued by the european medicines agency (“ema”) relating to pemetrexed fresenius kabi (ema/chmp/407425/2016) (“epar”); and
8. d)other documents identified throughout this report. 3. what is the technical problem that the ‘508-patent is intended to solve in your view? 3.1 the patent describes an invention to reduce the toxic side effects of antifolate drugs, used for treatment of various cancer forms by administrating the antifolate drug in combina- tion with vitamin b12 or vitamin b12 derivatives and optionally with a folic acid or a de- rivative thereof without impairing the therapeutic efficacy of the antifolate drug. more specifically the patent concerns the reduction of toxicity observed in cancer patients treated with an antifolate, pemetrexed without adversely affecting its therapeutic effica- cy. 4. from your point of view, would you deem the invention covered by the ‘508- patent as successful/significant or not? 4.1 the invention described in the patent solves a life-threatening toxicity problem (severe side effects) for cancer patients undergoing antifolate cancer therapy with- - 117 - out reducing the therapeutic effect. we consider this a very good example where the benefit/risk ratio is improved to the benefit of the patient. thus, the invention must clearly be deemed as successful and significant seen from a patient perspec- tive and therefore also from a health care perspective. 4.2 this is also apparent from the article “pemetrexed and cisplatin in mesothelioma” by vogelzang et al. j clin oncol 21:2636-2644, 2003, where it is concluded that treatment with pemetrexed plus cisplatin and a combination therapy with vitamin b12 and folic acid resulted in superior survival time, time to progression, and re- sponse rates compared with treatment with cisplatin alone in patients with malig- nant pleural mesothelioma. addition of folic acid and vitamin b 12 significantly re- duced toxicity without adversely affecting survival time. 4.3 another clear documentation of the significance of the invention is the smpc for both the lilly and the fresenius kabi products, alimta and pemetrexed fresenius kabi, respectively. from both smpcs it is evident that pemetrexed products should not be administered without the administration of vitamin b12 and folic acid to avoid the severe toxic effects of pemetrexed. 4.4 in our opinion, the improved therapeutic efficacy of pemetrexed on a fatal cancer form accompanied by a significant reduction in mortality and pemetrexed induced toxicity by the combination treatment with vitamin b12 and folic acid shown in the study reported by vogelzang et al. confirms the significant advantage obtained by the invention according to the ‘508-patent. 5. is there any technical difference or not between fresenius kabis product and their instructions for use on one hand and the ‘508-patent on the other hand with regard to the solution of the technical problem? 5.1 the only complete information that we have about the use of fresenius kabis product (pemetrexed diacid with tromethamine) is the marketing authorisation (including the smpc) and file documents for pemetrexed fresenius kabi. pemetrexed fresenius kabi is a powder for concentrate for solution for infusion (allegedly in the form of pemetrexed diacid). the excipients in the formulation are according to the smpc for pemetrexed fresenius kabi, section 6.1, mannitol (e421), hydrochloric acid concentrated (e507) (for ph adjustment) and trometamol (for ph adjustment). as we shall explain below in section 7, this composition of the aque- ous formulation after reconstitution of the powder is equally well regarded as a so- lution of pemetrexed ditromethamine formed in situ. 5.2 the active anticancer substance, i.e. the anion pemetrexed, in the formulation ready for administration to cancer patients is the same in pemetrexed fresenius kabi as the product described in the patent. according to the epar on pemetrexed fresenius kabi, the fresenius kabi application for marketing authorisation has been submitted as a generic application and “has the same active substance (different salt) and the same excipients in comparable amounts (page 7)… “[t]he aim of the pharma- ceutical development was to develop a finished product generic to the reference medicinal product, alimta (eli lilly nederland b.v). the active substance in pemetrexed fresenius kabi is pemetrexed diacid instead of pemetrexed disodium (alimta). since the active moiety in the solution for infusion remains the same irrespective of the salt form used for manufac- ture it has no impact” (page 10, last paragraph of the epar). it is mentioned several times in the smpc (e.g. section 4.2 and 4.4) that the patients must also be treated - 118 - with vitamin b12 and folic acid in order to reduce treatment-induced toxicity. it follows that during their use the same therapeutic (technical) problem, i.e. reduc- ing the pemetrexed-induced toxicity without compromising the therapeutic effect, is solved in an identical manner. 6. is fresenius kabis product deemed obvious or not for the skilled person in the light of the ‘508-patent? how are therapeutically active compounds (acids or bases) and their salts, esters etc. normally considered from a regulatory point of view? 6.1 according to ema guideline “note for guidance on the investigation of bioavailability and bioequivalence” cpmp/ewp/qwp/1401/98 – emea 2000 (exhibit 3), medicinal products are “pharmaceutical alternatives if they contain the same active moiety but differ in chemical form (salt, ester, etc.) of that moiety or in the dosage form or strength” (section 2.2, line 68-69). the guideline also considers two medicinal products to be bioe- quivalent “if they are pharmaceutical equivalent or pharmaceutical alternatives and if their bioavailability after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same” (sec- tion 2.4, line 84-87). bioavailability is according to the guideline “understood to be the extent and the rate to which a substance or its active moiety is delivered from the pharma- ceutical form and becomes available in the general circulation” (section 2.3, line 76-78). the bioavailability of a compound is per definition 100% if it is given intravenous- ly as a solution. this means that the two products (alimta and pemetrexed frese- nius kabi) have the same bioavailability and therefore fulfil the ema requirements and are “similar “ to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same. please give a brief general explanation about ema’ requirements for granting market authorisation for another form of an already approved active substance (the reference medicinal product) in terms of documentation of efficacy and safety. 6.2 according to the ema guideline mentioned in section 6.1: “a medicinal product is essentially similar to an original product where it satisfies the criteria of having the same qualitative and quantitative composition in terms of active substances, of having the same pharmaceutical form, and of being bioequivalent unless apparent in the light of scientific knowledge that it differs from the original product as regards safety and efficacy” (section 2.5, line 97-101). if these requirements are fulfilled the applicant for a marketing authorisation can be granted as a “generic” which means that the applicant can get a waiver for clinical efficacy and safety by referring to published clinical literature in the dossier. as discussed in section 6.1, pemetrexed fresenius kabi is according to the definition a generic product compared to alimta. this is also clearly illus- trated by the ema assessment report: “the applicant fresenius kabi oncology plc submitted on 21 may 2015 an application for marketing authorisation to the european medicines agency (ema) for pemetrexed fresenius kabi, through the centralised proce- dure under article 3

(3)of regulation (ec) no. 726/2004– ‘generic of a centrally author- ised product”. the eligibility to the centralised procedure was agreed upon by the ema/chmp on 21 november 2013 (page 5, section 1.1). - 119 - would the skilled person in june 2000 and 2017, respectively, understand that it is the pemetrexed anion, which has the therapeutic anti-cancer effect in an intrave- nous infusion liquid containing pemetrexed disodium or would he or she believe that the sodium cations also have a therapeutic effect? 6.3 the pemetrexed anion is the therapeutically active moiety and it would be obvious to the skilled person both in 2000 and in 2017 that the sodium cations in the prod- uct would not have any therapeutic effect. would the skilled person in june 2000 and 2017, respectively, in the light of the pa- tent and his or her general knowledge, expect that pemetrexed disodium could be replaced by the fresenius kabi product pemetrexed diacid (with tromethamine) and maintain the therapeutic effect? if not, what would be the reason for his or her doubt? 6.4 the skilled person would both in 2000 and 2017 have very good reasons to believe that pemetrexed disodium could be replaced by fresenius kabis product pemetrexed diacid (with tromethamine) and still maintain the therapeutic effect as the therapeutic moiety in all cases is the pemetrexed anion. 6.5 the skilled person would expect that it was possible to obtain the same amount of pemetrexed anions in a solution for infusion of pemetrexed disodium as in a solu- tion of infusion of pemetrexed diacid (ph adjusted with tromethamine) and thus maintain the therapeutic effect. 6.6 if we had to identify areas where the skilled person might potentially have ques- tions then that would be in relation to the solubility and stability of the drug. however, the skilled person would not think that this was relevant when reading the ‘508-patent. would the skilled person in june 2000 and 2017, respectively, in the light of the pa- tent and his or her general knowledge, expect that pemetrexed disodium could be replaced by fresenius kabis product pemetrexed diacid (with tromethamine) with- out affecting the reduction of toxicity achieved by the combination therapy with vitamin b12 and folic acid? if not, what would be the reason for his or her doubt? 6.7 the skilled person would both in 2000 and 2017 expect that pemetrexed in the form of pemetrexed diacid (with tromethamine) could be exchanged while main- taining reduction of the toxicity achieved by the combination therapy with vitamin b12 and folic acid because the active moiety which causes the toxicity is the pemetrexed anion and it would be obvious to the skilled person that the beneficial effect of vitamin b12 and folic acid would be independent of the source of the pemetrexed anion. does the smpc for pemetrexed fresenius kabi specifically mention whether pemetrexed fresenius kabi must be administered in a combination treatment with vitamin b12 and folic acid? does it appear or not from the safety concerns in the epar that non-compliance with the vitamin b12 and folic acid regimes is consid- ered a major risk factor? 6.8 according to the smpc for pemetrexed fresenius kabi it is clear that patients must be pre-treated with both vitamin b12 and folic acid to reduce toxicity (see 4.2, 4.4, - 120 - 4.8, 5.1, 5.2). furthermore, the epar mentions non-compliance with folic acid and vitamin b12 regimens as an important safety concern (see page 16-18). would the skilled person agree or not, that it is fair to say that the prescribed use of pemetrexed fresenius kabi only differs from the combination treatment according to the literal wording of patent claims 1, 2, 9 and 10 by the use of a different pemetrexed form? if not, please indicate reason. 6.9 it is clear for the skilled person that the prescribed use of pemetrexed fresenius kabi according to the smpc only differs from the literal wording of the ‘508-patent claims in relation to difference in the pemetrexed form. would the skilled person agree or not that the use of pemetrexed fresenius kabi in accordance with the instructions in the smpc has the same functional result as the solution according to the patent? if not, please indicate reason. 6.10 yes, the skilled person would agree that the use of pemetrexed fresenius kabi in accordance with the instructions in the smpc has the same functional result as the solution according to the patent. finally, would the skilled person conclude or not that the fresenius kabi product would be deemed obvious to the skilled person in 2000 and alternatively in 2017? 6.11 yes, the fact that a sufficiently high pemetrexed concentration in aqueous solution for providing therapeutic effect had been shown and the fact that a salt of pemetrexed had been obtained, i.e. the pemetrexed disodium salt, would strongly suggest and provide ample guidance to the skilled person that one or several alter- native pemetrexed formulations for injection could be developed. 6.12 the pemetrexed salt (or acid) in the fresenius kabi’ products would be obvious as explained in our answers to question 7. 7. would salt screening be necessary or not for arriving at fresenius kabis prod- uct? introduction 7.1 salt formation is commonly applied in drug development for a number of different reasons. formation of a crystalline salt during the production process is a means for removal of impurities and purification of the acidic or basic active pharmaceu- tical ingredient. in relation to oral administration of solid forms, improvement of solubility and dissolution rate enhancement are primary reasons for salt formation as changes in these parameters can affect bioavailability and in turn pharmacoki- netics. increased chemical and physical stability and improved manufacturability constitute additional drivers for exploration of different salt forms. for injectables, the aim is higher aqueous solubility. 7.2 we have been instructed by plesner to provide our view of the task facing the pharmaceutical formulation scientist assuming that he or she was informed in 2000 (or 2017) that pemetrexed (ly231514, mta) had shown effects against various - 121 - forms of cancer by intravenous infusion of pemetrexed disodium in isotonic saline and was asked to propose one or more alternative forms of pemetrexed. our con- clusion is summarised below. how would the pharmaceutical formulation scientist define a suitable alternative? 7.3 the existence of the solid pemetrexed disodium salt would show that pemetrexed is capable of forming solid salts. based on this observation, the pharmaceutical formulation scientist would immediately be able to propose a number of possible counter ions other than sodium potentially forming solid salts with pemetrexed and potentially providing the desired solubility and acceptability required for in- travenous administration. 7.4 confronted with the task of defining one or more alternative forms of pemetrexed, the pharmaceutical formulation scientist would start by making a background study in various databases to find out what was known about pemetrexed at the time

