Immunocompetent

H5N1 Related Patent Activity: An Updated Overview

perezoso — Tue, 23 Sep 2008 10:39:26 -0500

Although some, like US and European governments, would like to pretend it isn't happening, it's no secret that there has been a huge increase in international patent applications claiming bits and pieces of H5N1 viruses and related vaccines and other treatments.

The overall trends can be monitored by searching on PatentScope, a free international patent application database published by the World Intellectual Property Organization (WIPO). If you are new to patents, it might be intimidating at first - patent talk is not plain English - but with a bit of experimentation, searching PatentScope is something anyone can learn to do.

There are three such searches that I have been monitoring for nearly two years now. The results aren't pretty, and they are getting worse. The tidal wave of H5N1 patent claims shows no signs of abating, and is on track in 2008 to meet or exceed 2007, which was already the biggest year of such patent claims on record.

The trend is clear: An emerging "patent thicket" threatens to impair H5N1 research and make vaccines and other treatments unaffordable. But don't count on the US or European governments doing anything about this - they're still in denial mode.

The first search is a simple query of the International Patent Classification for influenza vaccines (PCT Class A61K 39/145). This search includes seasonal and animal vaccines. Here's the result (click on the image to enlarge):

In 2007, there were 54 patent publications on influenza vaccines. (Patent applications are published months or even years after they are actually filed) In 2008, to date, 33 new patent applications have appeared. Over 36% of all applications since 1983 for influenza vaccines (118 of 326) have been published since 1 January 2006. If this isn't a hug increase in patent claims, what is?

The second search is a bit more specific. It is a search of the same patent class, except restricting the results to those applications that contain the term "H5N1" in the patent claims (a specific and most important part of the application). Understand that you can still patent an H5N1 vaccine without specifically mentioning H5N1 in the claims (e.g. a vaccine against all influenza A types); but the appearance of H5N1 in the claims gives some potential indication of the intent of the applicant:

Here an interesting thing to immediately note is that although H5N1 first appeared in 1997, there was only one patent application matching the search until 2006. There is recent dramatic growth in H5N1-related claims. In 2006 there were five claims, followed by eleven in 2007, and seven in 2008 to date. US and EU companies account for nearly all applications (see below).

The third search broadens the horizon beyond vaccines. It includes vaccines, medicines, diagnostics, genes, and pieces thereof wherein the term H5N1 appears in the claims. (Geeks: PCT Classifications A61K/P, C07H/K, C12N/Q, G01N.) Here again, there is a tremendous spike in patent claims:

The amazing thing here is that between 1983 and September 2008, 102 total matching patent applications were published, and of these applications, 83 were published after 1 Jan 2007. That is, more than 80% of the matching patent applications over the last nearly 25 years have appeared in the last 18 months.

And where do these patent applications come from? Hint: It's not the Indonesians that are making proprietary claims over H5N1 viruses, it's the Americans and Europeans. A whopping 53% of these patent applications originate the US, and most of the rest come from Europe. What little is left over primarily comes from Australia, Japan, and Singapore.

The results here speak for themselves. Developing countries like Indonesia are not the people trying to privatize H5N1. In fact, the real culprits of ownership claims over Bird Flu are the companies and government labs of Europe and North America.

Are CDC's PR Hacks Lying about Patent Claims?

perezoso — Wed, 27 Aug 2008 07:45:35 -0500

If secondary sources are to be believed, such as this one, then CDC's PR hacks have sallied forth with a pack of lies about their patent claims on Indonesian, Thai, and other H5N1 genes, which were first brought into the public eye by this blog.

There are two main arguments that CDC has been quoted to me as making with respect to my article and related items that have come out in the press. I will refute both of CDC's claims.

