Keeping secrets: protecting the smallpox vaccine

One week after the September 11 attacks in 2001, letters containing anthrax spores started appearing in the US postal system. Infected envelopes were sent to media offices and two US senators. The attack killed five people in what the Federal Bureau of Investigation described as one of the worst biological attacks in American history.

The incident sparked fears of a similar attack, followed by calls for a strategy to manage potential outbreaks of infectious diseases, including smallpox.

Although smallpox was declared officially eradicated after a global vaccination programme led by the World Health Organization, the virus still exists in laboratory archives and repositories controlled by the UN.

Because of advanced understanding of genes and how they work, the cost of creating a virus has fallen substantially, and an individual may order all the necessary base pairs to create a smallpox virus for as little as $2,000, according to US military commentator Thomas Hammes.

Smallpox is easily transmitted, and if caught, is often fatal. If deployed in densely populated areas connected by air travel, it could spread rapidly.

Denmark-based Bavarian Nordic has a contract with the US government to develop a vaccine for smallpox, to be rolled out on a large scale in the event of a terrorist attack. It is a biotechnology company that specialises in the development of vaccines for the prevention and treatment of cancer and infectious diseases. Its goal in the infectious disease area is to develop a portfolio of vaccines that protect against a range of biologic agents.

The company has two divisions working on different projects: as well as developing preventive vaccines for biodefence programmes and other infectious diseases, it works on creating therapeutic vaccines to slow the development of certain cancers by stimulating the immune system to recognise and destroy cancer cells.

Bavarian Nordic works with a virus called MVA-BN as a backbone for its therapies. MVA-BN is a live, attenuated virus that Bavarian has developed to be replication incompetent, so that it cannot reproduce inside a human host.

It uses MVA-BN as a delivery vehicle for recombinant vaccines, by taking the MVA-BN virus and adding specific antigens to it, depending on what disease it is destined to treat, according to Li Westerlund, Bavarian Nordic’s vice president of global IP.

Emergency vaccine

Bavarian Nordic’s smallpox vaccine, known as IMVAMUNE® in the US, is currently in phase 3 of clinical trials. Although not yet approved by the US Food and Drug Administration, IMVAMUNE® has received emergency use authorisation so it may be used to treat the general public with compromised immune systems in a terrorist attack.

Bavarian Nordic initially approached the government with its smallpox vaccine. It has now sold 20 million units to the US Emergency Strategic Stockpile, and is currently contracted to develop an improved freeze-dried formula that may eventually replace the stockpiled version.

Its current contracts with the US government for the research, development and supply of IMVAMUNE® are worth $900 million. The company has entered into other development contracts with the government as well. The smallpox vaccine is called IMVANEX® in Europe, where the company has already filed for regulatory approval, and received a positive opinion. Regulatory approval has also been filed for in Canada.

In the pipeline

Bavarian Nordic has a variety of products in its pipeline for the treatment of breast, lung and ovarian cancers, and is developing vaccines to protect against infectious diseases including anthrax and respiratory syncytial virus (RSV).

It works with two patent families: one oriented around the MVA-BN ® virus, and another called VF-Tricom, which covers immunotherapy products CV-301 and the lead programme in the company’s cancer pipeline, PROSTVAC®, a product that targets advanced prostate cancer.

For its immunotherapy division, Bavarian Nordic licensed patents from the National Institute of Health, says Westerlund. The patents had been developed by the US National Cancer Institute, which Bavarian Nordic continues to collaborate with in the development of PROSTVAC® and other cancer immunotherapies.

“MVA-BN is a live, attenuated virus that Bavarian has developed to be replication incompetent, so that it cannot reproduce inside a human host.”

It exclusively licenses the patents covering PROSTVAC® and CV-301, which comprise two portfolios of approximately 27 pending patent applications and 153 granted or issued patents. CV-301, a candidate applicable to more types of cancers, was also in-licensed by Bavarian Nordic, Westerlund explains.

