{blr 1256} hgp - pto - venter - est

4

Click here to load reader

Upload: stephen

Post on 29-Mar-2017

214 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: {BLR 1256} HGP - PTO - Venter - EST

11 Biotechnology Law Report 1 (January-February 1992)

A New Year, a New Look

With Volume 11 of BLR, this journal is slightly revising its format. From now on,stories on related topics will be grouped under an appropriate heading, such as PatentLitigation or Regulatory Affairs. Given the BLR Law of Relevant Developments (Themost important action of any 2-month period takes place no earlier than 2 days before theissue is due at the Publisher"), the stories may not always be consecutive, but we will beable to group them in the Table of Contents. We will also be doing more short items on

business actions and scientific developments with legal implications.We hope these changes will make BLR more useful to you.

Commentary{BLR 1256} HGP

-

PTO-

Venter-

EST

Misplaced Concerns Surround Venter/NIH Patent ApplicationCovering Human Genes

By Stephen Bent, J.D.

When the June "Frontiers in Biotechnology" issue of Science highlighted Dr.Craig Venter's work on sequencing complementary DNAs (cDNAs) in the humanbrain, there was no hint of the international controversy which was soon to follow.

What sparked the uproar was the National Institutes of Health (NIH) announce-ment that it had filed a related U.S. patent application on behalf of Dr. Venter andothers at the National Institute of Neurological Disorders and Stroke. The NIH Officeof Technology Transfer, which spearheaded preparation of the Venter patent applica-tion, did not foresee the extent to which its action would elicit media attention anddivide the large research community that is trying to decipher the human genome at themolecular level.

Indeed, an article in Nature claimed the patent application would spark a"patent Gold Rush," and the Industrial Biotechnology Association (IBA) warned that itwould hinder small biotech firms in the development of new recombinant products. In a

Washington Post op-ed piece, Jessica Mathews, vice president of the World ResourcesInstitute, questioned the right to lay claim to intellectual property rights over the humangenome and decried its potential impact on developing countries.

Expressed Sequence TagsThe Science paper written by the Venter group ("Adams et al.") describes the

partial sequencing of 609 cDNA clones chosen at random from three commerciallyavailable human brain cDNA libraries were produced from hippocampus, temporalcortex, and fetal brain mRNA. The scientists called the partial cDNA sequences"expressed sequence tags" (ESTs) because each EST is a unique identifier of an ex-

Page 2: {BLR 1256} HGP - PTO - Venter - EST

11 Biotechnology Law Report 2 (January-February 1992)

pressed gene.

Among the applications for ESTs is in mapping cDNAs to chromosomes, whichis reminiscent of the use of random genomic sequences called "sequence-tagged sites"(STSs) as unique chromosomal markers. Unlike STSs, however, ESTs point directly toan expressed gene. Moreover, Adams et al. found that more than 80% of the nuclear-encoded genes identified via ESTs had no match in the GenBank (DNA sequences),PIR (protein sequences generally), or ProSite (special protein "motif" sequences)databases, which meant that they represented new, previously uncharacterized genes.

Dr. Venter's group also employed the polymerase chain reaction (PCR) toscreen somatic hybrid cell lines, each with defined sets of human chromosomes, for thepresence of a given EST. In this way, they mapped a few dozen of the unique ESTs tochromosomes.

Based on the results of what they termed a "pilot project totest the use of...ESTs in a comprehensive survey of expressed genes," the Venter teamconcluded that their fast approach to cDNA characterization will facilitate the taggingof most human genes in a few years, at a fraction of the cost of complete genomicsequencing. They said their method would also provide new genetic markers and serveas a resource for diverse biological research fields.

Dr. Venter has noted that the EST-based approach may advance gene identifica-tion, an important objective of the Human Genome Project (HGP), by 10 to 15 years.He estimates that his group alone can identify about 1,500 genes a month, compared tothe total of about 3,000 genes identified so far.

Patent Issues

Because the NIH Office of Technology Transfer has yet to make the Venterpatent application available to the public, what claims and supporting disclosure theapplication actually contains are unknown. According to a recently circulated policypaper on the Venter application by the Association of Biotechnology Companies (ABC),the application claims "350 unique cDNA sequences" (the ESTs themselves), "theentire cDNA coding sequence associated with each" EST, the "protein product" encod-ed by each cDNA coding sequence, and "a method for obtaining and interpretingcDNAs."

Since an EST is a chemical compound, it unquestionably falls within the cate-gory of "compositions of matter," which the U.S. patent law prescribes as statutorysubject matter. That the Venter application may claim hundreds of ESTs does not altertheir legal status in this regard. In fact, many patents have claims that circumscribehundreds or even thousands of chemical compounds, the majority of which were neversynthesized or tested by the patentee.

Instead, generic coverage of this sort is obtainable when the claim in question isdrafted so as not to encompass anything that already exists (the "novelty" requirement),that would have been an a priori predictable extension of what was known (the"nonobviousness" requirement), or that is accessible in practice only with the sort ofexperimentation that those skilled in the relevant technical field would consider unduefor that field (the "enablement" requirement).

Page 3: {BLR 1256} HGP - PTO - Venter - EST

11 Biotechnology Law Report 3 (January-February 1992)

In addition, the claimed invention must have some utility, apparent at the timethe application is filed, which is other than furthering basic research (the "practicalutility" requirement).