First, CDC is said to have rather remarkably claimed that they aren't part of the patent application. This is patent bullshit, as I will show. Secondly, and somewhat contradictorily, CDC's hacks are said to claim that the patent application is (to paraphrase), "for a vaccine and not a virus, so the Indonesian and other strains aren't claimed." This too is wrong. To demonstrate that, I will walk readers through the text of one of the (many) claims, so you can read it for yourself. The claims analysis is a bit tedious; but it's not rocket science. Wade through it, and you will be rewarded with a clear explanation of why CDC is wrong. We'll deal with the CDC arguments one by one:

First, CDC is said to have bizarrely claimed that they aren't part of the patent application. This would be a remarkable thing for the CDC hack to say, because CDC is indicated as a patent applicant on the first page of patent application (quoting directly):

APPLICANTS: THE GOVERMENT OF THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES [US/US]; National Institutes of Health,, Office of Technology Transfer, 6011 Executive Blvd., Suite 325, Rockvillle, Maryland 20852-3804 (US) (All Except US).

THE GOVERMENT OF THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES [US/US]; Centers for Disease Control and Prevention, 4770 Biford Hwy (K79), Atlanta, Georgia 30333 (US) (All Except US).

Clear as can be. Is there really a need to say more? There shouldn't be; but I'm afraid there is.

That's because an ancillary argument that the CDC hacks are said to be advancing is that the US National Institutes of Health (NIH) is really responsible for this and CDC should not be held accountable for its name on the patent.

Off the top, I find it very hard to believe that a patent application can be submitted in CDC's name without CDC knowing about it. But more importantly, this CDC red herring needs to be put into context. Both CDC and NIH are part of the US Department of Health and Human Services (i.e. the health ministry). CDC hosts the WHO Collaborating Centre, and both it and NIH conduct flu research. And while it is true that most of the inventors listed in the application are from NIH, it's more than slightly disingenuous for CDC to try to beg off by foisting the blame on its HHS sister institute. In the international context, it's simply not credible to have one half of the health ministry (CDC) saying "no patents", while it is passing the material to the other half of the health ministry which is patenting away. So, in many senses, whether it is CDC or NIH or both is immaterial, because they are ultimately part of the same organzation (HHS) that has a WHO Collaborating Centre.

Turning to the claims analysis: CDC's hacks are said to have claimed that the patent application is (to paraphrase), "for a vaccine and not a virus, so the Indonesian and other strains aren't claimed."

The government spokesman bullshit detector of anyone with a whit of common sense would start ringing loudly just looking at the cover page of the patent (click it), which has an illustration of a genetic construct, claimed in the patent, that incorporates the "codon optimized" HA gene of A/Indonesia/5/05. It even says so right on the picture.

Could it be any clearer? Not really; but just be sure, we can turn to the most important part of patent, the claims, where the applicants specifically articulate the alleged invention that they are seeking patent for. Typically (but not always), the first claims are the most important in a patent. Let's turn to Claim 1 of the CDC/NIH application:

	WHAT IS CLAIMED IS:

		1. A nucleic acid molecule comprising a polynucleotide encoding an influenza
	protein selected from the group consisting of hemagglutinin A (HA),
	neuraminidase (NA), M2 Protein, and nucleoprotein (NP), wherein said
	polynucleotide comprises
			 
	(a) a plasmid taken from Table 1 (or its insert), or
			 
	(b) an analog of said plasmid or insert having at least 95% identity thereto.
	 
	
The first thing to note about this claim is that it is a claim on matter. That is, it is not merely a claim on the use of a particular type of matter (not that that would make it innocuous), it is a claim to the thing itself, full stop. Specifically this claim is for any polynucleotide (i.e. DNA or RNA) that encodes specific polypeptides (i.e. proteins), including some specific HA, NA, M2, and NP genes from influenza. And for good measure, anything 95% or more like them.

But which specific DNA or RNA is claimed, it's not spelled out explicitly in the quote above? Good question.

And what does that phrase "or its insert" mean? Another good question.

If you read the claim again, you will see that determining what specific DNA / RNA is claimed requires referring to "Table 1", and looking at the patent text in order to establish what "insert" means in the context of this patent application.

The meaning of insert can be quickly clarified. It is this: The plasmids refered to in Claim 1 are longer DNA constructs designed as vaccines, and which are pieced together with genes from multiple organisms. The picture on the cover page (click above) is one of these plasmids. The "insert" is/are the influenza pieces that are placed into the longer plasmid. Mostly "codon optimized" HA genes that have been copied into DNA from the viral RNA.

