DAF-K Award Winning Essay

Imatinib mesilate – the controversy surrounding it
Dr. Ananya Datta
Postgraduate Trainee – Department of Pharmacology
Institute of Postgraduate Medical Education & Research (IPGME&R)
244B Acharya J. C. Bose Road, Kolkata – 700020


Introduction
Imatinib mesilate is an anticancer medicine with a novel mode of action that is indicated in chronic myeloid leukemia and acute lymphoblastic leukemia, two of the most prevalent forms of blood cancer, and in certain other malignancies such as gastrointestinal stromal tumors and dermatofibrosarcoma protuberans. It is a potent and specific inhibitor of the enzyme tyrosine kinase which is involved in malignant proliferation of tumor cells in many cancers. In chronic myeloid leukemia it is recommended as first-line treatment if the cancer is Philadelphia chromosome positive and also offers the possibility of rescuing patients who have failed previous chemotherapy. The drug is given orally and lacks the typical adverse drug reactions of cytotoxic anticancer drugs. Imatinib is the first drug in its class to be licensed for use and has possibly brought about a major therapeutic advance in the treatment of malignancies because of its novel mode of action. Treatment with the drug may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

The controversy
Imatinib is produced and marketed internationally by the Swiss multinational pharmaceutical manufacturer Novartis. Novartis markets imatinib worldwide with the brand name GLEEVEC in the United States of America (US) and GLIVEC outside of the US. In India, Novartis’ product costs approximately Rs. 1,20,000 (US$ 3000) per patient per month. Various Indian manufacturers, such as Cipla, Hetero and Ranbaxy, have commenced manufacture of imatinib and generic versions of the drug are priced at about Rs. 8,000 (US$ 200) per patient per month in the Indian market. Such a huge difference in cost of a potentially life-saving drug, the treatment with which has to be continued indefinitely, is a matter of grave concern and obviously, the innovator brand would be unaffordable and therefore inaccessible to the majority of Indian patients.

The compound imatinib mesilate – in its alpha and beta crystalline forms as well as the amorphous substance – has been known since prior to 1995 and its use for treatment of blood cancer was approved by the Food & Drug Administration (FDA) in the US in 2001. Separate patents covering the original compound (which would also include all its forms) were claimed and granted in several countries during 1992-1995 but were not claimed by Novartis in India, probably because under the Indian Patent Act of 1970, only process patents were allowed.

In 1998, Novartis filed an application in the Chennai Patent Office for a patent on imatinib mesilate (GLIVEC). At that time, India still did not grant patents on pharmaceutical products, but in November 2003, Novartis was able to obtain exclusive marketing rights (EMR) on GLIVEC for a period of five years, based on a temporary provision of the Patent Act which was undergoing amendments to comply with the requirements of the Trade-Related Aspects of Intellectual Property (TRIPS) agreement to which India was a signatory. The granting of EMR was a TRIPS obligation for countries like India, which did not grant patents for pharmaceutical products before 2005. The EMR operated like a patent monopoly, preventing seven of nine Indian pharmaceutical companies from producing affordable generic versions of imatinib mesilate. They were forced to withdraw the production and sale of generic versions of the drug in India and other developing countries.

In 2005, India made its patent law fully TRIPS-compliant and Novartis’ patent application on GLIVEC came up for examination by the Chennai Patent Office. The Indian Patent Act allows for any person or group to oppose a patent application before it is granted. When Novartis restrained Indian companies from marketing generic versions of GLIVEC, the Cancer Patients Aid Association (CPAA) filed a pre-grant opposition on behalf of cancer patients in the Chennai Patent Office. In addition to the fact that CPAA, who were purchasing generic versions of the drug, found it very difficult to support treatment of its patients due to the high cost and limited availability of GLIVEC, there was also a technical ground for CPAA’s opposition in that Novartis was attempting to patent a particular form (beta crystalline form) of imatinib mesilate which is not a novel drug that satisfies patentability standards.

In January 2006, the Chennai Patent Office rejected Novartis’ patent application on the ground that the application pertained only to a ‘new form of a known substance’. This decision brought relief to numerous cancer patients as it not only prevented a patent monopoly till 2018, but also automatically cancelled the EMR.