The uniqueness of any claimed EST, relative both to tissue distribution and todata-base screens, is likely to be an important factor in satisfying several of these pat-entability requirements. Uniqueness in the context of GenBank and other sequence data-bases fairly assures that the EST meets the novelty requirement. The relation betweenan EST and a gene that is specific, say, to brain means that a forensic utility—a use indetermining the nature of a tissue sample-is plausibly asserted even if it is unrelated tohow the EST is actually employed.

Also, an association between a particular EST and a new brain gene probablycould not have been predicted beforehand, undercutting any assertion that the EST is"obvious" under patent law. Finally, the combined disclosure of an EST sequence and aprotocol as set down by the Venter group in all likelihood permits knowledgeable prac-titioners to make and use the EST routinely, thereby satisfying the enablement require-ment of the patent statute.

If, then, a sizable number of the ESTs described by Adams et al. are patentablein principle, how do the complete cDNAs and corresponding proteins, which theVenter application is said to claim, fare under a similar analysis?

Parallel TreatmentThe assessment of novelty and nonobviousness in this regard

should parallel the treatment vis-à-vis the ESTs themselves. On the other hand, the dis-closures of the Venter application relating to complete cDNAs and proteins, unlikeESTs, must largely be prophetic, if only because the approach of the Venter group doesnot provide direct information about the function(s) of a new gene or its expressionproduct. This fact may detract from the credibility of an asserted utility. It also maycomplicate the applicants' task, imposed by the enablement requirement, of effectivelyplacing all EST-denoted genes and encoded proteins, as claimed, in the hands of skilledpractitioners without their having to engage in experimentation that is not routine.

The law mandates only that a patent application set forth a use, which may ormay not be the ultimate or preferred use of a claimed invention. It is not surprising,therefore, that the practical-utility requirement has not often been an intractable hurdlefor even the most forward-looking patent applicant. For example, experience with theflood of prophetic patent disclosures that accompanied major advances in organicsynthesis some 30 years ago suggests that the practical-utility requirement likewise neednot preclude the patenting of EST referents or their respective expression products.

The enablement requirement may pose a more significant difficulty for claimsdirected to scores of genes or proteins highlighted in the context of an endeavor em-ploying the Venter group's approach. In the first instance, an applicant seeking suchclaims may well have to convince the U.S. Patent and Trademark Office (PTO) thatmolecular biologists consider the path from EST to gene to protein as traversable withno more or less difficulty and uncertainty than generally affect the task of cloning andexpressing heterologous genes.

In the past, the PTO often has shifted to the applicant the burden of proving that

Page 4: {BLR 1256} HGP - PTO - Venter - EST

11 Biotechnology Law Report 4 (January-February 1992)

a claimed biotech invention is enabled to this extent. On the other hand, the question ofadequate enablement is amenable to proof, for example, with evidence that othersactually did progress from EST to gene to protein, with only routine experimentationand without having to engage in independent inventive activity, along the lines de-scribed in the Venter application.

Thus, whether Dr. Venter and his coinventors are able to convince the PTO onthe all-important enablement issue may turn on how widespread (in relation to thebreadth of the Venter patent claims) are the successes in implementing the propheticagenda for "routine" experimentation which the Venter application must embody.

ProspectsThose responsible at the PTO for examining biotech patent applications typically

adopt a conservative, claim-restrictive perspective on enablement. As a result, theyfavor claims that correspond as closely as possible to what an application actuallyexemplifies. Claims that rely on disclosures of a prophetic nature are viewed with a

jaundiced eye and, not infrequently, are waylaid until the applicant decides to cut themback significantly or abandon them altogether.

The PTO also is disinclined to examine, in a single application, more than a"reasonable number" of "distinct" species. The agency may force NIH to prosecuteonly certain of those species in one application and to divide the remainder amongseveral additional cases, to be prosecuted separately.

The commensurately higher costs to the NIH might be ameliorated, however, iffurther research allows NIH to focus its efforts at the PTO on a smaller number ofEST-denoted genes thought to have greater commercial (and licensing) potential.

While these considerations do not bode smooth administrative sailing for theVenter application, they pertain in many cases where an applicant has claimed in amanner consistent with an important innovation. The technology the Venter applicationapparently describes, as reflected in the article by Adams et al., seems to qualify assuch an innovation. Indeed, the EST-based approach of the Venter group promises toquicken, not only the pace of the HGP, but also the tendency away from patentingDNAs corresponding closely to natural counterparts.

In other words, the dissemination and elaboration of conventional (functional)cloning methodology over the last decade gradually has made it more difficult to obtainpatent claims to isolated genes per se and, conversely, has favored the patenting ofDNAs that are modified from a model in nature. As the full potential of the EST-basedapproach is realized, the trend toward protection of "second generation" polynucleo-tides and their "mutein" expression products likewise may be vastly accelerated.

This would benefit small biotech firms and, more generally, would dampen theprospects of the "patent Gold Rush" predicted by some commentators.

Stephen Bent, J.D.,M.S., is a partner at Foley & Lardner, a law firm with officesnationwide, and heads the firm's Biotechnology Practice Group in Alexandria, Virgi-nia. This article also appears in Genetic Engineering News, January 1992.