So, what's specified in Table 1? I have extracted Table 1 from the patent application, and you can click here to read it yourself (PDF format). It is 6 pages long, and includes no fewer than ~~151~~ 150 separate genetic constructs claimed by NIH/CDC, most of which are either "plasmids" or "inserts". (Remember that the plasmids are claimed in their entirety, including the inserts... which are also claimed apart from the rest of the plasmid.)

If it's a plasmid or an insert in Table 1, then it is claimed. On the first of the 6 pages of Table 1, there are 8 different constructs incorporating Thai H5N1 genetic material and one plasmid incorporating (i.e. with an "insert") of Indonesian genetic material. On the second page, there are 4 more constructs with Thai material. On the third page, there are 6 plasmids with Chinese (Hong Kong) genetic material, 2 with sequences from South Korea, and another Thai one. On the fourth and fifth pages there are 8 more with Thai genenic material. On the sixth page, there are 2 constructs with Thai genetic material, 6 with Hong Kong genetic material, and 2 with South Korean genetic materials.

The Indonesian construct ("VRC 9123") is the first listed and is the exemplary construct of the invention. Also, because the Indonesian HA gene is an "insert", it is claimed both as part of the VRC 9123 plasmid and by itself, alone. The same holds true for the other H5N1 inserts in Table 1.

Then NIH/CDC goes a step further, and says anything 95% or more like those genes is also claimed.

I hope that clarifies the nature and scope of CDC's patent claims. If CDC representatives have been accurately quoted as saying that they are not part of the patent application and that the application in any event does not claim Indonesian (and other) H5N1 materials, then the CDC representatives are spreading clearly false information, and the leadership of CDC should be reprimanded for permitting them to do so.

[Edited for clarity - 27 Aug PM]

Synthetic Influenza and In Silico Collections

perezoso — Fri, 15 Aug 2008 09:24:43 -0500

This post is really about synthetic biology and influenza; but I want to start by clarifying one thing: If I were free to decide, I'm pretty sure that I would not enshrine into law sovereign rights over creatures great and small.

But I don't get to make the rules, nor do virologists (and not even The Imperial Laurie Garrett, heretofore "TILG", no matter how intolerably super-sized her ego gets). Maybe in another post, on another day, I'll explore how the present legal and treaty situation came to be; but that's not the point now. Instead, let's make the best of the hand we've been dealt. Hint: Folks searching for a gene sovereignty bogeyman can blame, in significant measure, the large mainline environmental organizations.

Today's ugly bellyaching about sovereignty and microbes in the flu science crowd is pretty much identical to the whining I heard over a decade ago from agricultural researchers and other kinds of biologists. The latter groups have mostly stopped complaining and are instead learning to live with reality. Live productively and happily even. Unfortunately, the flu science crowd (with ample corporate encouragement) is stuck in some retrograde 1980s intellectual trickle-down time warp.

The issue I want to point out today is that of in silico collections. If you know the Biodiversity Convention, you probably get my reference. An issue that has bedeviled that treaty are questions about sharing the benefits from use of plants and other types of life found in "ex situ collections". These are your botanic gardens, seed banks, microbial repositories, etc. Questions like this: Say Kew Gardens in the UK has mounds of Malaysian rainforest trees and, hypothetically, one of them turns out to hold the permanent cure for 'erectile dysfunction'. Say Kew (and its corporate collaborators) make a fortune selling it to rich old men that can't get it up.

Is anything owed to Malaysia? It often is even more complicated: What if some Malaysian indigenous people used the plant as an aphrodisiac, helping Kew identify the drug. They're getting their homeland bulldozed while some pharma exec is buying a new yacht AND entertaining his girlfriend.

There certainly are ex situ collections of influenza - mounds of frozen vials in Memphis, Atlanta, and many other places. Who they belong to is a good question. Some labs seem to consider them personal property. This is undoubtedly wrong. Another topic for another day. I still haven't gotten to today's point...

