The purpose of this paper is to discuss, based on the experiences the author has made over the last few years both in his own professional activities in the field of licensing pharmaceutical know-how and patents and his involvement in Health Care Committees in both LES Germany and LES International, the following questions of interest: the role of licensing in the field of pharmaceuticals, financial elements of pharmaceutical license agreements, and legal aspects, under the general theme of which specific questions of license agreements affecting countries of the European Union (EU), like export bans, parallel imports and compulsory licenses, will be dealt with.
2. The Rising Importance Of Licensing In The Field Of Pharmaceuticals
Since more than 10 years, a distinctly rising importance of licensing in the pharmaceutical field could be observed. The number of license agreements covering pharmaceutical inventions concluded per year has increased a lot faster than the world-wide turnover of the pharmaceutical industry, so that it appears as worthwile to have a close look at the reasons for the increasing licensing activities in the pharmaceutical field, the more since in other areas of technology, possibly with the exception of software-related inventions, the discrepancy between growth of world-wide total turnover of the respective industry and increase of number of license agreements concluded per year seems to be far smaller.
2.1. Emptying Pipelines
As a general observation in pharmaceutical industry all over the world, one may duly state that a heavy demand for new drugs exists. Particularly caused by the long duration of R&D between start of research for a new drug until NDA (New Drug Approval), exceeding 10 years as nowadays estimated as an average to reach as long as 12 years (two additional years taken for NDA approval as such after finishing Phase 3 clinical study), and also because of the fact that obviously only about 10 %, i.e. one out of 10 candidates, of drugs selected from primary research and going into preclinical studies finally are approved and launched in the market place, the pipelines of at least the big global players in pharmaceutical business are no longer well filled. To fill the pipelines better based on own R&D activities, is very costly and in many instances goes beyond the capacities, if not the financial ones, then of manpower, of even big drug manufacturers. As a consequence, the big players have started, and are increasing their activities insofar steadily, to look around in the outside world in order to find new pharmaceuticals, or at least new substances which can be considered as candidates for further selection.
In this connection, it might be appropriate to mention that the terms Phase 1, Phase 2, and Phase 3 clinical studies in this paper are understood in the usual way, i.e. Phase 1 starts when the new drug is first applied to human patients in order to determine human toxicity, metabolism, absorption, elimination etc., in Phase 2 clinical studies being conducted to determine safety and performance further, including more extended investigations with patients, and Phase 3 comprising expanded trials in order to get additional information about effectiveness and safety. Looking at the overall duration from start of research to NDA approval and launch, Phases 1, 2, and 3 of clinical studies often are designated as R&D stages 3, 4, and 5, following R&D stage 1, describing the basic research until the selection of preclinical drug candidates, and R&D stage 2, determining the time from the end of R&D stage 1 until the selection of clinical drug candidates for entering clinical studies, in such scheme R&D stage 6 describing NDA and launch of the drug in the market place.
The aforementioned scheme, as well as extremely valuable considerations in relation to financial aspects to be discussed lateron, may be found in a more detailed form in an article by Motohiro Yamasaki, "Les Nouvelles" September 1996, pp. 112 - 114. The aforementioned article also describes attrition rates, as percentages, after R&D stages 1 - 6, as well as R&D times, the figures therein corresponding to the experiences in Germany, too, i.e. a duration of R&D stage 1 of about 3,5 years, duration of R&D stage 2 1,5 years with an attrition rate of 70 %, duration of Phase 1 (R&D stage 3) 1,5 years, attrition rate 70 %, duration of Phase 2 (R&D stage 4) 1,5 years, attrition rate 50 %, duration of Phase 3 (R&D stage 5) 2 years, attrition rate 50 %, and duration of R&D stage 6 2 years, attrition rate 80 %.