(2000). this would turn up references describing the mechanisms by which pemetrexed penetrates the cancer cells and inhibit multiple enzymatic pathways involved in the cell growth. also the efficacy on various forms of cancer accompa- nied by dose-dependent haematological toxicities, e.g. neutropenia and granulo- cytopia and non-laboratory toxicities, e.g. nausea, fatigue and vomiting would be described. 7.5 moreover, it should be noted that the search would also uncover patent literature, e.g. the ep patent 432677 (the ” ’677-patent”) issued in march 1996, which de- scribes certain glutamic acid derivatives, including pemetrexed diacid (claim 7, when r5’ is an amino group, claim 8 and “compound c”, page 14) as well as claiming the respective acids “and pharmaceutically acceptable salts thereof” (claims 1, 7 and 8). a list of possible examples is given and we note of particular in- terest to the present case alkali metals, such as sodium and potassium, but also “mono-, di and trisubstituted amines” among which “monosubstituted amines“ in- cludes e,g. tromethamine, meglumine and diethanolamine. 7.6 in light of the above, it would be obvious to the pharmaceutical formulation scien- tist that lilly had envisaged that pemetrexed could be used both as the free acid and in the form of a number of well-known pharmaceutically acceptable salts, in- cluding the tromethamine salt effectively used by fresenius kabi. 7.7 for the patent issue in question, relating to the treatment with pemetrexed in com- bination with vitamin b12 and folic acid, the selection of a specific alternative form to pemetrexed disodium is not relevant – irrespective of whether it is the diacid or an alternative salt – since they would all have the same therapeutic effect caused by the pemetrexed anion which also gives rise to the same toxicity problems which would be counteracted by the vitamin b12 and folic acid. however, the develop- ment of alternatives to pemetrexed disodium would be a conceptually straight forward task for the pharmaceutical formulation scientist in