Interestingly, with advances in synthetic biology, the most important ex situ collections of influenza may be in silico collections. I mean computer data. That's because with reverse genetics and advances in gene synthesis, it is becoming increasingly easy - a matter of a few days now, if in a hurry - to download a flu virus sequences and create the actual living bug. Of course, keeping the original isolate in the freezer somewhere will remain prudent; but for many functions, viruses (and genes and their parts) assembled from internet sequence data will come to replace sharing of actual physical viruses. For example, reverse genetics-produced H5N1 is already used as a challenge agent in vaccine trials (with animals, obviously), indicating the high level of confidence that some researchers have in the ability of the technology to faithfully reproduce the natural bug.

Not only do internet databases form a set of in silico collections from which the original biological article can be reproduced; but they also provide the grist for increasingly sophisticated sequence analysis tools. Remember that very small, even single nucleotide, mutations can make a world of difference in flu strain pathogenicity for chickens, cats, or even humans. Applying predictive analytical methods to the sequence data, therefore, may eventually produce genetic "riffs" on H5N1 particularly useful for vaccines (or to produce so-called "virus-like particles"). There are products in development that use this approach.

So, in a few years, it is entirely plausible that we will have influenza research labs that don't generally receive strains in biological form. They download them. Or point their gene synthesizer (or gene synthesis company) to a URL and, from there, the process is more-or-less automated. Make the genes in the lab, or have them synthesized, put them into well-known and standardized DNA plasmids, and let the strains assemble themselves in culture. Granted that doing it is not as easy as saying it; but it's not going to stay hard for long. Flu isn't a big organism. It has about as many letters in its entire genetic code as there are on the front page of each day's New York Times (~12,500). There are parallels here with the "biological parts" concept that the eager-beaver synthetic biologists are promoting, some of whom are also tied up in questions about intellectual property.

This presents a lot of problems when it comes figuring out how to make the virus sharing system more equitable. If labs and companies are only required to share benefits when they receive the virus in biological form, it will only propel them to develop their synthesis capabilities more quickly. Why "pay" for the virus, by receiving a physical specimen, when you can make it with no strings attached? Clearly, if it has any hope of success, the WHO system is going to have to confront the in silico collection issue head-on.

It's one of trickiest aspects of reforming the WHO system. Excluding a few problematic sequence hoarding labs, almost everyone agrees that influenza sequence data should be available to all. So, how do you make it available without encouraging proprietary claims and piracy? More inquiring minds than mine are thinking about this issue. It may prove that other areas, particularly writing and computer science, will offer adaptable models for how one can 'get things out there' without getting ripped off.

Flu Patent Claims: What planet do some people live on?

perezoso — Tue, 12 Aug 2008 09:13:19 -0500

What planet do the people who claim that flu vaccines aren't patented live on? If they lived here on earth, then a quick search would tell them that there are numerous patent claims on H5N1 and other flu strains, frequently on viral sequences used in possible vaccines.

This morning I ran a quick a search on the World Intellectual Property Organization's PatentScope database for patent applications on (all) influenza vaccines. (Nerds: Int'l Class A61K 39/145.) The graphic above illustrates the result.

Yes, earthlings, there is a huge spike in patenting of influenza vaccines. A lot of it has to do with the move away from egg-based technology, in part because of the particular difficulties presented by H5N1.

But do some of these patent claims actually grab virus genes that were sent to the WHO system? You bet they do.

One of the worst offenders, MedImmune (now part of AstraZeneca), has claimed dozens of H5N1 sequences as its "intellectual property". To show that, I'm including here a page from one of MedImmune's patent applications indicating sequences it claims.

Vaccine patents will be frequent topic at this blog and this post is just to introduce the theme. For a more comprehensive analysis prepared last year, you can click here (PDF download). But patents are moving so fast, even that 2007 paper is now dated. There are dozens more patent applications out there now.

Quick Sketch of a New Global Virus Sharing System

perezoso — Mon, 11 Aug 2008 16:36:23 -0500

Back when I ran the Sunshine Project, and with the help of Third World Network, I wrote a brief item describing how the WHO Global Influenza Surveillance Network could be reformed. We distributed this at a meeting of the WHO Pandemic Influenza Preparedness Intergovernmental Meeting (WHO PIP IGM). (Yes, it's a mouthful.)

The jist of the following nearly year-old article is still about right. I should have given more attention to sequence data, with the rapid rise of synthetic biology; but it's there in rudimentary form. Take a gander at this short piece if you want to know what some of us are thinking about for a New Global System.

