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News from Patent-News regarding biotechnology patents
PATNEWS: Eli Lilly beats UCal; other bio news; NAS letter to PTO
Date: Wed, 23 Jul 1997 23:40:31 -0400
From: srctran@world.std.com (Gregory Aharonian)
Reply-To patent-news@world.std.com
!19970724 Eli Lilly beats UCalif; other biotech news; NAS letter to PTO
CAFC rules that UCal's insulin patent is invalid
CAFC rules Genentech's hGH patent is invalid
Chimeric adenovirus PCT patent application
Amgen sues Transkaryotic Therapies and Hoechst Marion Russel
Researchers upset about DuPont's transgenic mouse patent
Doctors upset about terms of use of Down's syndrome test
Squabbles over DNA-chips technology
Letter from NAS to PTO asking for clarification over ESTs
====================
IPO reports:
On Tuesday, the U.S. Court of Appeals for the Federal Circuit upheld
a ruling by an Indiana district court on a heavily litigated patent
infringement case that has been followed closely by the biotech
community.
They ruled that a UC patent for a microorganism containing a form of
human
insulin is invalid for failure to provide an adequate written
description of
the invention. The Federal Circuit also agreed that a second UC insulin
patent
was not infringed by Lilly, because the claims cover only "direct"
expression
of the insulin, while Lilly was making insulin via a fusion protein. UC
surrendered coverage for expression via a fusion protein during
prosecution
of the claims in the USPTO. The Federal Circuit also dealt with issues
of
jurisdiction, venue and enforceability (lawsuits were filed in both
Indiana
and California before being consolidated in Indiana).
====================
In April, the U.S. Court of Appeals for the Federal Circuit not only
vacated Genentech's preliminary injunction against Novo Nordisk that had
prevented its importing and selling human growth hormone in the US, but
also that Genentech's patent on cleavable fusion expression for the
production of human growth hormone (5,424,199) is invalid. The CAFC
decision reversed a US District Court for the Southern District of New
York decision. The CAFC ruled that the '199 was not enabling.
Nice article in the April 15 1997 issue of Genetic Engineering News,
written by Chester Bisbee, a Boston area biotech lawyer (508-475-5264).
====================
One popular technique for transferring genes into cells is to use
viruses
as vectors, since viruses are good at getting their DNA into cells.
Take out
their DNA, insert your DNA, and you have a good delivery vehicle. One
popular virus to use is the adenovirus, but at the price of the
side-effects
of the virus. In January, Nature Biotechnology (15 January 1997, page
52)
reported that a group of scientists in France has developed an
artificial
adenovirus shell, a dodecahedron made of adenovirus penton bases using
one
or two adenovirus proteins instead of the 11 contained in the natural
adenovirus, and with none of the virus' genome.
A related development is described in PCT application WO 97/20051,
titled
"Vectors and methods for gene transfer to cells", being sought by GenVec
(Rockville, MD), which provides a chimeric adenovirus coat protein,
which
differs from the wild-type coat protein by the introduction of a
nonnative
amino acid sequence.
There have been a fair number of PCT applications involving
adenoviruses
over the past few years. Some combination of all these technologies
should
result in useful gene delivery vectors in the years to come.
====================
A few weeks ago, Transkaryotic Therapies (TKT - Cambridge, MA) and
Hoechst
Marion Russel (HMR - Kansas City, MO) asked the Federal District Court
of
Boston to dismiss Amgen's (Thousand Oaks, CA) erythropoietin (EPO)
patent
infringement suit against them, filed last April.
Amgen has already successfully defended its patents against Genetics
Institute (Cambridge, MA). What makes this case different is that TKT's
use
of EPO to date has only been for FDA testing purposes, for activities
that
TKT has contracted with HMR to commercialize and market.
TKT is arguing that under the Waxman-Hatch Act (35 USC 271(e)(1),
there
is no infringement when a drug is made "solely for uses reasonably
related
to the development and submission of information" to the FDA. Amgen has
also asked for declaratory relief, asking for an infringement
determination
whenever and whoever markets TKT's version of EPO.
Nice article in the July 1997 issue of Genetic Engineering News,
written
by Chester Bisbee, a Boston area biotech lawyer (508-475-5264).
====================
The July 4th issue of Science reports that researching are upset
with
DuPont with regards to their policy dealing with their patented
transgenic
mice (CreloxP mice). DuPont is insisting that researchers using the
mice
acknowledge the company's rights to the animals, share any money that
may
be made on discoveries from the technology, and distribute the animals
only
to other researchers whose institutions have agreed to these terms.
This is a tight squeeze on researchers, since the largest breeder of
research mice, the Jackson Laboratory (Bar Harbor, Maine) has decline to
sign an agreement with DuPont and is not distributing any such mice.
The
NIH is talking with DuPont, protesting the company's restrictions. Dr.
Varmus (the NIH official trying to get the PTO to explain its EST
policy)
will be meeting with DuPont this summer and people believe compromise is
possible.
