Among four patent families identified by the Key Patent Indicator (KPI) (Table 2), the first key family protects the Nateglinide active ingredient. Within this family USRE34878 will expire in early September 2009. The term of the equivalent patent in Germany, France and the UK has been extended through SPC until March 2011 and therefore provides much longer protection of the active ingredient in these countries compared to the US. Generic developers who are planning to launch a generic version of the Starlix product in Europe will encounter even greater challenges since the data exclusivity will not expire until April 2011. This will prevent them from filing applications for approval of their products and consequently delay the launch of their products well beyond the expiry date of the data exclusivity. Data exclusivity would not affect launch dates in the US, Canada and Australia in this case as they have a much shorter term than 10 years granted in Europe for this product.
Interestingly, no patent filing activity has been identified in Australia and Canada for this patent family, yet no authorisation of any generic products are identified by the Regulatory Information section, suggesting there are other factors which may be constraining the launch of a generic version of the Nateglinide product. Given that the data exclusivity period has expired more than two years ago in both of these countries, there are two possible explanations: a) that a relatively small market size has been discouraging generic developers to launch the generic version in these countries, and/or b) that there are later expiring patent constraints, at least in Canada and Australia.
In Australia, the absence of Starlix on the Pharmaceutical Benefits Scheme (PBS) list would significantly affect market size and therefore attractiveness to generic developers given the relative cost of generic approval-related activities. However, in Canada where no such great market-related constraint exists, there appears to be a patent-related constraint to generic launch that extends beyond the expiry of the first ‘molecule’ patent family.
Table 2: Nateglinide Key Patent Indicator
The second identified key patent family in the KPI (expanded in Table 2) relates to crystals of Nateglinide having one of three defined properties, defined by X-ray diffraction, Infra Red spectroscopy or melting point. Within the second key family, US5463116 and US5488150 will expire in October 2012 and January 2013 respectively. The term of the equivalent patent in European countries extended through SPC until September 2015 in Germany, UK and France and April 2016 in Spain. Due to the broad claims of these granted patents, they will likely provide extended protection of Stralix from generic products containing crystalline Nateglinide other than perhaps those containing an amorphous form of Nateglinide or a different salt form, if found to be suitable.
Another important piece of information that can be seen from the Pipeline Selector report is that Par submitted an abbreviated new drug application (ANDA) for Nateglinide 60 mg and 120 mg tablets, containing a paragraph IV certification with regard to the patents listed for this product in the Orange Book. The ‘Litigation alert’ for these patents shows that Par filed a suit seeking declaratory judgment of invalidity and non-infringement of all the Orange book listed patents, with the exception of USRE34878, the active ingredient patent, in a US District court in Pennsylvania. Depending on the outcome of the trial, Par may be awarded 180 days of the marketing exclusivity for the product therefore may prevent other generic competitors from entering the US market for that period.
Clearly, based on the lack of generic launch in Canada and the PIV filing by Par, there is some difficulty in circumventing patents in this second family to obtain a bioequivalent generic product.
The third key family protects tablet compositions of Nateglinide containing a cellulose-based disintegrant and an optional filler until 2017 in the major territories providing that no extension of patent terms will be applied in the future. The patents belonging to this family may not be a great concern for generic developers since there are almost unlimited possibilities in using different excipients for preparing a tablet composition. However, extreme caution is required when selecting a formulation to circumvent patents in this family since a great number of patents claiming different types of oral formulations are already filed and/or granted for this product according to the information in the corresponding Pipeline Developer report for this molecule (see below).
The fourth key family seeks to protect another oral formulation of Nateglinide products, as well as the use of a combination of Nateglinide with other anti-diabetic agents, until 2020 in the major territories. Within this family the claims of published US patents and applications are currently restricted to oral compositions comprising a sugar and microcrystalline cellulose, but this family should be carefully monitored to ensure that abandoned claims to use of Nateglinide combinations are not reintroduced in the form of a continuation or divisional application. Further, Canadian and European patent applications belonging to this family claim use of a combination of Nateglinide with other anti-diabetic agents. Since the claims of these patents, if granted, may affect the ability of generic suppliers of the product to list the full indications until expiry of the relevant patent, they should also be monitored carefully. These cases underscore the fact that generic developers often require a different strategy for different territories since a patent is only valid in the jurisdiction in which it is issued.
The Patent Filing Trends (Figure 1), based on comprehensive patent data (details of which is accessible by subscribing the corresponding Pipeline Developer), shows solid patent filing activity prior to the first major launch of the product in the US in 2000, most of which has been undertaken by the Innovators as a part of their active life cycle management of the product. A remarkable increase in patent filings from 2002 suggests that generic pharmaceutical companies have become interested in developing the products. Furthermore, a high proportion of molecule and formulation type applications suggests that the generic companies are more focused on developing new polymorphs, salts or formulations of the product to circumvent the existing key patents in this area as highlighted above. We are yet to see if patenting in the molecular form area will result in opportunities for early launch by some, more proactive generic companies who may circumvent the second identified key patent family above.
Figure 1: Nateglinide Patent Filing Trends
Vigorous life-cycle management by the innovators is reconfirmed by the Analysis of Top Patent Applicants (Figure 2). Innovator companies Ajinomoto combined with Novartis top the chart, occupying 38% of patents relevant to Nateglinide, more than six times the number of the second largest filing generic company Ranbaxy, an almost unprecedented number in the 250+ molecules that GenericsWeb has complied this data for.
Figure 2: Nateglinide Top Patent Applicants Analysis
In conclusion, the market for Nateglinide has been well protected by innovators beyond the life of the active ingredient patents. Later patenting of crystal forms and formulations will provide strong protection beyond the life of the molecule patent, but a few generic developers may be in a position to circumvent the later expiring key patents with their own polymorphs, salts or formulations. The number of different expiry dates produced by patent protection and data exclusivity surrounding Nateglinide demonstrates the complexity in bringing a generic product to market at the earliest possible time, and shows how important a tool the Pipeline Selector report is in understanding generic launch constraints.
GenericsWeb Pipeline Selector reports are also available in 'Core' and 'Extended' formats for any active ingredient upon request Comprehensive data for patent families relating to Nateglinide that is based on professional patent searching may be accessed by subscribing to the GenericsWeb Pipeline Developer report. Subscriptions include twelve monthly updates to keep you abreast of recently published patents and applications.
For questions and comments about this article please contact the author at d.oh@genericsweb.com
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