Ian Frazer's patent problem

As 2006 Australian of the Year, Professor Ian Frazer has become a household name. Famous already in the international scientific community, he has been ranked by readers of Readers Digest as the second most trusted person in Australia, beaten only by fellow scientist and last year's Australian of the Year, burns specialist Dr Fiona Wood.

Frazer is most well known as the inventor of the cervical cancer vaccine, which received approval from the US Food and Drug Administration last month and is set to become commercially available in Australia later this year. Drug giant Merck is already marketing Gardasil to American women on its website.

While this should be a happy day for women all over the world and for the researchers responsible for its development, there is unrest within the international scientific community as to how much credit the individual researchers, including Ian Frazer, should be receiving. The issue reflects recent patent decisions that are causing equal disquiet.

Robert Rose, associate professor of medicine at the University of Rochester in New York, says Frazer has been given too much credit for the vaccine discovery.

"To say that the vaccine was developed in Ian's laboratory is a stretch in the papillomavirus research community," Rose says. "We certainly don't want to take away from the sense of pride that Australia has in Ian's work, but it's not really correct in our view to see the vaccine as something he invented."

The University of Rochester is one of four research institutions claiming to be responsible for original work leading to a cervical cancer vaccine. The other three are the US' National Cancer Institute (NCI), Georgetown University in Washington DC and the University of Queensland. A Georgetown University Medical Center (GUMC) press release issued the day the FDA approved Gardasil explains researcher Richard Schlegel's role in the vaccine's development but says nothing about the other efforts involved.

GUMC claims that the vaccine's technology was generated by a team from the university in the early 1990s and then licensed for commercial development.

"It's a researcher's dream ... to see something that started as a very cerebral idea in the laboratory to advance through animal and clinical trials, gain FDA approval and ultimately have a major global impact," Schlegel says in the press release. "It's highly unlikely but extremely gratifying to see it through so far."

Frazer is rather nonplussed about the claim and counter-claim, but insists he co-invented the vaccine with University of Queensland colleague Dr Jian Zhou in 1991.

"Jian Zhou died in 1999, but he was an equal partner in that transaction," Frazer says. "People like to know who did things first. I'm not quite sure why. But if it makes people feel happy, I think we probably taught people significantly how to do things."

Patent decisions

Frazer and Zhou filed a provisional patent covering their human papillomavirus (HPV) research in June 1991 and presented their findings at a scientific meeting in the US in September that year.

"When Ian made this breakthrough in early 1991, we were aware of what he was doing and immediately indicated our desire to be involved and to support him," says intellectual property consultant John Cox, who works for the Australian biotechnology company CSL. From there, Merck negotiated a deal with CSL to exclusively license Frazer's discovery and also non-exclusively licensed the National Institutes of Health's NCI patents.

GlaxoSmithKline, on the other hand, exclusively licensed patents through the biotechnology company MedImmune from the University of Rochester and Georgetown University, and also non-exclusively licensed the National Institutes of Health's NCI patents.

According to Matthew Rimmer, a senior lecturer at the Australian National University who specialises in intellectual property, what resulted was a "three-way battle between the University of Queensland and CSL Ltd, the University of Rochester, and the National Institutes of Health."

In Australia, despite Frazer's patent being lodged first, a recent decision handed down by the Australian Patent Office found that the scientists at the University of Rochester were the first to make virus-like particles (VLPs) from HPV16, a strain of human papillomavirus found in 50 per cent of cervical cancers.

VLPs contain no viral DNA so they are non-infectious but can be used to stimulate the immune system to produce antibodies to the virus. That makes their production a crucial part of creating an effective vaccine. The Australian Patent Office found that Frazer's patent had not disclosed immunologically correct VLPs from HPV16.

"Therefore the later patent applications could be considered to be novel and inventive in light of the earlier 1991 Frazer patent," Rimmer says. However, Frazer's patent still stands.

"Our patent was granted in Australia, it is the dominant patent in Australia and covers all virus-like particles," he said. "It is a generic patent, so anyone who wants to sell a vaccine in Australia made with virus-like particles has to get a licence to our patent."

Cox agrees. "Certainly in Australia, regardless, the earliest and dominant patent is that granted to Frazer and that patent was not challenged." In the US, Georgetown University was found to have the dominant patent for its contribution to the 'background science'.