This means, in other words, and the author can follow the aforementioned paper fully insofar as these numbers have been confirmed by asking quite a few European pharmaceutical companies, that, if after R&D stage 1 10 substances (compounds) are selected from preclinical studies, after R&D stage 2 7 drugs remains, after R&D stage 3 5 drugs, after R&D stage 4 2 drugs (the assumption of the aforementioned paper that it could be three, instead of two, not being confirmed), after R&D stage 5 1 drug (maximum, also here the European experiences seem to be somewhat worse than assumed in the above mentioned paper, where "1 - 2" have been assumed), so that in and after, resp., R&D stage 6 only 1 drug remains for marketing.
2.2. University Licensing
Particularly in relation to pharmaceuticals, university based research plays an ever increasing role, particularly in U.S.A. and Canada. The universities become more and more aware of the commercial value of their inventions, less and less agreeing to their researchers freely cooperating with industry under agreements which from the very beginning provide for inventions coming out of the research work done by the University on behalf of the respective industrial entity automatically and without any license considerations belonging to the company.
Industry, which on the other hand appreciates very much the university work as a source for new substances to be tested for becoming drugs, therefore is faced with a situation in which reseach and development by universities makes it more and more necessary to determine license conditions right from the beginning, in order to give the researcher and his/her university, respectively, a fair share of the profit later possibly be made by the respective company based on the development made in the university.
In any case, the increasing role of university licensing, even if the university develops a drug until hypothetical R&D stage 1 to be finalized, makes licensing steadily more important for the pharmaceutical scene.
2.3. Start-Up Firms As Intermediates
Somewhat related to the importance of university research and licensing of its results as discussed under 2.2. above, it has to be observed that in many instances, just after certain research work done at universities and the like resulting in substances that might be interesting in a later stage to find pharmaceutical applications, start-up firms are founded by members of the university, in many instances together with capital investors, in order to develop drug candidates, having come out of a R&D stage 1 as defined above, for pharmaceutical applications, at least until the end of R&D stage 2.
For such start-up firms it is very typical that in normal instances they do not develop drugs further than to R&D stage 2, the clinical studies becoming by far too expensive for many start-up firms, so that the major goal of such firms consists in becoming licensors to the pharmaceutical industry after R&D stage 2.
2.4. Biotech Intermediates
A very special role in the development of pharmaceuticals offered to the pharmaceutical industry for licensing is played by firms specializing in biotechnology. Since biotechnology plays a significant role in developing new drug candidates, the role of such type of companies as licensors for big pharmaceutical companies (global players) cannot be over-estimated.
Typically, biotechnology companies develop substances to a similar level as start-up firms usually do, i.e. until the end of R&D stage 2 as indicated above, the respective drugs at that time becoming candidates for licensing to pharmaceutical industry. Biotechnology requiring extremely specialized skills, many pharmaceutical companies more or less systematically have focussed on not developing biotechnologically created substances by their own R&D departments, rather transfer such technology from companies specializing in biotechnology, some times in the form of joint-venturing with not only isolated biotech firms, but joining efforts with other pharmaceutical manufacturers in order to make the respective costs more tolerable.
3. Financial Elements In Pharmaceutical License Agreements
In the following, an attempt will be made to describe some rules that apparently are followed in determining typical financial elements of license agreements, with a specific view to license agreements in the pharmaceutical field. Here, as well as above and in the following, only license agreements will be considered which at least partially are directed to technology/substances protected by patents or at least by trade secret rules.
A typical element of license agreements, not only in the pharmaceutical field, is a downpayment or advance payment being payable by the licensee to the licensor at the time of or shortly after the signature of the license agreement, and at least in case of exclusive license agreements such downpayment apparently is considered as being indispensible. The question is how the downpayment should be determined.
In the above mentioned paper by M. Yamasaki a different, very attractive approach is described, which in U.S.A. apparently is followed in quite a number of patent licensing agreements and which is based on a more precise calculation of the cost of developing a substance for pharmaceutical application from R&D stage 1 to R&D stage 6. The downpayment in this model depends on the stage in which the drug is handed over, i.e. the technology transfer from licensor to licensee is realized by the coming into force of a respective license agreement.