Third World Network
The Sunshine Project

INFORMATIONAL HANDOUT

November 2007

Intergovernmental Meeting on Pandemic Influenza Preparedness: Sharing of influenza viruses and access to vaccines and other benefits

A Quick Sketch of a New Global System for Sharing of Influenza Viruses

In the interest of public health and access to affordable medicines, a new international system is needed for the sharing of influenza viruses. The purpose of this short paper is to describe, in simple terms, the basic principles and methods of operation of such a system, without delving into great detail about problems with the present system. Here some important underlying concepts for the new Global System are presented, followed by a practical description of how it would operate.

In this document, viruses are understood to include sequences, virus genes and proteins (and subunits of both), as well as materials specifically derived therefrom, such as antibodies and complementary DNAs (and genetic constructs encoding the same).

The Global System must not allow patenting of influenza viruses. A fundamental problem currently is that transfer of viruses into the system is resulting in piracy of influenza viruses by companies and other labs, and even by some WHO Collaborating Centres themselves. These patents are ethically unacceptable and ignore the rights of donor countries and influenza victims. They will result in economic and social injustices including more expensive and less accessible treatments. Therefore, all transfers of biological materials and data into and out of the WHO system, including publication of sequence data, shall be with the legal stipulation that these items shall not be subjected to intellectual property claims.

The Global System must respect national sovereignty over influenza viruses. Sovereignty over genetic resources found within a country’s borders is established in international law and most prominently enshrined in the Convention on Biological Diversity.(1) Sovereignty should not be confused with ownership. Respecting sovereignty does not mean that a government owns influenza viruses occurring within its borders, rather, it means that the government has rights in determining how they are used. These rights must be preserved and applied when the viruses are transferred into and out of the Global System.

Specifically, in the new Global System, sovereignty means that governments must grant their prior informed consent to uses of the viruses that they contribute. For key functions such as surveillance and development of vaccine seed strains, this prior informed consent can be pre-negotiated and applied in the form of an agreement like those already routinely used for transfer of biological research materials. For other purposes, including commercial ones, it may be necessary to specifically request consent from the donating country.

The Global System must require the commitment of all participants to the fair and equitable sharing of benefits that arise from influenza virus research. The Global System must provide real, tangible benefits to participating countries, particularly developing countries, who receive next to nothing in return of participating in the current system. This would be the best way to avoid frustration with the system, which in turn could lead instead to mainly bilateral arrangements. The precise benefits will vary depending upon the situation, however, under the umbrella of the New Global System, for developing countries they may include: (1) free access to and assistance with vaccine production such as equipment and know-how (e.g. cell culture systems and adjuvants), (2) vaccine stockpiles under WHO physical control which would be distributed on the basis of public health needs, (3) free or discounted set-asides of a percentage of prepandemic and pandemic vaccine production lots; (4) free or discounted access to other influenza medicines, and (5) commitments of non-enforcement of influenza-related intellectual property rights. How would a New Global System operate? As a practical matter, there would be a number of major changes from the current system for sharing influenza viruses. These include:

Rewriting the terms of reference between WHO and the Collaborating Centres and enforcing them. Current WHO Collaborating Centres are governed by loose and unenforced arrangements. Because of intense commercial interest in influenza viruses and actual and potential conflicts of interest at some Centres, the terms of reference must be radically revamped. In particular, WHO itself will assume responsibility for virus use and transfers, meaning that in these areas, the Centres will no longer have any latitude to do as they see fit. In those matters, they will act only on behalf of WHO and only as specifically authorized in the new Terms of Reference. This means that transfers of virus into and out of the Centres will effectively be governed by the terms of agreement between donor countries and WHO and not ad hoc or peculiar arrangements, or lack of arrangements, between the Centres and donor countries.

In general, movements of viruses will be covered by Material Transfer Agreements.Presently, no such agreements are executed between donor countries and WHO Collaborating Centres meaning that, in effect, the viruses are a no-strings-attached gift from developing countries to the Centres, for the Centres to treat as they see fit. As benefits have not been shared and this practice has led to piracy, this unacceptable situation must be changed, and WHO must no longer tolerate, endorse or encourage it.

