The US patent for Abiraterone (Zytiga) has been declared invalid

[Wendy_Winnall]

A key US patent for the use of Abiraterone (Zytiga) for treating metastatic prostate cancer has been ruled invalid by a US court. This could lead to cheaper versions of Abiraterone becoming available in the US. This sounds like great news for US patients. This week’s blog explores the pharmaceutical industry behind prostate cancer drugs and what this new development means for Australian patients.

Drug development by the pharmaceutical industry

The discovery and development of new medicines to treat cancers and the journey of these new drugs to market is a long and expensive process. It starts with drug discovery. This can come from laboratory research by grant-funded researchers, or from pharmaceutical companies that specifically look for drugs to slow the growth of cancers. The second step in the process is drug development. This includes pre-clinical studies in the laboratory, animal experiments, clinical trials in humans and regulatory processes. Patent applications are an important part of this process. The development of new drugs takes about 8 to 10 years and costs close to 1 billion dollars. Some estimates put the price well above 1 billion.

Steps in the development of a new cancer drug

 A new cancer drug is approved if it is effective at treating the cancer and it is considered safe in terms of its side effects. All drugs bring a risk of side effects. The benefits of the drug must outweigh these risks. Much of the effort in drug development goes into establishing evidence that the drug is both effective and safe.

Pre-clinical phase

Once a potential new drug has been identified, it must be tested in pre-clinical studies. These are experiments conducted in laboratories and in animals. Pre-clinical studies need to identify the physical and chemical properties of the drug, determine how it can be administered to people and how stable it is over time. Animal experiments are used to ask whether the drug is effective in treating cancer and whether it has toxic effects on the body. They also show where the drug goes in the body, for how long it is active and whether it’s broken down into toxic components. Animal experiments are used to determine which doses are likely to be safe and effective, before trials in humans are conducted.

Clinical trials

Clinical trials involve experiments in humans. The aim of clinical trials is to determine whether the new drug is safe and effective for human use.

Phase 1 clinical trials start with the “first-in-human” experiment. The first dose is usually very low. Subsequent volunteers are given gradually increasing doses. These volunteers are usually monitored 24 hours a day in a facility adjacent to a hospital in case something goes wrong. Phase 1 trials are usually short, taking only a few weeks. The aims of phase 1 trials are to determine the effects of the drug on the body (usually only looking at toxicity) and the effects of the body on the drug – how long does it last? is it broken down quickly? does it stay active? Phase 1 trials for cancer drugs usually start with healthy volunteers, but often include cancer patients in later trials. People joining phase 1 trials take a risk in joining the trial, and almost certainly don’t benefit from the drug. Without these brave people, drug development would not be possible.

Phase 2 clinical trials test the safety and effectiveness of the new drug in humans. These trials are usually small, with approximately 50 to 100 people. Phase 2 trials should compare the new drug to a control treatment. For prostate cancer, this would normally be the usual treatment for patients at their stage of cancer. This is an important concept. A new drug needs to be a better alternative than the current therapies available, not just better than “no treatment”. It’s rare that a new drug would be compared to no treatment. The only time this happens is during trials for cancers for which there is no treatment available at all.

Phase 3 clinical trials test drugs that successfully pass phase 2 clinical trials, but on a much larger scale. While phase 2 clinical trials are usually conducted at one, or a small number of hospitals, phase 3 trial are much broader. Phase 3 trials are designed to show that the drug will be effective for a wide range of people, in many countries, under many different health systems. They are usually conducted over a long period of time. Phase 3 clinical trials are very expensive, often costing millions, or tens of millions, of dollars. To make it to a phase 3 trial, a drug needs to pass phase 2 clinical trials, be well-protected by patents, and likely to make a considerable profit. A company will not put up the many millions of dollars needed for a phase 3 trial unless they can recoup this money in sales of the drug in the future.

Patenting of new drugs

The drug development process for a new cancer drug often costs 1 billion dollars or more. To put this on context, in 2016 it was estimated that 6.5 billion in total was spent on health and medical research in Australia. This includes all government and private sector spending. The Australian government spends approximately 0.6% of its GDP on science, research and innovation. In 2014, this rate was at a historic low.

The huge cost of drug development means that it is mostly done by large companies with the money to cover the costs. This means that most new drug development is aimed at making a profit. If a drug won’t be sufficiently profitable to recoup the 1 billion it takes to develop it, then it won’t be developed by a company. Crucial to this profit is the patent system. Having a patent allows the company to have exclusive rights over the sale of its new drug for at least 20 years. After this time, cheaper “generic” forms of the drug can be made and sold by any company.

A patent application is usually submitted at the start of the drug development process to protect the use of the new drug. A patent is a form of intellectual property that gives the right to exclude others from selling the invention. It doesn’t give the company the right to sell the drug, rather that is determined by regulatory bodies such as the American FDA and Australian TGA. But it gives the company the right to exclusively sell an approved product. This allows them to charge a very high price, in order to recoup the money spent on drug development. Without patents, no company would spend the huge amount of money necessary for developing a new drug.

The system is far from ideal. Companies will usually choose drugs that are highly profitable to make profit in the long run. Profits from a successful drug are usually used to fund the development of the next drug. Many drugs do not make it past the trials and regulatory processes to get to the market. So numerous different new drugs must start development in order to ensure success from the 1 or 2 that eventually  become highly profitable. This is a terrible system for rare disease, as drugs for these diseases won’t be make much profit. Fortunately, it is not the only way to get new drugs approved. Charitible donations and government funding can help to develop less-profitable drugs. But the system does work for prostate cancer, since this is a very common disease. Prostate cancer drugs are profitable, so they are more likely to be developed. There have been many new drugs approved for prostate cancer in the past 10 years.