Background to the controversy
Many decades ago, India took the conscious decision to restrict monopoly rights in the field of pharmaceuticals by recognizing only 'process patents'. Under the Patent Act of 1970, product patents were not recognized and pharmaceutical companies were free to devise a non-infringing process of manufacturing a drug even if the same was protected by a process patent in India. This situation changed when India agreed to switch over to the product patent regime by becoming a member of the World Trade Organization (WTO) which worked out the TRIPS agreement. This required every member country to provide product patent protection for pharmaceuticals. Though India became a member of the WTO in 1995, as a developing nation, it was given a 10-year transition period to fulfil the obligations of TRIPS by amending its patent law to effect the change from process patents to product patents regime, along with a 20-year patentability period.

While this is accepted, debate pertains to the standard of patentability under the amended Indian Patent Act. TRIPS, as a minimum standards agreement, requires WTO members to grant patents for inventions in all fields of technology for a period of 20 years if they satisfy the universally accepted criteria of patentability. The first notable external interference with the Indian patent law came when the US and European Union filed a complaint against India before the WTO dispute settlement panel alleging that it had not complied with its obligations under TRIPS. That case was decided against India and the Patent Act had to be amended to introduce provisions for accepting patent applications through an advance 'mailbox' arrangement (to be opened and examined in 2005) and for granting an interim patent-like monopoly right, termed EMR, in certain cases, pending consideration of the patent application.

The time that Novartis chose to enter India with GLIVEC was a period in which such changes were being made to the Indian law. As soon as the law changed, Novartis filed a patent application for the beta crystalline form of imatinib mesilate (GLIVEC) in 1998. Imatinib as a free base molecule was invented by Novartis in 1992 and patented in the US and other countries in 1993. Novartis however chose not to apply for a patent for the imatinib free base in India then [It is pertinent to note that the 1993 US patent of imatinib disclosed the salt imatinib mesilate]. When it applied for the beta crystalline form of imatinib mesilate in 1998, the Chennai Patent Office ruled that it is a new form of a known substance and therefore not patentable under Section 3(d) of the Indian Patent Act which states that patents will not be granted for "the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance." Knowing fully well about this requirement of the Indian law, Novartis tried to demonstrate that there was indeed enhancement of efficacy and submitted data indicating enhanced bioavailability of 30% in studies conducted on rats. Bioavailability is one of the key parameters that decide how much of a drug would be available at its site of action in the body but there is no clear-cut or universally applicable criteria to judge to what extent alteration of bioavailability affects the efficacy of a drug. Further, results from animal studies cannot be directly extrapolated to human beings. Novartis did not demonstrate how 30% increase in bioavailability in rats could make a difference to efficacy in humans when compared to known efficacy. Therefore, the Patent Controller rejected this submission and held that Novartis had failed to demonstrate the enhancement in efficacy as required under the Act

Subsequent turn of events and portends for the future
On 17 May 2006, Novartis filed two sets of cases in the Chennai High Court – the first challenged the order of the Chennai Patent Office, which had rejected the GLIVEC patent application, following a pre-grant opposition by the Cancer Patients Aid Association. The second challenged the constitutionality of Section 3(d) of the 2005 Indian Patent Act that was specifically introduced by the Indian parliament as a safeguard against the misuse of the product patent regime. Novartis in its petition claimed that the section is not in compliance with the TRIPS Agreement and hence should be declared unconstitutional.

Section 3(d) of the Indian Patent Law is an important public health safeguard aimed at preventing pharmaceutical companies from obtaining patents on trivial improvements or new medical uses of known molecules. The law does not consider such innovations as inventions, unless an enhancement in efficacy is proven. This does not violate the TRIPS agreement, since TRIPS does not define what an invention is and allows WTO member countries to freely determine the appropriate method of implementing the provisions (Article 1) of TRIPS. Indeed the Doha Declaration requires that the TRIPS agreement is implemented in such a manner that it allows for measures to ensure access to medicines for all. Section 3(d) is an example of such a provision, incorporated in India law.

Novartis’ petition before the court challenging the constitutional propriety of Section 3(d) of the Indian Patent Act, on the grounds that its provisions were vague and arbitrary, is actually a contradictory stand since the company had tried its best to plead its case on the lines of Section 3(d) before the Patent Controller. On August 6, 2007, the Chennai High Court dismissed the challenge to Section 3(d) of the Act, but it directed the transfer of the other batch of writ petitions, requesting quashing of the Controller’s order, as a statutory appeal to the Intellectual Property Appellate Board (IPAB), by now constituted as an appeal mechanism under the Patent Act. The court did not rule on whether 3(d) is compliant with TRIPS, declaring that this issue is within the jurisdiction of the WTO rather than the court.