The cancer immunotherapy platform is a big and growing part of the company, she adds. Its products for the treatment of cancer are not prophylactic, as most cancers are not based on viruses such as the human papillomavirus (HPV).

“For HPV you can get a prophylactic to prevent the disease. But other cancers are not caused by viruses so you can’t prevent them by vaccination.

“However, you can use immunotherapy to prolong life and to slow down the disease, which is what we hope for,” she says.

The company manufactures its treatments for infectious diseases in its facility in Kvistgård, Denmark, though it isn’t keen to patent the process.

“We prefer not to patent our manufacturing process,” says Westerlund. “We’d rather keep it as a trade secret, for the obvious reason that once you have a patent, it’s public and you’re giving the recipe to the rest of the world.”

Bavarian Nordic’s trade secrets cover two different methods of vaccine production. The traditional roller bottle method is used for PROSTVAC®, while the company uses a new manufacturing method in its Kvistgård facility.

The patent portfolio

While the PROSTVAC® patents were in-licensed, all patents related to MVA-BN are based on the company’s own research.

Bavarian Nordic has approximately 350 pending patent applications for MVA-BN and more than 750 granted or issued patents. Its IP position gives the company the exclusive right to manufacture, sell and market its MVA-BN-based treatments around the world. Has the company ever been stymied in its patenting efforts?

“I can’t say we have,” Westerlund says. “We have normal dealings with the patent offices so we’ve been very fortunate, and we’ve had good products with patenting. Several companies have done their best to kill them in oppositions, but so far, so good,” she says.

The company’s most significant dispute started in 2005, when it filed patent infringement cases against British pharmaceutical company Acambis (now owned by Sanofi) at the US International Trade Commission and, subsequently, at the Commercial Court in Vienna, Austria, and a theft of trade secrets case at the US District Court for the District of Delaware.

Bavarian Nordic claimed Acambis’ MVA3000 smallpox vaccine, which it was manufacturing in Austria, infringed its patent related to its MVA-BN technology.

The case eventually settled, with Bavarian Nordic granting a licence to some of its MVA patents in return for an upfront payment from Acambis.

There were initially eight companies opposing Bavarian Nordic’s core patent for the vaccine at the European Patent Office (EPO), Westerlund says, with two companies appealing against the Opposition Division’s decision to maintain the patent to the Boards of Appeal.

Westerlund says Bavarian Nordic employs different law firms or patent firms to protect its patents, depending on the jurisdiction and whether the cases concern litigation or opposition. In Europe Bavarian Nordic will go to a patent firm when protecting its patents in opposition proceedings at the EPO and general law firms in arbitrations or if the company would have a case at a European court.

“In Europe it’s divided. In the US you find the prosecutors and the litigators at the same firm. But in Europe you have law firms doing litigation and patent firms doing the prosecution.

“In Sweden, for example, you can’t even hire a patent prosecutor in the law firm—it’s not allowed. In Germany you can—for arbitration cases we use a law firm in Germany, and for our opposition cases we use patent firms,” she says.

In a field where the potential to create profit is plain, does Bavarian Nordic ever encounter imitators? “We have no indication that anyone is copying what we’re doing on the cancer side,” Westerlund says.

“PROSTVAC® is an extremely complex product. It’s complex to make properly, and it’s complex to administer. It consists of two different viruses with prostate-specific antigens and molecules, and practically, it wouldn’t be very easy to copy,” she says.

“The sheer amount of work that would be needed by someone who wanted to copy us will probably make them think twice.”

Bavarian Nordic’s MVA-BN patents are due to expire in Europe in 2020, not counting possible extension based on Supplementary Protection Certificates, and in 2021 in the US, if not allowing for regulatory delays or potential patent term extensions or adjustments for delays at the US Patent and Trademark Office.

Westerlund’s strategy for after they expire, like the company’s manufacturing process, is a secret. But given its strategic importance, perhaps that’s no surprise.