Rush is on for patents on avian flu viruses and vaccines

Geneva, 29 Oct (Sangeeta Shashikant) -- Even as health authorities increasingly worry about the possible occurrence of a deadly avian influenza pandemic, there has been a dramatic rise in international patent applications related to the influenza virus, and vaccines and treatments related to it.

This trend is of grave concern to public health officials and civil society groups in developing countries who fear that patents relating to avian flu will threaten the access of the poor and of people in developing countries to affordable vaccines and treatment.

Many of these countries have been freely sharing avian influenza viruses under the WHO's Global Influenza Surveillance Network, in the hope that they will be able to obtain timely, affordable and sufficient access to vaccines and other benefits to battle a pandemic should it occur.

However, if the viruses or vaccines and technologies and methods to make them are patented, the prices of the vaccines may become higher and other producers may also be hindered from making the vaccines.

A recent research paper titled "Some Intellectual Property Issues Related to H5N1 Influenza Viruses, Research and Vaccines" by Edward Hammond from the US-based The Sunshine Project has revealed a recent spike in the number of patent applications covering the influenza virus (or parts of it), as well as vaccines, treatments and diagnostics.

Until 1993, there had been little or no such patent activity. The paper shows that in

2006 however, more than 30 international patent applications were filed under the Patent Cooperation Treaty (PCT) on influenza vaccines alone, making it the year with the highest number of applications on such vaccines.

World Intellectual Property Organization (WIPO) data indicate that during the first half of 2007, as many influenza vaccine patent claims have been filed as in the whole of 2006, meaning that this year is on track to at least double the record set in 2006.

More than 80% of these applications originate from developed countries, with at least 50% of these applications originating from the US.

The paper also identified 39 PCT patent applications between 2001 and 2007 for medicines, vaccines, microbes, peptides, nucleic acids and immunoassays with the term "H5N1" in the claims. They include patent applications on diagnostics, detection technologies, sequences, etc.

H5NI is a subtype of the Influenza A virus that can cause illness and death in humans and animals, and there are fears that the virus could mutate to be spread through human-to-human transmission, and lead on to an influenza pandemic.

The paper found that 87% of these applications had been filed in the last 18 months (i. e. 14 in 2006 and 20 in the first half of 2007 alone). Patent applicants from the US account for 46% of the applications.

The study reviewed recently published US and international patent data and identified patent applications that cover H5N1 genes, gene sequences (smaller pieces of genes), variations of those genes and their use.

The recent rate of growth of flu vaccine patent applications that make claims specifically on H5N1-type influenza has surpassed that of influenza vaccine claims in general.

Hammond stated that "because of the moving target' nature of influenza, it may be assumed that further claims on recent isolates exist but are not yet available due to delays in submission of applications and publication of patent claims".

The author adds that what is most important are the worrying trends and kinds of claims being lodged. These indicate a near-term (and long-term) future in which H5N1 strains and all manner of technologies related to using them in vaccines will be patented.

The WHO has declared a phase 3 pandemic alert (i. e. with no or limited human-to-human transmission) and has cautioned that the world is now closer to another influenza pandemic than at any time since 1968.

Thus, the recent increased enthusiasm in patenting comes as no surprise, as the private sector and other institutions would see this situation as a profit opportunity.

According to Hammond, "Some increase in patents is arguably to be expected given rising concern about H5N1 and renewed interest in vaccines from major pharmaceutical companies, not only for influenza, but for "biodefence" and (often only from the North's view) emerging infectious diseases".

"The ultimate value of the currently claimed sequences and technologies is uncertain, but if any prove critical to combat a pandemic, it may be enormous", Hammond states in the paper.

This has major implications for who can manufacture the vaccines and other related treatment products, whether there will be sufficient supplies of vaccines in the event of a pandemic, and who can afford the medical products.

In a number of patent applications, companies and other institutions have made proprietary claims over viruses and their parts that originate from developing countries. These include viruses contributed by countries such as Indonesia, Vietnam, China and Thailand, to the WHO-designated collaborating centres and reference laboratories in the Global Influenza Surveillance Network.

These laboratories are national institutions in the US, UK, Australia and Japan that conduct tests to identify the virus strains that become WHO-recommended vaccine seed strains, from which vaccines and diagnostics can be developed. These strains have so far been made available to vaccine developers and other institutions.

The fact that different players in the system have been seeking patents over materials shared in good faith for public health reasons is a matter of serious concern.

Patents grant an exclusive right that means that a patent holder can deny others access to its patented subject matter including gene sequences, research tools, diagnostic kits, vaccines or other products. Concerns about patenting have frequently been raised amongst the international community as it could drastically hamper research and development as well as access to essential medical products.

An example of such a patent application is that made by St. Jude's Children's Hospital from the US, a laboratory designated by WHO to do certain tests.

Its patent application on "Modified Influenza Virus for Monitoring and Improving Vaccine Efficiency", published on 8 February 2007, claims small changes to influenza HA genes. These changes are intended to strengthen the immune system reaction to the genetically engineered virus. This might improve possible pandemic influenza vaccines because people vaccinated may exhibit a stronger immune reaction against H5N1.

