Better scientific understanding of drug interactions with enzymes at the molecular level has allowed some old, ‘failed’ molecules to be used for novel purposes.
Thalidomide is notorious as the drug that caused catastrophe when it was prescribed in the 1950s for nausea and insomnia in pregnant women, but the drug was resurrected in 1998, when Celgene received approval from the FDA to market thalidomide as a treatment for leprosy.
It has since found use as a treatment for multiple myeloma with significant global sales. The benzoxazinone family of compounds was initially patented in the 1960s for their anti-convulsant, tranquilising and anti-Parkinsonian properties. Much later, in the early 1990s, patent protection was filed for the use of the benzoxazinones as inhibitors of HIV reverse transcriptase, with Bristol-Myers eventually marketing efavirenz (as the product Sustiva®) for this indication.
Market Exclusivity for ‘Repurposed’ Molecules
Biotechnology companies are now using proprietary screening technologies to detect novel interactions between drug molecules and disease targets, such as enzymes.
‘Drug repurposing’ – looking again at old molecules for new clinical applications – can be an attractive commercial proposition, not least because some of the cost of development is ‘de-risked’: one is working with a molecule that is already known to have some clinical effect. However, a possible limitation of drug repurposing is the ability to protect the resulting new indication with patents.
Usually, by the time that an old product (whether previously approved or abandoned during initial development) arises for consideration in a repurposing project, it will have ceased to be the subject of protection offered by patent claims covering the specific chemical structure of the molecule. Companies interested in repurposing must therefore fall back on ‘second medical use’ (or ‘method of use’) patents, claiming, for example, the use of the molecule in the treatment of a specific illness.
These types of patents have historically been considered weaker, in terms of their ability to withstand challenges to validity from competitors, but this perception has arisen because second medical use patents have often been thought of simply as part of a defensive strategy for surrounding blockbuster products with patent thickets (‘lifecycle management’), rather than as legal monopolies protecting genuine innovation.1
Yet innovative clinical research on known compounds can form the basis of valuable European patent rights, as we are now starting to see, both in the practice of the European Patent Office and in some recent decisions of the national courts in Europe.
Patenting Second and Subsequent Medical Uses in Europe: a Short History
Under the provisions of Article 52(4) of the European Patent Convention 1973 (‘the EPC 1973’), methods for the treatment of the human or animal body by surgery or therapy are not regarded as inventions that are susceptible to industrial application and thus are not patentable.
The original rationale behind this provision was to ensure that non-industrial, medical activities such as those carried out by doctors on patients were exempted from patent protection, so that there could be no direct interference by patent monopolists in the practices of physicians. Initially, ‘method’ claims purporting to protect a novel and inventive use of an otherwise old drug product were thought not to be available under the EPC, because they were said to claim a method of treatment. There was therefore little incentive to investigate possible further medical uses of old substances.
The Decision in Eisai
In Eisai/Second medical indication (‘Eisai’),2 the Enlarged Board of Appeal ruled that the EPC 1973 did not exclude second (and further) medical indications from patent protection. The Enlarged Board decided that a claim for a second medical use would be valid if phrased in the form set out in a statement of practice issued by the Swiss Federal Intellectual Property Office,3 namely, ‘the use of compound X in the manufacture of a medicament for the treatment of disease Y’ (hence the terminology, a ‘Swiss form’ of claim).
The specific wording of these claims was considered permissible because manufacture of substances for a new therapeutic use satisfied the requirement of novelty and the claim was for the manufacture of the substance and not to a method of treatment.
The Enlarged Board also considered the circumstances in which such a claim would be novel. It specified that where a medicament had novel technical features there should in principle be no difficulty on the question of novelty. Novel technical features could include ‘a new formulation, dosage or synergistic combination’.
Following the decision in Eisai, the EPO’s Technical Boards of Appeal have considered further features that can support novelty in second medical use claims, including features such as different modes of drug administration4 and a different patient group affected by the original disease.5
The Decision in Genentech
Subsequent to Eisai, the Technical Board of Appeal further considered second medical use claims under the EPC 1973 in the case of Genentech/Method of administration of IGF-I (‘Genentech’).6 The case concerned claims for a novel dosage regime for an insulin-like growth factor. The claims specified the timing of administration of the medication.
The claims had been refused by the Examining Division on the basis that they related to activities which would normally be performed by a physician and therefore were considered to describe a method of treatment, but the Board stated that it ‘could see no reason why the person who develops a novel therapy by looking for the most effective way in which a known composition can be administered should a priori be said to lack merit to such an extent that even the limited form of patent protection of the second medical use form can be denied without an examination of whether the therapy is indeed novel and inventive’.
The Board interpreted Eisai as allowing Swiss form claims ‘where the novelty of the application might lie only in the dose to be used or the manner of application’ of the medicament. The Board thought that the decision in Eisai did not impose any special conditions that a claimed second medical use had to fulfil.
