Drug In Focus January '10

            

 
The Gatifloxacin Key Patent Indicator (KPI) in Table 2 shows four patent families. Patents in the first family protect the Gatifloxacin active ingredient via claims to its chemical formula. In this family, US4980470 will expire on 15 June 2010 due to the grant of 6 months paediatric exclusivity, in addition to the USC s156 patent term extension grant of 721 days.  US5043450, claiming other analogues of Gatifloxacin, expired in August 2008. The British and French patents in this family expired in 2007, but the German equivalent will not expire until 2012 due to a granted SPC application. AU610491 will expire in January 2012 due to a grant of s70 extension. Both the Australian and German extensions are based on the marketing authorisation of the Tequin products, which are now discontinued in those countries. This is also suggested by the Regulatory Data in the Pipeline Selector report, where no marketing authorisation holders for any Gatifloxacin products exist in Australia, France or Great Britain. Canada has the latest expiring member of the family with CA1340316 being valid until January 2016 due to its term being calculated from the issue date.  It is clear that any generic manufacturer would need to wait until at least the expiry of appropriate patents in this family before commercialising a generic equivalent.
 
The second KPI family protects a sesquihydrate of Gatifloxacin. The normal term of members of this patent family expires in December 2015, however US5880283 expires in June 2016 due to the grant of a paediatric extension.  This family may not be a great concern for generic manufacturers since those who conducted their patent research in advance would possibly be able to circumvent this family by developing and using different hydrates of Gatifloxacin in the finished dosage form. This type of thinking is confirmed by information found under the Gatifloxacin Drug Master Files (DMF), showing 5 generic companies holding active DMFs.  Among them, Apotex is using Gatifloxacin hemihydrate whilst Cadila is using anhydrous Gatifloxacin as an active ingredient instead of the protected Gatifloxacin sesquihydrate.  The use of a different hydrate for manufacture of the dosage form by Apotex could be one of the reasons that Allergan did not sue Apotex for infringement of US5880283 when they filed an ANDA with Paragraph IV certification in October 2007 (as identified in the ‘Litigation Alert’ and ‘Paragraph IV’ sections of the Pipeline Selector report). 

The third KPI family protects aqueous liquid formulation comprising Gatifloxacin and disodium edetate, which is one of the inactive ingredients found in the Zymar product. Australian, Canadian, and European members of this family all expire uniformly in August 2019, while US6333045 expires in February 2020 due to the grant of paediatric exclusivity. This family would be a great concern for generic developers since they would either need to invalidate the patent or find a way to formulate their version of the product using a different chelating agent which has similar properties to disodium edetate and which does not fall into the scope of “Doctrine of Equivalents” test, if applied by the US courts.

The Pipeline Selector Litigation Alert for US6333045 shows that Allergan sued Apotex in the district court of Delaware in November 2007, asserting infringement of the US6333045 patent only following Apotex’s submission of the ANDA with a Paragraph IV certification to manufacture a generic Zymar. In response, Apotex counterclaimed, declaring the US6333045 patent invalid and unenforceable because the patentee did not disclose important information during prosecution at the USPTO.  The outcome of the trial is not yet known (the trial began only last week), the FDA has already granted the only tentative approval for Apotex’s generic Zymar in June last year, suggesting that Apotex have a good chance to be the first generic developer to enter the US market with this product.  Although other Paragraph IV filings were made earlier by other generic companies such as Teva, these were in relation to the withdrawn Tequin oral Gatifloxacin product, thus Apotex may benefit from a 180-day market exclusivity for generic versions of Zymar in return for being the first filer with  Paragraph IV certification, if their patent challenge is successful. 

The final KPI family protects a formulation comprising crystalline co-precipitate of Gatifloxacin and a fatty acid selected from stearic acid, palmitic acid and mixtures thereof. Interestingly, US6589955 has been delisted from the Orange book as it can be seen from the update column of the Patent Publication Detail (Table 3), which is one of the new features of Pipeline Selector reports.

Table 3: Gatifloxacin Patent Publication Detail
 

One of the reasons for de-listing could be the fact that the discontinued Tequin products contain one of the fatty acids while the currently marketed Zymar product does not contain the fatty acid. All the equivalent patent applications in other territories have been withdrawn. This family does not appear to be a barrier for generic manufacturers to develop the Zymar product.

To summarise the key patent families, it appears that the Apotex tentative approval will become final upon expiry of the molecule patent in June 2010 (although this could not be confirmed at the time of writing).  At this stage, Apotex would then need to make a ‘Launch at Risk’ decision in regard to the ‘045 patent, assuming that a) their product falls within the scope of the patent and b) any appeal following the initial judgement would not have been heard before such time. The final key patent family has been delisted and is clearly not relevant to the current Zymar product, however the ‘283 sesquihydrate patent may have been considered differently by the innovator following a recent case relating to Ropivacaine (thanks to IP Think Tank).  This involved expert testimony that hydrates may not fully dissociate in solution and so a hydrate patent may still be infringed even if the active ingredient has been dissolved into a true solution.  The main support for Apotex in this case would have been that the subject of their DMF is the hemihydrate form, thus the assertion that the sesquihydrate exists in solution would be a difficult one to prove.

When the generic strategy is to circumvent Orange-Book listed patents, extreme caution is required when selecting a formulation since a great number of patents claiming different types of formulations, which are not listed in the Orange book, might have already been filed and/or granted for this product. This situation can be confirmed by the Patent Risk Analysis section of the Gatifloxacin Pipeline Selector report (Figure 1), based on comprehensive patent information (details of which are available by subscribing the corresponding Pipeline Developer report). It indicates that the patenting activity relating to this drug has focused on formulations, with almost half of the total number of Gatifloxacin related patent families falling into this category.

Figure 1: Gatifloxacin Patent Category Distribution

This is further re-confirmed by the Patent Filing Trends (Figure 2) which shows significant increase of overall patent applications, particularly formulations related applications, since the major launch of Gatifloxacin products in 2001. This abrupt increase in filing suggests that generic pharmaceutical companies have become interested in developing a generic version of this product and this suggestion can be confirmed by the corresponding Pipeline Developer report for this drug.

Figure 2: Gatifloxacin Patent Filing Trends

               

In summary, although the Tequin products are withdrawn from the market, there still appears to be strong interest by at least one generic pharmaceutical company to enter the US market with a generic equivalent of the remaining Zymar product. The innovators have undertaken active life cycle management by not only relying on the patent protecting the active ingredient but also seeking patent protection regarding molecular forms and formulations, something that may prove valuable in the coming months and years.  Nevertheless there will always be an opportunity for proactive generic pharmaceutical companies to share the market with the innovators. It is likely that Apotex will be one of the first generic to enter the market with their proactive approach regarding this product.  However, other generic developers still have an opportunity to enter the market with their own generic version of formulations regarding this product once any 180 day exclusivity period has expired.

Generic developers are strongly advised that a comprehensive search of the patent landscape laid around Gatifloxacin is a crucial step before any technical development takes place in order to avoid costly litigation, particularly in regard to formulations. 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 Gatifloxacin, 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 d.oh@genericsweb.com