Amongst the G20 countries, Argentina, India and Indonesia score lowly for innovation. Partly to blame are significant weaknesses in their intellectual property systems, including a ban on patenting of many kinds of medical inventions that benefit patients, national healthcare systems and local industries. These inventions include new dosage forms, formulations, combinations and uses of existing medicines.
IP-skeptics charge that these inventions are little more than a way for pharmaceutical companies to cynically prolong patent life and maximize profits, without providing any meaningful innovation.
This rather simplistic view misunderstands how the patent system works, and the role of patents in incentivizing drug discovery and development. In reality, many of today’s most significant medicines owe their existence to the ability of medical innovators to secure patents for novel new forms and new uses of existing treatments. This short article considers the evidence on three major categories of pharmaceutical invention: combination drugs, enantiomers and new medical uses for existing drugs.
Combination drugs, in which two already known drugs are combined, provide significant therapeutic benefits to patients. The management of HIV infection has famously been revolutionized by fixed dose combination drugs that suppress the virus. Combination drugs are being increasingly used in the treatment of cancer and cardiovascular disease. Combinations of two or more “checkpoint inhibitor” immunotherapies have the potential to extend the lives of cancer patients considerably beyond what is currently possible, and is a major focus of commercial drug development efforts.
Combination drugs also reduce the administrative costs associated with multiple, separate drugs – such as dispensing costs, insurance co-pays and separate packaging – as well as the number of prescriptions required for a patient. They can also improve patient adherence to treatment regimens by reducing the pill burden, which in turn delivers substantial cost savings to healthcare systems by averting avoidable hospitalizations.
Combining existing drugs is a simple idea. But putting them together, determining exactly how they act on disease, their side effects and quantifying any potential risks to patients is not a simple process. It requires scientific insight, high-tech innovation and significant investment in research and clinical trials.
The combination of different active ingredients could lead to unexpected results in patients, such as potentially harmful side-effects. Other risk factors that need to be quantified include drug-drug interactions in patients on additional courses of medication; loss of therapeutic flexibility, depending on the amount of each active ingredient needed to be effective; and physical design of the combination drug (e.g., a pill that proves too large or difficult for some patients to swallow).
Drugs cannot therefore just be spliced together and launched on the market. Potential combination drugs must undergo a rigorous process of multi-stage clinical trials in volunteers. The incentives that patents provide by granting a temporary period of protection for new inventions is the best way of mobilizing the considerable financial resources required to undertake these costly trials.
But what of claims that patents on combination products constitute a ‘backdoor’ to lengthening the period of market exclusivity conferred by a patent? Patents awarded to combination drugs represent a new patent for a new product. That new patent does nothing to extend the patent term of the individual drugs that form the combination. Generic manufacturers are therefore not blocked from manufacturing the separate component medicines, so long as they are off-patent.
Enantiomers are an increasingly important weapon in the therapeutic arsenal, including widely used statins such as atorvastatin (marketed as Lipitor) and simvastatin (marketed as Zocor). Statins are responsible for averting 80,000 heart attacks every year in the United Kingdom alone, according to a 2016 study in medical journal The Lancet.
The notion that enantiomers are in general unworthy of patent protection comes from the fact enantiomers are derived from ‘flipping’ their already identified molecular partners, and for a person skilled in pharmaceutical R&D, it is obvious to identify and isolate the therapeutically active enantiomer. The government of India subscribes to this view, for example, and sets an unusually high bar for granting patents for enantiomers.
However, such arguments overlook the fact that enantiomers can be both novel and non-obvious – something that has been repeatedly confirmed by courts in high-profile patent cases.
As an example, in 2008 Canadian generic company Apotex mounted a validity challenge against patents for Sanofi’s anti-coagulant drug clopidogrel. Experts testifying for both parties agreed that the separation of enantiomers is an extremely technically difficult proposition. The high degree of similarity between the two enantiomers makes it very challenging to separate them from each other, the experts observed. Further, the safety and efficacy of the enantiomer greatly exceeded reasonable expectations, the Court concluded.
They also agreed that, since there is no general methodology for separating enantiomers, it must be undertaken through trial-and-error on a case-by-case basis – in other words, at great expense and significant commercial risk to the companies involved.
Despite the marked similarity of their chemical formula, enantiomers must also undergo exhaustive clinical trials before they can be marketed as safe and effective. This is because the two versions of the molecule – the original and the mirror – can act in very different ways on the body. Clinical trials are therefore needed to identify and delineate the benefits and risks to patients.
Take the example of Naproxen – a common over the counter drug used for the relief of joint and arthritic pain. Its mirror-image molecule (R-Naproxen) has an identical chemical formula but an inverse chemical structure. This version has no pain-relieving properties, but instead is highly toxic to the liver.
It is therefore unsurprising that jurisdictions with significant innovative industries, including the United States and Europe, offer patent protection for enantiomers. The temporary period of market exclusivity afforded by patent rights gives the rights holder a chance to recoup some of this investment, incentivizing them to carry out this kind of important research in the first place.
New medical uses for existing drugs is another area in which national patent laws differ widely, despite the enormous potential this field holds for medicine.
Take, for example, the drug erlotinib. Originally developed to treat non-small-cell lung cancer, erlotinib was subsequently approved as a treatment for pancreatic cancer. Beyond this, it has also shown potential as a treatment for cancers of the breasts and ovaries, as well as hepatitis C, psoriasis and type-1 diabetes.
In fact, up to 15% of given indications for drugs on the WHO’s Essential Drugs List are follow-on indications. Approximately 90% of medicines most used by patients are approved by the FDA for diseases other than their original approval (so-called “secondary indications”).
Repurposing existing drugs is not simply a case of changing the packaging. It is almost always the result of extensive research and clinical trials. It is therefore an expensive and risky process that requires appropriate incentives, including patent rights.
Second medical uses tend not to be recognized by biomedical researchers until long after patent protection has been obtained on the original indication – and often, so long after, that the patent has expired and generic competitors have already entered the market.
This means that innovators that have developed drugs for one indication will likely have lost much, if not all, of the market exclusivity offered by the patent on the first medical use by the time that potential second medical uses are revealed. This effectively makes the development process around second indications very risky, since the diminished period of patent exclusivity reduces the innovator’s opportunity to recoup their R&D spend and secure returns on investment.
Jurisdictions that are home to successful innovative industries therefore accept that the only way to square this circle is to offer patent protection for new medical uses. These include Europe, the United States — and even China.
In the end, the fact that Argentina, India and Indonesia set a very high bar for these kinds of patents does them no good in the long run. Drug repurposing, drug combination R&D and the development of enantiomers not only deliver value for patients and national healthcare systems, but are often an entry into fully-fledged de novo drug development, enabling generic companies with emerging R&D capabilities to move up the value chain. In fact, new forms and new uses for existing medicines are commonly patented by generic firms.
In drug repurposing, generic companies also undertake proof of concept studies on existing molecules and out-license them to more established R&D companies, or alternatively in-license molecules from established pharma companies, screen and validate them, and license them back to the parent companies for development. These kinds of business models help local industries build their innovative capacities and in turn generate high quality jobs and sustainable economic growth – but this transformation will be difficult to achieve in the absence of favorable patent laws.