Fortunately, in pharmaceutical industry it is quite well known that nowadays the R&D expenses for developping a new substance from start of research to launching in the market place reach about U.S. $ 200.000.000,--, as a worldwide average. If one now uses the attrition rates as discussed under 2.1. above, obviously the cost for a certain substance, as spent by the licensor until turnover of the respective technology to the licensee, depends on the R&D stage. Assuming that the total cost for the development is, as indicated above, U.S. $ 200.000.000,--, i.e. for one single drug finally launched in the market place, taking into into due consideration the attrition rate will lead to the fact, assuming that a Phase 3 clinical study will cost U.S. $ 10.000.000,--, that the accumulative cost per compound after completion of Phase 2, i.e. R&D stage 4, will be U.S. $ 90.000.000,-- per substance. If one furthermore assumes that the cost of Phase 2 is U.S. $ 5.000.000,--, the cumulative cost per substance after Phase 1 (i.e. R&D stage 3) is U.S. $ 40.000.000,--, and similar considerations lead to respectively lower values for substances after R&D stage 2 and after R&D stage 1.
Further details of this calculation, as well as the appropriate assumptions, can be found in the above mentioned paper by M. Yamasaki, which quite reliably reflects experiences one also can make in European pharmaceutical industry, as already stated earlier in this paper.
It appears as fair that the downpayment should cover the costs of licensor arisen until the time of technology transfer. In the above mentioned example, that would mean that a downpayment, assuming that the pharmaceutical is ready to launch (i.e. after R&D stage 6), should be U.S. $ 200.000.000,--, compared with only about U.S. $ 25.000,-- after R&D stage 2.
As a matter of course, the aforementioned figures have to be understood as examples. In practical licensing negotiations, also in the pharmaceutical field there exists a rather broad range of variation from the aforementioned calculations. Nevertheless, the afore described method of determination seems to be generally accepted at least to come to a commercially viable basis for further negotiations.
3.2. Royalty Rates
Royalty rates in recent pharmaceutical license agreements can be observed as ranging from a very few percent up to 20 % or even more. The determination of such royalty rates generally seems to follow the well-known "25 %-rule" e.g. described by Robert Goldscheider in "Les Nouvelles" September 1996, pp. 115 - 120. One assumes in this model that the total commercial success of the substance in the market at 50 % will depend on effects not linked with the competitive edge as given by the respective patent protection, and therefore belonging solely into the court of the licensee, the other 50 % being related to the protected invention, i.e. the competitive edge achieved by licensee because of the technology licensed from licensor. One furthermore assumes that the marginal profit should be equally shared between licensee and licensor, leading to 25 % of the net profit before taxes as made by licensee as being a reasonable royalty.
Again, the above mentioned article by M. Yamasaki is an extremely valuable source for finding a reasonable basis for calculating royalty levels in pharmaceutical industry, the assumption and its results fitting remarkably well with royalty rates that can be found in pharmaceutical license agreements with effective dates stemming from the about last 5 years:
The approach is based on the observation that the research and development expenditures of big pharmaceutical companies, according to e.g. "Annual Survey Report 1989 - 1991" of PMA (U.S. Pharmaceutical Manufacturer`s Association), can be considered as about 10 % of the total sales of such pharmaceutical companies. In other words, pharmaceutical companies in general spend about 10 % of sales volume to generate new drugs. If one takes into consideration, again based on the aforementioned PMA report, that about 30 % of the R&D costs are for R&D stage 1, about 30 % of total R&D costs are for R&D stage 2, and about 40 % are for R&D stages 3, 4, 5, and 6, one comes to the result that, if a certain substance after finalization of R&D stage 1 is licensed in, i.e. thereby saving 30 % of R&D costs of in total 10 %, the licensee should pay 3 % royalty, based on net sales, just from a cost viewpoint. The respective "justified" royalty rate before R&D stage 3, i.e. before starting clinical studies, would be 6 %, because 60 % of the development costs would be saved, and, finally, 10 % for the finished product, ready to be marketed.
