"GENE" PATENTING (for The Scientist)

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Yi ttorie Sgaramelila

Rockefeller University, New York (on leave from the University of
Calabrie, ITALY )

Thére is no a priori reason to deny a patent or other legal
p: otection to an intellectual product solely because it is a
"gene" sequence: although genes, as DNA molecules, may be
considered "immortal", thanks to their semi-conservative
replication, a similar feature could probably be attributed to
other biological structures such as cell membranes, and most
hery to their molecular building blocks (and, if immortality is
the issue, certainly to their constitutive atoms!). Thus it
shone there is hardly anything sacred in genes, as some, not
nbcousaridy bioethicists, may believe (Nature 358: 272, 1992).

siniieriy, there is no a2 priori reason to grant patents solely
bhoause the relevant inventions are (based on) genes. Certainly
gines are important structures, arguably the most important in an

b

cfganisn, as carriers of the genetic information. But in order to
¢ patentable, the relevant findings must be novel, useful and non

obvious, as traditional and proper for patents. Genes are not
Adlaain's lamps for biotechnology, as many, not necessarily
venture capitalists, seem to expect.

atter laboriously gaining the approval of rigorous critics, and
mollifying the opposition of stern antagonists, the complex but
£ agate creature known as the Human Genome Project, like a novel
Saturn, is on the verge of being devoured by its own sons,

ndddened by the hubris that scientific power, when it is ly
fictitiously magnified. Making use of a more recent mythology its
apprentices occasionally seem deranged as if blinded by the sight,
or by the illusion, of the Holy Grail.

A brief chronicle of such a tragical plot is due.

The request of patent for several hundred "gene" sequences last
summer, and a few thousand later on, was forwarded to the US
Patent and Trade Office by the NIH. As it is known, these
institutes together with the US Department of Energy are
responsible for coordinating the whole Project in the US, and thus
essentially in the developed world. This role has been recognized
to the NIH mainly thanks to the scientific authority and the
political expedience, even if not always supported by an adequate
diplomacy, of Nobelist. Jim Watson, appointed director of the NIH-
Sponsored Project a couple of years ago. One of the strongest
reasons for the preferential funding claimed by Watson for the
Project was its highly beneficial impact on mankind's fight
against diseases (J. D. Watson, Hospital Practice 26: 45~49,
1991). |

The unexpected and controversial NIH request to the PTO for
patents on "gene" sequences amounted to an opening to the
privatisation of the Project: as such it would pose the Project
exactly on a collision*route with Watson's stated principles, or
at least drastically anticipate a change expected only for a later
phase. In addition to this social aspect, a few disturbing
scientific flaws made the NIH request hardly defendable. The
request concerned results obtained by Dr. J. Craig Venter, then a
researcher of the National Institute of Neurological Disorder and

Stroke, through an automated sequence analysis of pieces of cDNA
from a human cDNA library. The thrust of Dr. Venter's contribution
has been essentially the subcloning of a commercially available
CDNA library and the sequencing of random pieces of few hundred
bases. These results have been made possible by routine
procedures, albeit stretched to a hardly matchablie limit: .a
reported impressive pace of 70,000 bp a day. But their accuracy
should be checked, to avoid embarassing analogies with
"dinosaur's” DNA possibly represented by plasmid vector sequences
(Nature 358; -271, 1992).

In an extensive coverage by the generally reliable Science section
of the New York Times (July 28), the merits of Dr. Venter have
been implicitally equated to the other epochal fulminations, such
as that which hit Saul on his way to Damascus, or that which
almost sank Archimedes while buoying in the warm waters of the
Sicily sea, or, disguised as a famous apple, fell on Newton's
head. So science historians and future generations are informed
that “Dr. Venter, like hundreds of other scientists, frustrated by
the snail's pace at which he was able to decipher the human
genetic material, one day, on a plane from Tokyo had an
lnepiration and suddenly realized that an obvious shortcut would
ed him right to the genes themselves". But in spite of that, Dr.
Venter's achievements did not impress much his colleagues, and
even less his coordinator in the Human Genome Program. Watson was
instead reported to be indignant at the NIH request ("shear
lunacy"), and somehow underrated Dr. vVenter's claims to both
patents and glory as work which "virtually any monkey" could do

(animal Pprotectionists should relax: no offense was meant for
monkeys, since good sequencing is still quite a demanding
effort).

It is fair to state that most of the scientists share Watson's
blunt xeaction rather than the agiographic tone of the New York
Times coverage.