1. would pemetrexed diacid be deemed as an obvious replacement to pemetrexed disodium or not to the pharmaceutical formulation scientist in 2000? 7.8 pemetrexed is a diprotic acid. given that the drug is to be administered by injec- tion, the key point for consideration is solubility; dissolution rate considerations - 122 - will be of lesser importance. the pharmaceutical formulation scientist would ex- pect that pemetrexed diacid can be used provided the solubility is sufficient for administering pemetrexed at an effective dose. the pharmaceutical formulation scientist would be aware that the solubility of the diacid may be increased by ph adjustment thereby converting the diacid to the corresponding more soluble anion- ic form of pemetrexed. the pharmaceutical formulation scientist would thus select the acid as an obvious alternative based on his common general knowledge. 7.9 to confirm the solubility, the pharmaceutical formulation scientist would not have to perform extensive experiments. the pharmaceutical formulation scientist would know that the solubility of an acidic or basic compound is ph dependent. the sol- ubility behaviour is commonly described by a so called ph-solubility profile of which examples can be found abundantly in literature (stahl and wermuth, hand- book of pharmaceutical salts, 2002, (pages 20-27 and 137-149 in exhibit 4) dittert et al. j. pharm sci. 1964, 53, 1325-1328, serajuddin and jarowski. j pharm sci. 1985, 75, 148-154). from the ph-solubility profile for a given acid, the solubility that can be obtained by ph adjustment is easily determined and the ph required for obtaining a desired solubility or target concentration for a liquid formulation is readily pre- dicted when the acid and not the salt is limiting the solubility. this would show that pemetrexed diacid is relatively poorly soluble in water and that a ph adjust- ment by a suitable base therefore is necessary for providing the more soluble pemetrexed anions facilitating administration of an intravenous solution. this ap- proach is frequently used to simplify the development of parenteral solutions (stahl and wermuth 2002 (pages 105-106 and 158-159 in exhibit 4)), e.g., through dissolution of the free acid in aqueous medium (under stirring) and adjustment to the desired ph by a suitable base such as naoh, koh or tromethamol (tro- methamine). this procedure, referred to as “in situ” salt formation by stahl and wermuth 2002 (page 35 in exhibit 4) may provide the same benefits as dissolving a preformed salt if the desired product is a solution for injection. selection of a suita- ble base for ph adjustment follows the same criteria as described below for salts. the in situ salt formation provides a simple approach to test and prepare a range of salt solutions and the principles outlined above were well-known by the phar- maceutical formulation scientist in
2. it will therefore easily be understood by the pharmaceutical formulation scientist that when pemetrexed diacid is dissolved in the concentrated solution for infusion in the presence of tromethamine “for ph – adjustment”, in situ formation of the ditromethamine salt takes place. this is also confirmed in the epar (page 11 and 16). however, the discussion about whether the diacid or the ditromethamine salt is used as an alternative to the disodium salt is purely academic. it is all about converting pemetrexed diacid into dianions at the same concentration as provided by alimta with the assistance of trometamol. 7.10 conclusively, pemetrexed diacid would be deemed as an obvious replacement to pemetrexed disodium to the pharmaceutical formulation scientist in
3. what salt forms would be deemed as obvious replacements to pemetrexed disodi- um to the pharmaceutical formulation scientist in 2000? 7.11 as an alternative to using the pemetrexed diacid (as an in situ formulation), salt formation constitutes the obvious alternative. a range of pharmaceutically ac- ceptable counter ions are available (berge et al. j. pharm sci., vol 66, no. 1, january 1977 (1-19) (exhibit 5) and stahl and wermuth, 2002 (exhibit 4)). the pharmaceu- - 123 - tical formulation scientist would make a short list based on information available in berge et al. and similar sources and through routine procedures perform a small salt screening (detailed below). selection of an alternative salt would be an obvious choice because it would be well-known that in relation to parenteral administra- tion the specific nature (pharmaceutical acceptability of the counter ion presumed) of the counter ion would not affect the efficacy and safety of pemetrexed. 7.12 salt screening and salt selection are routine activities in pharmaceutical industry. for the investigation whether a specific acidic or basic drug substance will form a suitable salt with a particular counter ion certain practises, preferred counter ions and rules of thumb have been developed. a pharmaceutical formulation scientist would start his salt selection by consulting stahl and wermuth or similar sources. although stahl and wermuth was not published until 2002, it reflects the common general knowledge of the person skilled in the art as of
4. the appendix lists the 15 most frequently occurring bases in salt formation (page [331] exhibit 4). the appendix also shows monographies for the individual bases (page [267-325], ex- hibit4). the bases listed are used in pharmaceutical products and are therefore like- ly to be considered pharmaceutically acceptable by the authorities. the pharma- ceutical formulation scientist would be able to select preferred salts as obvious al- ternatives based on his general knowledge. 7.13 in practice, the pharmaceutical formulation scientist would make a shortlist from the selected salts (or a similar compilation) and the short list would provide the pharmaceutical formulation scientist with alternatives that he would deem obvious to disodium as described in the patent in the light of his general knowledge. to confirm that the alternatives would fulfil the regulatory requirements for drugs, the pharmaceutical formulation scientist would test them for solubility and stabil- ity required for regulatory approval. knowing that pemetrexed is able to form salts, and thus, having the disodium salt as reference compound, these tests are routine tests which do not require undue experimentation. 7.14 as for the tromethamine salt, the existing use in pharmaceutical products (6 drugs mentioned for tromethamine salt in stahl and wermuth 2002) and anticipation of the formation of a soluble salt, and knowledge about the use of “tris“-buffers, war- rants inclusion in the short list. 7.15 we deem it obvious that the pharmaceutical formulation scientist would consider and investigate salts appearing in the compilations of berge et al. and stahl and wermuth. the approaches described above providing in situ formed salt solutions of pemetrexed or solid salts of pemetrexed with identical performance as the origi- nal product alimta would be obvious to the pharmaceutical formulation scientist in
5. it would be obvious to the pharmaceutical formulation scientist that coun- ter ions and bases, with very high probability, providing similar effica- cy/performance as compared to alimta can be found. would the answer to the questions above be different in 2017? 7.16 as relates to the task of proposing one or more alternative forms of pemetrexed in 2017, the considerations related to use of the diacid would be the same as in
6. the pharmaceutical formulation scientist would also have the smpc for alimta available and could verify the concentrations, ph values, excipients, etc. for inspi- ration. the pharmaceutical formulation scientist would also have access to the up- - 124 - dated list of salts in stahl & wermuth 2011 (exhibit 6). this would confirm the ear- lier choice of potential counter ions. overall the suggestions and approach for de- fining alternatives to pemetrexed disodium of the pharmaceutical formulation sci- entist would be essentially the same in 2000 and in
7. conclusion 7.17 it should be noted that in order for fresenius kabi to get marketing approval for the alternative solution, it would also be necessary for fresenius kabi to provide and demonstrate adequate stability. this will involve stability testing which must be considered a routine activity in pharmaceutical industry and can be performed according to ich guidelines. in practice, this encompasses development of a stabil- ity indicating assay, e.g. an hplc method, and incubation of the formulation in a suitable container at controlled conditions with respect to temperature and humid- ity. as mentioned in section 6.6 above, the pharmaceutical formulation scientist would not think that this was relevant when reading the ‘508-patent. 7.18 the invention according to the patent is based on the surprising recognition that the toxicity accompanying the beneficial therapeutic effect of pemetrexed on cancer patients as potentially fatal side effects could be alleviated or reduced without re- ducing the therapeutic effect, by a combination treatment also involving admin- istration of vitamin b12 and preferably folic acid. the application of fresenius ka- bis product differing merely with respect to the selected counter ions in the salt so- lutions provided would obviously lead to the same beneficial effects described in the patent. in fact, as highlighted by the fresenius kabi smpc, it is unlikely that the fresenius kabi product will be used without co-administration of vitamin b12 and preferably folic acid as it is directly stated in the smpc for pemetrexed frese- nius kabi and in the clinical overview that patients must take folic acid and must receive vitamin b12 during treatment.
8. summary 8.1 in light of the invention according to the ’508-patent, we deem that the form of pemetrexed is not relevant with reference to the technical problem and the solution as set forth in the ’508-patent. the technical effect of the pemetrexed ion and the combination therapy with vitamin b12 and folic acid would be the same regardless if pemetrexed would be in the form of pemetrexed disodium or pemetrexed diacid (with tromethamine). 8.2 if the form of pemetrexed would be deemed relevant, it is our assessment that fresenius kabis product (pemetrexed diacid with tromethamine) would be obvi- ous for the skilled person if confronted with the task to find an alternative to pemetrexed disodium for use in the invention. 8.3 the facts and matters set out in this report are within our own personal knowledge and we honestly believe that the facts and matters to be true. all opinions ex- pressed represent our true and complete professional opinions on the matters to which they refer.” - 125 - sven frøkjær og jesper østergaard har afgivet en supplerende erklæring den
9. august 2017: ”supplerende eksperterklæring undertegnede sven frøkjær, solvej 6, dk-2840 holte og jesper østergaard, nordtoftevej 52, dk-3520 farum, er af advokat peter-ulrik plesner og advokat mikkel vittrup fra plesner advokatpartnerselskab bedt om at afgive denne sup- plerende erklæring i forlængelse af vores erklæring afgivet
10. juni 2017 (bilag 10) og på baggrund af erklæring afgivet af professor claus selch larsen af
11. august 2017 (bilag h):
12. under henvisning til claus selch larsens svar på spørgsmål 3 i erklæringen af
13. august 2017 (bilag h) bedes i oplyse, om i fastholder jeres svar på spørgs- mål 3 i erklæringen af
14. juni 2017 (bilag 10). ja, vi fastholder vores svar på spørgsmål 3 i vores erklæring af
15. juni 2017, hvil- ket bl.a. er begrundet i patentet dk/ep 1313508 t5 side 3, linje 19 til side 4, linje
16. her anføres det bl.a. generelt om opfindelsen, jf. s. 3 linje 21-24, at toksiske bi- virkninger ”bevirket med antifolater som en klasse kan reduceres væsentligt ved nærvær af et methylmalonsyresænkende middel, såsom b12, uden ugunstigt at påvirke terapeutisk virkningsfuldhed”. endvidere anføres det, jf. s. 3, linje 32-37, at den foreliggende opfindelse angår "generelt en anvendelse til fremstilling af et medikament til reduktion af toksiciteten forbundet med indgivelse af et antifolat til et pattedyr ved til nævnte pattedyr at indgive en effektiv mængde af nævnte antifolat sammen med et methylmalonsyresænkende middel, såsom vitamin b12". efterfølgende angives det, jf. s. 4, linje 25-29, at opfindelsen "tilvejebringer specifikt anvendelse af antifolatet pemetrexeddinatrium til fremstilling af et me- dikament til anvendelse i kombinationsterapi til at inhibere tumorvækst i patte- dyr, hvor nævnte medikament skal indgives sammen med et methylmalonsyre- sænkende middel, der er udvalgt blandt vitamin b12 og farmaceutiske derivater deraf". det er derfor fortsat vores opfattelse, at opfindelsen angår et behandlings- regime som angivet i vores svar på spørgsmål 3 i erklæringen af
17. juni 2017, og vi er ikke enige med claus selch larsens svar, hvorefter opfindelsen alene angår det specifikke dinatriumsalt af pemetrexed, se også vores svar på spørgsmål 3 nedenfor.
18. under henvisning til formuleringen af spørgsmål 8 i erklæringen af
19. august 2017 (bilag h) og claus selch larsens svar herpå, bedes i oplyse, om den fag- mand, patentet '508 retter sig imod, vil læse patentet uden samtidig at orientere sig om de aktivstoffer, der beskrives i patent '
20. som nævnt i svaret på spørgsmål 1 ovenfor, vil det for fagmanden være klart, at opfindelsen angår et behandlingsregime til reduktion af toksiciteten af antifolater uden samtidig reduktion af den terapeutiske virkningsfuldhed. en ekspert i for- mulering af lægemidler med interesse i behandling med antifolat- lægemiddelstoffer herunder pemetrexed, vil i sagens natur ikke alene se på '508 patentet. fagmanden vil drage nytte af sin almene viden og umiddelbart indse, at pemetrexeddinatrium kan omdannes til den korresponderende syre (pe- metrexeddisyre), samt indse muligheden for at fremstille alternative salte af di- carboxylsyren pemetrexed. fagmanden vil endvidere orientere sig bredere om - 126 - pemetrexed og i den forbindelse finde stofpatentet ’
21. ved læsning af stofpa- tentet ’677 vil fagmanden komme på sporet af pemetrexeddisyren, og vil i den forbindelse, sammen med en forståelse af "læren" i '508 patentet, kunne identifi- cere øvrige pemetrexed salte, som vi tidligere har redegjort for i vores erklæring af
22. juni 2017, afsnit 7.3-7.
24. på baggrund af jeres svar på spørgsmål 2 bedes i oplyse, om fagmanden, der læser '508-patentet, vil forstå opfindelsen i '508 patentet til også at omfatte an- dre salte af pemetrexed. ved læsning af ’508 patentet (eksempelvis side 3, linje 19 til side 4, linje 24) vil fagmanden forstå, at opfindelsen relaterer til reduktion af toksiske bivirkninger ved behandling med antifolater generelt. det fremgår af patentet, at der er andre antifolat-lægemiddelstoffer end pemetrexeddinatrium. ved læsning af patentet i sin helhed vil fagmanden forstå, at opfindelsen er baseret på lilly’s produkt alimta®, som indeholder pemetrexeddinatrium, og hvor man har fundet, at de alvorlige bivirkninger ved antifolater kan medieres ved det i patentet beskrevne behandlingsregime, dvs. en kombinationsterapi med vitamin b12 og eventuelt folsyre (eller derivater heraf). ved læsning af patentet i sin helhed vil fagmanden bemærke, at der ikke er fremhævet nogen særlig gevinst eller betydning af at an- vende natriumionen som modion, og at der ikke er beskrevet fravalg af andre sal- te eller den neutrale forbindelse, pemetrexeddisyren. efter vores opfattelse, vil fagmanden indse, at årsagen til at ’508 patentkravene udelukkende indeholder pemetrexeddinatrium ved navns nævnelse er at forsøgene, som ligger bag opfin- delsen, blev udført med pemetrexeddinatrium. sammenholdt med fagmandens generelle viden om muligheden for at danne forskellige salte af stoffer indehol- dende carboxylsyregrupper, e.g., pemetrexed, fagmandens erkendelse af at den toksiske effekt er relateret til pemetrexeddianionen og at den toksiske effekt ikke vil afhænge af valget af modion, såfremt modionen i øvrigt er farmaceutisk ac- ceptabel, er det nærliggende at ’508 patentet tillige omfatter andre salte af pe- metrexed. efter vores opfattelse må fagmanden nå den konklusion, at der ikke er sket en bevidst fravælgelse af pemetrexeddisyre og andre salte af pemetrexed og- så af den grund at et sådant fravalg af beskyttelse ikke er meningsfuld.
25. under henvisning til claus selch larsens svar på spørgsmål 9 og 10 i erklærin- gen af
26. august 2017 (bilag h) bedes i oplyse, om de overvejelser om saltud- vælgelse, der redegøres for i disse svar, også gælder, hvis der allerede forelig- ger et produkt med aktivstoffet på en given saltform. på det overordnede plan finder vi professor emeritus claus selch larsens overve- jelser omkring saltudvælgelse korrekte og beskrivende for udvikling af en ny po- tentiel lægemiddelkandidat (nce) for oral eller parenteral administration i den farmaceutiske industri. vi finder det dog nødvendigt at pointere, at kompleksite- ten og omfanget af det forestående arbejde med at identificere et alternativt salt til pemetrexeddinatrium reduceres betragteligt af, at der ikke er tale om en ny lægemiddelkandidat, men et allerede eksisterende lægemiddel/lægemiddelstof. herved er form og kritiske stofegenskaber (for at bruge claus selch larsens ter- minologi) i højere grad defineret. som beskrevet i vores erklæring af
27. juni 2017, afsnit 7.9, lettes udviklingen af et alternativt salt til pemetrexeddinatrium, som f.eks. ditromethaminsaltet, endvidere af at der er tale om et produkt til injektion, da ph-justering førende til in situ dannelse af en saltopløsning dermed vil udgø- re et acceptabelt alternativ til et fast krystallinsk salt. - 127 - vi fastholder, at saltudvælgelse, og hermed udvælgelse af et alternativt salt til pemetrexeddinatrium, er en konceptuelt ligefrem opgave og at saltudvælgel- se/salt screening er en rutineopgave i den farmaceutiske industri. det er korrekt, som anført af claus selch larsen, at det ikke på forhånd er muligt kvantitativt at forudsige det enkelte salts fysisk kemiske egenskaber og at der ikke på forhånd kan gives sikkerhed for, at det for et givent stof er muligt at identificere et salt med de ønskede fysisk kemiske egenskaber. dette ændrer dog ikke ved at salt- udvælgelse er en opgave, som udføres rutinemæssigt i den farmaceutiske indu- stri. hertil kan bemærkes, at stahl & wermuth (2002, side 329) rapporterer om 1820 salte af lægemiddelstoffer fundet i 1995 udgaven af index nominum samt at serajuddin anfører, at ud af ca. 300 nce’er godkendt af fda fra 1995 til 2006 var 120 på salt form (serajuddin, advanced drug delivery reviews 59

