Second medical use patents and the skinny label issue

Patent protection of newly discovered uses as well as dosages, dosage routes and dosage regimen of the new forms of use constitute an important part of managing the IP rights of pharmaceuticals. In the pharmaceutical area, a different field of use of a known molecule can be subject to a patent. If such a use is a secondary or further use, this type of patent is called a second medical use patent. In line with the basic principles of patent law, a second medical use should meet the criteria of novelty and inventive step in order to be lawfully granted patent protection. The novelty comes from the novel curative use of an already known substance. In other words, the substance in question is already known but the curative use for a particular illness is not yet known.

Since there was no explicit provision under EPC 1973 regarding the second medical use, patentability of this use was controversial in some countries until the EPC 2000 amendment. Yet, with the decision G5/83 of the EPO Enlarged Board of Appeal, patentability of the second medical uses was accepted on the condition that they are presented in a special type of claim called a Swiss-type claim. In order to overcome the inconsistencies between the decisions taken by different countries, Article 54/5, which explicitly permits patentability of the second medical use, was incorporated into EPC 2000, which ended discussions of this topic.

As a result, pharmaceutical companies now have their second medical use patents for certain uses of drugs, where the original patent terms have expired, which may further delay the entry of generic pharmaceuticals into the market. However, the additional protection conferred by these second medical use patents has sometimes been difficult to enforce.

As is known, in most countries including Turkey, it is necessary to obtain a marketing authorisation (MA) from the healthcare authorities for a particular pharmaceutical in order to sell it and the sale of these pharmaceuticals is only possible after completion of certain requirements, which change from country to country, such as pricing and sales permits. Generic pharmaceutical companies can make abridged applications for their generic products which are mainly similar to a previously licensed original product by referring to the dossier of such original product upon expiry of the data exclusivity term, if any, which is provided to the original product and which again changes from country to country. MA applications can be made for one or more indications. In this way, the generic pharmaceutical companies can limit their MA applications for specific indications and remove the indications which are still under protection of second medical use patents from the summary of product characteristics (SmPC) and Product Information Leaflet (PIL) of the products by a method called carve-out. The labels in which the carve-out method is applied reflect a more limited scope in terms of approved indications as opposed to the original products and, thus, are known as skinny labels.

Generic pharmaceutical companies which apply this method are in the position of declaring an intention not to use those pharmaceuticals for the indications which are under continuing protection of the second medical use patents, and therefore they avoid direct infringement lawsuits which can be filed against them. However, carving out the patented indications from the generic pharmaceutical does not always mean that this pharmaceutical would not, in practice, be used for those indications.

In a scenario where a physician prescribes a pharmaceutical product to a patient for the use of this product in relation to a patented indication but the prescription only specifies the name of the original pharmaceutical product without any notes on the specified indication, and the pharmacy has the authority to substitute the original product with a generic, the pharmacy may give a generic product to the patient in lieu of the original. As a result, the generic pharmaceutical would be used for the patented indication. In fact, pharmacies cannot know the exact indications for which the pharmaceutical is prescribed in a system where the indications are not noted in the prescription and the original product, which is actually patented for the indication that it is prescribed for, may be substituted with a generic product by the pharmacist.

When it is taken into consideration that generic pharmaceuticals costs less compared with the originals, substitution of an original product with a generic pharmaceutical by the pharmacist is a very common situation which is even supported by the healthcare authorities in order to decrease healthcare spending. Therefore, in these cases, the problem which can be considered as an infringement of a second medical use patent arises.

As mentioned above, the most commonly known case relevant to this subject is the lawsuit filed in England by Warner-Lambert against Actavis. Warner-Lambert, one of the group companies of Pfizer, was the owner of a second medical use patent for the active ingredient pregabalin for the treatment of neuropathic pain. Warner-Lambert marketed its pharmaceutical named Lyrica with the active ingredient pregabalin, for the treatment of epilepsy, anxiety disorder and neuropathic pain. Thereafter, Actavis made an MA application for a generic pharmaceutical named Lecaent including pregabalin as the active ingredient by limiting the use of the applied pharmaceutical to only the indications not protected by the aforementioned patent. In other words, the approved indications of the generic pharmaceutical of Actavis did not include the patented indication that belonged to Warner-Lambert.

