Restricting Patents on New Combinations and Uses of Medicines Makes No Sense

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 – non-superimposable, mirror image versions of existing molecules – are another valuable invention that critics argue should be denied patents due to a lack of novelty.

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.

The Author

Philip Stevens

Philip Stevens is the founder of Geneva Network, where he oversees all research, writing, communications and fundraising. Phillip has worked for the World Intellectual Property Organization (WIPO) in Geneva, in its Global Challenges Division where he worked on a range of IP and health issues. At WIPO, he also coordinated the agency’s cooperation with the World Health Organization and World Trade Organization in these policy areas.

Prior to his time with WIPO, Philip worked for several London-based policy think tanks, and has worked as a political risk consultant. He is also a Senior Fellow at the Institute for Democracy and Economic Affairs, Malaysia. He holds degrees from the London School of Economics and Durham University (UK).

For more information or to contact Phillip, please visit his Company Profile Page.

Philip Stevens

Jack Ellis is an Associate Researcher at Geneva Network and a freelance journalist.

Previously, Jack was the Asia-Pacific editor of Intellectual Asset Management magazine. He has also worked in a number of editorial and research roles covering intellectual property, the legal services market and the non-profit civic sector.

For more information or to contact Jack, please visit his Company Profile Page.

Warning & Disclaimer: The pages, articles and comments on IPWatchdog.com do not constitute legal advice, nor do they create any attorney-client relationship. The articles published express the personal opinion and views of the author and should not be attributed to the author’s employer, clients or the sponsors of IPWatchdog.com. Read more.

Discuss this

There are currently 5 Comments comments.

  1. Ashok Chand Mathur July 8, 2017 12:35 pm

    The authors have misunderstood what the Indian patent system bans.
    It provides for new patents to be issued to combination drugs or mirror molecules PROVIDED THE APPLICANT IS ABLE TO DEMONSTRATE SIGNIFICANT THERAPEUTIC BENEFITS TO THE PATIENTS.
    SHOULDN”T US LAW ALSO BE THE SAME?

  2. Gene Quinn July 9, 2017 11:10 am

    Ashok-

    You ask if U.S. law should have a requirement that inquires about whether there is a significant therapeutic benefit in order to obtain a patent. The answer is simple, clear and indisputable. The answer is no. That inquiry has no place anywhere in U.S. patent law and it would an extraordinary departure from over 200 years of patent law for such a radical and unproductive idea to be accepted. Such a narrow view of what is patentable gets in the way of the advance of science and technology.

  3. Anon July 9, 2017 1:04 pm

    Perhaps a bit of an added explanation for Ashok….

    Innovation is not linear. Innovation very much often does not “all at once” obtain the fantastic benefit that is perhaps the aim of the “demonstrated significant… benefit.”

    That is simply not how innovation works.

    I have studied innovation throughout my career, minoring in the history of science and technology as an undergrad, and then later while in law school double dipping into the University’s MBA program for innovation management classes.

    While “sounding good,” the path that India has staked out is a proven path of sub-optimization.

    Innovation works best on a path when the system rewarding innovation is thought less of a “street-paving” plan, and more of a “parking lot paving” plan.

    Innovation works best when innovation is rewarded in a myriad of a multitude of little, and, at the time, seemingly unconnected tiny steps.

    The “pave a parking lot” mentality allows the ability to turn on a dime, in most any direction, infusing those seemingly disparate advances into truly giant steps. Eliminate the “fuel” for the tiny steps and the giant steps will occur far, far, far less often.

    Further, it is well known that even for the “big step” disruptive innovations, the very first forays often represent a step backwards as to measuring against “proven items.”

    You may consider Gene’s response to be a bit brusque, but do not be put off by the directness. Time and again, the best innovation is tied to those system that have strong and generous patent systems. But such thinking has now been under a relentless (and ungrounded) attack from multiple different philosophical systems, and the brusqueness you see (I dare say) is generated from the (apparent) need to repeat what those of us who have studied innovation may take for granted.