(2007)603– 616). claus selch larsen citerer i øvrigt i sit svar på spørgsmål 10 bd anderson (1985, side 253): ”quantitative relationships between structure and the physicochemical properties of salts are virtually nonexistent”. vi finder, at det for fuldstæn- dighedens skyld ville have været passende også at citere afsnittets næste sætning: “as we saw in the case of nonelectrolytes, however, various qualitative relation- ships are recognized”. ved saltudvælgelse eksisterer der kvalitative relationer, som fagmanden kan drage nytte af. som ét eksempel, blandt andre, og måske af særlig relevans for tromethamin, anfører bd anderson (1985, side 253): ”… it is normally assumed that hydrophilic salt-forming ions such as polyhydroxyl- containing acids or amines would confer extensive water solubility to a salt [21]”. 5. i forlængelse af spørgsmål 4 bedes i oplyse, om i er enige i følgende præmis (præmis 69) i uk supreme court's dom i actavis v eli lilly af 12. juli 2017, sa- gens bilag 29): "[…] it seems to me clear that the notional addressee of the patent would appre- ciate that each of actavis products would work precisely in the same way as pemetrexed disodium when included in a medicament with vitamin b12. when it comes to different versions of pemetrexed medicaments, it is clear that the use of a free acid, and of ditromethamine […] salts was in each case well established as at the priority date - see para 26(

