Drug In Focus August 2012

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Drug In Focus: Duloxetine

The following data is extracted from GenericsWeb Pipeline Patent Intelligence and is intended to give a brief outline of factors affecting the potential launch of generic Duloxetine equivalents of Eli Lilly’s blockbuster serotonin-norepinephrine reuptake inhibitor (SNRI) (Cymbalta®, Andepra®, Ariclaim®, Xeristar® and Yentreve®). Global Cymbalta® sales generated US$4.16 billion in 2011.

General information

Duloxetine is currently available as delayed-release oral capsules in eq. 20, 30 and 60 mg base strengths. Cymbalta® is indicated for use in the treatment of major depressive disorder, diabetic peripheral neuropathic pain, generalised anxiety disorder and also in the US and Canada for the management of fibromyalgia and chronic musculoskeletal pain. In Europe it is also marketed as Yentreve®, indicated for use in the treatment of stress urinary incontinence in women. The Duloxetine molecule was discovered and marketed by Eli Lilly and was co-marketed and developed under a collaborative agreement with Boehringer Ingelheim (excluding the US and Japan) until March 2010.

Figure 1: General Information table for Duloxetine

INN Constraint Comment

Whilst API patent protection expired in Canada in June 2009, protection extends to December 2013 in the US courtesy of a 6 month paediatric extension to the 5 year s156 term extension (see Figure 3). The validity and enforceability of the US patent was upheld after Paragraph IV challenges by Wockhardt and several other generic competitors. The maximum 5 year patent term extensions have also been granted in Australia and most European markets, extending patent protection for the API until December 2012.  

However data exclusivity constraints in Europe extend beyond the expiry of patents in the API family, preventing applications for a generic MA until August 2014 due to a lengthy period elapsing from patenting to first marketing authorisation. This means that generic versions containing Duloxetine are unlikely to be approved until late 2015 at the earliest.  Due to an even later market authorisation date in Canada, data and market exclusivity periods should prevent the launch of a generic MA until May 2016. The 5 year data protection period in Australia available for new active agents expired in March 2012 (see Figure 3); potentially delaying the launch of a generics beyond the expiry API patent protection in December 2012 as sponsors wait for approval of their MA.

Patent families US15812193A and US10037798P (see Figure 2) protect approved indicated uses for Duloxetine, so are considered to be a constraint for those uses. Patent family US15812193A claims the treatment of urinary incontinence and protects the authorised indicated use for Yentreve®. Granted SPCs in most ‘Core’ European countries, except Germany where the application has lapsed, extend Eli Lilly’s monopoly for Yentreve® and prevent generic companies launching products carrying that indication until August 2019. Patents in family US10037798P claim use of Duloxetine in the treatment of persistent pain, pain associated with diabetic neuropathy and fibromyalgia. The Canadian, European and US members only claim treating fibromyalgia and will only be a constraint for that indicated use. Treatment of depressive disorders appears not to be protected specifically beyond expiry of the molecule patent discussed above.

Patent family US27623294A claims enteric coated pellets comprising Duloxetine and protects the currently marketed formulation. The Australian member of the family, AU686384, has had its term extended, expiring in July 2020, however this family is not considered a constraint to generic competition as the protected technology is likely to be circumvented by generic reformulation.

Figure 2: Key Patent Indicator; the most significant patents protecting products containing Duloxetine

Figure 3: Patent Family View priority application US94512286A

Figure 4: Marketing Authorisations for products containing Duloxetine in Key Countries

In the US Lupin Pharms, Apotex and Dr Reddy’s Lab gained market authorisation upon expiry of the molecule patent and Sandoz in June; all for the capsule form in all dosage strengths. Ziprasidone is not an authorised medicine in the UK, however several generic companies have been identified in Europe holding market authorisation for Ziprasidone capsules. Launch is expected upon expiry of the molecule patent in Europe. No generics have been identified in Canada due to a later MA and unexpired data exclusivity preventing an applicant from filing an application for a generic MA until August 2013 and launching until August 2015. No generics have been identified in Australia due to molecule patent protection preventing the launch of generics. There is currently no evidence of any market authorisation obtained by generic companies relating to the oral suspension or the IM injectable dosage forms.

Figure 5: Top Patent Applicants

A representation of patentees who have filed the most patent families for this INN. Note that generic competitor Teva is the highest individual filer in the top five, their patenting activities focusing primarily on molecular form, process and formulation. The patenting focus of BASF relates to the synthesis of Duloxetine. Cypress Bioscience's has centred on the manufacture of a competing SNRI, Savella® (Milnacipran) - most of their patenting actives relating to Duloxetine are for general use of a SNRI. Of particular interest are families identified which claim use of a SNRI in treating fibromyalgia.

Figure 6: Patent Filing Trend

Represents the timing of the earliest priority filing date for each patent family identified for this molecule as well as the type of claims found in the applications. Note the consistent patenting by generic companies post-approval in the area of molecular form, process and formulation.

Figure 7: Patent Category Distribution

The types, number and relative distribution of patents that have been filed for Duloxetine obtained via a comprehensive patent search (Pipeline Developer report). Note the dominance of process patent families, of which over 50% relate to intermediates, their synthesis and use in the preparation of Duloxetine. Of the formulation patents over 70% relate to oral formulations, the majority filed by generic companies. This shows that proactive generic competitors have filed patents trying to circumvent innovator patents and protect their technologies.

In summary, Eli Lilly’s protection remains in force in the US until December 2013 after its validity and enforceability was upheld, but competition will be strong upon expiry of the extended patent term. Data exclusivity is the major constraint to generic entry in Europe and Canada, extending beyond API patent protection. Data protection provisions in Australia may delay launch of generics until after expiry of API patents, with a likely launch date in mid 2013. Further patenting strategies by Eli Lilly will lead to generic competitors having to carve out indications and patenting of processes will make API synthesis complicated without a good picture of the patent landscape. Innovator formulation patents are likely to be circumvented as evidenced by patent filing trends and the volume of generic competitors holding tentative FDA approvals expected to launch upon expiry of the API patent in the US, however caution should be exercised when circumventing innovator formulation patents, as many formulation patents are held by generic competitors, underscoring the importance of developing an IP strategy earlier in the development process.

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August 2012
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