The patent process

In medicine, it’s difficult to say whether a new drug is actually an invention, as they are usually biological molecules. Patents for pharmaceutical drugs protect the use of those drugs. So, for instance, a patent may be granted for the use of a specific amount of a biological molecule for treating a specific stage of prostate cancer. This does not stop the drug from being used for other disease or in laboratory research. To be granted a patent, the drug must be new, and can’t be a logical next step for a known process (i.e. something that people would easily predict). In Australia, to be patented, an invention must be:

• new
• involve an inventive step
• be able to be made or used in an industry.

These requirements are assessed by patent examiners. If there is some evidence that someone has thought of this idea before, then the patent won’t be granted.

The process starts by submission of a provisional patent. In Australia, this is an inexpensive process that is simply an outline of the idea and claims. Filing a provisional patent means that the date it is filed becomes the date that the new invention was first reported. So long as no-one else has an invention that pre-dates this time, then a patent is possible.

Twelve months after a provisional patent is filed, a standard patent application must be filed with the Australian Patent office. If the patent is granted, then long-term protection is given over the use and sale of the invention in Australia. This protection lasts 25 years for pharmaceutical substances in Australia. In reality, the first 8 to 10 years is used for drug development, so no profit is made in that time.

A Standard Australian Patent only provides protection in Australia. Once this patent has been granted, the next step is to apply for patents in other countries, to protect the sale of the new product in these regions. A pharmaceutical company will apply for patents in many different countries, depending on the expected use of the drug. This is a time-consuming and expensive process that takes many years. A new application needs to be made and defended in each different country. The fees for submitting applications are not usually very high. However, the patent applications are best written and handled by patent lawyers, which is why applying for international protection will end up costing millions of dollars.

Generic drugs

Once a drug comes off patent, it can be made and sold as an identical chemical, by companies that are not restricted by the patent. Production and supply of the drug is not particularly expensive, compared to the research and development needed to get it approved. These versions of the drug should work just as well as the original drug. They are called “generics”.

The patents for Abiraterone (Zytiga)

Abiraterone (Zytiga) is a drug that was first approved for treating metastatic castration-resistant prostate cancer. It stops the production of testosterone and similar hormones, slowing the growth of prostate cancer. The first patent for Abiraterone was filed in 1993. Subsequent patents covered different uses of the drug. Abiraterone was approved for sale in the US in May 2011 and in Australia in 2013.

In the US, there is one remaining (unexpired) patent that protects the sale of Abiraterone. If you are having problems sleeping, you might benefit from reading it, via this link. The patent is expected to expire on 24^th August 2027. This gives the company 9 more years in which to profit from sales of Abiraterone.

The Abiraterone patent contains a list of “claims” that are protected by the patent, as well a detailed description of the “invention” and its use. When applying for a patent, the company tries to make broad claims on the use of its new product, but not too broad such that the patent is invalid or infringes on another patent. The Abiraterone patent is owned by the American company Janssen Biotech. Janssen Biotech are owned by American multinational Johnson & Johnson.

Unfortunately for the owners, the last patent protecting the sale of Abiraterone was recently ruled invalid in the US. This means that, at least in the US, the drug could be made and sold by any company.

Johnson & Johnson announced the decision last week. The company plans to appeal and states that they “strongly disagree with the decision”.

Why was the patent granted but then ruled invalid? After a patent is granted, its validity can be challenged in the courts. If the patent is ruled invalid, other companies can produce and sell cheaper generic brands of the drug.

A company called Argentum Pharmaceuticals challenged the Abiraterone patent. The process started in 2016, when Argentum’s petition was successful for an inter partes review of all 20 claims in the sole remaining US patent for Abiraterone. In January 2018 the US Patent and Trade Office concluded that Argentum "satisfied its burden of demonstrating, by a preponderance of the evidence, that the subject matter of claims 1–20 would have been obvious," and then ordered "that claims 1-20 are held unpatentable." The process continued in a District Court of New Jersey that ruled the remaining patent invalid on 26^th Oct 2018. An appeal is planned by Johnson & Johnson.

Argentum Pharmaceuticals specialise in generic drugs and challenging patents. Their website describes their mission as “we intend to reduce the overall cost of prescription drugs by challenging patents that are not innovative and which artificially support high drug prices”. This appears to be a very noble cause. By winning such cases, they are certainly able to make drugs more cheaply available. However, Argentum do not discover and develop drugs. They only sell drugs that have been developed by others. Under the current system, when patents are ruled as invalid, reducing the amount of money that can be made from these drugs, this reduces an important source of money that is used to pay for drug development.

What does this mean for Australian men with prostate cancer?

If the appeal by Johnson & Johnson is unsuccessful, generic forms of Abiraterone will become available in the US. These drugs will be much cheaper than the current versions. For US men with health insurance, the difference may not be so noticeable. But for men without health insurance in the US, this could make a big difference.

Abiraterone is covered by an Australian patent expiring 23^rd Aug 2027, and patents in Europe that expire in 2022. In Australia, Abiraterone is subsidised by the PBS for use by men with metastatic prostate cancer. Therefore its cost to a patient is reasonably low, at a maximum of $39.50 per 120 tablets of 250mg. However, the cost to the Australian government for subsidising the drug is much higher, at $3604.58 for the same packs. So generic forms of the medicine would save the government a lot of money, making more available on the PBS budget to subsidise other medicines.

It’s possible that the Australian patent will be challenged in the future. If successful, this could mean the entry of generic forms of Abiraterone into the Australian market, saving the PBS some money. There is no guarantee that generic forms of abiraterone will be much cheaper for Australian men than the current form available.