Drug In Focus: Tocilizumab Tocilizumab is monoclonal antibody that inhibits the interleukin-6 (IL-6) receptor.

It was co-developed by Chugai and Roche and is marketed by Roche as the brands RoActemra (Europe) and Actemra (outside Europe). Marketing authorisation was granted in Europe and Australia earlier this year and the product is currently under review for approval by the FDA in the US. This month's drug in focus will analyse the patent landscape surrounding Tocilizumab based on information contained in GenericsWeb's Pipeline Selector report for this molecule. According to the General Information (Table 1), Tocilizumab is indicated for the treatment of moderate-to-severe rheumatoid arthritis in combination with Methotrexate and, in Australia, this indication extends to include combinations with other non-biological disease modifying antirheumatic drugs (DMARDs). Table 1: Tocilizumab General Information

The Tocilizumab Key Patent Indicator (KPI) (Table 2) lists three patent families. The first contains multiple patent filings per territory as a result of two different groups of priorities. The first of these, based on US5480796, claim a B-cell stimulating factor-2 receptor protein (BSF-2, which is another name for the interleukin-6 receptor) and an antibody capable of binding to it. The second group of patents, based on

US5670373, claims an antibody to the interleukin-6 receptor (IL-6r) and its preparation. Both of these patent groups are relevant to Tocilizumab. The single Australian patent in this KPI family and several European and US patents expired earlier this year, however for each of the European territories and the US this KPI family still contains patents in force and due to expire July 2010 in Europe and from Dec 2009 to Dec 2015 in the US. An application for extension has been filed in Great Britain and also just recently in Spain which, if granted, would extend the expiry of EP0409607 in these territories until July 2015. The recent application for extension in Spain indicates a possible intent by the innovator to apply for extension of this patent in other EU territories. This information will only become available over time due to the variation in publication times between territories. Paediatric SPC extension periods of six months may also be applied for once the SPC is granted. The longest lasting patent protection in the first KPI family is in Canada with both patents, CA2021594 and CA1341152, still in force and the latter expiring in Dec 2017. On the positive side for generics companies pursuing follow-on biologic opportunities in Canada is Health Canada's recent approval, in April 2009, of Sandoz's OmnitropeTM. This generic version of recombinant human growth hormone is Canada's first follow-on biologic or 'Subsequent Entry Biologic' (SEB) to be approved. The approval was granted using their existing legislative and regulatory framework which applies to all pharmaceutical and biologic products, however further clarification of submission and approval requirements regarding SEBs is being sought, with consultations on the second draft of a guidance document closing in May 2009. Thus notwithstanding patent protection, the future of generic competition for blockbuster biologics in Canada is looking bright with an adaptive legislative and regulatory system. Patents of the second family, based on WO9219759, claim a chimeric human-mouse antibody and its production and these represent the molecule patent for Tocilizumab. The earliest of the three US patents, US7479543, expires in July 2013 which includes an extension under 35 U.S.C. 154(b). Patents in European territories and Australia share the same expiry of April 2012. Like the first KPI family, an application for extension has been filed in Great Britain and also in Spain which, if granted, would extend the expiry of EP0628639 in these territories until July 2017. As the patentee of this second family is different to that of the first identified key patent family, the EU SPC law does not preclude the grant of multiple SPCs in one territory. SPC applications in respect to other countries should therefore be expected in the future, further extending patent protection across this patent family if granted. In addition, an s156 extension of term of up to 5 years may be expected of the US patent once the FDA approval is granted.

Patents of the third family, based on WO9611020, claim the use of an IL6r antibody composition for the treatment of rheumatoid arthritis and suppression of synovial cell growth with expiry dates in June 2015 for European territories and Australia, and in April 2017 for the US. If granted with the current claims, the European patent may also be the subject of SPC applications which block generic competition until 2020 (the prior grant of an SPC in the same country to the same applicant for the same marketing authorisation precludes a later SPC from being granted, but it has been known for a patentee to transfer ownership of the patent to a third related party for the purposes of allowing a second SPC to be granted). However, the IP file history (accessible via a direct link from the Pipeline Selector Report) shows that observations have already filed by a third party objecting to the grant of the patent, and the filing of a divisional will likely delay the outcome even longer. In the US the patentee may select this patent for s156 extension of the product which would extend expiry to the later of 14 years from FDA approval or 5 years from the normal patent expiry date, however it is possible that the patent is considered by the patentee to be too 'weak' and susceptible to challenge to rely on it for the additional patent term. Only time and careful monitoring of this patent family will assist in determining the expiry of patent protection for the Tocilizumab products. Table 2: Tocilizumab Key Patent Indicator

