The Ropivacaine General Information (Table 1) indicates that the approved active is in the hydrochloride monohydrate form, formulated as a solution in an ampoule for injection in 2, 5, 7.5, 10 mg/ml dosage strengths and as a 2 mg/ml solution for infusion for use in surgical anaesthesia and pain management. A co-formulation product of Ropivacaine hydrochloride and Fentanyl citrate, in 2mg/ml and 2, 4 mcg/ml infusion dosages for injection, is available in Australia. It is indicated for the management of post-operative pain.
The Ropivacaine Key Patent Indicator (KPI) in Table 2 identifies three patent families protecting the NaropinŽ product. Patents in the first family, with priority number SE8600017A, protect Ropivacaine hydrochloride monohydrate, the active ingredient in the NaropinŽ products, and its uses as a local anaesthetic. The European member of the family, claims the Ropivacaine hydrochloride monohydrate per se except in the contracting states of Austria, Spain and Greece, where the patent only claims a method for preparation of Ropivacaine hydrochloride monohydrate. An SPC extension was granted in Great Britain, Germany and France further extending patent protection until September 2010. No SPC application was granted in Spain, Portugal and Greece, as SPCs were only allowed after 1998 with no retrospective filing allowed, so the patent expired in 2006. Although the infusion dosage form available in Europe carries paediatric indications, the lack of a published PIP suggests that this product is not eligible for a 6 month extension to any SPC term. The US member US4870086 ('086) was granted a 1,400 day s156 extension which expires in September 2010. The Australian member AU592392 was granted a s70 extension which expires in January 2011. Due to a lack of a patent extension scheme in Canada, the Canadian equivalent expired in November 2007, 17 years after grant/issue.
The data exclusivity (DE) for Ropivacaine has expired in all key territories, but there is currently no generic NaropinŽ product on the market in Europe, the US, Canada or Australia. However, there seems to be some generic interest in Ropivacaine in Europe, for example marketing authorisations have been granted to Teva in the UK and Mylan in Finland. Even though the active ingredient patent protection and DE has expired in Canada there is no generic available. This could be due to a small market size, or other key patents listed in the Canadian patent register constraining market entry (see below). In the US there is also some generic interest in Ropivacaine with the Pipeline Selector report identifying six DMF filings and one Paragraph IV filing and Navinta having a tentative approval (discussed in more detail below). The absence of a generic equivalent product on the market in these regions could be due the strength of this molecule patent family in protecting the active ingredient in the NaropinŽ product and an unwillingness of generic companies to launch for fear of costly litigation.
Table 2: Ropivacaine Key Patent Indicator
The second key family identified by the KPI protects the use of a local anaesthetic for the treatment of ulcerative proctitis or ulcerative colitis. This family has a US and a Canadian member only, both expiring in 2012, although the claims do not appear to relate to the authorised indications in either of these countries, the Canadian equivalent is listed in the Canadian Patent Register for reference drug NaropinŽ. Generic companies interested in developing a generic Ropivacaine product, particularly in Canada, must be aware of this patent family and take appropriate measures to avoid possible infringement.
The final key patent family protects the use of low concentrations of Ropivacaine to treat and manage pain (less than 0.25 or 0.5%). Expiring in 2014, the patent members for this family protect only the analgesic indication for NaropinŽ, allowing generics a possible opportunity to launch products with only the anaesthetic indication. When filing for market authorisations with partial indications extreme caution must be taken so that a generic product will not induce or contribute to the infringement of these types of use patent as discussed in the Navinta litigation in detail below. The question over whether European counterparts could be held to infringe on the same basis may possibly be answered in courts in the near future, although the issue of deleting indications is one that appears to have been dealt with in EU legislation.
The Pipeline Selector Litigation Alert for the '086, '524 and '489 patents shows that Abraxis and APP Pharmaceuticals filed an infringement suit in the District Court of New Jersey on the 5 March 2007 upon receipt of the filing of an ANDA with Paragraph IV certification by Navinta for all three Orange Book listed patents. During a bench trial at the end of July 2009, a week before the 30 month stay of approval expired, Abraxis argued that the monohydrate form of Ropivacaine hydrochloride was not fully dissolved in the solution due to the stability of the hydrate form in solid state and in solution, and therefore Navinta's ANDA infringed the '086 patent by containing the hydrate form. Abraxis also claimed that Navinta's generic Ropivacaine products would wilfully induce or contribute to the infringement of the '524 and '489 patents claiming use of low concentrations of Ropivacaine to treat pain. This case hinged on conflicting expert testimony on the extent of the dissolution of hydrates in a true solution. The court regarded the testimony of the Abraxis expert more highly, concluding that in solution some of the monohydrate form remains undissolved, and thus Navinta was found to infringe the claims of the '086 patent. The court also found that Navinta's product information encouraged the infringement of the claims of the '524 and '489 patents and ordered that Navinta's ANDA could only be (tentatively) approved with a date no earlier than 23 September 2014, the expiry date of the '524 and '489 patents. The FDA granted a tentative approval on 26 August 2009 and Navinta has appealed the decision. If Navinta is successful on appeal this could see the launch of a generic version of NaropinŽ on the US market in the near future, but until such time it can only wait the courts' final decision.
Figure 1: Ropivacaine Patent Category Distribution
Study of the Patent Risk Analysis section, based on comprehensive patent data (details of which are accessible in the corresponding Pipeline Developer subscription) indicates that patenting activity relating to Ropivacaine is mainly concentrated on formulations. This can be seen in the Ropivacaine Patent Category Distribution with over half the patents filed relating to formulations (Figure 1), possibly due to a large number of platform technology patents relating generally to anaesthetics. The large proportion of small stake individual filers, as seen in the Top Patent Applicants Graph (Figure 2), further supports this trend. When developing a generic product it is important to understand all the patents surrounding the drug, so that an appropriate strategy can be developed to avoid infringement and consequently costly litigation. Therefore an understanding of all these platform patents and their application to anaesthetics would allow the development of a generic product that minimised the risk of infringement. As can be seen in Figure 2, Astra was the highest individual filer showing that they have undertaken some lifecycle management by filing patents to preserve their monopoly on the Ropivacaine market.
Figure 2: Ropivacaine Top Patent Applicants Analysis
In summary, the key patents protecting the NaropinŽ active ingredient, Ropivacaine hydrochloride monohydrate will expire later this year in most European countries and the US and have already expired in Canada and Spain. AstraZeneca have undertaken limited lifecycle management to protect their monopoly on Ropivacaine. However patents filed to protect the use of specific concentrations of Ropivacaine in treating pain, have been litigated and successfully defended in the US, highlighting the importance of such patents in protecting the entire product range in the US. Interestingly, the same patents in Europe will probably not constrain generic competition beyond expiry of the active ingredient patent SPCs later this year. Thus in Europe, with Teva and Mylan waiting to launch with granted marketing authorisations, it is likely that a generic Ropivacaine product will be on the market in September 2010.
Generic developers are strongly advised that a comprehensive search of the patent landscape surrounding Ropivacaine is a crucial step before any technical development takes place in order 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.
Comprehensive data for patent families relating to Ropivacaine, based on professional patent searching, may be accessed by subscribing to the GenericsWeb Pipeline Developer report which includes twelve monthly updates to keep you abreast of recently published patents and applications. GenericsWeb Pipeline Selector reports are available for any active ingredient upon request.
For questions and comments about this article please contact the author at c.bray@genericsweb.com.
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