"Ironically, the Georgetown patent specifically said they did not produce VLPs," Dr John Schiller, from the National Cancer Institute group that also filed HPV patents in the 1990s, says.

Despite the US patent decision currently undergoing an appeal, an agreement in February 2005 between Merck and GSK means that the cervical cancer vaccines continue to progress to market.

"Because of the level of uncertainty, Merck and GSK cross-licensed the important patents that they held in the area so that each had the ability to proceed to commercialise the vaccine," Cox says. "The whole purpose of it was to make sure that the development of the vaccine wasn't held up by patent squabbling and that has absolutely been achieved."

"Patents are all to do with licenses and making money and selling vaccines," Frazer says. "Which is quite a different business to scientific inventorship."

---PB---

Who was first?

Merck and GSK have independently developed two HPV vaccines. Both vaccines, which are nearly identical, are based on the ability of the L1 protein of HPV to self-assemble into virus-like particles (VLPs).

Merck's Gardasil covers four major HPV strains: 16 and 18, which account for 70 per cent of HPV-related cancer cases, and strains 6 and 11, which cause 90 per cent of genital wart cases.

"Frazer and Zhou did their initial work with HPV16, which is the most important serotype," Cox says. "Subsequently, when they completed their patent a year later, they included further data on ... HPV6 and HPV11, which are the two dominant causes of genital warts in humans." The provisional patent filed by Frazer and Zhou in 1991 and a subsequent paper published in Virology described their discovery of how to assemble VLPs using the L1 and L2 proteins of the human papillomavirus.

L1 and L2 are capsid proteins that make up the outside coat or shell of HPV particles. During early stages of HPV infection, they interact with surface molecules of human cells to gain entry for viral DNA.

"Frazer actually made an error in his first work," Cox says. "He believed that you needed the L1 and L2 capsid proteins to make VLPs for HPV16. But he subsequently showed that you only needed the major capsid protein to make VLPs."

John Schiller says Frazer and Zhou reached an erroneous conclusion that L1 alone does not assemble into virus-like particles. "Both of the vaccines ... are based on L1 only VLPs," he says.

Also, to clone a gene, you need a start codon and a stop codon. These codons inform the cell how long to make a protein. "The reason why Frazer and Zhou succeeded for the first time was that they made a rather interesting breakthrough," Cox says. "They discovered the correct start codon."

Three publications followed Frazer's: Georgetown University, for research which did not make VLPs but showed that L1 was recognised by antibodies; the National Cancer Institute (NCI), which showed that L1 from bovine papillomavirus made VLPs which induced antibodies that prevented virus infection; and Rochester University, showing that L1 from HPV11 self-assembled into VLPs which were later shown to induce antibodies.

A fourth publication in the Journal of Virology in 1993 by the group at NCI showed that there was a so called 'wildtype' and 'protoype' strain of HPV16 and that the wildtype was needed to make functional VLPs.

"There was this belief in the world that Ian Frazer had used the so-called prototype and not the wildtype in making his VLPs," Cox says.

Frazer did in fact use a wildtype, he confirms. "We subsequently showed that and sequenced it and filed that sequence with Genbank and deposited it in a genetic depository in the United States at the same time we filed the patent. So we actually used the right L1 code," Frazer says.

Rose, however, says that if they did use the wildtype sequence, "there's every expectation that their results would have been vastly different".

Credit where credit is due

According to Rimmer, the cervical cancer patent dispute is a battle not only in terms of patent priority but also in terms of the apportionment of scientific credit and kudos between different players.

"In some ways the second issue is really a question for the scientific community to decide in terms of apportioning who should be given the credit," he says.

While all groups involved acknowledge that contributions to the original research into HPV were made by various people, who deserves the most credit may never be resolved.

"I know that there were a large number of people worldwide that worked towards this and it was disconcerting to me as an individual that there was no effort made by Dr Frazer to make a similar acknowledgement," Rose says. "He basically allowed the perception to grow that he was the sole inventor of the vaccine and that's not accurate."

Frazer queries whether it all matters in the long run. "No it doesn't," he says. "We're going to get a vaccine. The vaccine will be of benefit to women. Who invented it probably doesn't matter very much.

"I've had a fair bit of publicity for it in Australia. I'll be the first to admit that that has helped the cause of medical research in Australia no end at all. The money will come in large measure to Australia and that's also good, because it helps to argue a case for more funding for medical research (here)."