Material Transfer Agreements under the New Global System could be of three general types – 1) those from a country of origin to a WHO Collaborating Centre, 2) those of virus seed stock from a WHO Collaborating Centre to a vaccine manufacturer, and 3) all other transfers. The first two transfer types can largely or even completely be governed by pre-negotiated terms elaborated in a standard form.

Such Material Transfer Agreements are not onerous and are by no means unprecedented. In fact, similar MTAs are already the norm for transfers of biological research materials in developed countries. In many cases, MTAs already commonly used for influenza virus transfers between Northern institutions are more restrictive than those likely to emerge under a New Global System.

In the case of a standard MTA between the country of origin to a WHO Collaborating Centre (acting on behalf of WHO), the main purpose is to authorize the Collaborating Centre to perform its important responsibilities (such as identification and characterization of the strain) set forth in the Centre’s Terms of Reference and to preserve national sovereignty over the virus. /Such MTAs will make stipulations and preserve sovereignty in the event of transfers to third parties beyond the Centre that, in most cases, will require execution of a new MTA between the third party and the country of origin. In some cases, for example transfers between Centres and reference labs, or for research by a third party contracted to a Collaborating Centre for research in accordance with the Centre’s WHO Terms of Reference, there may be latitude for transfer for those purposes under the first MTA.

In the case of a standard MTA between WHO and a vaccine manufacturer for transfer of vaccine seed strain, the main purpose is for the vaccine manufacturer to obtain authorization from the country / countries of origin of the seed strain virus and for the manufacturer to make commitments for benefit sharing as pre-negotiated under the umbrella of the New Global System (as described at the top of page 2). This MTA will enable the manufacturer to use the seed strain for vaccine production or further development for vaccine production and will bind the manufacturer to fair and equitable sharing of benefits.

In the case of other transfers, prior informed consent of the donor country will be required, and execution of a new MTA with the country of origin will be necessary if requested by the donor. These include transfers of viruses that are not vaccine seed strain to companies, and use of virus by the Centres in ways not specifically authorized by the Terms of Reference. Because these transfers may be to very different kinds of institutions for widely varying purposes, no complete single set of terms may be applicable. WHO, governments, scientists, and NGOs should discuss these transfers with a view to establishing standard procedures and boilerplate MTA language, which perhaps may evolve into standard MTAs in the future. Importantly, setting final definition of terms of some of these types of transfers aside for the time being will not prevent establishment of a New Global System.

WHO Collaborating Centres and other entities will renounce influenza-related intellectual property claims as a condition of their participation in the New Global System. These include claims on viruses, genes, sequences, proteins, and their use in human and animal vaccines and diagnostics. This will ensure the availability of the system’s resources and outputs for public health uses. In the current system, some Collaborating Centres have made patent claims or argue that they should be made "defensively". "Defensive" patenting is not a solution, it is a symptom of the problem of privatization. Instead of worsening the condition by increasing the amount of patenting, the New Global System should renounce it, and seek to inoculate its resources and products from such claims.

Access to New Global System sequence data will not be impeded, and subject to the first MTA can be made available online. Important conditions will include that all data be available to all persons, and that all who access it must agree not to sell or make any type of proprietary claim to it or for its use. Models of these types of systems can be found for software and other media and these can be adapted for use with New Global System sequence information.

Virus transfers will be comprehensively tracked by WHO, which will maintain a database of them as it will be advised of all such transfers by virtue of its revised relationships with the Collaborating Centres. This data should be available to Member States and the public.
Donor countries will have certain other research-related rights, including those of immediate material return and provision of characterization data, other research results and publications.

Footnote: (1) It has been suggested by some that influenza viruses do not fall under the Biodiversity Convention because they are a potentially harmful type of genetic resource that humans seek to control. This is not only an incorrect assessment of the language of that treaty, in fact, the operations of the Global System and influenza research are very clearly aligned with the intent of the CBD. The collection, obtaining, distribution, and preservation of influenza diversity is a core purpose of the Global System, as that diversity is critical to treating influenza. The fact that governments value such diversity and its preservation is illustrated by the extreme lengths that have been resorted to in order to recreate the 1918 influenza virus.