The General Information (Table 1) shows that Pantoprazole is available as sodium (including sesquihydrate) and magnesium salts in dosage forms powder for injectable solution, enteric coated tablets and an oral suspension. It is indicated for the treatment of various acid reflux diseases such as duodenal and benign gastric ulcers and also for the prevention of gastroduodenal ulcers induced by non-selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).
Table 2: Pantoprazole Key Patent Indicator
Eight patent families have been identified by the Key Patent Indicator (KPI, Table 2) as being key in preventing generic versions from entering the market. Such families are identified as “key” by at least one equivalent being US Orange-Book or Health Canada listed, being the subject of a patent term extension or being associated with some form of litigation. Patents in the identified families for Pantoprazole protect the compound per se, oral and injectable formulations, therapeutic uses, and combinations.
The patent members in the first Key Patent family, which protects the Pantoprazole active ingredient, have been extended in Australia, delaying expiry until January this year. In the US, a full 5-year extension has been granted by the USPTO and, together with a 6-month paediatric extension, extends expiry of the US equivalent to 19/01/2011. Supplementary Protection Certificates (SPC) were granted in Germany, France and Great Britain and all expired in May last year. The corresponding Canadian patent expired in 2006 due to a lack of patent extension scheme in Canada.
The fourth and the eighth Key Patent families, both licenced from Byk Gulden by Wyeth, protect the marketed Pantoprazole enteric coated tablets and the oral suspension forms respectively. US 5997903, specifically claims an enteric coated tablet and protects the marketed PROTONIX® oral delayed release tablets. This patent is also subject to a 6-month paediatric extension and will expire 07/06/2017. Applications for extension have not been identified in any other monitored territories hence the corresponding patents will expire in 2012. The fact that there are already some generic equivalents of PROTONIX® on the market in countries where the patents in this family is still in force, suggests that the scope of protection is not sufficiently broad to prevent generic competitors from circumventing the claims with an alternative formulation. The eighth family claims a multiparticulate formulation to specifically protect the marketed oral suspension product. At present 3 patent applications have been granted in the US, and with paediatric extensions they are expected to expire in 2025-2026. Equivalents in Europe have not yet been granted, but will offer protection of suspension formulation until 2024 or 2026 if not successfully litigated.
Wyeth has also filed patents in the seventh family to defend its Pantoprazole injectable product PROTONIX IV®. Patents in this family have been granted by the respective patent offices around the world, all expiring on 17/11/2021, except in the US where the patents also have the benefit of 6-month paediatric extension.
Patents in the third KPI patent family claim the use of Pantoprazole in the manufacture of oral formulations for combating Helicobacter bacteria and are still in force in several European countries and Canada, where CA2092694 is (allegedly incorrectly) listed on the patent register. An equivalent application has not been published in the US, however the chance that one exists cannot be ruled out as many unpublished applications are still pending at the USPTO. Aside from its tactical use in patent linkage, this family has very limited effect in blocking generic entries, since it does not appear to protect any approved indication.
A patent family claiming the combination of a Helicobacter-inhibiting anti-microbial agent and Pantoprazole has also been identified in the KPI. SmithKline Beecham has rejected an application for an SPC based on the German equivalent, but this family is unlikely to impact generic entry. However, a Pantoprazole magnesium salt patent has been granted an SPC in Germany extending protection by approximately 9 months to 10/05/2020. In Germany and Canada Nycomed has registered several enteric coated tablet products with Pantoprazole magnesium salt as the active ingredient. However, based on the EU regulation governing SPCs and the associated explanatory memorandum, this SPC should not have been granted since there is already an SPC granted for this INN, EP0166287 in the molecule patent. The information shows that the basic patent upon which this second certificate is based, EP 1105386, has lapsed in Germany and therefore the associated certificate will also lapse.
The Pipeline Selector data also shows that data exclusivity has expired in all major territories except in the US, where exclusivity will prevent generic products from including the paediatric indication until 12/05/2013.
