Patent Post

Indian innovation at crossroads?

While TRIPs is good news for India, Clause 3d is not so. Prof Trevor M Jones tells us why

India has a proud record of innovation in a number of fields, e.g. satellite technology, mathematics, and particularly, pharmaceutical chemistry. Recently, the economic and social growth of India has made it a world focus for investment in innovation across a broad spectrum of industries; notably in IT, nanotechnology and pharmaceutical/ biotechnology R&D. Whilst the low-cost base of science and technology in India has been an attraction for inward investment; in recent years, the world class technical (and often young) skill base that it has grown, together with the national enthusiasm and commitment to innovative successes, has provided an added dimension to a future of collaborative and indigenous growth.

This new spirit of endeavour was highlighted in 2004 by the then Director General of the Council for Scientific and Industrial Research (CSIR), Dr R A Mashelkar, in his convocation speech to the Indian Institute of Foreign Trade, "India is becoming a global R&D hub, especially for companies from the West. Over 100 companies around the world have set up their R&D centres in the country during the last five years. The demographic shift in the Western world means that a country like India, with its relatively favourable demographic profile and a large proportion of working and talented young people, can become a global innovation hub. India has over 250 universities and 1,500 R&D units. It has the world's largest chain of publicly funded R&D institutions. This is an extraordinary rich resource, which was under-utilised even within the Indian space of R&D opportunity. India's emergence as a global R&D hub has a social, economic, political and strategic significance."

Since then, progress has been made in the pharmaceutical sector, as evidenced by Dr G V Prasad, CEO, Dr Reddy's Laboratories, in a statement at the March 2007 Economist Conference, "Seventy-five percent of the world's top 50 companies are conducting clinical development trials in India. The next area to develop in the country will be pre-clinical and early-phase discovery. It is forecasted that the value of outsourced contract research carried out in India will be close to $2 billion by 2010." (PharmaTimes.com-Clinical News, March 2007, 14).

Article 27

It was the recognition of the emerging force and the status of India's science and technology on a world stage that resulted in a change to Indian patent laws so that India could be compliant with the WTO's so-called TRIPS agreement. Surprisingly, in the pharmaceutical and biotechnology context, the amendments to the Patent Act include restrictions as to what would be regarded as patentable inventions.

Throughout the world it has been the convention to grant patents for "inventions" as distinct from "discoveries". Article 27 of the TRIPS Agreement states, inter alia, that "patents shall be available for any inventions, whether products or processes, in all fields of technology, provided that they are new, involve an inventive step and are capable of industrial application"—in other parlance, they "have utility". Article 27 also states that "patents shall be available and patent rights enjoyable without discrimination as to the place of invention, the field of technology and whether the products are imported or locally produced". The two important points in Article 27 relevant to recent changes in patent law in India are the words "in all fields of technology provided they are new, involve an inventive step and are capable of industrial application".

The new Indian law includes a clause (3d) which, for pharma-ceutical/biotechnological inventions, excludes certain inventions, viz, "For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substances shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy". One of the fundamental problems with the clause as it is constructed is that a test, such as that of "efficacy", is almost impossible to perform at a time when the patents are filed.

Clause 3d contravenes the mandate that is contained in Article 27 of the TRIPS agreement, and if not amended or withdrawn, it could seriously compromise the ability of entrepreneurs in India, and indeed, established companies in India from fulfilling their ambitions to be world leaders, let alone the inward investment in R&D from foreign companies to share in India's future growth and success. It would be a tragedy for India if the success that has been achieved in recent years is compromised in this way.

Regarding the two concerns relating to clause 3d; firstly, the fact that it is very specific and precise with respect to pharmaceutical and biotechnology would seem to be contrary to the requirement of Article 27, that TRIPS conditions apply in all fields of technology. Secondly, and importantly, it severely restricts innovation through incremental steps. Incremental innovation, which is the way in which the vast majority of advances in medical science has occurred, is often confused, sometimes deliberately, with the term "evergreening".

What’s the difference?

"Evergreening" is a term used in the USA for activities with which companies seek to extend the market exclusivity of a pharmaceutical product by introducing small changes just before patent expiry and, thus the entrance of competitor products (eg introducing a capsule dosage form when previously the only dosage form available was tablets; changing the colour and/or shape of a tablet, etc.). This practice was roundly condemned by the Bush administration and is no longer practised. In fact, nowadays, it would not provide a sufficient basis to ensure market exclusivity following the introduction of generic bioequivalent products.