A Swiss form claim for a further medical use would be permissible, irrespective of the detail of the use that was specified, provided that the claim was both novel and inventive. A therapeutic use would not, however, be considered to be new where it was directed to any physiological or pharmacological effect or mechanism underlying a previous therapy which had not yet been identified. Claims which represented simply more information about the use of a known medication, for example by disclosing the method of action, would not be allowed.
The Impact of the EPC 2000
It should be noted that the cases referred to above were decided under the EPC 1973. Under the EPC 2000, Article 54(5) now provides that a known substance will not be precluded from patentability in relation to a specific new therapeutic use (for example, a second medical use). Further, there is now no need to draft the claim in the rather convoluted Swiss form. Under certain transitional provisions, the new rules apply to all European patent applications pending at the date of coming into force of the EPC 2000 (13 December 2007).
An ongoing case under these transitional provisions is Kos Life Sciences,7 which concerns a claim where the only novel feature is a new dosage regime for a medication used to treat hyperlipidaemia. The claim specifies that the medication should be taken ‘once per day prior to sleep’.
The relevant EPO Technical Board of Appeal decided that the question of whether second and further medical use claims – where the only novel feature is a dosage regime – are patentable under the EPC 2000 is an important one and referred a series of questions to the Enlarged Board of Appeal, including the matter of whether there are any special considerations applicable when interpreting and applying the relevant provisions of the EPC 2000. The Enlarged Board is not expected to give its decision until some time in 2010.
Further Medical Use Claims in Europe – a Summary
In summary, the criteria for the patentability of second and further medical use claims have arguably become more favourable in Europe in recent years, with the European Patent Office’s position having crystallised with Eisai and Genentech. The formal requirement for these claims to be drafted in a specific format has now been dropped with the coming into force of the EPC 2000. However, it is not thought that there has been any substantive change in the law as a result of the EPC 2000.
The Explanatory Notes to the Basic Proposal for the Revision of the European Patent Convention stated that ‘as regards the second or further medical uses, the case law evolved by the EPO Enlarged Board of Appeal should be enshrined in the Convention.’ It therefore seems likely that Eisai, Genentech and the related cases remain good law, although the Enlarged Board in Kos Life Sciences will rule on this specific issue, in due course.
Facing up to the Validity Challenge
Once a patent application claiming the use of an old medicine in a new method of treatment has been prosecuted through to grant at the European Patent Office, the question remains as to whether the resulting patent confers commercially valuable rights that will be upheld by the national courts and respected by competitors.
Some of the courts in the EU have historically had a reputation for scepticism insofar as second medical use patents are concerned. In the Taxol case (at first instance), the English Patents Court famously referred to the ‘Byzantine logic of patent law and jurisprudence’ in this area and the ‘obvious difficulties’ with the Eisai decision.8 Yet more recently, in Germany, the Supreme Court has held novel, and not a claim to a method of treatment – but nevertheless obvious – a Swiss form claim to a dosage regime.9
While some of the doubts about lifecycle management practices and second medical use patents still linger, the recent case law seems to show that the courts can distinguish patents that claim genuine, new and inventive applications for old molecules.
Actavis v Merck
The best recent example is the judgment of the English Patents Court in relation to non-obviousness, in the contest between the generic drug manufacturer Actavis and the research-based company Merck & Co. Inc.10 The case concerned the active pharmaceutical ingredient finasteride, that had previously been patented by Merck in 1978 and marketed (in tablet form) for the treatment of benign prostatic hyperplasia with a dosage of 5 mg per day.
In October 1994, Merck filed European patent application no. 0,724,444 (A1) (via the PCT international filing route) which was to a ‘Method of Treating Androgenic Alopecia with 5-Alpha Reductase Inhibitors’. Androgenic alopecia is a type of baldness that affects both men and women. Claim 1 of the granted patent was to:
The use of [finasteride] for the preparation of a medicament for oral administration useful for the treatment of androgenic alopecia in a person and wherein the dosage amount is about 0.05 to 1.0 mg.
Actavis challenged the validity of the patent for lack of novelty and lack of inventive step.
In relation to novelty, the English Court of Appeal, following Eisai, confirmed that ‘Swiss form’ claims will be considered novel where they disclose a new dosage regime or other form of administration for a known medication for a known condition. Although such claims must demonstrate a novel therapeutic application, this need not be for a different medical condition. So whilst finasteride was known at the relevant priority date (15 October 1993), the new dosage regime of 0.05 to 1.0 mg for the treatment of androgenic alopecia was enough to defeat Actavis’ attack on validity, based on lack of novelty.
The Court of Appeal was at pains to point out that this finding did not mean that, as a matter of generality, ‘... just specifying a new dosage regime in a Swiss form claim can give rise to a valid patent. On the contrary nearly always such dosage regimes will be obvious – it is standard practice to investigate appropriate dosage regimes.’