The aforementioned considerations to determine the reasonable royalty rate are, as a matter of course, "minimum" royalty rates, just based on costs saved by the licensee. If one takes into due consideration that the risk for the development until the licensing stage has been borne fully by the licensor, one might consider it as justified that at least 50 % of the aforementioned royalty rates are added to the cost-based ones, in this manner leading to royalty rates for substances determined as candidates for clinical studies of at least 4,5 %, selected ones for clinical studies of at least 9 %, and after clinical studies and approval of at least 15 %. The author believes that the aforementioned figures will look very familiar to professionals in the pharmaceutial licensing field.
It should be duly noted that running royalties usually will start only after the putting into the market place of a certain product, a latest date very often being agreed on, however, after which running royalties would have to be paid by the licensee even on a fictive net sales scale.
3.3. Minimum Royalties
Minimum royalties in pharmaceutical licensing agreements play a similar role as in agreements in different fields of technologies: They have to be considered as an insurance policy, in favour of the licensor, against lack of activities by the licensee.
Accordingly, it can be observed that the minimum royalties, usually on an increasing scale, are set to be at least 50 % of the estimated cumulative annual running royalties expected by the parties of a license agreement for the respective years during the lifetime of the agreement.
It is difficult to determine whether in the majority of cases minimum royalties only function as an "insurance policy", as described before, i.e. non-payment of which gives the right to terminate the agreement to licensor, or whether such minimum royalties have to be paid under all circumstances. In view of the fact that the marketing of substances is only possible for the licensee after having heavily paid in terms of downpayment and/or R&D costs, the tendency that licensees do not use a licensed pharmaceutical technology sufficiently seems to be rather low, so that licensors in many instances accept the "insurance policy" function of minimum royalties at least in such cases where the licensing of the technology takes place at a rather late stage of R&D, i.e. shortly before marketing.
Typically, it can furthermore be observed that minimum royalties of only a more or less nominal height are agreed on for the years before the estimated time of marketing for the respective product, with a sometimes sharp increase thereafter.
4. Legal Aspects Of Licensing Under EU Rules
License agreements in the pharmaceutical field, as other license agreements, must observe the competitional rules of the European Union. Amongst those, Article 85 (1) is of greatest importance, which in principle considers at least exclusive patent and know how license agreements as potentially interfering with the principles of free competition and trade inside the European Union, so that as a base rule only such license agreements are exempted from the general prohibition of Article 85 (1) of the Treaty of Rome which are block-exempted under the existing Block Exemption Regulation for Technology Transfer of the European Union, i.e. Regulation 240/96. The aforementioned Regulation cannot be discussed in detail here, but it is strongly recommended that it is strictly followed when formulating licensing agreements in the pharmaceutical field having effect for the territories of the European Union.
4.1. Territorial Restrictions Under EU Rules
Specifically suspicious in the eyes of the Commission of the European Union are territorial restrictions in patent and know-how license agreements, and particularly in case of agreements in fields where because of considerable differences in price level in different territories inside the European Union it might be attractive for a licensor to separate the territories of various licensees as much as possible. Under certain assumptions, one may assume that the pharmaceutical field belongs to the aforementioned "suspicious" category.
4.1.1. Direct Export Bans
In view of the circumstances as discussed above, Block Exemption Regulation 240/96, in the following just called the "Regulation", according to its Article 1 permits direct export bans only in a very restricted sense.
Three different situations should be duly observed:
a)For the maximum permitted exclusivity period, i.e. in patent license agreements the life time of the longest running of the patents already being in existence, at least in the application stage, at the time of signature of the agreement, the licensor can prohibit that its licensee conducts any use of the licensed technology in territories reserved by the licensor for himself. In other words, the licensee for the aforementioned exclusivity period can neither manufacture in the territory of the licensor, nor import into that territory, neither conducting an active marketing policy nor following unsolicited orders.
b)As far as territories of other licensees are concerned, the licensor can prohibit the licensee to conduct an active marketing policy there for the time of the exclusivity period as discussed under a). The same applies to manufacturing in other licensees` territories.
c)As far as following unsolicited orders is concerned, the licensor can prohibit a licensee to follow such orders from the territories of other licensees only for five years after the first putting into the market place of the respective product by licensee inside the European Union.