1. ii)to (
2. iv)above. furthermore, the notional ad- dressee of the patent would regard investigating whether pemetrexed free acid, pemetrexed ditromethamine […] worked as a purely routine exercise - see para 25(
3. i)above." vi er enige i præmissen i uk supreme court´s dom anført ovenfor. da salte af pemetrexed vil dissociere i vandig opløsning og effekt og bivirkninger hidrører fra pemetrexed anionen, ville fagmanden vide, at et medikament til in- jektion indeholdende alternative saltformer af pemetrexed (pemetrexedditro- methamin for actavis´vedkommende) ville virke på samme måde som et medi- kament med pemetrexeddinatrium, når det blev givet sammen med vitamin b12. i vores erklæring af 7. juni 2017, afsnit 6,4; 6,5; og 7,9-7,15 har vi redegjort for, at fagmanden vil anse pemetrexeddisyre og et tromethamin salt af pemetrexed for oplagte alternativer til pemetrexeddinatrium, hvilket også er essensen af præmis 69 (paragrafferne 26(ii – iv)). vi anser også saltscreening som en rutine aktivitet som anført af uk supreme court i præmis 69 (paragraf 25(i)), og som redegjort for i vores svar til spørgsmål 4 og erklæring af 7. juni 2017. - 128 - 6. vedrørende claus selch larsens svar på spørgsmål 12 i erklæringen af 14. au- gust 2017 (bilag
4. h)spørges, om der gælder særlige udfordringer, hvis fagman- den skal udvikle et alternativt frysetørret produkt i forhold til eli lilly's pro- dukt, således at det alternative salt også frysetørres. vi deler ikke claus selch larsens synpunkt. efter vores opfattelse forøger forhol- det at produktet skal være frysetørret ikke kompleksiteten ved valg af et egnet salt. som angivet i vores svar på spørgsmål 4 ovenfor forenkles udvælgelsen af et alternativt salt (i forhold til ”de almene selektionskriterier”) tvært i mod af, at der er tale om et frysetørret produkt med henblik på injektion, da ph-justering fø- rende til in situ dannelse af en saltopløsning dermed udgør et alternativ til et fast krystallinsk salt. herved gives mulighed for at anvende modioner, som kan om- danne pemetrexeddisyren til den opløselige pemetrexeddianion uanset om mo- dionen vil danne et fast krystallinsk salt med pemetrexed eller evt danner et amorft salt. selve udvælgelsen af et alternativt salt forenkles, da selektionskriterierne typisk vil være lempeligere i forhold til et fast oralt lægemiddel. frysetørring er en vel- kendt proces til fremstilling af tørstofpræparater. i det aktuelle tilfælde vil fag- manden have en klar forventning om, at aktivstoffet vil kunne frysetørres. fryse- tørring betegnes også lyofilisering (lyofil af græsk lyo, opløse, opløsningsmiddel og –philos –elskende), hvilket har sin begrundelse i, at et frysetørret produkt let befugtes og opløses i opløsningsmidlet (vand). frysetørrede produkter vil gene- relt udvise en hurtigere opløsningshastighed på grund af produktets struktur end udgangsstoffet. vi er uenige i professor claus selch larsens generelle pro- blematisering af kompleksiteten og uforudsigeligheden omkring frysetørring og frysetørrede produkters opløselighed/opløsningshastighed. 7. vedrørende claus selch larsens svar på spørgsmål 13 i erklæringen af 14. au- gust 2017 (bilag
5. h)spørges, om valget af trometamolsaltet af pemetrexed er nærliggende, også når der er tale om et pulver til koncentrat til infusionsvæ- ske? ja, vi anser alternative salte til pemetrexeddinatrium, herunder ditrometha- minsaltet, for nærliggende valg uanset, om der er tale om et pulver til rekonstitu- tion (f.eks. et frysetørret produkt) eller et koncentrat til infusionsvæske på bag- grund af ”læren” af ’508 patentet, jf. svarene på spørgsmål 1 og 3 ovenfor, og fagmandens generelle viden, jf. vores svar til spørgsmål 4, 5 og 7 ovenfor. 8. i bedes uddybe jeres tidligere svar på spørgsmål 7.13 og kommentere claus selch larsens svar på spørgsmål 16 i erklæringen af 14. august 2017 (bilag h). en komplet saltscreening med henblik på at opnå et salt med de ønskede fysisk kemiske egenskaber kan være omfattende om end det er en rutineopgave, når det drejer sig et helt nyt potentielt lægemiddelstof. i det aktuelle tilfælde vil fagman- den dog vide, at pemetrexeddinatrium har de fysisk kemiske egenskaber, herun- der en opløselighed/opløsningshastighed i vandigt medium, der gør det egnet som lægemiddelstof i et frysetørret markedsført produkt. på den baggrund vil fagmanden forvente, at en saltscreening med henblik på at finde en anden mo- dion end natriumionen vil være overkommelig og tage udgangspunkt i en liste over de mest hyppigt anvendte farmaceutisk acceptable baser til saltdannelse. 9. i bedes oplyse, om fagmanden, der læser patent '768 (bilag a), vil forstå, at det er formålet med den heri beskrevne opfindelse at løse angivelige stabilitets- - 129 - problemer for opløsninger af pemetrexed og tilvejebringe en stabil opløsning af pemetrexed, der kan markedsføres i hætteglas? ja, fagmanden vil forstå at opfindelsens formål er at fremstille en stabil opløsning af pemetrexed, alternativt en stabil frysetørret sammensætning indeholdende pemetrexed, til brug for injektion, se f.eks. afsnit [0011]. endvidere fremgår det af fremgangsmåderne til fremstilling af sammensætningerne, at de er påtænkt op- bevaret i hætteglas, se f.eks. afsnit [0018] og [0019].” erklæringer fra dr.med. christian manegold eli lilly har under sagen fremlagt en erklæring fra dr. med. christian manegold, der er afgivet den 23. december 2016 i forbindelse med en sag ved de svenske domstole mellem eli lilly og medicinalproducenten actavis: “expert report i, christian manegold, do hereby declare as follows: 1. introduction 33166-105\10993840v1 1.1 i have been asked by håkan borgenhäll and malin malm waerme of advokatfir- man vinge, who represent eli lilly and company (”lilly”) in a dispute against ac- tavis group ptc ehf and actavis ab (hereafter jointly referred to as “actavis”) to provide this opinion. as regards the dispute between lilly and actavis, i am in- formed that actavis has requested the court to declare that its sale of certain pemetrexed products does not infringe on lilly’s patent rights. i understand that lilly has disputed such declaration. 1.2 i have attached my personal cv to this report that shows my academic back- ground and work experience. 1.3 i am independent from the parties and their legal and technical advisors. lilly has through its counsels’ asked me to opine on certain aspects relating to the patent. advokatfirman vinge has helped me to prepare this report but the opinions ex- pressed within it are my own. 1.4 i have read the european patent no. 1 313 508 granted to lilly. i have been told that proceedings are pending at the patent and market court in stockholm, case no. pmt 2097-15 that actavis conducts against lilly. i have been asked to answer some questions that relate to the patent. on the one hand, some of those questions concern the teaching of the patent, its perception by a skilled person and my expe- rience of the applicability of this invention. on the other hand i was asked to an- swer questions in relation to the different forms of pemetrexed that are subject of the above mentioned patent infringement action. - 130 - 2. material instructions 2.1 the substance of the material instructions on the basis of which this report has been written are as follows:
6. c)i was asked to consider lilly’s patent european patent no ep 1 313 508 (the “patent” or “the ‘508-patent) and my view of the technical problem underlying the patent;
7. d)i was also asked to consider the medicinal products containing pemetrexed proposed by actavis in view of the patent; and
8. e)to provide my opinion on technical matters raised by actavis in the dispute. 2.2 in preparing this report i have read the following:
9. e)the patent;
10. f)the summary of product characteristics for armisarte;
11. g)the ema:s assessment report of armisarte; and
12. h)other documents identified throughout my report. 2.3 i have also read the expert report of professor seckl dated 22 september 2016 filed with the court. the views i express in this report were formed before i read his re- port. however, i have not found any reason to modify my opinion after having read these reports. 3. personal background 3.1 i am by training an internist, sub-specialized in haematology and medical oncolo- gy. i have been involved in the care of cancer patients and specifically for the man- agement of thoracic cancers in academic affiliations in heidelberg and mannheim for almost three decades (department of medical oncology, chest hospital, uni- versity of heidelberg, university medical center mannheim, medical faculty mannheim-university of heidelberg). 3.2 these occupational activities have included leadership positions in a great number of pivotal clinical trials such as national and international study leader and leader or member of an independent data monitoring committee (idmc) with specific reference to lung cancer and the clinical development up to registration of innova- tive chemotherapeutic agents. in this regard i have been the author or co-author of more than 300 scientific communications focussing on issues of solid tumor, main- ly thoracic cancers. this includes publications to treatment consensus-guidelines (ref. 63-70 in annex 2 below) and text book chapters (ref. 71) as well as presenta- tions of national and international conferences. 3.3 i was the chairman of the european organisation of the research and treatment of cancer -lung cancer group (eortc-lcg) from 2000-2004. i am currently one of the members of the board of directors of the international association for the study of lung cancer (bod-iaslc), a senior scientific advisor of the interdiscipli- nary cancer center mannheim – university of heidelberg, and a visiting professor at the medical university in bialystok, poland with teaching responsibilities and - 131 - leadership function in the international phd program. at the same time i am an advisor of the bialystok university medical center in the management of patients with thoracic cancers. 3.4 my curriculum vitae is annexed hereto (annexes 1 and 2). 3.5 i have acted as an investigator or consultant for a number of pharmaceutical com- panies including lilly, f. hoffmann la-roche, novartis, astrazeneca, boehringer ingelheim, glaxo-smith-kline, pfizer, agennix, baxter, msd, bayer, sanofi- aventis, abbott, daiichi-sankyo, taiho, cellact and bms. i have assisted and ad- vised lilly for almost two decades in the clinical development of a number of chemotherapeutic agents including the antimetabolites/antifolates gemcitabine (gemzar) and pemetrexed (alimta) in thoracic cancers (ref. 1-29, 38-53, 59). from the beginning i was very much involved in the clinical development of the anti- folate pemetrexed (alimta) in malignant pleural mesothelioma (ref. 1-17) and non- small cell lung cancer (ref. 18-29). 3.6 i confirm that i have no personal interest in the outcome of these proceedings. i provide this declaration on the basis of my own knowledge and convictions. 3.7 i am aware that my own (current) knowledge and understanding of the invention is not identical with that of a “person skilled in the art” in the year 2000. this “per- son skilled in the art” does not represent a real person, but is a theoretical person having average skill and several years of professional experience in the respective relevant technical field and if necessary may consist of a team of different persons. on the basis of my own knowledge and experience i am quite familiar with the perspective of such a “person skilled in the art” in 2000 in the field of chemothera- py treatment of neoplastic diseases (cancer). my following statements regarding the knowledge and assessments of the "person skilled in the art" refer to this time unless otherwise stated. 3.8 in the following, the questions which i am happy to answer are stated in bold let- ters heading the respective section. 4. what is it that the skilled person after studying the patent description under- stands as the subject matter of the patent, i.e. what is the patent about? 4.1 the subject of the patent is that with a supplementation therapy of a patient with vitamin b12 the toxic side effects of chemotherapy with pemetrexed (alimta) can be reduced without at the same time adversely affecting the efficacy of the antifo- late. neither the antifolates described as known to the skilled person (cf. para 2 of the patent) or their equally known modes of action are in the focus of the patent but rather the benefit of a combination therapy with vitamin b12 for the toxic ef- fects brought about by the antifolates. 5. what is your personal assessment of the use of vitamin b12 supplementation? 5.1 i was involved in a phase ii study in advanced non-small cell lung cancer (ref. 22) and a phase iii study in malignant pleural mesothelioma (mpm) (ref. 1, 3) involv- ing pemetrexed (alimta) without supplementation by vitamin b12 and folic acid. - 132 - 5.2 i participated in the phase iii trial in advanced malignant pleural mesothelioma, which was amended during the trial to include vitamin b12 (and folic acid) sup- plementation (ref. 1). because there had not been any experience with that kind of supplementation in pemetrexed therapy and it would have been expected that vit- amin b12 and folic acid would interfere with the antifolate pemetrexed's (alimta'
13. s)efficacy, the mere toxicity reducing effect of vitamin b12 (and folic acid) supple- mentation at that point in time came as a surprise. i did not expect that the addi- tion of folic acid and vitamin b12 would reduce toxicity without adversely affect- ing survival time (ref. 3). after the toxicity reducing effects of vitamin b12 and fo- lic acid supplementation had been observed, it was clear to me that vitamin sup- plementation is a prerequisite for the alimta application in humans to avoid life threatening toxicities (antifolate-group toxicity). 5.3 as far as my experience with other antifolates is concerned i have some experience with methotrexate supplemented by leucovorin rescue - in my early clinical oncol- ogy practice i treated young patients with osteosarcoma. leucovorin rescue is common in the use of methotrexate in this particular disease to avoid life- threatening toxicity. my experience with raltitrexed (tomudex®) is also not exten- sive. here i was involved in a raltitrexed (tomudex) study of the eortc lgc in malignant pleural-mesothelioma (ref. 55) and a small phase ii trial in advanced nsclc (ref. 54). i am not aware of the use of vitamin b12 with either of these agents in the treatment of cancer. 6. please characterize the "skilled person". how would the skilled person have as- sessed the invention in june 2000? 6.1 my understanding from reading the patent is that the addressee is someone who would be involved in the treatment of cancer patients with chemotherapy agents (and in particular antifolates), including dealing with the associated toxicities from such chemotherapy – for example, an oncologist with some pharmacological ex- pertise and experience with the use of antifolates for cancer, or an experienced pharmacologist with experience researching antifolates for cancer and an under- standing of the clinical use of antifolates for cancer. as at june 2000, and given my years of working in the field, i am aware of the likely views of other oncologists in the field and my comments below stem from that interaction and trying to place myself back in the position of not knowing of the invention in the patent where that is necessary for the respective question. 6.2 i consider my reaction, described above, would have been typical of my peer group – the addressees of the patent in june 2000. the toxicity reducing effects of vitamin b12 supplementation, but without a similar reduction in efficacy, had not been expected and were surprising at that time. however, they were quickly ac- cepted in the community following the reported results of the phase iii study (ref.3) and it is now the standard of care. 7. what was your own experience in the clinical application of alimta? 7.1 my personal experience with the clinical use of pemetrexed (alimta) supplement- ed by vitamin b12 and folic acid since its registration in malignant pleural meso- thelioma in combination with a platinum containing compound or as a single agent as well as in second-line therapy of advanced non-squamous nsclc and in first-line therapy of non-squamous nsclc as well as in the maintenance setting - 133 - has been very positive in regard to toxicity and efficacy. pemetrexed (alimta) is ef- fective in clinical practice in an extension as documented in the registration studies (ref. 3, 19, 26) and as in the registered indications. pemetrexed (alimta) is very well tolerated in most of the patients with malignant pleural-mesothelioma and ad- vanced non-squamous nsclc with very little severe toxicity. my clinical experi- ence with pemetrexed (alimta) indicates, in the rare and inadvertent circumstanc- es, where vitamin supplementation is not taken the risk of severe toxicities increas- es. after publication of the study results (esp. ref. 3) and even today, nobody would consider chemotherapy with pemetrexed (alimta) without vitamin b12 (and folic acid) supplementation. 7.2 i recall that the results of the phase iii study of pemetrexed (alimta) in malignant pleural mesothelioma i was involved in were presented at the american society of clinical oncology conference (asco) in the year 2002 (ref. 1). the presentation at asco 2002 as well as the publication of the study in the year 2003 underlined that pemetrexed (alimta) has been the first agent tested in a randomized phase iii trial in a socially very “sensitive” thoracic cancer because of being highly considered of occupational origin (asbestos). therefore, it was not very difficult for the oncologi- cal community after registration to immediately accept pemetrexed (alimta) as part of the chemotherapeutic standard because of its well documented efficacy (tumor load reduction; improvement of tumor associated symptoms) and little se- vere toxicity if supplemented by vitamin b12 and folic acid. 7.3 the invention according to the patent – the supplementation of pemetrexed with vitamin b12 and optionally, folic acid – was and is in my view very important in the oncology field. the invention made it possible to use pemetrexed in cancer treatment because toxicity was reduced without decreasing efficacy. the invention made a significant difference in the way to treat the specific forms of lung cancer. without the discovery of how to reduce the toxicity of pemetrexed, alimta would not have been authorised. thus, the combination therapy is a very important in- vention which allowed a new treatment to be brought to patients. 