In relation to obviousness, Actavis mounted a strong attack on validity, citing a prior art document which made an overt suggestion to the effect that the prevention of the formation of the active androgen in the balding scalp using a 5α-reductase inhibitor (that is, finasteride) ‘may be a viable treatment option’.
However, Merck contended that the skilled person believed at the priority date that the specific type of isoenzyme (isozyme) present in the scalp would not be inhibited by finasteride. There was, therefore, a prejudice against trying it for the treatment of androgenic alopecia. The judge at first instance had accepted Merck’s expert evidence on this issue and the Court of Appeal endorsed this decision.
Merck had made an invention that would have been surprising to the skilled person at the relevant priority date and it was therefore non-obvious.
Availability of Supplementary Protection
Clearly, patent rights are available to companies involved in drug repurposing and the rights conferred by second (and further) medical use patents can be valuable in preserving market exclusivity. Given that regulatory approval for new indications on existing drugs may sometimes be as protracted as the approval process for new molecular entities, are patent extensions ever available?
In the European Union, supplementary protection certificates (‘SPCs’) can provide up to five years of additional market exclusivity for certain medicinal products, based on an extension of the rights conferred by the basic patent designated in the application for the SPC. Regulation (EC) No. 469/2009 of 6 May 2009 concerning the supplementary protection certificate for medicinal products specifies in Article 1(c) that a ‘basic patent’ can be a patent that protects a product as such, a process to obtain a product or an application of a product, that is, a patent which protects a second (or further) medical use of a product.
It is also a requirement for the grant of a SPC that there is a valid authorisation to place the relevant medicinal product on the market and that this is the first such authorisation in time.11 There have been two cases that have recently been referred to the European Court of Justice on old drug products that have been redeveloped for new indications, giving rise to new patent rights and SPCs.12 In both cases, the validity of the SPCs has been challenged and questions of interpretation of Regulation (EC) No. 469/2009 have been referred for clarification.
Alkinol Memantine (containing memantine hydrochloride as the active pharmaceutical ingredient) was first marketed as a drug for the treatment of Parkinson’s disease in Germany in the 1970s. Merz Pharma GmbH then developed memantine hydrochloride for the treatment of Alzheimer’s disease and obtained a patent, European patent no. 0,392,059 B1, and eventually a new marketing authorisation for memantine hydrochloride, rechristened as the drug product Ebixa®. A SPC was obtained. In the United Kingdom, the validity of this SPC (SPC/GB02/046) has been challenged on the ground that memantine hydrochloride had already been marketed in the European Community when the SPC was applied for. Similarly, galanthamine is an old molecule that was used in the 1960s for the treatment of polio.
Synaptech developed the drug for use in the treatment of Alzheimer’s disease and obtained the second medical use patent, European patent no. 0,236,684 B1, which expired on 16 January 2007. However, a UK SPC (SPC/GB00/033) will protect the marketed product Reminyl® from generic competition until 15 January 2012, unless the European Court of Justice rules in a way that favours the challenge to the validity of the SPC.
Whilst specific issues have arisen in relation to granted SPCs where a drug product has already been the subject of a previous marketing authorisation in the Community, when an old molecule has never actually been the subject of a prior marketing approval for human use, there would appear to be no problem in principle with second medical use patents forming the basis of valid supplementary protection.
For example, in the United Kingdom, SPC/GB00/035 provides efavirenz with an additional few months of protection, after patent expiry (until 19 November 2013). The SPC was granted on the basis of the first authorisation of the product Sustiva® in 1999 and European patent (UK) No. 0,582,455 B1, which is a second medical use patent. Supplementary protection certificate SPC/GB02/010 currently protects the active pharmaceutical ingredient ribavirin in the UK until 15 April 2010.
Ribavirin is now marketed as Rebetol® for use in combination with interferon alfa-2b for the treatment of hepatitis C, but it is an old molecule that was first found in the 1970s to be active against viral infections. The basic patent, European patent no. 0,643,970 B1 (filed in 1985), claims a very specific, further medical use of ribavirin, ‘for the treatment of viral diseases in humans caused by arboviruses’.
As it becomes increasingly difficult to find new small molecule drugs that can be patented per se and which show a demonstrable benefit over existing treatments, it seems likely that companies will increasingly seek to re-examine old molecules for novel therapeutic effects.
The decision in Actavis v Merck may prove to be a landmark, in that it demonstrates that the courts are prepared to uphold second and further medical use patents granted as a result of research into new clinical applications of old molecules.
This is important for those companies involved in drug repurposing, who may need to rely on such patents in order to protect their investment in researching and developing these treatments.
Supplementary protection may also be available, in certain circumstances.
by Duncan Curley and Amanda Easey, Innovation Legal, London
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