Incremental innovation, however, is very important, in fact, the major means through which significant benefit to the health of patients worldwide has been, and can continue to be, improved. It is also an area of research activity in which India has very well-developed skills. Breakthrough innovations are extremely rare, hugely difficult and often serendipitous in medical research and in virtually every other field of science and technology. For example, in the field of flight, arguably the only three "breakthroughs" in technology were the original propeller engine flight machine, the helicopter, and the jet engine aeroplane. All other developments, from the Comet airplane to the Boeing 747 and Concord, were "incremental". Similarly, in land transport, since the chariot and horse and cart, there have been only three "breakthroughs"—the bicycle, the petrol engine motor car, and the train. All other developments have been "incremental", that is, from the De Dion Bouton or the Ford Model T motor car to the latest Lamborghini.

Clause 3d, which seeks to exclude most incremental innovations, fails to appreciate that such inventions have utility and value not just in improving therapeutic/clinical efficacy; but in providing significant benefit in terms of patient safety, compliance, manufacturing efficiency (and hence product cost)—a point made in the CIPIH report. These innovations can improve product stability during storage and transport; which is important in India and the developing world, where logistics and healthcare infrastructure are deficient. As it stands,

Clause 3d will exclude these developments which, arguably, should be a significant component of the next stage of economic growth for pharmaceutical and biotech R&D in India, in parallel with its growing ability in more fundamental drug discovery (as witnessed by companies such as Dr Reddy's, Ranbaxy, Nicholas Piramal, Wockhardt, Lupin, Sun, Cadila, Dabur, Glenmark and Orchid).

It is important to remember that patents for inventions, based on elements that are currently excluded by Clause 3d, would only be acceptable if they conform to the internationally well-established criteria of being "new, involv(ing) an inventive step and (being) capable of industrial application", i.e., they are not "obvious".

Salts, esters, ethers, and polymorphs

Changing the salt form may, for some drug substances, be "obvious". For example, using a sulphate rather than a hydrochloride to ensure solubility might not be considered patentable. However, for particular drug substances it may be established that changing from a base to a salt or changing the salt form, for example, from a hydrochloride to a mesylate or a besylate, could confer increased stability in warmer storage zones and conditions, and hence provide patient benefit. Further, different salts can increase or decrease the solubility of a drug substance, which can increase or decrease the rate at which they dissolve. Innovations such as this might result in an improvement in the clinical effectiveness or in a decrease in the likelihood of side-effects. An example of such an improvement would be to avoid sudden "spike" surges of drug concentrations in the blood stream or high localised concentrations in the stomach or intestines, giving rise to gastric/duodenal or other intestinal irritation.

Drug substances can occur in various physical forms, such as liquid, semi-solid, amorphous, or crystalline materials. Indeed, the crystalline states can vary significantly; by analogy, the element carbon can exist as soot, graphite, or diamond depending on how it was crystallised. Such differences are usual for pharmaceutical materials, whether they are the drug itself or ingredients (excipients) in the formulation. Inventive research and development that leads to the selection of, for example, a particular "polymorphic" form of drug substances can result in significant improvements in production processes, e.g. synthesis, isolation as a bulk chemical, formulation and final product manufacture. These innovations could make production more convenient and less expensive, hence opening up the possibility of cheaper products from the manufacturer.

India has been particularly successful in this area of innovation which, as outlined above, may affect the manufacture of the product, its potential safety and efficacy, as well as its storage and shelf life in the marketplace. Annexure IV of the December 2006 Report of the Technical Expert Group on Patent Law Issues (recently withdrawn) lists 48 Indian companies which have filed PCT applications in the field of drug and pharmaceuticals, mostly pertaining to different forms of the same substance.

Particle size

The particle size and size distribution of a drug can be critical to the rate at which it dissolves in the body after administration, and hence its speed and extent of absorption. Once a product is widely used in various patient populations over years, evidence might emerge that further optimisation of these physical characteristics of the drug could result in safer or more effective treatment. In addition, for babies, children, and many elderly patients, it may be necessary to provide medicines as oral suspensions for ease of administration and use. Optimising the particle size and size distribution in a liquid formulation can be critical to the physical stability of the suspension; otherwise, an incorrect dose may be administered or the product may "cake" in the bottle during transport and storage. India has produced many world class pharmaceutical scientists with expertise in this area of formulation technology (including the diaspora in the USA and EU), and there are a growing number of small companies in India with these skills— Rubicon, Ciron, Radico, and Medico, to name a few. It would be a great pity if their innovative skills could not be rewarded with sufficient IPR.

