As can be seen in Table 1, Losartan, an angiotensin II receptor antagonist, is indicated for the treatment of hypertension, optionally in combination with other antihypertensives, diabetic neuropathy, optionally in combination with hypoglycaemic agents, chronic heart failure and in combination with Hydrochlorothiazide (HCTZ) for decreasing the risk of stroke. It is available in the potassium salt as tablets with the strength of 12.5, 25, 50 and 100mg and also available as a 2.5mg/ml powder for suspension. A combination product of Losartan with HCTZ (Hyzaar) is also available as tablets with the strength of 50mg/12.5mg, 100mg/12.5mg and 100mg/25mg.
The Key Patent Indicator (KPI) (Table 2) identifies three key patent families for Losartan. The first family protects the Losartan active ingredient and its use in combination with a diuretic including HCTZ. Within this key family, SPC protection of EP0253310 relating to the active ingredient expired in September 2009 in France, Germany, and the UK. However, a paediatric SPC extension has been granted for this patent in France and Germany further protecting the molecule until March 2010. As it can be seen from the litigation alert, initially, a paediatric SPC extension in the UK was not granted on the grounds of not providing a statement of compliance with an agreed paediatric investigational plan. However, this decision was reversed by the Court of Appeals in September 2009, and consequently a paediatric extension to the SPC in the UK was granted, which will not expire until March 2010. The equivalent patent in Spain expired in 2007 due to no SPC application being filed. SPC extensions based on EP0733366 have been granted protecting the use of the combination of Losartan with HCTZ until February 2010 in France, Germany, the UK and Spain.
In the US, US5138069 relates to the active ingredient and US5153197 relates to the use of the combination. Both expired in August and early October 2009 respectively, however paediatric extensions for both patents were granted until February and April 2010 respectively. Among the other 4 US patents listed in this family, US5128355, US5155118, US5210079 relate to the use of Losartan for treating heart or renal failure, while US5354867 protects imidazole derivatives other than the Losartan molecule. The equivalent patents in Australia and Canada will expire much later than those in Europe and the US. In Australia, s70 term extensions have been granted for the patent protecting the Losartan molecule until October 2010 and for the combination of Losartan/HCTZ until August 2011. While in Canada the patent expiry has been calculated using the old term based on 17 years from grant date instead of 20 years from application date as is now common in Canada and in most other countries.
In many cases, data exclusivity is a major barrier for the launch of a generic equivalent as it provides protection for the information gained by the innovator through clinical trials regarding the safety and effectiveness of the drug formulation referenced by the generic applicant. However, in the case of Losartan products, it is not a concern for generic developers since the data exclusivity period expired at least 5 years ago in the major territories as can be seen in the Data Exclusivity expiry column in Table 2. In spite of the expiry of data exclusivity, no generic version of Losartan products are available in the US. The reason for this is the strength of the molecule patent and the inability for generic competitors to circumvent it. The fact that there are 24 DMF submissions with the FDA and companies such as Teva, Aurobindo, Apotex and Zydus already receiving tentative approvals shows the interest generic companies have in launching the products in line with the expiry of key patents.
Table 2: Losartan Key Patent Indicator
The second key family protects polymorphic form I and II of Losartan characterised by X-ray powder diffraction pattern and DSC melting point. Within this family, US5608075 has been granted a paediatric extension until September 2014. Teva was the first to file an Abbreviated New Drug Application with a paragraph IV for US5608075, certifying that the patent could be held invalid, unenforceable or not infringed by their bioequivalent product. Merck subsequently requested that the FDA delist the patent from Orange Book. Equivalent patent applications in Australia, Canada and Europe are no longer active due to the withdrawal of the applications.
The third key patent family, protects polysilicate microgel and polyaluminosilicate microgel compositions, however, they do not disclose the use of Losartan or its combination in the said compositions. This family was included in the KPI since Du Pont applied for an SPC on EP0642466 for the Losartan combination product in Ireland, which was subsequently rejected. The patents belonging to this family will not expire until at least 2012. Platform technology patents, such as this one, which are brand product specific, are identified by Selector if they are in the name of the innovator, in this case Du Pont as it is the molecule patent holder for Losartan. It highlights the importance of have a complete knowledge of how the innovator formulates their products and developing strategies to produce non-infringing equivalent products.
Although no key patent families protecting Losartan formulations have been identified by the KPI, extreme caution is required when selecting a formulation for generic equivalents since a great number of patents claiming different types of formulations are already filed and/or granted for the Losartan products (see figure 1 below) based on a comprehensive patent search found in the corresponding Pipeline Developer report. Other categories which contain a large number of patent families are process and use. Among the relevant patents filed 31% refer to the use of Losartan, and these need to be identified and carefully considered in order to navigate around them and avoid costly litigation. More than 25% of the relevant patent families claim processes for the preparation of Losartan. Although these types of patents are less useful in protecting a proprietor’s product from generic equivalents, it is important for generic companies who wish to add Losartan to their pipeline to be aware of these types of patents and consider them with appropriate strategies.
Figure 1: Losartan Patent Category Distribution
According to the Top Patent Applicant graph (Figure 2) the majority of patents have been filed by companies other than the innovator. This suggests generic companies’ interest in developing the Losartan products. The relatively high percentage of Novartis and Takeda filings could be related to patent families broadly claiming technology relating to the 'sartans', due to their respective patenting activities for Valsartan (Novartis) and Candesartan (Takeda) products.
Figure 2: Losartan Top Patent Applicants Analysis
In summary, it appears that the innovator has undertaken an effective and economic lifecycle management with the filing of extensions, the development of other new formulations and new indication for use in the paediatric population gaining them further extensions in key territories and a small number of patent filings in regards to Losartan products. However, the innovator faces significant challenges to maintain their monopoly on these products with the expiry of patents protecting the Losartan active ingredient and the fact that the polymorph patent is ineffective as competitors can develop other molecular forms to circumvent these. Already there is huge interest from generic companies to launch these products when the patents protecting Losartan products expire in early 2010. Comprehensive patent information ensures that you have an accurate picture of the patent landscape surrounding a drug of interest, avoiding infringing not only innovator patents, but also patents that have been applied for by generic developers in a bid to develop their own versions of the drug for launch at the earliest possible opportunity.
Comprehensive data for patent families relating to Losartan, based on professional patent searching, may be accessed by subscribing to the GenericsWeb Pipeline Developer report which include twelve monthly updates to keep you abreast of recently published patents and applications. GenericsWeb Pipeline Selector reports (Core and Extended) are available for any active ingredient upon request.
For orders placed before November 21st, GenericsWeb is pleased to offer a 20% discount off the standard price of the Losartan Pipeline Developer report (not available in conjunction with any other discount offer).
For questions and comments about this article please contact the author at c.bray@genericsweb.com.
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