However, as indicated above, even when a generic pharmaceutical has been marketed with a skinny label, it may still be possible to use this pharmaceutical for the patented indications in practice because of the regulatory systems. In England, where the incident that is the subject matter of the Warner-Lambert/Actavis lawsuit occurred, some prescription writing methods triggered this consequence. Therefore, Warner-Lambert filed a patent infringement lawsuit with a request for interim relief against Actavis. The court of first instance first determined, while setting forth the merits of the case in its decision, that the patent had been written in the form of a "Swiss type claim", in other words in the form of "use of pregabalin for manufacturing of a pharmaceutical for the treatment of neuropathic pain". Afterwards, the court declared that in order to determine whether Actavis infringed the patent or not, it was necessary to find an answer to this question: "Has the 'Lecaent' as a pharmaceutical, preparation of which includes pregabalin, been manufactured with the intention of treating neuropathic pain?".

In order to answer this question, the court set forth that it was required to discuss who may be associated with the intention and what should be the nature of this intention. The court was of the opinion that the physician and the pharmacy could not be associated with the infringement claims since they were not manufacturing the pharmaceutical. According to the court, the party who will be associated with the infringement should be the manufacturer of the pharmaceutical due to the claim type of the patent which was subject to this lawsuit and, in the case at hand, the manufacturer was Actavis. However, the court decided that Actavis had no intention of infringement since it did not intend to use the pharmaceutical Lecaent for the treatment of neuropathic pain. Because Actavis made an MA application by excluding the patented indication and also by exhibiting a proactive approach as it sent warnings to the pharmacies and related institutions not to prescribe and sell the relevant pharmaceutical for the treatment of the patented neuropathic pain indication. As a result, the court ruled that Warner-Lambert did not have a sufficient claim that should be heard.

On the other hand, the lawsuit filed by Pfizer against Actavis in Germany on the same grounds was concluded in favour of Pfizer and an interim injunction was granted against Actavis. In relation to the lawsuit filed in Spain, the court refused the infringement claim but at the same time it was possible to achieve some regulatory measures to be taken before the Spanish healthcare authorities for preventing possible infringement. As these examples reveal, the question of whether the products marketed with a skinny label cause patent infringement or not is interpreted controversially in different countries.

If the foregoing discussions on the applicability of the second medical use patents in practice are examined in relation to Turkey, we should first mention the Ministry of Health's circular setting forth that if an approved pharmaceutical product includes the same active ingredient in the same pharmaceutical form and dosage with a pharmaceutical product SmPC and PIL that have been published, then the SmPC and PIL of the new product should be prepared identically to the previous product's published SmPC and PIL. Yet, patented indications and non-pharmaceutical information (such as shelf life, formulation and storage temperature) are exempt from this requirement. Accordingly, generic pharmaceutical companies have the opportunity to remove a patented indication from their MA applications for their pharmaceuticals to be made before the Ministry of Health in Turkey by the carve-out method to avoid infringing patented indications.

At this point, we should briefly explain the regulatory system in Turkey. Some physicians in Turkey only write the name of a pharmaceutical product without stating the prescribed indication on the prescription. In the past, there have been frequent cases where some physicians tried to prevent the pharmacists from offering generic pharmaceuticals to the patients instead of the original pharmaceuticals specifically prescribed by the physician. However, the Ministry of Health once again issued the circular that substitution of an original pharmaceutical with generics by a pharmacist is scientifically and legally correct and ordered the physicians to cease their attempts to prevent substitution. It should be noted that the substitution of pharmaceuticals is legally possible and supported by health authorities in Turkey.

In addition, the electronic MEDULA system which is established for the use of healthcare stakeholders, including pharmacies, by the reimbursement authority, Social Security Institution, technically allows this kind of substitution. Public healthcare institutions and the private healthcare institutions contracted with the Social Security Institution use an e-prescription system which must contain indications. Pharmacists should be aware of the indications of products and should not substitute the original product with the generic products that have a skinny label for patented indications. For the substitution between some special products which are subject to different reimbursement rules per the Regulation, the MEDULA system requires exact indication conformity in addition to an explicit reference to the indication in the prescription. For these types of products, use of one for the other with skinny label is not technically possible within the system. This is because the pharmacist must match the indications for conformity in the system, otherwise the reimbursement is denied by the Social Security Institution. However, if prescriptions do not refer to indications, generic products which are not approved for a patented indication may be given by the pharmacists to the patients who were actually prescribed for an original product.