Interestingly enough, in the US several lawyers seem favorable to
the NIH move: this is understandable, given complex nature of the
legal issues plus the remarkable increase in lawyers number over
the last decade, and the consequent relative decrease in lucrative
litigations. —

Needless to say also the response of a group of capitalists-
philanthropists was prompt: they seized the opportunity of
benefitting at the same time US biotechnology and mankind (or at
least their own subset) and offered Dr. Venter a grant of 70
million $ to develop his genomic research outside NIH. Venter has
accepted and has left NIH with some thirty associates. The ranks
of the mercenary troops deserting the Project and eager to comb
the human genome map in search of genetic treasures are growing.
An erosion of the global dimension of the Project follows
necessarily, but possibly not of its spirit, since most of these
initiatives are started obviously under the banners of non profit
enterprises.

To complicate the issue on the international scene, it so happened
that as soon as the English human genome group at the MRC
{Medical Research Council) heard of the unexpected NIH move, they
felt obliged to retaliate. They threatened first to protect their
own conspicuous human brain cDNA sequences under the aegis of

commercial secret. Later, ostensibly "obtorto ccollo", decided to
follow suit “to protect the UK position", since other countries’
moves on the issue "could place the UK at a relative disadvantage"
(UK Science Minister's response to a parliamentary question on
March 4th, 1992). The whole patent system seems approaching a halt
for excess of applications. An easy solution would be if the PTOs
were to deny the patents: but at the present rate of their
functioning, years would be required even for a cursory
examination of the thousands and thousands of applications. But it
is comforting that a PTO refusal has been suggested in a petition
recently signed by some 36 dliustrious scientists. Oddily enough
g1s0 Dr. Venter has been reported to co-sign it (Nature 375: 525,
1992). An even better solution would be if NIH and MRC were to
withdraw their requests, and thus set an example even for the
tivate sector. This would be similar to what happened in the

80s when the private biotechnology companies not enjoying

eG

Financial support from NIH decided nevertheless to pay allegiance
to the guidelines imposed by NIH to their institutes and grantees
tor the reduction of the risks in the practice of genetic
engineering.

Indeed the public in general as well as the scientific and the
industrial communities (Nature 358: 272, 1992) seem to ostracize
the decision to apply for patents of this sort. The objections are
mainly based on the facts that the "gene" sequences for which
patents had been requested are incomplete and code for unknown
proteins. This is all right, but, at least inmy opinion, one
bhould go further.

accordinigy, my thesis here is to demonstrate that “gene"

Bequences do not meet the patent requirements even when they
{

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represent complete and identified genes ceeding for useful
products, as iong as the ygeues udder discussion gode for proteins.
Two reasons are presented. rirst, if it is a pavlein that meets
the patent requirements, patents should cover it, for both its
production and its use: to patent their "genes" is redundant and
unjustified, also because of the following considerations. Sacond,
the relationship between "genes" and proteins is hardly direct,
especially in the iight of by now classical molecular genetics.
The dogma of colinearity of gene sequonces and gene products has
great historical validity since Beadle and Tatum, but limited
generality nowadays: more than one gene often concur to code for a
unique protein (due to allelic polymorphisms as well as to non-
allelic configurations, or to trans-splicing) and more than one
protein could tbe coded for by a single "gene" (i. @ a
transcription unit, as in the case of the pituitary hormones).
‘This does not imply that "gene" sequences should not be patented.
It could be totally proper to patent “gene” sequences or better
“nucleotidic" sequences, thus including also the versatile RNA.
That should be the case when, of course, the relevant findings are
non obvious and novel, and, most important, the "gene" sequences
turn out to be useful ddrectly and "per se": as diagnostic probes,
promoters, antisense regulators, or in other unknown functions.
Patents or other forms of protection should be granted to DNA
sequences, provided they as such meet the three above mentioned
requirements; and, additionally, are properly disclosed. The
latter point is particularly relevant: it means that the "gene"
sequences ought to be made promptly availabie for scientific

investigations, without depriving them of a legitimate protection
1@-SET-1992 14:52 . PLS

against improper commercial exploitations. Patents or other

sources of litigation must not interfere with the free exchange of

vesearch data: AIDS docet.

Finally, in this paxticular perspective, dala arising from work
performed in publicly supported institutions or with communitarian
funds should be routinely made more available to researchers for

i
the benefit of (tax paying) mankind, as compared to those

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privately financed.