Genomics in the public domain

Genomics in the public domain: strategy and policy

Nature Reviews Genetics 1, 70-74 (2000)

SCIENCE AND SOCIETY

URL: http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrg/journal/v1/n1/full/nrg1000_070a_fs.html

Rebecca S. Eisenberg

Rebecca S. Eisenberg is the Robert & Barbara Luciano Professor of Law at the University of Michigan Law School, Ann Arbor, Michigan 48109, USA. rse@umich.edu.

The public domain has been conspicuous in media accounts of public

and private sector initiatives to complete the sequence of the human

genome. The issue of whether the human genome will be freely

available to the public or privately held as a proprietary resource has

captured the attention of the scientific, trade and popular press, the

financial markets, and even heads of state. Although some media

commentary has framed the issue as a conflict between ethics and

greed, strategic considerations go a long way towards explaining the

timing and quality of information disclosures on both sides of the

public–private divide.

Some descriptions of the relationship between Celera Genomics

Corporation and the Human Genome Project have painted a

black-and-white picture of a private firm racing to profit from patents while

the publicly funded project struggles to keep the genome in the public

domain. In fact, both sides of the picture are variegated. Even as it has

built a proprietary database and filed patent applications, Celera has

repeatedly promised that it will eventually make the raw sequence of the

human genome available to scientists free of charge1, although the timing

and details of this commitment are unclear and seem to have shifted. At

the same time, although the public sponsors of the Human Genome

Project have consistently affirmed the importance of prompt and free

public access to raw genomic sequence data ( Box 1), the United States

government reportedly holds more patents on DNA sequences than any

private firm2. Public and private strategies for publication and patenting

have overlapped throughout the brief history of genomics research3. An

important factor contributing to this convergence has been the policy of

the United States government, beginning with the passage of the

Bayh–Dole Act of 1980, to promote the patenting of

government-sponsored research results4. This policy has added strategic

complexity to decisions concerning public disclosure of research results, as

both academic and private institutions have become increasingly mindful

of the interaction between the public domain and the patent system.

Meanwhile, the increasing scientific significance of private sector research

accomplishments has underscored the importance of timely publication of

research results in both the public and private sectors.

What motivates these different players

to disclose information to the public? How

do the missions and priorities of different

institutions in the public and private

sectors affect the timing and quality of

their disclosures?

Reasons for disclosing research results

Scientific recognition and credibility. A

perennial motivation for publication of

new research results is to stake claim to

scientific achievements, thereby

triggering recognition. Public disclosure

subjects research results to scrutiny,

exposing errors and promoting

confidence in the validity of the results. It

also establishes a priority date for

purposes of scientific recognition. These considerations are particularly

important for controversial research claims and for disputed claims of

scientific priority in a close race.

The goal of scientific recognition undoubtedly motivates both academic

and private sector researchers involved in sequencing the human

genome. The sponsors of these research efforts depend on access to top

scientific talent and cannot afford to ignore the motivations of scientists to

achieve recognition in the scientific community. Rivalry for scientific

recognition has been aggravated in this particular context by past

statements from each side that the other is pursuing a scientific strategy

that will not permit satisfactory completion of the job5, 6.

This may be an important reason why Celera, although hoping to profit

from selling access to proprietary DNA sequence databases, has

nonetheless consistently promised to make the raw sequence of the

human genome freely available. Without such public disclosure its claims

to priority will be impossible for the scientific community to assess.

Researchers have expressed scepticism in the past about the claimed

accomplishments of private DNA sequencing firms that do not make their

data publicly available7. The scientific community gives more credence to

claims backed by publicly accessible data than to claims backed only by

press release and rumour.

Scientific credibility is also cited by members of the SNP Consortium (Box

2) as a motivation for making single nucleotide polymorphisms (SNPs)

publicly available. The pharmaceutical firms in the SNP Consortium hope to

use SNPs as pharmacogenomic markers to develop drugs for which safety

and efficacy depend on genotype. Regulatory approval for such products

is likely to depend on the reliability of genetic screening tests that predict

drug responses of particular patients. Consortium members hope that it

will be easier to win approval if the tests use markers that are in the

public domain, and are therefore subject to challenge and validation by

the scientific community8.

