Australia: Drug In Focus: Donepezil

Donepezil (Aricept®), an anti-dementia/anti-Alzheimer's treatment developed by Eisai and co-marketed by Pfizer, will lose key patent protection in some major territories in the near future. Currently, Aricept® is the world's best selling anti-Alzheimer's drug and generated sales of 303 billion Japanese Yen for Eisai and US$432 million for Pfizer in 2009. Based on the information contained in GenericsWeb's Donepezil Pipeline Selector report, this month's Drug In Focus will analyse the patent landscape surrounding the Aricept® product with a view of launching generic equivalents.

Table 1: Donepezil General Information

According to the General Information (Table 1), Donepezil is available as the hydrochloride salt in film coated tablet and orally disintegrating tablet (ODT) dosage forms in 5mg and 10mg dosing strengths and is indicated for the treatment of Alzheimer's type dementia.

Six different patent families have been identified by Key Patent Information (KPI, Table 2) as being important in protecting the innovator product and potentially in preventing generic versions of Donepezil from entering the market. All of these key patent families were filed by the innovator, Eisai. It can be easily seen from the Data Exclusivity section of the KPI that data exclusivity has expired in all major territories and does not constrain approval of generic versions of Donepezil.

Table 2: Key Patent Information

Donepezil Key Patent and Data Exclusivity Information

The members of the first patent family of the KPI, which protect the Donepezil compound per se, have been granted Supplementary Protection Certificates (SPCs) in most European countries and will expire in February 2012. A patent term extension has also been granted in Australia, extending the expiry until March 2013. In the US, the patent has been granted a s156 term extension yet will expire in November 2010. Despite a lack of patent extension scheme in Canada, the two Canadian equivalents will be in force until end of 2013 and 2015 as they benefit from the longer term of 20 years from application date or 17 years from grant date.

The patents in the second and third families identified in the KPI claim crystalline polymorphic forms of Donepezil hydrochloride and Donepezil free compound. In the second family, the patent members will be in force until 2016 in the US and 2017 in Australia, Canada and Europe, however all the patents in the third family will expire in 2018. Since the commercial product contains the hydrochloride salt, it would seem unlikely that a patent protecting a crystalline form of the free compound could protect those products. However, US6245911 is listed in the FDA Orange Book against the standard oral tablet dosage form, and not the orodispersible dosage form. It is clear from the patent that Donepezil is a precursor to Donepezil hydrochloride but why it is listed at all, let alone against only one of the Eisai products, is a mystery that is likely being untangled in the ongoing litigation in the US (discussed later).

Equivalent patents in the last key patent family claim a composition comprising Donepezil and an organic acid and relate to the marketed formulation. All of the patents in this family were granted by the respective patent offices and will expire at the end of March 2019, however since the formulation of the Aricept® products does not contain an organic acid according to many sources this patent appears to offer no significant protection of the commercial product. This obviously raises the question over the purpose of it's listing in the Orange Book.

Two patent families specifically protecting the marketed ODT product have also been identified by the KPI. Both US equivalents (US7727548 and US7727552) were granted on 1st June 2010 and recently listed in the Orange Book. The term of US7727548 has been officially adjusted by 479 days and will expire on 23rd June 2022. Due to orodispersible tablet formulations in the prior art and the specific nature of these identified key patents, it is not thought the US patents will serve to prevent generic competitors from developing and launching their own orodispersible formulations.

According to the Marketing Authorisation Holders (Table 3), Teva and Mutual have obtained final FDA approval for the tablet and orodispersible tablet respectively, despite the fact that the molecule patent of Donepezil is still in force. The Teva final approval came upon expiry of the 30 month stay of approval of Teva's ANDA whilst litigation is ongoing. Should Teva have been tempted to launch 'at risk', Eisai blocked this opportunity by winning a preliminary injunction which orders Teva not to sell generic Aricept® as claimed in US4895841 until it's expiry in November 2010. Litigation surrounding the Aricept® product in the US as reported by the Litigation Alerts in Pipeline Selector is extensive and complex, full details of which are available in the full report.

Table 3: Marketing Authorisation Holders

Many generic equivalents to both Aricept® dosage forms have been identified in the UK, suggesting that European markets will be flooded by generics as soon as the molecule patent expires February 2012. A similar situation looks likely in Australia in March 2013, with Synthon already waiting in the wings with an ARTG listed generic. Although no generic product has been identified as being authorised in Canada at the moment (presumably due to the late expiry of the molecule patent), a number of generic companies have filed an application for Notice of Compliance (NOC) for a generic equivalent to Aricept®. Accordingly, lawsuits have been filed asserting infringement of the relevant Canadian patents.

A review of the Patent Filing Trends for Donepezil, based on the comprehensive patent search report contained in the Pipeline Developer, reveals process patents account for more than a quarter of all patent families identified. This indicates that synthesising, or sourcing of non-infringing API to use in the formulation may be problematic. This is compounded by the number of patents covering the molecular form, which account for 15% of all applications filed in relation to Donepezil. The high numbers of molecular form patents create a significant barrier for generic companies who want to circumvent the polymorphic form patents listed in the KPI by producing a different polymorph. It is therefore in the best interests of any generic company wishing to develop generic versions of any Donepezil products to be fully informed of the existence of these patents and consider them with appropriate strategies.

Figure 1: Donepezil Patent Category Distribution

According to the Top Patent Applicants chart (Figure 2), Eisai tops the chart and has filed 25% of all patent applications relevant to Donepezil. This indicates the innovator's strong intention of protecting the marketed product, despite the fact that it's Orange Book listed patents are being challenged by several generic companies. Many other companies have filed relevant patent applications, and this is due to patents broadly claiming "anti-dementia/anti-Alzheimer's' treatments" or "acetylcholinesterase inhibitors", as well as a large amount of generic competition.

Figure 2: Donepezil Top Patent Applicants

In conclusion, it appears that Eisai has spent a reasonable amount of resources laying down patent barriers to prevent generic competition on its Aricept® product, considering the large number of patent applications filed. However, the scope and strength of protection of these patents does not appear significant enough to prevent generic competitors from entering the market beyond expiry of the patent protecting the molecule per se. Therefore, a surge in generic activity is expected in the all markets once the molecule patent (and any 180 day exclusivity period if applicable) expires. In Europe, the molecule patent will be in force for a further 15 months beyond the US equivalent due to variations in the patent term calculations. Despite this, the patent landscape around Donepezil is heavily populated with many risks, and it is advised that this is comprehensively assessed by interested generic companies to avoid costly litigation. Obviously, this would not be possible without first comprehensively identifying relevant patents from the over 50 million published patent documents worldwide, and keeping this information up to date.

Comprehensive data for patent families relating to Donepezil, 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.

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