The patent itself isn't at issue, just the licensing terms.
====================
The May 23 edition of New York Times has a story illustrating the
complexities of dealing with patenting and the human body.
In 1986, Dr. Mark Bogart at the University of California at San
Diego
developed a congenital birth defect test for Down's Syndrome based on
levels of hormones in pregnant women. He immediately applied for and
won
a patent (at the time, UCSD declined to patent his discovery). He then
formed
a company, the Biomedical Patent Management Company, which recently has
been
sending letters arounding the country to laboratories asking for as much
as
$9 per test - which often is the net reimbursement level for doing the
test,
and threatening an infringement lawsuit if a license isn't taken.
Andrew
Dhuey, a lawyer in San Francisco, is representing BPMC.
The patent is controversial for a variety of reasons. First,
researchers
are upset in general over the patenting of what is essentially
observations
of natural phenomena of the human body. Robert Merges, a law professor
at
the University of California in Berkeley is quoted after reading Dr.
Bogart's
patent, "This does seem a little like patenting Newton's law of
gravity".
Second, Dr. Bogart's test by itself is of limited value. His
technique
uses one hormone, human chorionic gonadotropin, HCG, but is limited
because
it has a high false positive rate (identifying normal fetuses as having
Down's syndrome). A few years after his discovery, other scientists
refined
his technique, using HCG plus Alpha fetoprotein, a protein, and Estriol,
a
hormone. This triple screen rapidly became popular. When in 1990,
Bogart
received his patent, he approached labs demanding royalties for using a
test part of which used his HCG test. But since the HCG test had been
used
for many decades for other purposes, he was ignored.
In 1996, lawyers for his company approached Foundation for Blood
Research (in Maine), a large testing laboratory, and offered to provide
the
nonprofit group a percentage of royalties if it disclosed which labs
around
the country participated in a quality assurance program it conducts for
the
screening. This would let the lawyers know whom to sue for
infringement.
The foundation rejected the offer.
Yet faced with a lawsuit, the foundation settled. Even for patents
of
questionable validity, the legal and court costs can be so high that it
makes economic sense to settle. Echoing sentiments often heard in the
software industry (where there are orders more patents of questionable
validity), Professor Merges is quoted as saying, "The sad thing is that
it
is so expensive, and the down side so steep, that these patents have a
tendency to terrorize" those accused of infringement. Michael Epstein,
a patent lawyer with the New York law firm of Weil, Gotshal and Merges,
said after reading Dr. Bogart's patent, "I think the subject matter is
questionable . . . To the extent it covers simply a correlation of the
presence of a particular hormone with a certain biological
characteristic,
it may go too far under the patent laws".
Letters of notice of infringement have been mailed out, with some
labs
dropping the test (with no replacement), and others being sued. Since a
flurry of activity in the early part of this year, there hasn't been
much
public activity.
====================
May 15th Nature (page 221) reports on squabbles over patents
involving
DNA chips, which allow solid state sensing of gene products. Since
solid
state etching techniques allow very small surface and volume areas to be
defined and electrically accessed, DNA chips can allow the parallel
testing
of thousands of DNA sequences.
In 1989, the European Patent Office awarded a patent to Ed Southern
of
the University of Oxford (inventor of the non-patented and very popular
Southern blot process) for using oligonucleotide arrays as testing
platforms.
Challenging Dr. Southern and his company, Oxford Gene Technology, is a
hotshot (in the sense of the glowing articles in the business press) US
company, Affymetrix (San Francisco), 34% of which is owned by Glaxo
Wellcome.
Affymetrix and six other companies, including Hoffman LaRoche and Abbott
Laboratories, have filed an opposition with the European Patent Office,
claiming that Southern's claims are not novel, not inventive, and that
the
specifications are insufficient to support the claims of existing scope.
While lawyers for Southern and the University of Oxford (which
apparently
is licensing the patent to OGT or has a share of the company) admit that
the scope of the claims are maybe broader than justified (and they have
filed
amended claims of narrower scope), they argue that the techniques are
novel
and inventive.
Both sides seem willing to reach a compromise agreement. Which would
be nice for Affymetrix, which later this year will be facing complaints
in
the Northern District Court of California for infringing two 1993
patents
on DNA-chip technology held by another California company, Hyseq, which
is
also challenging Southern's patents.
====================
Sometime ago I reported on an exchange of letters between the NIH
and
the PTO on the confusion surrounding the patenting of ESTs. My last
news
item reported that the PTO's final message was perfectly satisfactory,
except it left a real large vague loophole. Typical bureacratic tactic.
Fortunately, the National Academy of Sciences decided to press the
issue,
and sent a letter to Lehman asking him to explain his vagueness. Stay
tuned.