Isomers

Chemicals can exist not only in different states and polymorphic forms, but in various shapes or conformations. Scientists like Louis Pasteur discovered this originally by observing how light was reflected through different crystalline forms of the same compound, e.g., crystals of vitamin C (ascorbic acid) can deflect light to the left (l-) or to the right (d-), depending on the shape of the crystals. This phenomenon is known as isomerism, that is, different "isomers" can exist. For more complex drug substances, this asymmetry can take multiple forms at different sites within the molecule and result in many different forms or "enantiomers". These enantiomers and isomers may behave the same in the body, but often possess different properties. For example, the pesticide Permethrin, which is in mosquito nets to prevent the spread of malaria and other vector born diseases, can exist in a so-called cis or trans isomeric form. These differ significantly in their toxicity, so it is necessary to select forms that reduce the potential for damage whilst retaining the anti-mosquito effect.

Furthermore, different enantiomers of the same chemical drug substance may have increased efficacy and/or stability. Indian scientists have proven, over many years, that their well-developed knowledge of organic chemistry can result in novel routes of synthesis of drugs, and it is important, going forward, that they can rely on patents to protect their innovative skills in finding novel isomers and enantiomers that have utility not only in yielding more effective treatments, but also more cost-effective products. Where otherwise will there be an incentive to compete and make the necessary investments in R&D to provide such progress? Surely India should want this to be within its nation. As it stands, arguably, Clause 3d discourages such local endeavours and encourages talented individuals to pursue their innovative activities elsewhere.

Metabolites

When a new drug is discovered, scientists in research-based drug companies set out to examine how it might be absorbed (A), distributed (D), metabolised (M) (broken down) and, finally, excreted (E) after it has been administered to the patient, whether by mouth, through the skin, inhaled or injected. This process is abbreviated ADME studies. The examination starts with tests on animals considered to be physiologically and biologically similar to man. This is followed by studies in healthy volunteers, and then finally, in always limited numbers of patients in clinical trials. We must remember that these trials, as extensive as they are, involving several thousands of patients prior to introducing the new product to market, can never be fully representative of the real situations that apply when the drug is eventually used in routine therapy worldwide (because of different diets, ethnicities, patients who concomitantly take many different drugs, co-morbidity of diseases that can affect drug behaviour, etc).

Nevertheless, together with other in-vitro and in-vivo tissue and animal data, we can get a sufficient amount of ADME and clinical data to determine (and for regulatory agencies to evaluate) whether the drug is likely to have acceptable properties in terms of safety and efficacy. Rarely is there a single metabolic process involved in breaking down the drug in the body for it to be excreted and eliminated. Several, often competing, metabolic pathways exist. The products that the body produces, i.e. the metabolites, may have the same, more, or less therapeutic activity and/or safety as the original, parent drug substance. In addition, metabolites may be more or less stable in different storage conditions. Such potentially new, novel derivatives of the original compound are not usually evident at the time the original drug is being tested. Furthermore, the amount of research that would be essential to find the preferred metabolite at that stage of research and development could delay patient access to the new, often life-saving, treatment by many years. Indeed, there is a well-known phrase within the R&D community that for new drugs, there is "the first…and the best" subsequently brought to the market. Thus metabolites present a new opportunity to introduce better drugs, whether this refers to efficacy, safety or more robust products during transport, storage and use.

Combination and "me-too" products

There are a number of reasons why two or more drugs are included in a single dosage form, such as a tablet or capsule. Two of the most important reasons are patient compliance and preserving the activity of the therapy. Getting patients to continue to take their medicines as prescribed (patient compliance) is a major problem in both the developed and the developing world. In chronic therapy, many patients simply forget to take the medicines at the frequency that is required or prescribed; more disturbingly, many patients stop taking their medicines after several months, either because they forget or because they consider that continuing the course of treatment in not necessary—they feel ok even though the underlying cause of the original health problem has not been adequately treated and requires further suppression or activity. Because patients vary in their response to different drugs, fixed dose combinations of drugs are not always appropriate. Where it is scientifically and medically not unreasonable to combine drugs in a single dosage form, it can be a more convenient and reliable method to improve patient compliance.

The particular combinations that may be required are not usually known at the time of the launch of a new drug, and may vary according to local clinical practice and the nature of the disease. It is important, therefore, that research on innovations that lead to appropriate combinations of drugs is encouraged. As written, Clause 3d does not encourage investment in such activity.