8. in the context of the invention, which relevance has the form pemetrexed is in prior to reconstitution and infusion into the bloodstream? 8.1 the skilled person knows (i.e. knew in the year 2000) that the antineoplastic effect of pemetrexed was based on inhibition of various enzymes, namely thymidilate synthase (ts), dihydrofolate reductase (dhfr) and glycinamide ribonuleotide formyltransferase (garft) (cf. also para 2 of the patent). more precisely, the inhi- bition is caused by pemetrexed in polyglutamated form, the polyglutamation hap- pening within the cell. pemetrexed ions that after infusion are in the bloodstream of the patient in dissociated form are transported into the cell via so called "folate carriers" and are polyglutamated inside the cell. 8.2 during preparation of the solution for infusion, pemetrexed salts dissociate in the solution. thus, a solution that contains pemetrexed ions and the corresponding counter ions (e.g. sodium ions) is infused. only the pemetrexed ions are relevant for therapeutic effect. the counter ions after infusion disperse within the blood- stream but do not have any relevance for the effect of pemetrexed. 8.3 also, the toxic effects of pemetrexed solely are based on the pemetrexed ions. the counter ion is not germane to that toxicity. to the skilled person it therefore is ir- - 134 - relevant in which form pemetrexed is in prior to the preparation of the solution for infusion as far as with the infusion pemetrexed ions are supplied. 8.4 this is true especially in the context of the invention because for the toxicity reduc- ing effect of vitamin b12 supplementation it is completely irrelevant in which compound pemetrexed was in prior to reconstitution, when that is the case, and di- lution. the counter ion does not have any influence on the reduction of the toxicity of the pemetrexed ion by vitamin b12, i.e. on the effect of vitamin b12. 8.5 of course the counter ion to the pemetrexed ion which is co administered to the patient would have to be tolerable for the patient in the amount administered. the skilled person knows which counter ions can be administered in which amount. in any case this question has no influence on the aspect that vitamin b12 supplemen- tation as described in the patent reduces toxic effects of pemetrexed without ad- versely affecting its efficacy. 9. from the point of view of the skilled person, would pemetrexed dipotassium, pemetrexed ditromethamine and pemetrexed diacid have the same effect as pemetrexed disodium? 9.1 i am not aware of any publications on the effect of pemetrexed dipotassium, pemetrexed ditromethamine or pemetrexed diacid. however, as i have already stated, the antineoplastic effect of pemetrexed – as well as the toxicities to be treat- ed with vitamin b12 supplementation – are based on the pemetrexed ion only. thus, for the skilled person all pemetrexed derivatives would be considered to have the same effect that after infusion supply the required pemetrexed ions. i be- lieve the skilled person would assume that dissociation of the pemetrexed ion and the respective counter ion when reconstituted/diluted before infusion would hap- pen in each of the said cases. potassium and sodium salts are typical pharmaceuti- cal salts. tromethamine is also used as pharmaceutical salt as of 1981 (cf. wer- muth/stahl, handbook of pharmaceutical salts, 1st ed., 2001). acids like pemetrexed diacid would be expected to dissociate in aqueous surroundings, par- ticularly if buffered. 10. for the skilled person – in knowledge of the teaching of the patent – was it ob- vious that instead of a sodium salt of pemetrexed he could use a potassium or tromethamine salt or a diacid form of pemetrexed? 10.1 for the skilled person it was obvious that he could choose any pemetrexed deriva- tive with which the pemetrexed ion would be administered to the bloodstream in dissociated state because he knew that for the invention only the supply of the pemetrexed ion was relevant. as salts and acids dissociate in aqueous solution for the skilled person all pharmaceutically acceptable salts as well as the acid form were obvious. 11. in the context of the invention, would the skilled person consider pemetrexed dipotassium, pemetrexed ditromethamine and pemetrexed diacid as equivalent to pemetrexed disodium? 11.1 yes, i think that is true. as i have set out above, the subject of the invention is the reduction of toxicity of chemotherapy with pemetrexed by vitamin b12 supple- mentation without adversely affecting the efficacy of pemetrexed. as i have also - 135 - stated, for the toxic effects only the pemetrexed ion is responsible, the counter ion being irrelevant in this regard. vitamin b12 supplementation can thus reduce the toxicity caused by pemetrexed without an adverse effect on the antineoplastic ef- fect of pemetrexed irrespective of the pemetrexed ion having dissociated from pemetrexed disodium, pemetrexed dipotassium, pemetrexed ditromethamine or pemetrexed diacid. 12. armisarte 12.1 in the context of the invention, would the skilled person consider armisarte as equivalent to alimta? 12.1.1 i know that actavis has been granted market authorisation for a pemetrexed prod- uct named armisarte. armisarte is a generic product with alimta as the reference product. i understand that the difference between armisarte and alimta is that armisarte is sold as a concentrate for solution for infusion, whereas alimta is sold as a lyophilized (freeze-dried) powder. alimta contains pemetrexed as pemetrexed disodium; armisarte contains pemetrexed as pemetrexed diacid (or equally termed pemetrexed free base) in solution with tromethamine. 12.1.2 i have read the assessment report from the european medicines agency for armisarte and noted that armisarte has an identical content of the active substance (as pemetrexed free base) as alimta. (p. 10 and 25 of the epar.). furthermore armisarte contains pemetrexed active moiety dissociated in an ionic solution in a similar manner. (p. 11 of the epar.) accordingly, this means that armisarte has the same anti-tumour effect as alimta since it provides a supply of pemetrexed ions for infusion. 12.1.3 i also noted that no new toxicology studies or pharmacokinetic studies were sub- mitted and that no bioequivalence studies were conducted by actavis (p. 22, 24 and 26 of the epar). since both alimta and armisarte are administered as iv solu- tion, it was considered that the bioavailability is 100 % and that the safety and effi- cacy of armisarte does not differ from alimta (p. 26 of the epar). moreover, the dosage instructions and administration schedule are the same for armisarte as for alimta, which also shows that the efficacy should be the same. the safety concerns of the ema relate to potential non-compliance with the folic acid and vitamin b12 regimen as prescribed in the smpc (p. 28 and 29 of the epar). the ema’s con- cerns in this regard show the importance of complying with the significant aspects of the combination treatment and also that the ema does not have any safety con- cerns related to the change of form of pemetrexed. from this it is clear that the dif- ference in form does not affect the efficacy of the pemetrexed ions and that the combination therapy with vitamin b12 and folic acid as described in the smpc of armisarte ensures that the toxicity of pemetrexed is reduced in the same way as for alimta. 12.1.4 from the point of view of the skilled person, the pemetrexed in armisarte has the same effect as pemetrexed disodium in alimta. additionally, the prescribed com- bination therapy with vitamin b12 and folic acid solves the same problem as the one underlying the patent. in my opinion this shows that armisarte provides an equivalent means for fulfilling the same objective as pemetrexed disodium and that the prescribed combination therapy provides an equivalent means for solving the same problem as the one underlying the patent.“ - 136 - dr. med. christian manegold har til brug for nærværende sag udfærdiget en supplerende erklæring af 18. oktober 2017: “supplementary expert report i, christian manegold, do hereby declare as follows: 1. introduction i have been asked by peter-ulrik plesner and mikkel vittrup of plesner advokatpart- nerselskab ("plesner") who represent eli lilly and company ("lilly") in a dispute in denmark against fresenius kabi, fresenius kabi ab and fresenius kabi oncology plc. (hereafter jointly referred to as "fresenius kabi") to provide this supplementary opinion to my original opinion dated 23 december 2016. i am independent from the parties and their legal and technical advisors. lilly has through its counsels’ asked me to opine on certain aspects relating to the patent. plesner has helped me to prepare this report but the opinions expressed within it are my own. i have again read the european patent no. 1 313 508 granted to lilly. i was asked to an- swer questions in relation to pemetrexed fresenius kabi that is subject of the above men- tioned patent infringement action. 2. material instructions 2.1 the substance of the material instructions on the basis of which this report has been written are as follows:
14. f)i was asked to consider lilly’s patent european patent no ep 1 313 508 (the "pa- tent" or “the ‘508-patent)
15. g)i was also asked to consider the medicinal product containing pemetrexed sold by fresenius kabi in view of the patent; and
16. h)to provide my opinion on technical matters raised by fresenius kabi in the dis- pute. 2.2 in preparing this report i have besides the material i read in preparation of my first opinion read the following:
17. i)the summary of product characteristics for pemetrexed fresenius kabi
18. j)the european medicines agency's (ema) assessment report of pemetrexed fresenius kabi
19. k)page 10 of the english translation of fresenius kabi's reply which addresses my first expert report
20. l)d2: us 5405839; and - 137 -
21. m)other documents identified throughout my report. i confirm that i have no personal interest in the outcome of these proceedings. i provide this declaration on the basis of my own knowledge and convictions. based on information that i have received from plesner, i am aware that my own (cur- rent) knowledge and understanding of the invention is not identical with that of a "per- son skilled in the art" in the year 2000. this "person skilled in the art" does not represent a real person, but is a theoretical person having average skill and several years of professi- onal experience in the respective relevant technical field and if necessary may consist of a team of different persons. on the basis of my own knowledge and experience i am quite familiar with the perspective of such a "person skilled in the art" in 2000 in the field of chemotherapy treatment of neoplastic diseases (cancer). my following statements regar- ding the knowledge and assessments of the "person skilled in the art" refer to this time unless otherwise stated. i understand that as regards the dispute between lilly and fre- senius kabi, the relevant "person skilled in the art" is a team consisting of an oncologist and a pharmacologist. in the following, the questions which i am happy to answer are stated in bold letters heading the respective section. 3. in the context of the invention, would the skilled person consider pemetrexed fresenius kabi as equivalent to alimta? 3.1 i know that fresenius kabi has been granted market authorisation for a pemetrexed product named pemetrexed fresenius kabi. pemetrexed fresenius kabi is a generic product with alimta as the reference product. i understand that both pemetrexed fresenius kabi and alimta are sold as a lyophilized (freeze-dried) powder. alimta contains pemetrexed as pemetrexed disodium; pemetrexed frese- nius kabi contains pemetrexed as pemetrexed diacid together with tromethamine. 3.2 i have read the assessment report from the ema for pemetrexed fresenius kabi. it is stated on page 14 that "since the active moiety in the solution for infusion remains the same irrespective of the salt used for manufacture it has no impact". similarly on p. 8 "both products are intended for intravenous use and must be reconstituted and diluted pri- or to use. when reconstituted and diluted for administration, the active moiety remains the same irrespective of the salt form". accordingly, this means that pemetrexed frese- nius kabi has the same anti-tumour effect as alimta since it provides a supply of pemetrexed ions for infusion. 3.3 i also noted that no new toxicology studies or pharmacokinetic studies were sub- mitted and that no bioequivalence studies were conducted by fresenius kabi since "no bioequivalence study was deemed required as the finished product is to be administered in an aqueous solution containing the same active substance in the same concentration as the reference product" (p. 12 of the epar). moreover, the dosage instructions and administration schedule are the same for pemetrexed fresenius kabi as for alimta, which also shows that the efficacy should be the same. the safety concerns of the ema relate to potential non-compliance with the folic acid and vitamin b12 regi- men as prescribed in the smpc (p. 16 and 17 of the epar). the ema’s concerns in this regard show the importance of complying with the significant aspects of the combination treatment and also that the ema does not have any safety concerns related to the change of salt form of pemetrexed. from this it is clear that the dif- ference in salt form does not affect the efficacy of the pemetrexed ions and that the - 138 - combination therapy with vitamin b12 and folic acid as described in the smpc of pemetrexed fresenius kabi ensures that the toxicity of pemetrexed is reduced in the same way as for alimta. 3.4 from the point of view of the skilled person, the pemetrexed in pemetrexed frese- nius kabi has the same effect as pemetrexed disodium in alimta. additionally, the prescribed combination therapy with vitamin b12 and folic acid solves the same problem as the one underlying the patent. in my opinion this shows that pemetrexed fresenius kabi provides an equivalent means for fulfilling the same objective as pemetrexed disodium and that the prescribed combination therapy provides an equivalent means for solving the same problem as the one underlying the patent. 4. could you please clarify your answer in paragraph 5.3 in your first report in light of fresenius kabi's comment on p. 10 in its rejoinder? 4.1 in paragraph 5.3 of my first report, i discuss methotrexate and raltitrexed and con- clude that: "i am not aware of the use of vitamin b12 with either of these agents in the treatment of cancer." fresenius say that they are surprised by this statement in light of a us patent which was referred to by the european patent office during exami- nation of the patent. i have briefly reviewed the us patent referred to by fresenius, in particular example 15, and it does not change my opinion. i am not, and was not, aware of the use of vitamin b12 with either methotrexate or raltitrexed in clini- cal practice in 2000. the us patent is not a document that the oncologist would have been aware of in 2000. 5. could you please comment on the replies to questions 17-21 by claus selch lar- sen in the report of 14 august 2017 (exhibit
22. h)5.1 the skilled person would understand that the dosage regimen in the patent does not in any way restrict the use of the invention. the invention (combination thera- py of pemetrexed and vitamin b12 (and optionally folic acid)) is of general ap- plicability. for example, [0032] of the patent discusses the dosage amounts of b12 to be adminis- tered and says: "however, it will be understood that the amount of the methylmalonic acid lowering agent as vitamin b12 actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the ac- tual agent administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. in some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be em- ployed without causing any harmful side effect." [emphasis added] there would be no reason for the skilled person to believe that only the tested dosage levels of pemetrexed, b12 and folic acid in the patent would be effective in relation to treating the patient's cancer whilst reducing the toxicity of pemetrexed without nega- tively impacting efficacy. it appears from the summaries of product characteristics for alimta and pemetrexed fresenius kabi, respectively, that the recommended treatment regimens are identical. fresenius kabi have copied the alimta dosage regimen.” - 139 - erklæringer fra professor emeritus claus selch larsen fresenius kabi har under sagen indhentet en erklæring fra professor emeritus claus selch larsen, der er afgivet den 14. august 2017: ”undertegnede, professor emeritus, phd, dr. pharm., claus selch larsen, er af advokat anders valentin, advokatfirmaet horten, blevet anmodet om at besvare en række spørgsmål vedrørende europæisk patent dk/ep 1313508 t5 (herefter ”stridspatentet”), det af eli lilly markedsførte lægemiddel alimta ®, samt det af fresenius kabi markeds- førte lægemiddel pemetrexed fresenius kabi. for så vidt angår min faglige baggrund for at besvare disse spørgsmål, henviser jeg til mit cv, jf. vedlagte kopi. jeg er i forbindelse med besvarelsen (jf. nedenfor) blevet forsynet med kopi af: dk/ep 1313508 t5 (stridspatentet) dk/ep 0432677 t3 (stofpatentet) ep 2854768 b1 bilag 1 – produktresumé for alimta® emea 2004: scientific discussion related to the initial scientic discussion for the approval of alimta® lægemiddelkataloget 2005-2006: monografi for alimta® bilag 1 – produktresumé for pemetrexed fresenius kabi ema assessment report for pemetrexed fresenius kabi hanauske et al.