NATIONAL ACADEMY OF SCIENCES
2101 CONSTITUTION AVENUE, N.W.
WASHINGTON, D.C. 20418
June 19,
1997
The Honorable Bruce A. Lehman
Assistant Secretary of Commerce and
Commissioner of Patents and Trademarks
U.S. Patent and Trademark Office - Room 906
Crystal Park Building 2
2121 Crystal Drive
Arlington, VA 22202
Dear Commissioner Lehman,
I write to encourage you to make every effort to insure that any
future
patents granted for DNA sequences do not unfairly impede research and
innovation in biomedicine and biotechnology. I write on behalf of the
Council
of the National Academy of Sciences (NAS) to express our concern. I will
make this letter and subsequent correspondence public to advance the
debate.
The NAS Council discussed your recent correspondence with Dr. Harold
Varmus at its last two meetings. It found your reply of April 2
reassuring,
but was puzzled about how to interpret the following sentence from your
letter:
"Under appropriate and limited circumstances, claims of a perceived
broad scope that are adequately supported by the disclosure under
35 USC 112 and the state of the art may be patentable, but such
claims do not necessarily preclude future patenting of the full
length gene."
This sentence raises questions about what criteria for enablement,
utility, novelty, and nonobviousness will be applied to EST patent
applications, and about the likely scope of allowable patent claims. In
our opinion, it is crucial to define more clearly how the US Patent and
Trademark Office (USPTO) will determine the "appropriate and limited
circumstances" you alluded to, how it will judge the adequacy of
disclosure
underlying patent claims, and how it will determine appropriate claim
scope
for ESTs.
The Council's concern stems in part from the central importance of
data
about DNA sequence in modern biology. Your sentence quoted above implies
that
the main concern is about the subsequent patentability of full length
genes
if EST patents issue. Blocking future patents is one concern, but it is
not
the only one or even the most important. We fear that EST patents will
become impediments to research, slowing progress in biomedical research.
As a major National Research Council study that I chaired in 1988 noted,
"Absolutely essential to the success of the [human genome] project will
be
cooperation between laboratories and centers--within the United States
and
internationally--and the ready availability of data and materials to all
participants" (see report, Mapping and Sequencing the Human Genome, pp.
99-100). The collection of genes in humans and other organisms is a
finite,
if only partially explored, resource of enormous potential value. It
would
be sad indeed if patent policies diminished the pace of discovery or
wealth
of practical applications; yet patents that allow an early group of
inventors
who have disclosed little new knowledge to constrain the actions of
subsequent
investigators threaten to do just that.
The main use of ESTs is to find genes that in turn lead to proteins
(or
nucleic acid products), which could themselves lead to therapeutics or
become
targets for drug development. We are concerned about patents that can
impede
the study of genes tagged by ESTs and their resulting gene products. We
suggest that DNA sequences per se should not be patentable unless the
patent clearly discloses specific "real world" utilities for the
particular
DNA sequences in question that can be implemented without substantial
further
developmental research. We are encouraged by sensitivity to this issue
in
your letter to Dr. Varmus, but the equivocal sentence quoted above
causes
some concern. This concern is aggravated by excerpts from the patent
examiners' training manual, which indicate that several speculative
utilities--such as use of ESTs for mapping, for forensic identification,
and for tissue typing--would satisfy the utility requirement for the
issuance of a patent. We urge you to question, however, whether the
patent
applicants have supplied a sufficient enabling disclosure for these
utilities.
Disclosure of DNA sequence alone is plainly insufficient to enable
scientists
to use an EST for any of these purposes. Data about the exact
chromosomal
site from which a DNA fragment arose are needed for mapping; data about
unique
expression in a particular tissue or physiological state are needed for
tissue typing or diagnosis; and data about polymorphism among
individuals are
needed for forensic uses. Inventors should be required to include the
relevant
data at the time of initial patent application to satisfy the
requirement of
an enabling disclosure.
The perceived threat of EST patents is based in part on the
experience
of the research community with patents on other research tools,
including
transgenic animal patents and related site-specific recombination
techniques.
Some of these patents on research tools that lie far upstream of product
development are being used to "reach through" and extract rights to
future
discoveries. This complicates the commercialization of biotechnology
inventions, but more importantly it also hinders research into the
origins
of disease, because access is limited to only those institutions willing
to
abide by the restrictions. Initial licensing of the Harvard oncomouse
(US
Patent 4,736,866, assigned to Harvard and licensed to E. I. DuPont de
Nemours
and Company) raised this concern years ago, and DuPont's licensing of
its
patent on site-specific recombination (US Patent 4,959,317) raises it
again.
Similar use of EST patents could be devastating to the study of human
biology
and disease by limiting access to the finite set of human genes. Our
concern
is that patents are being used in ways that create obstacles to
conquering
human diseases through both federally and privately funded research. We
recognize that the USPTO does not control the terms of patent licenses,
but we nonetheless call these practices to your attention to illustrate
the
potential difficulties that can arise for research when USPTO issues
broad
patents on research tools.
In summary, we urge you to exercise caution and restraint in
applying
patent law standards to ESTs and in determining the appropriate scope of
patent claims.
Sincerely,
Bruce Alberts, President
On behalf of the Council,
National Academy of Sciences