Depending on the outcome of the patent situation above, Data Exclusivity may provide even greater protection for the RoActemra and Actemra products. Given that Europe's recent marketing authorisation was based on an application filed on 29 November 2007, the minimum period of 8 years data exclusivity would protect Tocilizumab from filing of generic applications until early 2017 in the EU, but additional marketing exclusivity will extend protection for an additional 2 years until January 2019 (with an extra year available where the product is approved for an additional indication of significant clinical benefit) meaning, for European countries, expiry of the third key patent family (with an SPC extension) and expiry of marketing exclusivity could be around the same time in

2020. If, however, the innovator is able to exploit the European 8+2+1 rule for data exclusivity, by providing research evidence of additional indications for Tocilizumab or paediatric studies, then data exclusivity may become the more powerful form of protection preventing generic launch in Europe until January 2021. The impact of US data exclusivity on the marketing of generic Tocilizumab products is even greater. Just this month a US senate committee on Health, Education, Labor and Pensions approved a 12-year data exclusivity clause for biologic drugs despite other parties, including the president, pushing for only 7 years. Although the senate committee recommendation still requires approval by the full senate and House it is still of great concern to generics companies attempting to enter the US market with follow-on biologics. Pending the final political decision and the patent extension strategy of the patentee in the US, it is possible that the effect of the data exclusivity will mean that generic versions are not available for launch until well after the loss of patent protection in the US. This emphasises an important point that the generics industry has been arguing in the US, that extended data exclusivity for biologics may easily extended the monopoly period beyond patent protection. The number of different expiry dates produced by patent protection and data exclusivity surrounding Tocilizumab demonstrates the complexity in bringing a generic product to market at the earliest possible time. In turn, this further highlights the need for up-to-date information. The Patent Risk Analysis section, based on comprehensive patent data (details of which is accessible in the corresponding Pipeline Developer subscription) indicates that the patenting area of greatest activity for this therapeutic is related to use, with over one-third of the total patent families falling into this category (Figure 1). This is perhaps not surprising as innovator companies are possibly trying to find new uses for this class of product which, as mentioned above, could extend data exclusivity or block other companies from potential markets in the future. Interestingly a great deal of patenting can be found in the molecular form category, suggesting that certain aspects of the physical API other than the chemical structure are protected. Figure 1: Tocilizumab Patent Filing Trends

Innovator company Chugai tops the Top Patent Applicants chart (Figure 2), filing 37% of patents relevant to Tocilizumab, more than three times the number of the second largest filing company Genentech. In fact at least two-thirds, possibly more, of all patents filed relating to Tocilizumab has been done so by innovator companies. This is likely to be due to the large number molecules belonging to this class of compound being developed by many companies, with some cross over into each others products. Figure 2: Tocilizumab Top Patent Applicants Analysis

In conclusion, at this very early stage in the patent landscape of Tocilizumab is dominated by Chugai and Roche. This is confirmed by the absence, so far, of any major generics company in the above information. As time progresses the lifecycle management of Tocilizumab products by the innovator companies will affect and be affected by steps generics companies take now. The uncertain nature of data exclusivity and approval legislation and regulation surrounding follow-on biologics may cause generics companies to hesitate when deciding whether to invest valuable resources in the development of Tocilizumab products. Given these uncertainties it is even more essential to intimately understand the patent landscape of a future generic product, very early in the lifecycle of the innovator product, to ensure that a suitable

IP strategy is adopted and to avoid being locked out of potential blockbuster markets by fellow generic competitors. For those generics companies with follow-on biologics capabilities this is a great opportunity to start the development of Tocilizumab in your generics Pipeline, and with professionally searched and easily accessible GenericsWebs Patent products, the process is made easier for you. Comprehensive data for patent families relating to Tocilizumab and other many other drugs, including biological drugs, 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. GenericsWeb Pipeline Selector reports are also available in 'Core' and 'Extended' formats for any active ingredient upon request. For questions and comments about this article please contact the author at s.robinson@genericsweb.com
Stuart Robinson Patent Analyst GenericsWeb July 2009 s.robinson@genericsweb.com

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