Further territorial restrictions would clearly fall under the so-called Black List of clauses under the Regulation, and therefore would make it necessary that individual exemption from the prohibition of Article 85 (1) is sought for. If that is not done, the agreement would not only be unenforcable in relation to the territorial restrictions, but the parties thereof would have to be aware of severe penalties, a situation which any reasonable party in a license agreement certainly wishes to avoid.
4.1.2. Parallel Imports
So-called "Parallel Imports", i. e. imports of articles protected by intellectual property rights, like patents or trademarks, into a country where a certain party is the owner of exclusivity rights under a patent and a trademark, respectively, are a particular problem in relation to goods the prices of which traditionally have been rather dramatically different in the various countries involved. This is particularly true for the pharmaceutical market in Europe, bearing in mind that certain pharmaceuticals for nearly decades, just as an example, have been five times, in many instances, more expensive in, e. g., Germany than in Spain. Accordingly, knowing both the general rules of Parallel Imports and their unavoidability on one side, but also the absolutely legal possibilities to prevent such Parallel Imports in certain situations where from a first viewpoint Parallel Imports might be considered as - but truly are not! - being admitted, is of great importance particularly when considering pricing policies etc. in the European market.
In the following, the principle of "Parallel Imports" in the EU, closely being related to the "Principle of Territoriality" of intellectual property rights and the exhaustion of such rights, will be explained in some detail.
For the purpose of the aforementioned explanations "Parallel Imports" mean imports of goods from a third country, where a patent or trademark protecting the respective product may or may not exist, into a certain country of the EU or the European Economic Area (EEA) where such product is protected by a patent or a trademark. The right based on a patent or trademark will be considered as "exhausted" if the owner of the respective right, or its licensee, is not entitled to make any further use of the respective right to prevent third parties from freely disposing e. g. of a product protected by the respective patent or trademark.
Patents covering any country of the territory in question always are national patents restricted to the respective territory or country, irrespectively of whether the patent in question was obtained by a national patent application, a PCT-application designating one or several countries of the European Patent Convention (EPC), or a direct EPC-application, since also the latter "international" applications after patent grant result in a bundle of national patents. The effect of such patents is strictly limited to the respective country, with the effect that only the owner of the patent, or a party deriving its respective right from the patentee, is entitled to locally use the teaching of the patent, including manufacturing, offering and sale of products in accordance with the patent. Accordingly, in principle the patentee can prevent third parties from importing goods corresponding to the respective patent from a third country into the "protected" country.
22.214.171.124.1. Products First Distributed (Sold) Outside EU/EEA
According to the national law of the broad majority of the countries in question, and in line with the EU laws insofar covering also EEA, the putting into the marketplace of a product outside EU/EEA, e. g. in U.S.A., does not exhaust any patent right in Europe, whether the product was sold outside EU/EEA by the patentee itself, or with its explicit consent, e. g. by a licensee; in this regard, the principle of "Consent" will be dealt with in more detail lateron in this paper. That means that the owner of a patent in a certain EU or EEA country can prevent importation of such goods into the respective country.
126.96.36.199.2. Products First Distributed (Sold) Inside EU/EEA
The principle generally excepted in all EU/EEA countries is that whenever a product was sold in a country inside EU/EEA, irrespectively of whether a patent protecting that product in the country of first sale does exist, by the patentee or with its consent, the patentee having a patent in another EU/EEA country cannot prevent importation of the respective product into the country where the patent in question exists.
In other words, different from the sale of a product in a country outside EU/EEA, such sale in a country inside EU/EEA enables parallel imports, provided that the consent of the patentee to the respective sale was given directly or implicitly.
As in the case of patents, all trademarks existing in any EU/EEA country, are national trademarks with national effect only, the exclusivity rights based on which are strictly limited to the respective territory, irrespectively of whether the trademark was obtained by a national trademark application, or by international registration using the provisions of the Madrid Agreement or Protocol, or as a Community Trademark.
