|
Ke Wang joined GenericsWeb in January 2008 as a patent searcher and analyst. Ke studied biochemistry and biotechnology, and since graduating from university has worked in the biopharmaceutical industry as a therapeutic protein purification technologist. Ke now utilises his knowledge and technical experience in the pharmaceutical industry to provide comprehensive and reliable patent information to GenericsWeb clients. |
 |
Drug In Focus: Gemcitabine
Gemcitabine (Gemzar®) is an anti-tumour nucleoside analogue used for the treatment of a range of cancers including ovarian cancer, non-small cell lung cancer, breast cancer and pancreatic cancer. It is Eli Lilly's third best selling drug of 2007 with global sales of over US$1.59 billion. As patent protection in some major territories is going to expire in early 2009, launching a generic version of Gemcitabine will be of great interest to generic pharmaceutical manufacturers worldwide.
Based on information contained in GenericsWeb's Pipeline Selector report for Gemcitabine, this month’s "Drug In Focus" analyses the patent landscape surrounding the Gemzar® product with a view to launching generic equivalents.
Table 1: Gemcitabine General Information
According to Table 1, Gemcitabine is available as an injectable powder formulation with Gemcitabine hydrochloride salt being the active ingredient.
As seen in the Gemcitabine Key Patent Indicator (Table 2), full 5-year patent term extensions have been granted to the active ingredient patents in major territories including Great Britain, Germany and Australia, and these will expire in early 2009. In the U.S, an extension of 1537 days was awarded as well as Paediatric Exclusivity, delaying expiration until November 2010. The Canadian patent covering the active ingredient has already expired due to the absence of a patent extension scheme. It is worthwhile noting that as well as designating the European patent application to Great Britain, Lilly also filed two separate patent applications in the UK. The two UK patents were revoked in 1989 the reason being that the European and UK patents granted to Lilly claim the same invention and have the same priority date. Based on the UK Patent Act 1977 s73(2), the comptroller may revoke the UK patents in this circumstance. Nevertheless, this “double patenting strategy” is an important effort Lilly has made to ensure that it obtained patent protection for Gemzar® in key markets, as the decision to grant protection comes from entirely different patent examination bodies.
Table 2: Gemcitabine Key Patent Indicator
Beside the active ingredient patent protection, there is a second patent family identified in the Key Patent Indicator that specifically protects all of the approved indications for Gemcitabine, suggesting that Eli Lilly has made some attempt to extend the lifecycle of this product by protecting more than one element of the authorised product. The patents in this family claim a method of treating susceptible neoplasms using Gemcitabine. Although the claimed coverage is relatively broad, the patent was still granted in major territories. However the fact that the equivalent patents in Australia, Germany and the UK expired before the corresponding extensions on the molecule patent meant that the protection afforded in these countries was not of any real value to Lilly. Interestingly, should Lilly have chosen to file for SPC on patents in this later family in Europe, they would have likely benefited from monopoly protection until March 2010 – an additional 12 months, based on the first EU marketing authorisation date and the 5 year extension limitation (Table 3). Similarly, the Australian protection would have extended until August 2010 if the later patents had been subject to S70 extensions (multiple extensions on single products are commonplace in Australia). One likely explanation for Lilly's choice could be that the broad coverage of claims make this patent more vulnerable to invalidation than the molecule patent in future infringement litigations. Therefore Lilly has filed SPC for the molecule patent, which is very unlikely to be invalidated and more reliably ensure extended protection until the granted SPC expires.
This later family did prevent generic competition in Canada until 2007, and an equivalent patent in the US remains in force until November 2012 (due to differing patent term calculations in the US) followed by six months of market exclusivity, providing it is upheld during separate litigations between the Eli Lilly and both Mayne Pharma (US) and Sun. GenericsWeb will continue to monitor the litigation surrounding this molecule.
Table 3: First Marketing Authorisation Dates
Table 4: Marketing Authorisation Holders
According to the First Marketing Authorisation Dates (Table 3) and Marketing Authorisation Holders (Table 4), data exclusivity has expired in all major countries. However, in the U.S this product was also granted exclusivity for use in combination of Carboplatin, exclusivity for additional clinical studies and paediatric exclusivity. Paediatric exclusivity will further extend protection by six months after the key patents expire in the U.S.
Regulatory agencies have already started to receive and approve applications for marketing generic Gemcitabine in many countries. News articles in the Pipeline Selector report identify that generic manufacturers such as Hospira, Sun and Teva have already obtained tentative approval of generic Gemzar® from the US-FDA. Also according to the Marketing Authorisation Holders section (Table 4), a number of companies such as Sandoz, Hospira and Novopharm have obtained marketing approval in Australia, Canada and/or Great Britain. Except in Canada where generic Gemcitabine are on the market already, these companies will have to wait until the expiry (or invalidation) of the key patents before they start to sell their products and therefore do not currently pose threat to Lilly's market share.
FDA Orange Book listed patents (amongst other methods) have been used to identify families to be included in the Key Patent Indicator. However, Figure 1 shows that a number of patents covering different developmental stages of Gemcitabine have also been filed, and these are not included in the Orange Book for many reasons. For example, patent families relating to processes of preparing Gemcitabine account for approximately 45% of total patents identified. Furthermore, it can also be seen that, although no formulation patent is listed in the Orange Book, over 35% of the total patents filed in relation to this molecule relate to formulations.
Figure 1: Patent Category Distribution
Figure 2 shows that prior to launch of the Gemzar product worldwide in the mid-90’s, most of the patent filing activity related to active ingredient manufacture, with very little focus on patent protection that has been effectively used by others to protect a brand product from generic competition – Molecular Form, Formulation and Use. Having said that the increasingly strong filing activity in relation to process and formulation patents is likely to be a sign of problematic development by some generics developers, who seek to protect their work-arounds for previously filed patents. The small effort made by Lilly towards protecting formulations of Gemcitabine prior to launch may have resulted in some significant patent protection. However, it could also be a sign of generic competitors seeking to improve the current marketed product in some form for the benefit of the patient or physician.
Figure 2: Patent Filing Trends
Regardless of the original intent of the filer, because these patent applications are made by innovators and generics companies alike, it is clear that caution should be exercised in determining the right to use generic versions of Gemzar by using the Orange Book alone. Although GenericsWeb recognises that identification of key patents is a good starting point for IP due diligence in relation to a generic development, it should never be the end point. Each of the patents identified in a comprehensive patent search should be investigated for relevance. 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 Eli Lilly has undertaken a small amount of effective lifecycle management in regards to Gemcitabine and has succeeded in laying down a number of constraints for generic competitors to overcome in addition to the active ingredient patent, particularly in the US. However, they appeared to have made a significant strategic oversight in Europe and Australia in regards to filing for extensions on the latter indication patents, a practice which is commonly seen with other innovator companies. What little patent protection that was laid down by Lilly prior to launch seems to have created some problems for less proactive generic manufacturers, but with many waiting in the wings to launch pre-approved generic versions, it is likely that this molecule will meet with a great deal of generic competition upon expiry (or revocation) of the remaining key patent protection in the near future.
Comprehensive data for patent families relating to Gemcitabine, 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 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