In Turkey, in view of the foregoing, it is controversial whether the above mentioned scenarios may constitute infringement of second medical use patents under the current legislation. It has been argued that a generic pharmaceutical manufacturer declares an intention to manufacture its pharmaceutical product only for the unpatented indications by carving out the patented indications from the label. In order to determine whether or not there is any infringement, one should evaluate if the activities of the generic pharmaceutical company despite the limited indications are encouraging and inciting the use of the pharmaceutical for the carved-out indications.

The Patent Decree Law sets forth special provisions for people who do not directly infringe but contribute to and participate in the performance of the acts that constitute patent infringement. Accordingly, the patent owner is entitled to prevent third parties from handing over to people who are unauthorised to use the patented invention, the elements or means which are related to an essential part of the invention that is the subject matter of the patent and rendering possible implementation of the patented invention. In this case, the use of a feature of the invention which is essential and enables implementation of the invention in a manner serving to infringe the patent is in question. If this feature is inevitably used in an infringing manner, the possibility of contributory patent infringement increases. However, if this essential feature is a commonly available product in the market which can be widely used outside the scope of the patent infringement, it is explained that additional indicators, in other words "acts inciting patent infringement", are required. For example, when it is known that a pharmaceutical product subject to a second use patent is indicated for various other illnesses and if there is no manipulation or incitement for the use of the main feature of the pharmaceutical for the patented indication, the possibility of patent infringement decreases. If there is manipulation or incitement, the possibility of patent infringement increases.

Is it possible to associate the physicians and the pharmacists to the infringing act in the event that they prescribe or sell the generic pharmaceutical for the patented indication? Primarily, it shall be noted that in accordance with Article 136/1(b) and 136/1(e) of the Patent Decree Law no 551, it is possible to associate the acts of physicians and the pharmacists with infringement in certain situations. For a product with a skinny label, it is necessary to evaluate on a case-by-case basis the situations where the liability of the physician and the pharmacist may occur by considering whether or not the carved-out indications are stated in the prescription by the physician; whether or not those skinny labelled products are defined in the MEDULA system as the generic of the original product; whether or not it is a special product where so-called "indication conformity" is required in the reimbursement rules; whether or not e-prescription is used and the circumstances in which the pharmacies do not pay attention to the indications. Still, due to the culture of the pharmaceuticals industry in Turkey, even when this liability is determined, it is not common practice for the pharmaceutical companies to sue physicians and pharmacies.

Deficiencies resulting from the regulations which cause the direct or indirect infringement of the rights of the pharmaceutical companies arising out of second medical use patents, should be eliminated by the healthcare authorities and pharmaceutical companies should take necessary measures to that end. As a matter of fact, in England, Germany, Spain where the Warner-Lambert dispute was faced, some measures in healthcare regulations were taken to prevent these kinds of infringements. We believe there are also several regulatory measures that the pharmaceutical companies can take to prevent the infringement in Turkey's healthcare system.

Selma Ünlü
		Selma Ünlü is a senior partner of NSN Law Firm in Istanbul, Turkey. She is qualified as an IP litigator and a trade mark and patent attorney, regularly recommended by Managing IP, WTR; IAM; Legal 500 and Chambers & Partners. She advises international clients, including pharmaceutical, medical device and food companies, in all aspects of IP. She is an accredited-court appointed expert in pharmaceutical patent disputes before IP Courts of Istanbul. Selma Ünlü is the author of the Turkey chapter of the Life Sciences Law Review.

Gülay Göksu
		Gülay Göksu is an associate of NSN Law Firm. She is qualified as a trade mark and patent attorney in Turkey and has extensive litigation experience. She advises and represents numerous international companies in areas such as pharmaceutical, food and beverage and textiles in all aspects of intellectual property. Her practice focuses mostly on patent portfolio management and litigation. She has been involved in many lawsuits related to complex pharmaceutical patents and transactions before the Turkish PTO. She also advises on all aspects of life science regulations.