This patent application claims any influenza HA gene modified in a certain way. It specifically claims the modified HA gene from an influenza virus isolated in Vietnam in 2004. This is the same strain whose entire HA and NA sequences have been claimed by MedImmune (now AstraZeneca).

The study cited a number of other recent examples of patent claims over genetic material originating from developing countries.

MedImmune (now AstraZeneca) and the US Government have filed a complicated set of national and PCT applications over "Influenza hemagglutinin and neuraminidase variants" that covers sequences from at least 29 influenza strains, in many cases the entire HA and/or NA genes. The patents cover producing influenza vaccines from them by placing the genes, or variants, onto a "backbone" of a lab-adapted influenza strain.

Three applications are relevant to the pandemic discussion. These are: (1) application WO2005116260 that claims the entire HA and NA sequences from viruses originating in Hong Kong and Vietnam; (2) application WO2005116258 that claims a series of 20 H5N1 and H9N2 HA and NA sequences from viruses originating in Vietnam and China; and (3) application WO2006098901, the newest member of the patent family to be published that claims 48 entire HA and NA genes from 24 different Influenza A and B viruses.

In this set of applications, the US government has rights. Some US and international patent applications list government inventors who are employees of the US Department of Health and Human Services (HHS). The US Centres for Disease Control (CDC), a WHO Collaborating Centre, is part of HHS.

Novavax, Inc. (US) has filed a US and PCT patent application over "Functional influenza virus-like particles" (VLPs). Novavax's technique is to place influenza HA, NA, and M1 genes into another virus and to grow the hybrid virus in an insect cell culture. This produces partial influenza viruses ("virus-like particles" - or VLPs).

These may be useful for vaccines because they can, like a whole virus, produce an immune reaction. In some cases, the influenza genes are changed ("optimized") for use in the insect cell system.

This patent application claims any influenza VLPs produced by its cell culture methods as well as specific VLPs. VLPs claimed include those made with HA and NA genes of virus strains from Indonesia and China, as well as VLPs made from sequences 90% or more homologous (close in genetic structure) to those particular sequences.

Another US company, Hawaii Biotech Inc., has US and PCT applications on "Influenza recombinant subunit vaccine".

This patent application, published on 22 February 2007, claims 12 variations on production of a new type of influenza vaccine made in insect cells and H5N1 vaccines made with the technology.

It specifically claims H5N1 genetic sequences from a virus isolated in Indonesia in

2005 and another isolated in China in 1997. It also claims sequences from an H3N2 virus isolated in China in 2002.

Yet another US company, Protelix Inc., filed a PCT patent application (published on 3 May 2007) on "Influenza Combinatorial Antigen Vaccine". This covers nucleotide sequences from influenza HA and NA genes, a method for selecting them, and their use in influenza vaccines.

An advantage that Protelix claims is that it can tailor vaccine composition to the virus strains from a specific geographic area. Protelix specifically claims HA and NA sequences derived from recent H5N1 isolates from Thailand and Indonesia, as well as slight variations on those sequences, for use in vaccines.

According to Hammond, such patent claims for dozens of HA and NA gene sequences used in current vaccines are one way that a microbial resource can be locked up. Another way is a "thicket" of smaller patent claims that gradually leads to an overlapping and confusing mess of claims. Currently, both types of problems are emerging for H5N1 viruses and vaccines.

In his paper, Hammond also explains the "homology fishing" strategy used by patent applicants to extend their patent controls. He states that much of the value of an influenza virus, from a patent perspective, lies in its particular HA and NA gene sequences.

However, as virus sequences change faster than patent applications can be processed, patent applications are trying to reach forward in time, and claims are written in a way that, expressed in plain language, are the equivalent of "we claim this gene and anything like it" (i. e. mutations that have not occurred).

While not entirely new, homology fishing, according to Hammond, may be reaching a new level of importance with influenza-related patents because of the potentially devastating effects of a pandemic.

The race to file patents amidst a public health disaster is not new. It is reported that following the outbreak of Severe Acute Respiratory Syndrome ( SARS'), a form of atypical pneumonia caused by a new strain of coronavirus in 2002, WHO coordinated a team of international scientists and researchers.

These scientists in Canada, Hong Kong and the US were able to sequence the SARS virus with remarkable speed but several of the public research institutions filed patent applications in respect of the complete genetic sequence of the coronavirus.

According to a WHO notification of May 2003, the detailed claims in these applications have not yet been made public but are reported to be sufficiently broad to allow their holders to claim rights in most diagnostic tests, drugs, or vaccines that have been or would be developed to cope with the outbreak.

Some of the university or governmental patent applicants have themselves begun negotiations with commercial partners to develop diagnostic tests and other products. During this time, fears were expressed that prospective patent holders might prevent or limit access to diagnostics, vaccines and pharmaceutical drugs which are being developed by commercial companies to address the SARS virus.

While SARS may no longer be a problem, similar questions have now arisen for influenza.