Drug In Focus

Leighton Howard is a patent information expert with extensive generics experience. He has worked within the professional patent information industry and major generic pharmaceutical firms and now provides consultancy services to the generics industry and government organisations via his company XIP Pty Ltd.  He is also the founder of GenericsWeb and remains instrumental in maintaining the high quality and accuracy of data contained in Pipeline Patent Intelligence. Please email any comments or queries.
Leighton Howard

Drug In Focus: Esomeprazole

A recent ruling by the EPO revoking a key patent protecting Astra Zeneca’s anti-ulcer medication Esomeprazole (Nexium) has raised many questions in the generic pharmaceutical industry.

Drug in Focus for January will therefore review the extent of protection for Esomeprazole products from generic competition based on the corresponding GenericsWeb Pipeline Selector report, with a specific focus on the European market.

The Esomeprazole General Information (Table 1) indicates that this product is generally available as a variety of dosage forms, including an oral suspension recently-approved in the US.  Whilst the injectable dosage form uses the active ingredient in the form of the sodium salt, a magnesium trihydrate form is present in the oral dosage forms.

Table 1: Esomeprazole General Information

esomeprazole general information

A quick analysis of the authorisation dates for Esomeprazole in major markets shows that data exclusivity no longer applies in Australia, Canada or the USA, indicating that the innovator product is relying on patents in those markets for protection against generic competition.  However, European countries benefiting from 10-year data exclusivity (most major markets) will not allow application for generic approval earlier than March 2010, restricting generic entry until at least 2011.

Table 2: Esomeprazole Regulatory Data
esomeprazole marketing authorisation dates

The Key Patent Indicator for Esomeprazole outlines the most significant patent protection (Table 3) for the suite of products.  This confirms that the patents relating to the Esomeprazole active ingredient per se (or at least salts thereof) are due to expire around 2014 most in key territories, with no extensions having been granted to the patent term of these patents. However, no patents are currently in force protecting key European markets following the revocation of EP 652872 in 2006.  It is clear to see that AstraZeneca has filed two applications which are divided out of the revoked parent, whose claims currently encompass the Esomeprazole products.  Examination of these applications is unlikely to reach a conclusion within the next few years, creating uncertainty about the final scope of their protection, however the publication of the decision in regard to ‘872 will offer some guidance as to what will be allowable.  The ongoing litigation in the US as a result of Ranbaxy’s Paragraph IV filing may result in stripping of the ‘basic’ patent protection from this product in its most significant markets.

Table 3: Esomeprazole Key Patent Indicator

esomeprazole key patent indicator

In response to the EPO decision, AstraZeneca announced that they have confidence in the intellectual property portfolio protecting Nexium.  A review of the number of key patents relating to the Esomeprazole suite of products suggests why they may have such confidence, with numerous patents and pending applications claiming molecular form, process, formulation and use patents.

Furthermore, a study of the Patent Risk Analysis section, based on comprehensive patent data (details of which are accessible in the corresponding Pipeline Developer subscription) indicates that, due to the age of it’s racemic parent Omeprazole and the amount of patenting activity generated by both AstraZeneca and generics in response, many patents thought to protect the Esomeprazole product could have inherent weaknesses over the prior art base (Figure 1).  AstraZeneca may therefore need to rely more on the financial costs of litigation as a deterrent to generic competitors rather than the actual strength of their patent portfolio.  Clearly such a strategy will not work against today’s generic giants. 

Figure 1: Esomeprazole Patent Filing Trends

esomeprazole patent filing trends

Looking at the categories that have been so heavily patented over the years (Figure 2), it appears that the more astute generic manufacturers will be able to find a way to launch a product as soon as the data exclusivity provisions allow (or the ‘basic’ patent in those countries where it is still in force).

Using the European example, patents protecting alkaline salts of Omeprazole (and its enantiomers) have already expired, the EPO decision removes later protection of alkaline salts of the Esomeprazole, whilst solutions to circumvent other patents relating to the specific salts and hydrates are likely to come from the large amount of molecular form patents filed or simply from the prior art.  Processes for preparation of the enantiomer were also disclosed in the revoked patent, clearing the way for at least one method of manufacture, although the process is possibly inefficient.  This may explain why a further process patent is under attack by Ratiopharm by way of EPO opposition proceedings.  Oral capsule formulations of such acid-labile compounds are now in the public domain, although the MUPS tablet formulation remains under patent for some time, and the indicated uses for Esomeprazole do not appear to be protected. 
Figure 2: Esomeprazole Patent Category Distribution
esomeprazole patent category distribution

However, due to the extensive filing of patents identified in the Pipeline Selector report in relation to this molecule, Esomeprazole is not a development for the ill-prepared.  Every month, new patent families are published that were applied for 18 months previously and the patent landscape becomes more complex, rendering reliable, accurate and relevant patent information an essential part of the process.

In summary, the ‘basic’ patent for Esomeprazole has now been removed in Europe, but there is a chance that related filings could inject some complications into generic development later on.  Nevertheless, the market is by no means completely open to generic competition after expiry of data exclusivity provisions due to the web of patents that has been cast by AstraZeneca and their intent to defend them. Only those generic developers that have taken a proactive approach to identifying and monitoring patent activity by the innovator and other generic manufacturers, and crafting an appropriate patent strategy are likely to benefit from this EPO decision, and any similar decision in the US.  In short, unless the data exclusivity itself is challenged (Canada’s new regulations do not award data exclusivity to enantiomers), we can expect to see at least a handful of generic products launched in major European markets in late 2011, or much earlier in the US if Ranbaxy is successful in its litigation. 

Comprehensive data for patent families relating to Esomeprazole, based on professional patent searching, may be accessed by subscribing to GenericsWeb Pipeline Developer reports which include twelve monthly updates to keep you abreast of recently published patents and applications.  GenericsWeb Pipeline Selector reports are available for any active ingredient upon request.

For questions and comments about this article please contact the author at l.howard@genericsweb.com.

Leighton Howard
Managing Director
January 2007
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