The antidiabetic active ingredient Repaglinide (Prandin, NovoNorm, GlucoNorm) supplied by Novo Nordisk, will lose molecule patent protection in the US in the near future. Significant growth in sales of the Prandin product worldwide in 2008 and recent US approval of a combination product (Prandimet) comprising Repaglinide and Metformin, suggests that Repaglinide products are likely to attract the attention of generic manufacturers around the world.
Based on information contained in the GenericsWeb Pipeline Selector 'Core' report for Repaglinide, this month’s Drug In Focus analyses the patent landscape surrounding the Prandin and Prandimet products with a view to launching generic equivalents. The Pipeline Selector 'Extended' format, containing increased coverage of key patent, data exclusivity and extension expiry data for up to 37 countries, for a single INN/molecule is now available as a significant enhancement to GenericsWeb's Pipeline Patent Intelligence suite of information products.
The Repaglinide General Information (Table 1) shows that, at present, two oral dosage forms containing Repaglinide are available in the form of tablets. The first dosage form contains Repaglinide base, which is indicated generally for the treatment of diabetes mellitus. The other dosage form contains a combination of Repaglinide and Metformin, which was approved in the US in June 2008 for the treatment of type 2 diabetes in adults who are already treated with Meglitinide and Metformin or who have inadequate glycaemic control on either Meglitinide or Metformin alone.
Table 1: Replaglinide General Information
Among three patent families identified by the Key Patent Indicator (KPI) (Table 2), the first key patent family protects the Repaglinide active ingredient. Within this first patent family, all US patents have already expired with the exception of USRE37035, which has been extended by s156 to expire in March 2009. The term of the equivalent patent in France, Germany and the UK has been extended via SPC until December 2009, however of the five SPCs applied for across the Spanish equivalents, the two granted SPCs expire a year or more later due to differences in patent term calculations and interpretation of the EU legislation across European countries. Due to an absence of pharmaceutical patent extension provisions in Canada and the withdrawal of the patent term extension application in Australia, the equivalent patents have already expired in these countries. Despite the expiry of these patents in Australia and Canada, , the Regulatory Information section does not show the authorisation of any generic products in these countries, suggesting that there are more factors which may constrain the launch of a generic version of the Repaglinide product than just this molecule patent family. On the contrary, DMF Filings in the US suggest that a number of generic API manufacturers are prepared to supply the active ingredient for generic products to be launched in the US market.
Table 2: Repaglinide Key Patent Indicator
The data exclusivity information, which is now located next to the patent expiry information within the KPI (Table 2), shows that the exclusivity expired in European countries in August 2008. Because applications for approval of generic products could not be filed until this time, it may still have some impact on the actual launch date of generic products in Europe if the approval process were to take more than 16 months from filing. The first to market in this case would therefore be the generic competitor with the most readily approvable dossier who filed it in a timely manner, presuming no other patent related obstacles delay the launch even further. Data exclusivity would not affect launch dates in the US, Canada and Australia in this case as these have a much shorter term than the 10 years granted in Europe for this product.
In addition to the molecule patent family, two other constraining patent families have been identified by the KPI, one relating to the use of Repaglinide and the other to the use of Repaglinide in combination with Metformin.
Within the second patent family, European patent EP0589874 protects, the uses of the Repaglinide enantiomer as a long term antidiabetic agent (it is effectively an enantiomer patent) and the approved strengths of 0.5, 1 and 2 mg of Prandin products, until 2011 in most countries. However, a secondary SPC in Germany and a s70 extension in Australia appears to extend the Prandin monopoly afforded by these patents until 2013 and 2014 respectively. Although no patent filings have been identified in this second patent family in the US (nor was the US designated on the PCT application), those intending to launch generic versions of Prandin should be wary that there may be an equivalent US patent application working its way through the USPTO, which has not been published due to the timing of any likely application in 1996, before applications were published. Only time will tell if there is a US ‘submarine’ patent in this family.
The third key patent family protects uses for the treatment of non-insulin dependent diabetes mellitus (NIDDM) as well as formulations comprising a combination of Repaglinide and Metformin until 2018 in the major territories.
It can be seen from the Pipeline Selector report that Caraco submitted an abbreviated new drug application (ANDA) for Repaglinide tablets, containing a paragraph IV certification with regard to US6677358 which is Orange Book listed against this product. The ‘Litigation Alert’ for this patent shows that Novo Nordisk then filed a patent infringement lawsuit against Caraco in US District Court in Detroit, Michigan, in response. Depending on the outcome of the trial, Caraco may be awarded 180 days of the marketing exclusivity for the product thereby may preventing other (non-authorised) generic competitors from entering the US market for that period.
The European equivalent EP1011673, has been revoked due to a successful opposition by Novartis, Ajinomoto and Merck, however, generic competitors should carefully monitor the situation with regard to divisional application, EP1097710 which may be granted in the future in a manner that protects the Repaglinide products when used in combination with Metformin (or containing instructions to do so).
The above key patent analysis suggests that Novo Nordisk have made some attempt to extend the lifecycle of its Repaglinide-containing products by protecting more than one element of the marketed products. The patent filing trends graph (Figure 1) shows some patent filing activity prior to the first major launch of the product in the US in 1997, most of which has been undertaken by the innovator. An increase in patent filings from 2003 suggests that generic pharmaceutical companies have become interested in developing the products and this suggestion can be confirmed by the information contained in the corresponding Pipeline Developer report for this molecule.
Figure 1: Repaglinide Patent Filing Trends
The Top Patent Applicants analysis (Figure 2) reconfirms generic interest in developing these products with significant filing activity from Actavis and Biocon.
Figure 2: Repaglinide Patent Applicants
In summary, it appears that the innovator has undertaken an effective and economic lifecycle management with a small number of patent filings in regards to Repaglinide products. These seem to be very fundamental to protection of the brand product and are unlikely to be circumvented by generics, meaning that true generic competition may not be seen in Europe until 2011, and uncertainties exist in other markets due to the patent systems in place. However, the small number of filings means that there is a relatively clear path for generic competitors to launch their products upon expiry of the key patents, suggesting that the market may become flooded. Indeed, the DMF filings and Top Patent Applicants analysis shows that some generic competitors appear to have already prepared to launch generic versions of Repaglinide products as soon as these patents expire.
Of course, none of this would be possible without comprehensive understanding of the patent landscape surrounding Repaglinde products. Comprehensive data for patent families relating to Repaglinide, based on professional patent searching, from the 50 million+ published patent documents worldwide, may be accessed by subscribing to the GenericsWeb Pipeline Developer report, now available in 'Core' and 'Extended' formats. Subscription includes twelve monthly updates to keep you abreast of recently published patents and applications. GenericsWeb Pipeline Selector reports are available in 'Core' and 'Extended' formats for any active ingredient upon request.
For questions and comments about this article please contact the author at d.oh@genericsweb.com
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