Drug In Focus October 2010

The Levofloxacin General Information (Table 1) shows that there are four dosage forms available, an oral solution, an injectable solution, oral tablets available in 250, 500, and 750 mg strengths, and ophthalmic drops. Levofloxacin is indicated for a variety of bacterial-related illnesses such as the treatment of pneumonia, sinusitis, bronchitis, skin and skin structure infections, bacterial prostatitis and mastitis, urinary tract infections, acute pyelonephritis, as well as inhalational anthrax.

The Key Patent Indicator (Table 2) identifies three patent families, the first of which protects the Levofloxacin active ingredient. The Australian and Canadian members of this family expired in June 2006 and 2009 respectively. The remaining members of the family protecting major territories are due to expire in June 2011 as a result of patent term extensions or SPCs, with the exception of the Spanish equivalent, which is not due to expire until June 2012 due to the relatively late expiry of the basic Spanish national patent (at the time the Spanish member was first applied for, the expiration dates for Spanish national patents were calculated as 20 years from the grant date, rather than the filing date). NCE Data exclusivity for all major territories has expired, however US exclusivity expiring in March 2011 but this relates only to a specific change to the labelling based on data submitted in response to a paediatric written request.

Despite Australia having patent term extension provisions for pharmaceuticals, the term of the Australian equivalent patent protecting the active ingredient has not been extended. This can be attributed to the fact that Levofloxacin is not currently licensed for use in Australia. According to Section 70 of the Australia's Patents Act states, in order for an extension to be granted, the active must be included in the Australian Register of Therapeutic Goods³. As Levofloxacin has not been listed, Daiichi Sankyo would not have been eligible to apply for an extension.

Daiichi Sankyo have been extremely active when it comes to protecting their product from generic competition, and have taken legal action in a number of countries against different companies attempting to launch generic Levofloxacin products, more details of which are available in the Pipeline Selector report.  Specifically in the United States, after successfully defending several paragraph IV challenges to the enforceability of molecule patent US5053407 ('407), Ortho-McNeil recently won an injunction to prevent Lupin from infringement during the extended term for this patent, which is assigned to Daiichi but exclusively licensed to Ortho-McNeil. Lupin had argued that Levofloxacin was an active ingredient of Ofloxacin, as Ofloxacin is a racemate comprising both the (-)-(R) and (-)-(S) enantiomers, of which Levofloxacin is the (-)-(S) enantiomer. They claimed that because Ofloxacin had previously been approved Levofloxacin had also been approved and, as such, the '407 patent should not have been eligible for a Patent Term Extension (PTE). The Federal Circuit ruled that Levofloxacin is a single active ingredient which is distinct from both the (-)-(R) enantiomer and from the racemate, and consequently the '407 patent had been properly granted a PTE. Also, generic Levofloxacin marketed by Novopharm, was available on the Canadian market from 2004 to 2006, before it was removed following the Supreme Court of Canada's ruling that Novopharm was infringing Johnson & Johnson and Daiichi Sankyo's Levaquin patents. 

The second patent family identified by the KPI claims an aqueous composition comprising Levofloxacin, and is also held by Daiichi. All members of this family have now expired, hence this family will not constrain the launch of a generic version of Levofloxacin. This highlights the critical timing of lifecycle management activities by the innovator in that patenting of dosage forms too early results in very little real protection as such patents will likely expire before patent term extensions or SPCs on the active ingredient.

The final family identified by the KPI is for a taste-masked liquid composition, assigned to Ortho-McNeil. Whilst equivalent patents were applied for in Canada, Germany, Spain, France, Great Britain and the United States, only the US equivalent patent, US6806256 ('256), was granted. The remaining family members were all withdrawn and, as such, offer no protection. Whilst '256 does not expire until August 2022 due to a paediatric extension, it is important to note that as the patent only protects a taste-masked composition comprising Sucralose, it would still be possible to launch a generic product in the US following expiration of the molecule patent discussed previously by developing a different formulation using a different type of taste masking agent.

Although the second and third families identified in the KPI should not prove to be a barrier to launch, it is an important part of any generic strategy to identify other possible patents which are not identified as a key, and which could still block the launch of a generic version. The Patent Category Distribution section (Figure 1) of the Levofloxacin Pipeline Selector report indicates that approximately 40% of patent applications for this drug are formulation based. The relatively low patenting activity in the area of molecular forms perhaps highlights and area where Daiichi should have focused patent applications in order to make life a little more difficult for generic competitors by seeking to further protect polymorphic forms, salts and hydrates beyond the life of the molecule patent.