Unfortunately, Novartis’ claim that its actions in India will not hinder the supply of medicines to the poor is invalid since it is obvious that the direct consequence of Novartis’ action of challenging section 3(d) of the Indian Patent Act 2005, if it were successful, would have led to removal of a key safeguard designed to deny frivolous patents and would have effectively restricted Indian companies from continuing to supply generic essential medicines at affordable cost. Indeed, the impact would stretch far beyond the realm of cancer and GLIVEC, and negatively affect accessibility and affordability of many essential medicines, including crucial antiretroviral drugs for HIV/AIDS patients.

Broader implications of the controversy and fresh challenges
The story of the breakthrough anticancer drug GLIVEC in India, centering on patent applications by the innovator Novartis during a period of radical transition for India's patent laws, is complex and forces a critical look at certain vital issues of global importance.

The recent Indian court ruling is not simply about infringing on a patent, as with compulsory licensing of antiretroviral drugs in Thailand, but rather expounds the judicial view that the pharmaceutical industry must be content to earn profits only on its initial patents on an active ingredient (the original innovation) and that the industry will not get renewed patent protection for subsequent small improvements (incremental innovation) in India unlike in the US. Incremental innovation is always a grey area since what constitutes significant improvement is always open to debate. But it is wrong to assume, as Novartis or its supporters would like us to believe, that Section 3(d) stifles innovation. What it actually does is to add the responsibility of demonstrating significant improvement of efficacy in order to qualify for renewed protection. It will not choke genuine improvements but will bar frivolous 'tweaking' which are then sought to be protected under the garb of incremental innovation. Indeed, Section 3(d) is a trendsetting provision, since such a check on frivolous patenting is not to be found in the patent legislation of any country and has been hailed as a model for the world.

Imatinib was an original invention, the Indian patent office reasoned, when Novartis patented it in the US and other countries in 1993. However, that date of discovery was two years before the 1995 date when drugs became eligible for patent protection in India. Imatinib mesilate was viewed as an incremental innovation for which Novartis was unable to substantiate significant enhancement of efficacy in its 1998. Novartis took a calculated risk of not applying for an Indian patent in 1993 and did so when the law changed to permit product patents. Having taken this route, which proved a risky one, it is not proper to denigrate Indian law because it could not achieve what it wanted. Further it is unfair to prod Indian courts to use WTO’s rules to strike down laws enacted by India's parliament.

TRIPS requires that patentable inventions be new and involve an ‘inventive step’. Novartis contends that TRIPS gives WTO members the option of providing patent rights more generous than these basic criteria would mandate but does not allow members to go in the opposite direction by implementing stricter requirements for obtaining a patent. However, TRIPS does not define an ‘inventive step’; it permits (but does not require) WTO members to equate this criterion with the ‘non-obviousness’ requirement of US patent law and thus gives member countries the flexibility to fine-tune their inventive-step criteria in consonance with their socioeconomic conditions. Section 3(d) of India's patent law does not necessarily impose stricter requirements than are used elsewhere; it suggests a general presumption of nonpatentability for modifications of known chemical compositions and shifts the burden of rebutting this presumption in each particular case to the patent applicant.

The irony is that while Novartis waged its legal battle to try to coax India towards the US stand on incremental innovation, the American view of the patent system was shifting closer to India's. Even the former president of Switzerland, Novartis' own country, who had chaired an Intellectual Property Commission for the World Health Organization (WHO), saw the drug company's moves as an attempt to prevent India and the developing world from using the flexibility on patents provided by international agreements.

The original Indian Patent Act of 1970 has had a far-reaching impact on India’s economy. Since it did not allow product patents on medicines, by producing cheaper generic versions of drugs that were patented in other countries, India became a key source of affordable essential medicines. From a country which had no worthwhile pharmaceutical industry to speak of at the time of independence, it is now the base of a world-class generics industry that is supplying medicines at affordable cost to a large number of developing as well as developed countries and has emerged as the ‘pharmacy of the world’s poor’. It is now the country with the maximum number of US FDA (this is arguably the most stringent drug regulatory authority in the world today) standards compliant manufacturing facilities outside of the US. The Indian government now supports the expanded availability of patent protection as a catalyst that may enable India's pharmaceutical industry to evolve from reverse engineering to innovation. However, if Novartis succeeds in getting its patent and further changing the Indian law to resemble patent laws in wealthy countries, that purpose would be defeated. Patents may be granted in India as extensively as they are in wealthy countries, but that would mean that fewer and possibly no generic versions of new essential medicines can be produced by Indian manufacturers during the patent terms of at least 20 years, which may even be extended further through ‘evergreening’ under the veil of incremental innovation. This will have a devastating impact on India’s domestic population as well on people around the world who rely on affordable medicines from India.