188.8.131.52.1. Products First Distributed (Sold) Outside EU/EEA
Until a few years ago, in many countries of the EU/EEA in relation to trademarks, totally different from patents, a fully international exhaustion principle was accepted. In other words, the countries following this principle, namely Austria, Belgium, Denmark, Finland, Germany, the Netherlands, Norway, and Sweden, would not give the owner of a trademark in a certain one of these countries the possibility to prevent importation of goods which where provided "with consent" anywhere in the world outside of this country with the respective trademark. The reason for this jurisdiction, at least as far as Germany is concerned, was that the right based on a trademark is considered as fully exhausted already if the trademark is "affixed" to a certain product etc., different from a patent where the right of use comprises not only the manufacturing of the respective good, but also the distribution, even the offering of the product etc.
Meanwhile, in accordance with the EU Trademark Directive, however, the aforementioned countries have changed their laws to the extent that exhaustion of a trademark will not be assumed if the respective product was provided with the trademark outside EU/EEA, whereby the same situation has been created as in relation with patents.
184.108.40.206.2. Products First Distributed (Sold) Inside EU/EEA
Because of the aforementioned Trademark Directive of the European Union, but also in accordance with the former practice in all EU/EEA countries except France and Greece, where still certain reservations did exist insofar, parallel imports cannot be prevented if the respective good was distributed/sold with the consent of the trademark owner in any EU/EEA country. The situation is somewhat different, however, in case of "split" trademarks, in which even two identical marks of same origin can be used for market separation if a whole business, together with its partial original mark, was sold by the owner of the originally one trademark.
220.127.116.11. The Principle Of Consent
As already explained above, the criterion for deciding whether a certain patent or trademark can be used to prevent parallel imports, i. e. particularly free circulation of goods inside EU/EEA, is whether the putting into the market place - bringing out of control of the distributor - of the respective product in a certain third country took place with the direct or implicit consent of patentee.
Such consent is always given, of course, if the patentee itself sells, without imposing any limitations on the kind how to use it, the respective product. Limitations of this kind, by the way, are null and void, usually, as far as they restrict the free circulation of goods inside EU/EEA, with a few exemptions as e. g. defined by the Block Exemption Regulations applicable here.
There are other kinds of consent, of course some of them, to be discussed in the following.
If a patentee or trademark owner grants a license to make use of the respective patent or trademark, the owner of the intellectual property right in general gives its permission, and its consent, to manufacture and sell the respective product. Accordingly, a product sold in a certain country under a license which not legally validly does contain restrictions for exportation from the respective country means a sale with a consent of the patentee and trademark owner, respectively. The consequences of such consent have been explained above.
18.104.22.168.2. Compulsory License
A compulsory license, by definition, is given against the explicit wish of the patentee or owner of a trademark. Accordingly, products manufactured and sold under such a compulsory license cannot be considered as having been brought into the market place with the consent of the owner of the respective right.
22.214.171.124.3. Right Of Prior Use
In all countries of EU/EEA, the institute of a right of prior use in relation to patents does exist. That means that somebody who had been in the possession of an invention, lateron patented by a third party, already before the priority date of the respective patent, cannot be prevented by the later patentee to use the respective inventive teaching.
The aforementioned rights of prior use are strictly limited to the country in which they have been originated. Also, such a right of prior use is not created by the consent of the patentee, but totally independently of the owner of the "parallel" invention that later on was patented. Accordingly, products manufactured and sold in certain EU/EEA countries under such a right of prior use cannot freely circulate inside EU/EEA.
Licensing both on an exclusive and non-exclusive basis, as well as joint R&D playing a more and more important role in the pharmaceutical field, it appears as advisable to come to more reliable methods of determining the value of technology to be licensed, with the aim of having instruments available for calculating the basis of reasonable, rationally plausible negotiations on financial conditions, like downpayment, royalty rates, minimum royalties, etc.
Furthermore, it appears as necessary, as always in licensing, to carefully watch the competition law provisions of particularly the European Union, if licensing takes place between entities affecting the European pharmaceutical market in a not neglectible manner.
The content of this article is intended to provide a general guide to the subject mater. Specialist advice should be sought about your specific circumstances.