Publication to the scientific community is inconsistent with long-term

secrecy, but it is not inconsistent with patenting. Patent disclosures are

made freely available to the public once the patent issues under United

States law, and pending patent applications are made public 18 months

after their filing dates in most of the world. Even before public disclosure

through the patent system, institutions may permit scientists to publish

while still preserving patent rights if they coordinate the timing of

publication with the filing of patent applications. In most of the world,

disclosure of an invention in a publication before patent filing results in a

forfeiture of patent rights9, but United States law permits the filing of a

patent application up to one year after publication10. So publication of

research results is no guarantee that the results are free of intellectual

property claims, nor is forfeiture of patent rights a condition for scientific

recognition.

Widespread dissemination and use. Apart from concerns about

recognition and credibility of research claims, some institutions might

choose to disclose DNA sequence information in publicly available

databases in order to promote widespread dissemination and use. Free

access is particularly important for encouraging users with limited financial

resources (such as academic researchers), who might otherwise be

unable to gain access to past discoveries for use in future research. In

addition to eliminating licence fees, free availability minimizes transaction

costs by eliminating the need for owners and users to find each other and

negotiate licences.

Apart from advancing the public interest in promoting future research, free

access might also advance the financial interests of its champions. For

example, the public sponsors of the Human Genome Project are also likely

to sponsor future research that makes use of genomic information. If the

information is held in proprietary databases or can only be used under the

terms of licence agreements, these research sponsors might expect to

pay more in the future than they would if the information were in the

public domain.

Some private research sponsors might also believe that it serves their

financial interests to promote widespread access to DNA sequence

information by putting it in the public domain. Life sciences firms that hope

to profit from developing and selling new products, such as drugs and

crop seeds, might expect to earn more profits sooner by accelerating

progress in fundamental biological research, thereby bringing new

commercial products into view. Rather than trying to do this fundamental

research themselves — an expensive job at which they have no

comparative advantage — they might prefer to let academic scientists do

the research with public funds. To the extent that free access facilitates

pre-market research in universities, these firms may find their interests

aligned with the interests of public research sponsors in promoting free

disclosure of DNA sequence information in the public domain. This may

explain why Monsanto recently decided to release a rough draft of the rice

genome in the public domain11, and why Merck was willing to invest in

university-based research to generate a database of expressed sequence

tags (ESTs) for the public domain12.

Defeating potential patent claims. Another consideration that seems to

be motivating public disclosures of genomic information by some

institutions in both the public and private sectors is a wish to prevent

patenting of DNA sequences. This seems to be one factor driving the

requirement that publicly funded investigators deposit all newly identified

DNA sequences and mutations in the publicly accessible GenBank

database within 24 hours under the 'Bermuda rules' (Box 3). This

accelerated timetable, which makes it difficult for grantees to get patent

applications on file before public disclosure, also leads to the prompt

creation of 'prior art' that could defeat potential patent claims of others. A

subsequent inventor cannot patent something that was already publicly

disclosed before the patent claimant discovered it13.

Of course, the requirement for prompt deposit in the public domain could

be justified as a way of giving the scientific community the benefit of free

access to as much sequence information as possible as quickly as

possible, without invoking an anti-patent motivation. But the Bermuda

rules are not the only evidence of an anti-patenting norm for raw DNA

sequence information within the Human Genome Project. The National

Human Genome Research Institute has explicitly discouraged grantees

from pursuing such patents ( Box 4).