Table 3: Marketing Authorisation Holders
It seems that Pantoprazole is firmly protected by the patent landscape laid by the innovator, especially on the formulation side as each marketed dosage form is specifically claimed in one or more patents. However, as mentioned above according to the Marketing Authorisation Section of the Pipeline Selector report (Table 3), current authorisations are held by a number of generic players such as Teva, Sun and Sandoz in territories including the US, Canada, Great Britain and Australia. Many of these authorisations were obtained well before the expiry of the above identified key formulation patents, suggesting that the patent protection is not as robust as the innovator’s expected.
During the period of 2004-2006, Altana (now owned by Nycomed) and Wyeth filed suits in the District Court of New Jersey against Teva, Kudco and Sun following the defendants’ ANDA with paragraph IV certifications to manufacture generic versions of PROTONIX® and PROTONIX IV®. The innovator’s alleged that the molecule patent, US4758579, was infringed. Nycomed and Wyeth also filed a motion for a preliminary injunction against Teva which was dismissed by the District Court (now upheld in the Federal Circuit). In August 2007, Teva’s ANDA was granted by the FDA and on 24/12/2007, roughly 3 months after the motion for preliminary injunction was dismissed, Teva launched-at-risk its generic product. Surprisingly, only 3 days later, Teva announced that it could not continue selling the product, without giving an explanation. Interestingly, Nycomed and Wyeth did not assert their specific oral formulation patent, US 5997903 in the suit. This patent has a relatively narrow scope of protection and relatively easy to circumvent because it specifically claims the structure of the tablet and the binder used in the tablet (polyvinylpyrrolidone and/or hydroxypropylmethyl-cellulose). Presumably Teva & Sun's formulations have successfully circumvented this patent and the innovators have to rely on the molecule patent to keep generic products off the US market. This suit still has a decision pending. The injectable formulation patent, US6780881 has also been under fire from generic companies including Teva, Apotex and Sandoz which have alleged invalidity and/or non-infringement in their paragraph IV filings. Subsequently, infringement suits have been started against these companies.
Due to a lack of patent extension scheme in Canada the molecule patent expired in 2006. Filing of generic applications has triggered a number of lawsuits in Canada between the innovators and generic companies such as Apotex, Cobalt and Pharmascience. Many Canadian patents in key patent families are still in force and have been asserted by the innovators in their legal battle against generic filers. Pipeline Selector reports will include the outcome of any relevant legal challenges in these countries in a timely fashion.
Figure 1: Patent Category Distribution
Since the innovators have done a fair amount of work in laying down patent barriers to protect their marketed formulations, generic competitors should also consider circumventing the patents using non-infringing bioequivalent formulations in addition to challenging the patents in the courts. According to the Patent Category Distribution chart (Figure 1), based on comprehensive patent searching found in the Pantoprazole Pipeline Developer report, more than half of all patent families have been filed in relation to various formulations of Pantoprazole. These patents are highly likely to pose a significant risk to the generic companies when circumventing innovator formulation patents. In addition, process patents account for nearly a quarter of all patent families identified. This suggests that synthesising, or even finding a source of non-infringing API to use in the formulation may also be problematic. It is therefore in the best interests of any generic company wishing to develop generic versions of any Pantoprazole products to be fully informed of the existence of these patents and consider them with appropriate strategies.
Figure 2: Top Patent Applicants
According to the Top Patent Applicants graph (Figure 2) the innovators have filed only 15% of all patent families identified. The diversity in patent applicants is due to patents broadly claiming “proton pump inhibitors” which should also be considered relevant to Pantoprazole.
In conclusion, the innovators of Pantoprazole have spent a considerable amount of resources undertaking life cycle management using patent protection. However, it appears that the outcome of such effort is not very successful, as suggested by generic approvals and legal challenges in the US and Canada. In the US, the oral suspension is the only marketed formulation left unchallenged by any generic companies and therefore it could be worthwhile for a proactive generic player to file another ANDA with paragraph IV certification to challenge the oral suspension patents since the 180-day exclusivity for this product appears to be still available. It is expected that a surge in generic activity will be observed in the US once the molecule patent expires in 10 month's time. In several European countries, the molecule patent has already expired meaning that the most effective barrier to generic launch is removed and generic companies are in a much better position to launch with lower risks. It is advised that the patent landscape around Pantoprazole be comprehensively assessed by interested generic companies to avoid costly litigations, 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 Pantoprazole, 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 me at ke.wang@genericsweb.com.
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