Novartis’ Gleevec Patent Challenged in the US?

“US drugs regulator food and drug administration (FDA) has accepted a generic challenge by India’s Sun Pharmaceuticals Industries Ltd against Glivec, a controversial mega-earner cancer drug of Novartis AG, potentially weakening the Swiss drug maker’s petition against an Indian ruling denying the drug a patent.

The challenge in the US, if it invalidates Novartis’ patent, will not only significantly stre-ngthen the plea of local drug makers here, but also open up a huge generics market for them in the US for this drug, which, last year, grossed some $2.5 billion (Rs11,605 crore then), equivalent to more than one-10th of Novartis’ revenues. Novartis’ patent on Glivec was challenged by Sun Pharma through what is called a Para IV filing with FDA.

The filing initiates a process with which a generics firm can seek marketing approval for an already patented product either by invalidating the patent, by proving there is fundamentally nothing novel in the product or by proposing to introduce a variant without infringing the patent. The appeal was listed early this month by FDA after a six-month surveillance by the regulator. Under the rules, Novartis is expected to respond to this challenge within 45 days of the date of listing.

At least two drug industry insiders confirmed the Sun Pharma challenge and the FDA listing. The filing is likely aimed at invalidating the existing patent as the Mumbai drug maker has found gaps in Novartis’ patent. An email sent to Novartis’ media relations office at Basel on Wednesday did not elicit any response and an India spokesperson said she was not authorized to comment. In 2006, the Chennai patent office refused Novartis’ claim on the ground that it is not an innovation.

An invalidation of the Glivec patent, if it happens through Sun Pharma’s Para IV filing, will help strengthen local drug makers’ claims against Novartis in India. “This very disclosure in the US will make Novartis’ appeal against the Chennai patent office’s decision to reject its patent application unacceptable,” said Gopakumar Nair, a patent expert in Mumbai.

Shamnad Basheer, an associate at Oxford IP Research Center, UK, echoed this view. “If the US, which is comparatively liberal in granting patents, invalidates the Glivec patent, it will look ridiculous for any (of the) patent court(s) in the world, which are (usually) more cautious, to grant a patent for this drug,” he said in a telephone interview. Novartis has challenged the Indian patent office’s decision to turn down its patent application through an appeal filed early in 2006 in the Madras high court.

The case has since shifted to the Intellectual Property Appellate Board, or IPAB, which hears such disputes in the country. In 2006, the Chennai patent office refused Novartis’ patent claim for Glivec—which is a beta crystal or polymorphic form of the known cancer drug Imatinib Mesylate—on the ground that it is not an innovation and the Indian patent law does not identify this as patentable.

One of the newly amended provisions in the Indian patent law, Section 3D, specifies that no derivatives or modified forms of known drug substances are patentable unless it enhances the therapeutic efficacy substantially. Following the refusal of its patent application in India on this ground, Novartis challenged this provision of the Indian law, saying the rule is not compliant to World Trade Organization’s globally accepted patent law.

This challenge was rejected by the Madras high court early this year. Rajeev Nannapaneni, chief executive of Hyderabad-based Natco Pharma Ltd, which is one of the corporate opponents in Novartis’ patent dispute at IPAB, said: “The US patent challenge gives us a most important message that the Glivec patent has been questioned not only in India, but elsewhere also.”

Meanwhile, Sun Pharma and Natco Pharma have also filed drug master files or DMFs with FDA for off-patent or generic versions of Glivec. Filing a DMF sets off the process for generic drug firms to get their products registered in the US pharmaceuticals market.

A Sun Pharma spokesman confirmed that the company has filed DMFs for six drugs in the US in April-June 2006, and one of them is the polymorph of imatinib, but declined further details on the Para IV filings.

I’m not sure when Sun filed its ANDA and para IV (if indeed it did file a Para IV). Some sources suggest that this was filed as far back as 2006. Though, it is likely that the 2006 filing was only a DMF (drug master file)–a filing that normally predates an ANDA filing.

If the para IV filing was in 2006, then the 45 day window that the patentee has (to sue the ANDA filer) has clearly passed. Under the Hatch Waxman Act, the mere filing of an ANDA under para IV is deemed to constitute a “patent infringement”. And the patent owner gets 45 days to sue. If it sues within this window, then the FDA automatically stays the ANDA application (i.e. the application by Sun claiming that it is bio-equivalent and therefore ought to be approved as a generic version of Gleevec) for 30 months.

If this is indeed a Para IV filing and Novartis hasn’t filed a law suit within 45 days, then clearly Sun’s application to be approved as a generic will proceed and most likely be granted by the FDA. In which case, will Sun be bold enough to introduce its generic version into the market and risk being sued by Novartis (and be held liable for damages)?

In order to avoid this uncertainty, Sun ought to file a declaratory suit, asking the court to hold that the patent is invalid or that it is not infringing. Chances of a declaratory suit being admitted are much stronger after the US Supreme Court decision in Medimmune.

It also needs to be noted that there are several patents protecting Gleevec:

1. The original patent covering the Imatinib free base (filed around 1993)
2. The patent covering the beta crystalline version of Imatinib Mesylate (filed around 1997 or so)

Even assuming Sun has actually challenged these patents, it is not likely to win against the basic patent (’93 one). Which means that Sun cannot enter the market with a product prior to the expiration of this basic patent (till 2013 or the date when the patent term extension expires). Rather, it’s likely win will be against the ’97 patent. In which case, it can enter the market as soon as the first basic patent expires. It will also obtain a 6 month exclusivity after its first entry into the market.

(Readers will be interested to know that Sun Pharma recently won a shared 180 exclusivity period in relation to Novartis’ Trileptal ( a drug for epilepsy).

Another possibility is that Sun is not actually challenging the ’97 patent (as being invalid) but is only claiming that it’s particular drug does not infringe this patent. As we stated in one of our earlier posts, the ’97 patent covers only one polymorphic form i.e the beta crystalline form. Therefore generics can enter with other forms, such as the alpha crystalline form. And published patent data from India show that Hetero has pending patent applications for some other forms (alpha as well as some amorphous forms).

The last possibility of course is what is stated in the news item. i.e. that 45 days haven’t passed as yet and Novartis may end up suing Sun Pharma within this time frame!

Without Sun or Novartis issuing a statement, we are all shooting in the dark. And to make matters worse, the FDA keeps such information confidential. SpicyIP is very interested in hearing from readers who know more intricate details about this case (nb: the confidentiality of sources will be maintained at all costs..)