INNsight articles by Duncan Curley

Drug combinations have an important role to play in the life cycle management strategies of the research-based pharmaceutical companies.   There are many successful drug combination products in many different therapeutic areas, including Lotrel® (a combination of amlodipine and benazepril used in the treatment of high blood pressure), Actoplus Met® (a combination of pioglitazone and metformin for the treatment of type 2 diabetics who do not use daily insulin injections) and Combivir® (a combination of the nucleoside analogues zidovudine (AZT) and lamivudine (3TC), used in the treatment of HIV infection). 

Data exclusivity will of course provide significant protection from generic competition for many such drug combinations; for example, Combivir® was first authorised for use in the UK on 18 March 1998 and so the data exclusivity period has only just expired.  However, it is often worth examining carefully the innovator’s patent estate for combination products.  Published prior art data on the individual components may point to an obvious benefit in combining the two, thus leaving any patent claiming the combination open to a claim of invalidity.   Although supplementary protection certificates can be granted for combination products, such SPCs often depend for their validity on the basic patent on the combination that is designated in the application for the SPC.  If the basic patent can be invalidated, the SPC will fall too. 

In the Seretide® litigation before the English Patents Court in 2004, a number of parties attacked the validity of UK Patent No. 2235627.  Seretide® is an asthma treatment that consists of an inhaler that administers simultaneous doses of the β2-agonist salmeterol and the steroid fluticasone propionate.  The principal allegation in the case was one of obviousness over an existing combination of salbutamol (also a β2-agonist) and beclomethasone dipropionate (a steroid) sold in a metered dose inhaler device (Ventide®) before the relevant priority date.    It was held that by the relevant date, it was well known that salmeterol was in clinical trials and that the best mode of treatment for asthma was based on the use of steroids together with β2-agonists.   The judge found that a person looking to formulate an improved combination for the treatment of asthma starting with salmeterol would quickly find fluticasone propionate.   Whilst it was not obvious that a combination of these two would be safe, it was a reasonable prediction that it would be.  The judge concluded that the combination of salmeterol and fluticasone propionate was an obvious one and revoked the patent.  The supplementary protection certificate (SPC/GB99/016) for the combination was not due to have expired until September 2013, but it was rendered invalid when the patent was revoked.   

Although it was not a case involving a combination of two pharmaceutical drug products, in 2007, the UK Court of Appeal in Angiotech Pharmaceuticals v Conor Medsystems made some interesting comments about obviousness, in the context of drug-coated stents.  The patent in question claimed a drug-eluting stent containing (inter alia) taxol.  The Court had found that the prior art disclosed the idea of a drug eluting stent together with a list of anti-replicate drugs that included methotrexate, azathioprine, fluorouracil and others.  The only difference between the prior art and the patent was therefore the specific use of taxol in a drug eluting stent.  The patentee argued that it was not self-evident that taxol would work (it was not “obvious to try”), but the Court of Appeal upheld the first instance finding that the use of taxol in a drug-eluting stent was not inventive over the prior art and the patent was revoked.  The question was not whether it was obvious to try taxol in a drug eluting stent, but rather “Was the invention obvious?”

More recently, one of the Boards of Appeal of the European Patent Office considered the validity of European Patent No. 0613371, which claimed another asthma treatment, the combination of the β2-agonist formoterol and the steroid budesonide (marketed as Symbicort®).   A prior art scientific paper contained teaching to the effect that the combination of a β2-agonist and a steroid was suitable for the treatment of asthma and listed as examples of the former both formoterol and salmeterol and as examples of the latter both budesonide and  beclomethasone.  The Board held that the specific combination of formoterol and budesonide was obvious.   In the EPO, a patent to a combination may sometimes be saved from a finding of obviousness if the combination has some unexpected advantage over the prior art, but the Board was not satisfied in this case that the patentee had demonstrated any unexpected, bonus effect of the claimed combination.  

An area that is replete with combination products but which remains relatively unexplored in terms of patent challenges in Europe is antiviral therapy and in particular anti-HIV agents.  The first drug licensed for the treatment of HIV in the mid-1980s was the nucleoside analogue AZT.   It was followed by many others, including dideoxyinosine (ddI, or didanosine) and 3TC.   The problem with many of the nucleoside analogues is that they are metabolised and incorporated into the genetic material of both the human host and the virus, often causing serious toxicity issues.   Another problem sometimes encountered with monotherapy is viral resistance. 

By the late 1980s, trials of AZT in combination with other nucleoside analogues were underway in order to surmount these problems.  This is reflected in some of the contemporary patent filings.  For example, a European patent application covering (inter alia) 3TC published in 1990 describes a class of nucleoside analogues with antiviral and in particular anti-HIV properties.  The invention is described in this patent application not only in terms of the individual chemical compounds but also in terms of combinations of these compounds with other nucleoside analogues (including AZT, ddI and others).  Bearing in mind the law in relation to obviousness (discussed above), the question of the effect of such disclosures on the validity of patents to anti-HIV combination products applied for after 1990 - such as European Patent No. 0513917 covering Combivir® - is an interesting one.  .