  4. Deepanashu July 10, 2017 7:38 am

    Dear Ashok-

    Please don’t be thrown off by the intellectuals in the comment, the way Mr. Quinn responded was a representation of a parochial mindset which does not make an effort to understand the others point of view. Mr. Quinn, with all due respect, just because something is old, like patent laws in US, doesn’t mean it’s the best and perfect and utopian.

    Ashok, if you observe the author made an effort to glorify the perspective that big pharmas want, he did not anywhere tell how important the generic medicine producers are as they are actually the ones who are providing medicine to the masses in developing and least developed countries who can’t afford the expensive patented medicine. Imagine if big pharmas can get patents extended by just showing an increase in efficacy of a few percent’s which not actually a big deal is for these pharmas as depicted in the article, which was referred to as ‘Evergreening of Patent’ by the apex court of India in the Novartis case.

    Arguments are vehemently put forward to show that patents are necessary (as they incentivize innovation), however no one discusses ‘what is the use of such an innovation which can only be afforded by the elite few and is far from the reach of masses?’. What US patent law doesn’t address is that many of its citizen have to come to countries with ‘sub-standard innovations ‘like India for medical treatments because the very same treatment is available at a fraction of a cost. What is the use of such innovation if your citizens have to run from it?

    Mr. Anon is giving all the proofs of his superiority in the topic of ‘innovation’. The contention that patents are a necessity for innovation doesn’t actually hold much ground if we consider that the ancient Greeks, Egyptian, Indian and Chinese civilizations did not have such patent laws and I guess everyone would agree that their innovations weren’t ‘sub-standard’. Nothing in the ancient Indian medicine knowledge of Ayurveda was patented and it should be appreciated that on many topics modern medicine knowledge seems puny in front of the depth of Ayurveda. This is because in the ancient times innovations were done for the sake of innovating and not for the sake of getting patent (basically right to earn money)

    Does the US patent law have the power to stop people like Martin Shkreli ?? ‘The answer is simple, clear and indisputable. The answer is no. That inquiry has no place anywhere in U.S. patent law and it would an extraordinary departure from over 200 years of patent law for such a radical and unproductive idea to be accepted’.

  5. Anon July 11, 2017 7:25 am

    Deepanashu,

    Respectfully, you want to reach back to ancient times to support a view that innovation works better without patent systems?

    You then want to interject your own personal belief that innovation in each of the various cultures was undertaken because of some altruistic “for the sake of innovating and not for the sake of getting patent (basically right to earn money)”?

    What basis do you have for such suppositions?

    You make what are essentially baseless claims as some type of counter to my “superiority,” when it is not even MY superiority that is at point. Perhaps you did not understand my post in that I have stated that I have studied innovation – and that means the innovation thought leaders of the modern world (and not my own views). And this studying was not merely “intellectual,” but involves world wide applications of innovation – and ALL that that means. If you have been paying attention to my posts for any appreciable time, you would know that I am no fan of those that are purely academics.

    What I state are not leading views because “I state them,” rather, I state them because they are leading views.

    Your post is the epitome of ad hominem – attempting to attack the messenger instead of dealing with the message.

    If you want to challenge the notion that strong patent systems go hand in hand with better innovation. you would be better off presenting a single modern example of a society that has advanced innovation by rejecting strong patent systems. Here is a tip for you: you will find no such modern example.

    I have no idea what point you think that you are making with the question of “Does the US patent law have the power to stop people like Martin Shkreli ??” How is that related to the discussion here? How is that related to anything that I have said?

    You use words like “parochial,” and “perfect and Utopian,” when such have no place in the conversation (nothing has been indicated as such).

    You think that people are “not understanding the other point of view” – as if the comparative analysis is made without understanding – this is just not so.

    Your plea of “afforded by the masses” confuses what patents are (a negative right) and some social engineering agenda. This ties to your “ancient times” proclamation without evidence and paints a picture of humanity that is simply not real.

    Further you confuse the ability to copy something (at a fraction of the cost) with the controls that patents do provide, mistaking “cost to treat” and “what is charged to treat” as if they were interchangeable.

    Make no mistake, I am no fan of Big Pharma. But I am less a fan of those that desire to denigrate strong patent systems for some romanticized and fallacious view of innovation.