Combination products are of particular significance in the treatment of a wide range of infectious diseases, such as malaria and HIV/AIDS, and for many other diseases. Parasitic micro-organisms, viruses and bacteria can quickly develop resistance to a new anti-infective drug, especially when the drug is present in the body in low concentrations due to poor compliance, or where residual amounts remain between treatment dosing intervals. Combining two or more anti-infective drugs can reduce the development of resistance. Since nature is very capable of outsmarting mankind when it comes to the development of resistance, we need a wide variety of anti-infective drugs to keep up with these changes; especially since the resistance that develops in one geographical location can be very different to that in another.

It is very fortunate and necessary, therefore, that we have a variety of apparently chemically similar drugs available to assist in the fight against resistance. Since the original development of the first anti-retroviral drug AZT by the then Wellcome Foundation, we saw the introduction of more than twenty anti-retroviral drugs. Some that are very similar in chemical composition have been referred to as "me-too" products, but all the drugs have been vital to the struggle against the pandemic of HIV/AIDS. Whilst the major effort that is in progress to find even more effective ARVs (and in time hopefully vaccines that are adequate in terms of effectiveness) continues, we need to rely on combination products. In fact, we need more, not less, "me-too" products. The same applies to the treatment, indeed cure, of malaria where novel combinations of naturally-derived drugs, such as Artemisinin, together with synthetic anti-malarial drugs, provides a continuing basis of therapy whilst the search continues for entirely new chemical entities. Novelty through selecting those combinations that possess not only adequate clinical efficacy, but also the preferred ADME properties and formulation stability in tropical and sub-tropical climates, is a vital component in the battle against this major cause of death in children and mothers in the developing world. Given the experience that Indian scientists have in this area, they and patients throughout the developing world would be better served if the restrictions of Clause 3d were removed.

Conclusion

India has demonstrated its capability and desire to continue its social and economic expansion as one of the world's leading developing economies through investment in innovation. Its signature to the TRIPS agreement in 1995 signalled the start of a new era as a significant player on the world stage of R&D. Encouraging and rewarding innovation was, and still is at the heart of that commitment. The introduction of Clause 3d into patent law in India seems to be incompatible with the obligations India has under Article 27 of the TRIPS agreement, which contains quite specific wording with respect to its scope.

It is argued by some that without the provisions of Clause 3d patients in India and in the wider context, developing countries would be denied access to life-saving medicines. This is absolutely not the case, since India and other countries have introduced safeguards in the form of price control, or as a last resort, compulsory licensing to deal with such emergencies. The sad fact is that despite the availability of the very cheapest, often generic, medicines in India and elsewhere, millions of patients have no access to medicines because of poverty, the absence of any healthcare funding, inadequate healthcare services and personnel, and poor logistics for distribution and supply.

Whilst it behooves both developed and developing nations alike, to address these dreadful imbalances in human health and welfare, the establishment of proper IPR that encourage rather than inhibit medical scientific innovation for the benefit of mankind must surely be a necessary way forward. Indeed, there is clearly a wish by leading innovators in India to move forward, as evidenced by these comments from Business Week Online from 18 April 2005, "[India] now has more than 50 drug research centres, and more are expected this year. The reason is India's new patent protection law, which brings Indian legislation in line with World Trade Organization norms. The law took effect in late March and its passage means Indian companies can no longer ignore the patents of multinational drug companies and produce unlicensed generics, as they have done for 30 years. What Indian pharma companies hope to do instead, is develop and sell around the world both licensed generics and their own branded, patented drugs, and thus, the spate of new research facilities. Indian companies are no longer going to be just copycats," says Dr Swati A Piramal, the Director of the Piramal Centre. "We want to take our rightful place at the head table with the developed nations.” And these from Investor Ideas from June 2006 by Dr Uday Lal Pai, "The patent change regime in 2007-08 would open a huge international market worth $65 billion for the Indian pharma industry." According to Sanjay Aggarwal, Pharmaceutical Sector Leader for KPMG in India, "Multinational companies that have re-entered the market since the new product patent system seek out the domestic industry's skills and infrastructures to boost their research and manufacturing activities in the sub-continent and also open up this vast, virtually untapped market."

India has almost limitless capability, through its talented scientists and entrepreneurs, to be such a leader, but Clause 3d puts it at a watershed. Reform of this aspect of India's patent law is surely essential.

(The writer is a Professor at King's College, University of London and a Member of WHO Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH)