According to Table 1, Spectracef is available as 200mg & 400mg film-coated tablets with Cefditoren pivoxal ester as active ingredient.
As seen in Cefditoren Key Patent Indicator (KPI) (Table 2) three patents are listed, claiming the Cefditoren molecule, Cefditoren pivoxil and the marketed oral formulation respectively. The first key patent family which claims the Cefditoren molecule (the active metabolite of Cefditoren pivoxil) specifically has expired in major European countries except Spain where an SPC has extended protection until February 2012. The lack of an SPC in France, Germany and the UK is presumably due to late expiration of data exclusivity in these countries as explained in detail later in the article. The US patent has been s156 extended for an extra 1,036 days and therefore expired in April this year. Due to an absence of a patent extension scheme this patent has also expired in Canada.
The second patent listed in the KPI claims the syn-isomer of Cefditoren pivoxil. Patents in this family have not been granted extension in any major territories and have already expired.
Table 2: Cefditoren Key Patent Indicator
Beside the two molecule patent families, the KPI identifies another patent family filed by the innovator that specifically protects the marketed oral formulation comprising casein. The members of this patent family have all been granted by the respective patent offices and are currently in force until expiry in October 2016, unless lapsed or revoked. If generic companies are planning to develop the generic version before 2016 this patent must be circumvented by an alternative formulation or challenged in court. This may explain, at least in part, that no ANDA has been lodged as yet. Interestingly, this product has not been authorised in Australia or Canada. This is possibly due to the small market size of these two countries and the innovators' expectation of a low return. It is therefore not possible for generic competitors to launch in Australia or Canada due to a lack of reference product. Interestingly, the innovator did file patent protection in Canada and paid the maintenance fees for the entire patent term, presumably having an initial intent to enter the Canadian market.
Another major obstacle in developing Cefditoren generic equivalents is the data exclusivity applying to the Spectracef tablets which prevents regulatory authorities from accepting applications for generic medicines during the exclusivity period. Data exclusivity has expired in the US in 2006 and thus the only significant barrier that needs to be overcome by generic companies in order to launch is the unexpired US patents. However, data exclusivity does not expire until much later in Europe. Because the product was approved relatively late in Europe (earliest marketing approval date is 23/03/2004 in Spain) and there is a relatively long period of data exclusivity enjoyed by these territories (10 years in Germany, France and the UK and 6 years in Spain for drug approvals applied before 31/10/2005), data exclusivity for this product extends to 23/04/2014 in Germany, France and the UK and 23/04/2010 in Spain. This could explain the lack of SPC filing in Germany, France and the UK because even if a full-5-year SPC were granted in these territories, it would expire in 2010 which makes the SPC application a meaningless effort whereas in Spain where SPC was granted, protection was extended to 2012 which is two years beyond expiration of data exclusivity. European generic activity would therefore not be expected until late 2015 in the UK and Germany, and 2012 in Spain.
Due to a combination of the constraints on launching this drug illustrated above, there are no approved marketing authorisations held by generic companies. However, at the moment it would seem worthwhile for the generic manufacturers to consider filing an ANDA with a paragraph IV certification alleging the listed formulation patent as invalid, unenforceable or not infringed, since the 180-day marketing exclusivity appears to be still available to first generic applicant who successfully challenges the Orange Book listed patents. However, as seen in Figure 1 (Cefditoren Patent Category Distribution), more than 40% of patent families identified by the GenericsWeb Pipeline Developer report protect various formulations of Cefditoren which create a potential barrier for generic manufacturers to market bioequivalent formulations. In addition, over 50% of relevant patent families claim processes of preparing the molecule. Although this type of patent is less useful in preventing development of generic equivalents, it is in a generic company's best interest to be fully informed of the existence of these patents and consider them with appropriate strategies.
Figure 1: Cefditoren Patent Category Distribution
Surprisingly, generic giant Orchid Chemical and Pharmaceuticals tops the Top Patent Applicants chart (Figure 2), filing 11% of patents relevant to Cefditoren. Another well-known generic player, Ranbaxy, filed 7% of all relevant patents. The Pipeline Selector report also shows that Orchid and Ranbaxy have filed a DMF which indicates that they are prepared to supply the active pharmaceutical ingredient to potential generic manufacturers, at least in the US. This strongly indicates that Orchid and Ranbaxy (and possibly other generic companies) are very keen to enter the Cefditoren market and have made an effort to protect their investment in developing generic equivalents by patenting their novel technologies.
Figure 2: Cefditoren Top Patent Applicants Analysis
The information above makes it sufficiently clear that caution should be exercised when determining whether to develop generic Cefditoren products using Orange Book alone. Each of the patents listed should be investigated for relevance to the generic product and it must be acknowledged that many patents protecting the Spectracef product held by the innovators and by other generic manufacturers will not be listed (such as formulation and preparation patents mentioned above). Generic companies are advised to have access to a comprehensive search of the patent landscape laid around the product well before any technical development takes place in order to avoid costly litigation. Obviously, none of this would be possible without first comprehensively identifying the relevant patents for the development from the 50 million+ published patent documents worldwide, and keeping this information up to date.
In summary, it appears that innovators of Cefditoren have undertaken a small amount of effective lifecycle management by patenting, but the late approval of products containing this active ingredient in Europe has resulted in significant constraints in the form of data exclusivity expiring later than any blocking patents. However, in regards to US market with a shorter data exclusivity term the oral formulation patent is the only unexpired key patent. Thus, given the amount of activity in regards to formulation patents, if this molecule were of significant interest to generic companies, one would expect to see at least a paragraph IV filing at this stage. If the formulation patent is the major obstacle (i.e.there is a technical problem, not a market problem) this molecule will likely meet with a great deal of generic competition in 2016 once this patent has expired, unless it is invalidated upon challenge by a proactive generic competitor.
Comprehensive data for patent families relating to Cefditoren, 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 questions and comments about this article please contact the author at k.wang@genericsweb.com.
Home
INNform