The creation of prior art may prevent the issuance of patents not only on

past discoveries that are publicly disclosed, but also on future discoveries

that become obvious in light of past disclosures14. This raises the

possibility of publishing early research results as a strategic move to

pre-empt the patenting of future discoveries by commercial rivals15, 16. It

might even be possible for a firm that is lagging in a race to forestall the

patent claims of a swifter rival through publications that enrich the prior

art enough to limit what may be patented in the future. This possibility

might explain why it is often the laggards rather than the leaders in DNA

sequencing races that sing the praises of the public domain. So, for

example, when Merck decided to sponsor the Merck Genome Initiative, at

least two private firms already had a significant lead over Merck in

generating private databases of ESTs17. By putting ESTs in the public

domain, Merck may have hoped to create prior art that would defeat

future patent claims by these or other firms to the corresponding

full-length genes, although it now seems unlikely that this strategy will

prove successful18, 19. The creation of patent-defeating prior art is an

acknowledged part of the strategy of the SNP Consortium. Again, the SNP

Consortium entered the race late, after numerous other private sector

SNP discovery efforts were well under way20. Under these circumstances,

patent-defeating publication may have seemed like the best hope for

Consortium members to preserve future access to information that would

otherwise become proprietary. But if the patent-defeating goal dominates

the goal of prompt dissemination of information, prompt publication in the

public domain may not be the best way to proceed.

In fact the SNP Consortium , in contrast to the Merck Genome Initiative

and participants in the Human Genome Project that comply with the

Bermuda rules, does not publish all of its information as quickly as

possible. Instead, it uses a patent law device called a Statutory Invention

Registration (SIR) to create prior art while delaying publication ( Box 2).

The mechanism for creating prior art before public release is codified at §

157 of the United States Patent Act. This provision authorizes the United

States Patent and Trademark Office (PTO) to publish a patent application

that has been converted to a SIR, without examining it for patentability, if

the applicant waives the right to receive a patent on the invention within

a specified period of time. A SIR has the 'attributes specified for patents',

but does not include the right to exclude others from making, using,

selling or importing the invention21. One attribute of a patent is that it is

effective as prior art for purposes of defeating the patent claims of other

applicants as of its filing date22, even though it might not be published for

some time thereafter. It is therefore possible to file a patent application

describing a discovery, wait a while before converting it to a publicly

accessible SIR, and have the SIR count as prior art as of its filing date,

even though the disclosure was not yet published on that date. Through

the use of this device, the SNP Consortium hopes to create prior art that

will prevent subsequent inventors from patenting their newly identified

SNPs, while deferring disclosure of the SNPs until after they have been

mapped. This strategy for prior art creation combines the benefits of

disclosure with the benefits of nondisclosure.

Reasons for withholding results

Institutions in both the public and private sectors may have compelling

reasons for withholding research results from disclosure. How these

reasons are balanced against the reasons for making disclosure will vary

depending on the priorities of the institution.

Retaining exclusive access for customers. An obvious reason to

withhold commercially valuable information from public disclosure is to

preserve its value for sale to paying customers. Nobody wants to pay for

something that they can get free. Firms like Incyte Genomics and Human

Genome Sciences that seek to profit from selling access to proprietary

databases are therefore understandably reluctant to give the same

information away free in public databases. Why, then, is Celera promising

to make the raw sequence of the human genome freely available?

Sometimes limited disclosure of information in the public domain is

consistent with selling a proprietary information product that offers further

value over the public domain version23. Celera's paying customers gain

access to sequence data before the public-release version becomes

available, as well as getting annotations and proprietary bioinformatics

capabilities that will not be released in the public domain.

Avoiding disclosure to rivals. Another reason to withhold information

from publication is that public disclosure lets your rivals know exactly what

you have accomplished and gives them the benefit of what you have

learned so far. This seems to be a concern for both public and private

sector researchers involved in sequencing the human genome. Celera has

cited concern that competitors will repackage their data and sell it in

competition with them to justify restrictions on use of the version of the

human genome sequence that they promise to make available free of

charge24. For their part, some participants in the public sector Human

Genome Project feel aggrieved by Celera's inclusion of data that they

themselves deposited in GenBank in its claim to have completed the

sequence of the human genome. Some scientists are particularly

indignant that Celera's publications might include data deposited in

GenBank by academic investigators who would not be included as

co-authors25.

In a race to accumulate information, everything one discloses in the public

domain becomes available to one's rivals and helps them get ahead. If

one side makes its data freely available and the other side keeps its data

secret, the rival that relies on secrecy will always know at least as much

as the rival that promptly discloses its data.

Sometimes information disclosures will be of more value to the secretive

rival than to the disclosing rival because of the cumulative value of

combining public data with private data. Suppose, for example, that two

rivals, Public University and Private Company, each sequence different

portions of the same gene. Suppose further that the patent system offers

more generous protection for full-length genes than for gene fragments.