(2001)pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. the oncologist 6, 363-373. ouellet et al

(2000)population pharmacokinetics of pemetrexed disodium (alimta) in patients with cancer. cancer chemother pharmacol 46, 227-234 morris et al.

(1994)an integrated approach to the selection of optimal salt form for a new drug candidate. int j pharm 105, 209-217. gould pl

(1986)salt selection for basic drugs. int j pharm 33, 201-217. berge et al.

(1977)pharmaceutical salts. j pharm sci 66, 1-19. serajuddin et al.

(1986)preformulation study of a poorly water-soluble drug, α-pentyl-3- (2-quinolinylmethoxy)benzenemethanol: selection of the base for dosage form design. j pharm sci 75, 492-496. anderson bd

(1985)prodrugs for improved formulation properties. in bundgaard h (ed) design of prodrugs, elsevier, amsterdam, chapter 7, pp. 253 boylan and fites

(1990)parenteral products. in modern pharmaceutics 2 nd edition (eds g.s banker and c.t. rhodes), marcel dekker inc, new york, p.510) expert report of professors sven frøkjær and jesper østergaard af 7 juni 2017 med bilag. spørgsmål 1 kan du bekræfte, at det af stridspatentets (dk/ep 1313508 t5) beskrivelse fremgår (jf. ek- sempelvis s. 3 linje 19 til s. 4 linje 23), at den heri beskrevne opfindelse vedrører opdagel- sen af, at det er muligt at reducere den toksicitet, som er forbundet med injektion af en ef- fektiv mængde af et givet antifolat lægemiddelstof ved samtidigt at indgive en kemisk forbindelse med methylmalonsyre-sænkende virkning? svar på spørgsmål 1 ja, det er velkendt, at behandling med antifolat lægemiddelstoffer (herunder pemetrexed) giver anledning til alvorlige toksiske bivirkninger. opfindelsen vedrører, at den toksicitet som ses ved anvendelse af et medikament indeholdende antifolatet pemetrexed dinatri- - 140 - um kan reduceres væsentligt i en ny kombinationsterapi involverende samtidig indgivel- se af en methylmalonsyre-sænkende kemisk forbindelse og evt. et folatbindende protein- bindende middel, eksempelvis folsyre. spørgsmål 2 kan du - i forlængelse af spørgsmål 1 – bekræfte, at det af stridspatentets (dk/ep 1313508 t5) beskrivelse tillige fremgår (jf eksempelvis s. 4 linje 25-29, s. 5 linje 4-9 og s. 5 linje 20- 26), at den deri beskrevne opfindelse angår muligheden for at reducere den toksicitet i pattedyr, som er forbundet med indgift af en tumor-inhiberende mængde af antifolatet pemetrexeddinatrium ved samtidigt at indgive vitamin b12 eller et farmaceutisk derivat af vitamin b12? svar på spørgsmål 2 ja, det kan jeg bekræfte. af stridpatentets titel (”kombination indeholdende et antifolat og methylmalonsyresænkende middel”, som er oversat fra det engelske ”combination containing an antifolate and methylmalonic acid lowering agent”) fremgår det, at opfin- delsen vedrører en kombination indeholdende et antifolat og et methylmalonsyresæn- kende middel. i stridspatentet er det yderligere præciseret, at ”opfindelsen tilvejebringer specifikt anvendelse af antifolatet pemetrexeddinatrium til fremstilling af et medikament til anvendelse i kombinationsterapi….sammen med vitamin b12 og farmaceutiske deriva- ter deraf” (s. 4 linje 24-26). at opfindelsen alene vedrører anvendelse af antifolatet pe- metrexeddinatrium til fremstilling af medikamenter til den påtænkte anvendelse i kom- binationsterapi fremgår ydermere af stridspatentets krav 1: ”anvendelse af pemetrexed- dinatrium til fremstilling af et medikament til anvendelse i kombinationsterapi til inhibe- ring af tumorvækst i pattedyr, hvorved medikamentet skal indgives sammen med vita- min b12……..”. det fremgår med andre ord helt klart af kravets ordlyd, at det er pe- metrexed dinatrium, som skal anvendes i en proces til fremstilling af et medikament. på helt tilsvarende vis angår stridspatentets krav 12: ”produkt, der indeholder pemetrexed- dinatirum….., som et kombineret præparat til den samtidige separate eller sekventielle anvendelse til inhibering af tumorvækst”. ingen af stridspatentets øvrige krav nævner anvendelse af andre antifolater til fremstilling af sådanne medikamenter eller produkter indeholdende andre antifolater, ligesom der heller ikke nævnes anvendelse af andre salte af pemetrexed til fremstilling af sådanne medikamenter eller produkter indeholdende andre salte af pemetrexed end netop pemetrexeddinatrium. spørgsmål 3 med henvisning til spørgsmål 3 (“what is the technical problem that the ’508-patent is in- tended to solve in your view?”) i expert report of professors sven frøkjær and jesper østergaard, p. 2, spørges du, om du er enig i ordlyden af den af sven frøkjær og jesper østergaard udarbejdede besvarelse 3.1? svar på spørgsmål 3 nej, jeg er ikke enig i den udarbejdede besvarelse. i svaret 3.1 anføres bl.a.: ”the patent describes an invention to reduce the toxic side effects of antifolate drugs, used for the treatment of various cancer forms……”. med henvisning til mit svar på spørgsmål 2 ovenfor skal det præciseres, at opfindelsen efter min opfattelse netop ikke angår en re- duktion af de toksiske bivirkninger af alle tænkelige antifolat-lægemiddelstoffer ved en samtidig indgivelse af vitamin b12 eller farmaceutiske derivater deraf. derimod fremgår det som nævnt ganske klart af stridspatentets beskrivelse samt krav 1 og 12, at opfindel- sen alene vedrører anvendelse af pemetrexed dinatrium til fremstilling af et medikament til anvendelse i en kombinationsterapi sammen med vitamin b12 eller farmaceutiske de- rivater deraf til inhibering af tumorvækst, og produkter indeholdende pemetrexeddina- trium til anvendelse i et kombineret præparat sammen med vitamin b12 eller farmaceuti- ske derivater deraf til inhibering af tumorvækst. spørgsmål 4 - 141 - kan du - i forlængelse af spørgsmål 1 og 2 – bekræfte, at det af stridspatentets (dk/ep 1313508 t5) beskrivelse tillige fremgår (jf s. 7 linje 10-17, at det ”antifolat” eller ”antifolat- lægemiddel”, der er anvendt ved den i stridspatentet beskrevne opfindelse, er pe- metrexeddinatrium, og at nævnte dinatriumsalt er anvendt i form af lægemidlet alim- ta® produceret af eli lilly & co.? svar på spørgsmål 4 ja, det kan jeg bekræfte, da (i) det anvendte antifolat eller antifolat-lægemiddel (eller ret- tere antifolat-lægemiddelstof) er pemetrexeddinatrium, jf svaret på spørgsmål 2 og 3, og (ii) i afsnittet ”fremgangsmåder” er pemetrexeddinatrium det eneste med navns nævnel- se præciserede antifolat. i dette afsnit er stort set konsekvent anvendt termen ”pe- metrexeddinatrium (alimta®)”. på eksempelvis siderne 10-12 er termen ”pemetrexed- dinatrium (alimta®)” nævnt mere end 15 gange. spørgsmål 5 i afsnittet ”fremgangsmåder” i stridspatentet (dk/ep 1313508 t5) er anført udførelsesek- sempler (jf s. 10 linje 33 til s. 14 linje 22). er du - i forlængelse af spørgsmål 1, 2, 3 og 4 – enig i, at samtlige disse udførelseseksempler alene angår en reduktion af den toksicitet, som er forbundet med indgift af pemetrexeddinatrium i form af det brugsfærdige læge- middel alimta®? svar på spørgsmål 5 ja, det er jeg enig i. det fremgår direkte af delafsnittene s. 10 linje 33 til s. 12 linje 27 og s. 14 linje 10-13 (se i øvrigt svar på spørgsmål 4). med baggrund heri sammenholdt med be- skrivelsen på s. 7 linje 15-17, må fagmanden slutte, at forsøgene, der er beskrevet fra side s. 12 linje 29 til s. 14 linje 8, også er udført under anvendelse af antifolatet pemetrexeddi- natrium (alimta®). spørgsmål 6 i forlængelse af spørgsmålene 1-5 spørges, om du kan bekræfte, at den reducerede toksi- citet af pemetrexeddinatrium, som ifølge stridpatentets udførelseseksempler (under af- snittet ”fremgangsmåder” fra s. 13 linje 34 til s. 14 linje 22) opnås, når pemetrexeddina- trium anvendes i kombinationsterapi med vitamin b12 i humane individer, alene er base- ret på observationer i patienter, som er indgivet pemetrexeddinatrium i form af lægemid- let alimta®? svar på spørgsmål 6 ja, det kan jeg bekræfte med henvisning til svaret på spørgsmål 5. spørgsmål 7 du bedes oplyse, om der i stridspatentet (dk/ep 1313508 t5), ud over pemetrexeddina- trium, er beskrevet andre saltformer af pemetrexed? svar på spørgsmål 7 nej, som nævnt i svaret på spørgsmål 3 nævner stridspatentet kun anvendelse af pe- metrexeddinatrium til fremstilling af en farmaceutisk formulering, som ifølge beskrivel- sen er ”pemetrexeddinatrium alimta®”. spørgsmål 8 kan du være enig i, at en fagmand inden for lægemiddelformulering, der læser stridspa- tentet, dk/ep 1313508 t5, ikke i patentet ville finde nogen tilskyndelse til at forsøge at identificere andre pemetrexed salte end pemetrexeddinatrium til de anvendelser, som stridspatentet angår? svar på spørgsmål 8 som anført i svar på spørgsmål 7 nævner stridspatentet kun anvendelse af pemetrexed- dinatrium. patentkrav 1 omfatter alene pemetrexeddinatrium som del af en kombinati- onsterapi med vitamin b12 eller et farmaceutisk derivat af vitamin b12. i krav 1 er speci- fikt anført 7 derivater, herunder hydroxycobalamin, alle med vitamin b12 lignende far- makologisk effekt. i patentkrav 2 anføres en udvidelse af kombinationsterapien beskre- - 142 - vet i krav 1 med et folatbindende proteinbindende middel, der er udvalgt blandt folsyre,