However, as of now the public health safeguard built into Indian patent law has successfully passed the test of judicial scrutiny. This means that it will be much harder for pharmaceutical companies now to gain patents for products that are based on minor changes to, or combinations of, existing drugs. At present, there are about 9,000 pharmaceutical patent applications being reviewed by Indian patent offices. Many of these may be for drugs that would qualify as essential medicines. It is less likely now that many of these drugs will be patented in the future. This may encourage generic manufacturers in India to continue developing drugs that will compete with high-priced innovator brands, thereby driving down prices. This impact may be profound on the treatment of cancer, HIV/AIDS and other diseases for years to come.

The battle for ‘patients not patents’ has been won for the time being but the challenge remains. Novartis is carrying on its patent campaign into the political arena, ignoring many voices of reason from around the world. It has threatened India by airing the opinion that its favored investment destination is China. Novartis does not have the right to appeal to WTO which can be exercised only by member countries and not individual organizations or groups. But it is a pharmaceutical manufacturer of awesome economic clout and might try to influence opinion at the WTO discreetly.

Only time can tell whether there is any truth in the assertion by Novartis that the judgment will hinder innovation in this country. The prophets of doom have signaled the end of cutting-edge pharmaceutical research activities in India. Yet, there is the disturbing fact that despite increased patent protection worldwide in the last two decades, drug innovation has actually declined. Do patent rights, as they are sought to be exercised today, facilitate or hinder innovation? Perhaps it is time for governments and thinkers to consider an alternative to the system of patents that would not only provide incentive for research and development of newer drugs and vaccines but also ensure the availability and affordability of these new medicines.

Making Novartis see reason
The self-styled protectors of the world’s innovation capability at Novartis have so far remained immune to all voices of reasons from around the world, including Heads of States and highly respected global humanitarian organizations such as Medecins sans Frontieres (MSF). Many approaches have been suggested and are being undertaken.

The boycott Novartis campaign has seen a degree of success. Yet indefinite boycott is probably not desirable since Novartis does manufacture essential medicines other than GLIVEC and many patients, in the developed and developing world, having been using these medicines to their benefit. Short-term intense boycott campaigns, however, can be useful by virtue of their dramatic nature.

Medical practitioners serve as the essential link between people and drug companies as the latter depend on doctors for sale of their products. Sensitizing medical practitioners to the issue and requesting their support in the campaign by selectively boycotting Novartis products (say 2 products per doctor) can possibly sensitize Novartis. This may not only help with respect to GLIVEC but will send shock signals to other pharmaceutical companies who would otherwise indulge in similar acts.

The final and most important, albeit also the most difficult, approach would be sensitize civil society at large to the issues in question, moving from cancer and GLIVEC to the issue of the fundamental right to healthcare and access to essential medicines. Creating public awareness, on a difficult issue such as this, has no short-cuts and results cannot be expected overnight. Yet, if there is one thing which any profit making enterprise is afraid of, it is adverse publicity that destroys its image. This is the only cry of shame that Novartis is likely to listen to and the job before access to essential medicine campaigners now is to kindle this collective cry of shame to force Novartis to abandon its unbridled ‘profits before patients’ mentality.


References
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3. Dabade G, Upadhyay R. Falling sick is no sin. Deccan Herald. August 12, 2007 (Accessed January 18, 2008 at http://www.deccanherald.com/Content/Aug122007/panorama2007081118582.asp)
4. Menghaney L. Indian law is a model. Deccan Herald. August 12, 2007 (Accessed January 18, 2008 at http://www.deccanherald.com/Content/Aug122007/panorama2007081118584.asp)
5. Bringardner J. Novartis' India missteps leave patent questions. Law.com. October 3, 2007 (Accessed January 18, 2007 at http://www.law.com/jsp/law/LawArticleFriendly.jsp?id=1191229387137)
6. Novartis loses Indian patent law case. Chemistry World news. August 6, 2007 (Accessed January 18, 2008 at http://www.rsc.org/chemistryworld/News/2007/August/06080703.asp)


Acknowledgement
Dr. Avijit Hazra. Reader – Department of Pharmacology, IPGME&R, Kolkata.