(Although the matter is not free from doubt, this seems to be consistent

with the position of the PTO as reflected in recently disclosed training

materials for patent examiners in applying the written description and

utility guidelines.)

If Public University freely discloses its portion of the gene in GenBank,

Private Company might add that information to the partial sequence it

already has, quickly complete the full-length sequence, and file a patent

application that it would not have been in a position to file without the

Public University disclosure. So prompt disclosure in the public domain can

be treacherous if your ultimate goal is to keep information freely available.

Although disclosure creates potentially patent-defeating prior art, it may

also enhance the value of complementary private information, and

perhaps even make it easier for rivals to get patents.

This may explain why the SNP Consortium defers disclosure of its newly

identified SNPs by filing SIRs instead of publishing. As well as delaying

additions to the proprietary SNP collections of their rivals, the

deferred-disclosure strategy allows the Consortium to conceal from its

rivals just what it has accomplished so far, creating uncertainty as to

which SNPs are worth patenting and which are already in the prior art.

However, the SIR strategy does not make as much information available

to the research community as quickly as prompt publication or posting on

a website would do, leaving those who need prompt access to SNPs with

nowhere to turn but proprietary collections. But as the SIR strategy

promises eventual disclosure, those with less urgent needs may be

content to wait, knowing that the Consortium's SNPs will soon be freely

available.

If the goal of promoting immediate public access dominates the goal of

defeating future patent claims, then publication might make more sense

than patent filing. This may be one reason why the sponsors of the

Human Genome Project, whose overarching mission is to promote

research, call on their grantees to deposit their data promptly in GenBank

in accordance with the Bermuda rules rather than to file patent

applications and defer disclosure pending conversion to SIRs. But the

public sector Human Genome Project has paid a price for this policy — it

has advanced the competitive position of their private sector rivals in the

race to complete the sequence of the human genome, and may have

enhanced their patent positions.

Preserving patent rights. A final reason for deferring disclosure of DNA

sequence information is to preserve the possibility of obtaining viable

patent rights in the future. This concern may motivate some institutions to

defer publication in precisely the circumstances that it motivates other

institutions to make prompt disclosure. The difference depends on

whether they believe that pre-empting future patents is good or bad.

Apart from concern about preserving their own patent rights, public

research sponsors and publicly funded research performers may worry

that premature public disclosure could prevent them from complying with

their mandate under the Bayh–Dole Act to promote technology transfer

and product development by patenting research results. Indeed, this

concern was cited by former NIH director Bernadine Healy in support of

the decision to file patent applications on the first ESTs identified by Craig

Venter when he was at NIH25.

In fact, it does not seem that publication of raw genomic DNA sequence

will prevent the issuance of patents on genes that are subsequently

found to lie within that sequence under United States law. The situation in

Europe is less certain and awaits clarification of national laws in response

to a 1998 directive of the European Parliament on the legal protection of

biotechnological inventions (Box 5). Although the patent system has not

yet resolved many of the legal issues that will determine what portions of

the human genome may be patented, for the time being there seems to

be little threat that disclosure of the human genome in the public domain

will leave future researchers who identify and characterize genes with

nothing left to patent.

Conclusion

Complex and interrelated strategies for endowing the public domain are

at work in the field of genomics. These strategies arise out of the varied

plans of different institutions for extracting value out of genomic

information, complicated by the interplay of the public domain with the

patent system. Public disclosure of genomic information advances some

interests while harming others, with no simple distinction between the

interests of public and private institutions. Understanding these interests

might do more to enlighten public policy debates about the importance of

the public domain in genomics research than appeals to ethical

imperatives.

Boxes

Box 1 | Bill Clinton and Tony Blair on genome data access

United States President, Bill Clinton and United

Kingdom Prime Minister, Tony Blair issued the

following statement concerning access to

genome sequence data, on the 14 March 2000.

"To realize the full promise of this research, raw

fundamental data on the human genome,

including the human DNA sequence and its

variations, should be made freely available to

scientists everywhere.