(6r)-5-methyl-5,6,7,8-tetrahydrofolsyre og

(6r)-5-formyl-5,6,7,8-tetrahydrofolsyre eller et fysiologisk tilgængeligt salt eller en fysiologisk tilgængelig ester heraf. for både vitamin b12 og folsyre er således præciseret alternative kemiske forbindelser inklusiv salte (folsyre), som potentielle kandidater til at indgå i omtalte kombinationste- rapi. for så vidt angår kombinationsterapien er ingen alternativer til brugen af pe- metrexeddinatrium nævnt/fremhævet. dette kunne eksempelvis være sket ved at modifi- cere indledningen i krav 1 til: ”anvendelse af pemetrexed i form af dinatriumsaltet eller andre farmaceutisk acceptable salte heraf til fremstilling af ……”. med baggrund i oven- nævnte forhold kan fagmanden derfor kun komme til den konklusion, at udelukkende pemetrexeddinatrium er relevant som antifolat til fremstilling af et medikament til an- vendelse i nævnte kombinationsterapi. jeg er endvidere enig med sven frøkjær og jesper østergaard i, jf. pkt. 7.5 og 7.6 i deres expert report af 7. juni 2017, at en fagmand, der læ- ser stridspatentet, også må formodes at have kendskab til det tidligere stofpatent for pe- metrexed (dk/ep 0432677 t3). fagmanden må derfor efter min opfattelse uundgåeligt komme til den konklusion, at der har været tale om en bevidst fravælgelse af andre salt- former af pemetrexed i relation til den kombinationsterapi, der er omfattet af stridspaten- tet, da eksempelvis krav 8 i det oprindelige stofpatent (dk/ep 0432677 t3) specifikt om- fatter pemetrexed (anført ved det systematisk kemiske navn for stoffet) ”og de farmaceu- tisk acceptable salte deraf”. spørgsmål 9 du bedes kort forklare den generelle baggrund for tiltag omkring saltudvælgelse i den farmaceutiske industri omkring prioritetsåret for dk/ep 1313508 t5

(2000). svar på spørgsmål 9 på nævnte tidspunkt var der i den farmaceutiske industri efterhånden skabt en voksende forståelse for, at saltdannelse ofte kunne bruges til at forbedre en lægemiddelkandidats fysisk kemiske egenskaber og dermed biologiske karakteristika uden at ændre på læge- middelkandidatens organisk kemiske struktur (gould, 1986). det blev derfor mere og mere almindeligt, at såfremt en potentiel lægemiddelkandidat, indeholdende en syre- el- ler basegruppe, viste sig ikke at være anvendelig på uladet form, ville den pågældende virksomhed forsøge at fremstille en række salte af den potentielle lægemiddelkandidat med det formål at forsøge at skabe det bedste grundlag for (om muligt) efterfølgende at udvælge den mest optimale form af stoffet, der skulle indgå i det brugsfærdige lægemid- del. spørgsmål 10 du bedes forklare, hvilke forhold og egenskaber, der skal tages stilling til, når et udvik- lingsarbejde startes for at finde et egnet salt af en given forbindelse, samt angive om et sådant udviklingsarbejde altid vil føre til identifikation af et salt besiddende de fysisk kemiske egenskaber, der er nødvendige for, at saltet af den aktive substans kan indgå i et brugsfærdigt lægemiddel. svar på spørgsmål 10 omkring saltudvælgelse har de fleste virksomheder i dag (hvilket også gjorde sig gæl- dende i 2000) deres egen måde at gribe tingene an på. saltene kan fremstilles og testes et efter et med udgangspunkt i den enkelte udviklingsenheds erfaring og normale procedu- rer, indtil der (forhåbentlig) identificeres et egnet salt. alternativt fremstilles serier af sal- te af den givne lægemiddelkandidat forud for en samlet saltkarakterisering (som en væ- sentlig del af en saltscreening). som grundlag for udvælgelsen af den endelige form af kandidaten (eksempelvis den fri syre/base eller et salt heraf) foretages en omfattende fysisk kemisk karakterisering af samtlige syntetiserede forbindelser. dette særdeles ressourcekrævende arbejde er nød- vendigt, da den enkelte forbindelses fysisk kemiske egenskaber er uforudsigelige. uanset - 143 - hvilken procedure virksomhederne anvender, vil det som oftest være rationelt at dele ka- rakteriseringen ind i flere faser startende med at bestemme de kritiske stofegenskaber (fysisk kemiske parametre), der skal være på plads, for at den pågældende forbindelse kan indgå i et brugsfærdigt lægemiddel. antallet af sådanne kritiske stofegenskaber (fy- sisk kemiske parametre) vil kunne variere betragteligt afhængigt af, hvilken farmaceutisk form det enkelte salt skal inkorporeres i (eksempelvis en tablet versus et pulver til kon- centrat til infusionsvæske, opløsning). almene vitale selektionskriterier omfatter lav hyg- roskopicitet, passende vandopløselighed samt adækvat fysisk og kemisk stabilitet (se ek- sempelvis morris et al., 1994). en review artikel fra 1977 (berge et al., 1977) indeholder en omfattende gennemgang af diverse salte af lægemiddelstoffer markedsført før ca. 1975. i dette første systematiske ar- bejde omkring farmaceutiske salte har forfatterne opstillet en række forskellige kriterier til brug for udvælgelsen af en egnet saltform af en given lægemiddelkandidat, hvor for- fatterne dog må konkludere: ”at present

(1977)selecting a salt form that exhibits the de- sired combination of properties is a difficult semiemperical choice”. dette underbygges af den væsentlige erkendelse af bd anderson

(1985): ”quantitative relationships between structure and the physicochemical properties of salts are virtually non-existent” eller med andre ord, at det ikke, på kvalificeret måde, er muligt at forudsige noget om (beregne sig frem til) saltes fysisk kemiske egenskaber ud fra deres kemiske struktur – et udsagn som efter min bedste overbevisning fortsat er gyldigt i år 2017. det er indlysende, at jo flere fysisk kemiske egenskaber et salt skal opfylde for at kunne bruges i et givent lægemiddel (medikament), jo sværere vil det, ud fra strukturen af et givent salt, være at udtale sig om, hvorvidt saltet vil besidde samtlige disse eftertragtede egenskaber. det er derfor dags dato fortsat en kendsgerning, at gennemførelse af en end- og særdeles omfattende saltscreenings-procedure på ingen måde giver sikkerhed for, at der kan findes en saltform af en given lægemiddel-kandidat, der besidder de egenskaber, der er nødvendige for udvikling af et brugsfærdigt lægemiddel (se eksempelvis serajud- din et al., 1986). spørgsmål 11 du bedes kort kommentere på oplysningerne anført dels i ep 2854768 b1 og dels pro- duktresuméet for pemetrexed fresenius kabi: - under sektion 3 (lægemiddelform): (

1. i)pulver til koncentrat til infusionsvæske, opløs- ning og (
2. ii)hvidt til off-white lyofiliseret (frysetørret) pulver eller fast stof, -under sektion 6.1 (hjælpestoffer): mannitol; saltsyre (til ph justering); trometamol (til ph justering), og - under sektion 6.6 (regler for bortskaffelse og anden håndtering) vedr. rekonstituering og fortynding før anvendelse. svar på spørgsmål 11 fremstillingen af den brugsfærdige infusionsopløsning af pemetrexed fresenius kabi in- deholdende det aktive pemetrexed foregår som en totrinsproces: 1. det frysetørrede pulver rekonstitueres (opløses) ved tilsætning af en 5% glucoseop- løsning til infusion, således at der efter oprystning opnås et klart koncentrat til infu- sion indeholdende 25 mg pemetrexed/ml. 2. koncentratet fortyndes passende med 5% glucoseopløsning til infusion forud for den intravenøse infusion blandt de farmaceutiske hjælpestoffer er mannitol en såkaldt ”bulking agent”, som ofte benyttes i fremstillingen af frysetørrede produkter. trometamol er en svag organisk base. jeg har fået oplyst, at fremstillingen af pemetrexed fresenius kabi sker i henhold til ep - 144 - 2854768 b1. heraf fremgår det, at man ved fremstillingen af pulveret opløser trometamol og mannitol i sterilt vand, hvorefter disyreformen af pemetrexed tilsættes. trometamol er tilsat i en mængde, således at der in situ dannes en pemetrexed-ditrometamol saltopløs- ning. opløsningens ph finjusteres med saltsyre og den færdige opløsning frysetørres (ep 2854768 b1 s. 4 linje 33-43 og s. 12 example 11). spørgsmål 12 forøger det forhold, at lægemidlet pemetrexed fresenius kabi er et ”pulver til koncentrat til infusionsvæske, opløsning”, efter din opfattelse kompleksiteten ved valget af egnet salt af pemetrexed med adækvate fysisk kemiske egenskaber? svar på spørgsmål 12 ja, det er helt klart tilfældet. ud over de almene selektionskriterier (se svar på spørgsmål 10) er en forudsætning for brug af denne farmaceutiske form, at opløsningshastigheden af det frysetørrede pulver (jf. spørgsmål 11), under dannelse af koncentratet til infusion, er tilpas hurtig. uforudsigeligheden af en frysetørringsproces på kemiske stoffer måtte fremgå af følgen- de citat fra en anerkendt farmaceutisk håndbog: ”the advantages of freeze-drying are stabilization of heat- and oxygenlabile drugs, often more rapid solubilization, greatly reduced levels of particular matters, and elegant appearance. disadvantages include the difficulty of achieving a product when a crystalline (rather than amorphous) form is re- quired for stability, limited solvent choices for a given drug, occasionally a reduced sol- ubility rate and longer reconstitution times, an increased haze in the reconstituted solu- tion with some drugs, and the relatively high expenses of the method” (boylan and fites (parenteral products) in modern pharmaceutics 2nd edition (eds g.s banker and c.t. rhodes), marcel dekker inc, new york 1990, p.510) spørgsmål 13 i forlængelse af spørgsmål 8 og 12 spørges om fresenius kabi’s valg af et pulver til kon- centrat til infusionsvæske, opløsning baseret på trometamolsaltet af pemetrexed efter din vurdering er indlysende ud fra, hvad en fagmand kan uddrage af stridspatentet? svar på spørgsmål 13 nej, en fagmand ville ud fra stridspatentet ikke være tilskyndet til at udvælge trometa- molsaltet af pemetrexed eller for den sags skyld andre salte af pemetrexed, jf. svaret på spørgsmålene 8 og 12. spørgsmål 14 i forlængelse af spørgsmål 12 spørges om, medikamenter, i form af lægemiddelformen ”pulver til koncentrat til infusionsvæske, opløsning”, generelt er at foretrække, når der er tale om udvikling af et nyt medikament (lægemiddel) beregnet til indgift ved injektion. sv