Unencumbered access to this information will promote discoveries that

will reduce the burden of disease, improve health around the world, and

enhance the quality of life for all humankind. Intellectual property

protection for gene-based inventions will also play an important role in

stimulating the development of important new health care products.

We applaud the decision by scientists working on the Human Genome

Project to release raw fundamental information about the human DNA

sequence and its variants rapidly into the public domain, and we

commend other scientists around the world to adopt this policy."

(Photo by Mark Wilson, Newsmakers.)

Box 2 | The SNP Consortium

Members of the SNP Consortium include the Wellcome Trust, APBiotech,

AstraZeneca PLC, Aventis, Bayer AG, Bristol-Meyers Squibb Company, F.

Hoffmann-LaRoche, Glaxo Wellcome PLC, IBM, Motorola, Novartis, Pfizer

Inc., Searle and SmithKline Beecham PLC.

"The SNP Consortium , Ltd. (TSC) has been formed to advance the field of

medicine and the development of genetic based diagnostics and

therapeutics, through the creation of a high density single nucleotide

polymorphism (SNP) map of the human genome. This map will be freely

available to all parties (members and non-members) at the same time."

The SNP Consortium candidly describes its intellectual property strategy

as follows:

"The overall IP objective is to maximize the number of SNPs the [ sic] (1)

enter the public domain at the earliest possible date, and (2) to be free

of third-party encumbrances such that the map can be used by all

without financial or other IP obligations. To meet objective (2), the [SNP

Consortium] intends to withhold public release of identified SNPs until

mapping has been achieved to prevent facilitating the patenting of the

same SNPs by third parties. Mapped SNPs will be publicly released

quarterly, approximately one quarter after they are identified. The

intellectual property plan is intended to maintain the priority dates of

discovery of the unmapped SNPs during the period between identification

and release, for use as 'prior art'."

Box 3 | The Bermuda rules

The Bermuda rules derive their name from an agreement entered into at

the International Strategy Meeting on Human Genome Sequencing held

in Bermuda on the 25–28 February 1996, sponsored by the Wellcome

Trust26.

"It was agreed that all human genomic sequence information, generated

by centres funded for large-scale human sequencing, should be freely

available and in the public domain in order to encourage research and

development and to maximise its benefit to society."

The Bermuda rules have been criticized for promoting public disclosure of

data that have not been checked for accuracy27.

Box 4 | NHGRI policy on release of human genome sequence data

The National Human Genome Research Institute issued the following

policy statement on the 7 March 1997.

"In NHGRI's opinion, raw human genomic DNA sequence, in the absence

of additional demonstrated biological information, lacks demonstrated

specific utility and therefore is an inappropriate material for patent filing.

NIH is concerned that patent applications on large blocks of primary

human genomic DNA sequence could have a chilling effect on the

development of future inventions of useful products...NHGRI will monitor

grantee activity in this area to learn whether or not attempts are being

made to patent large blocks of primary human genomic DNA sequence."

Box 5 | European Parliament directive on patenting

Directive 98/44/EC of the European Parliament and of the Council of the

6 July 1998 on the legal protection of biotechnological inventions, Official

Journal L 213, 30/07/1998 p. 0013–0021 Article 5:

The human body, at the various stages of its formation and

development, and the simple discovery of one of its elements,

including the sequence or partial sequence of a gene, cannot

constitute patentable inventions.

An element isolated from the human body or otherwise produced

by means of a technical process, including the sequence or partial

sequence of a gene, may constitute a patentable invention, even if

the structure of that element is identical to that of a natural

element.

The industrial application of a sequence or a partial sequence of a

gene must be disclosed in the patent application.

Links

COMPANIES

Celera | Monsanto | Merck | Incyte | Human Genome Sciences

FURTHER INFORMATION

Human Genome Project | Joint statement by Bill Clinton and Tony Blair |

The SNP Consortium | The Bermuda rules | National Human Genome

Research Institute policy on patenting of human genomic sequence |

Interim utility guidelines for Patent Examiners | Written description

guidelines for Patent Examiners | European Parliament directive on

patenting

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Acknowledgements

This research has been supported by a grant from the United States Department of Energy.