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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: firstname.lastname@example.org (Gregory Aharonian)
!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
Squabbles over DNA-chips technology
Letter from NAS to PTO asking for clarification over ESTs
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
They ruled that a UC patent for a microorganism containing a form of
insulin is invalid for failure to provide an adequate written
the invention. The Federal Circuit also agreed that a second UC insulin
was not infringed by Lilly, because the claims cover only "direct"
of the insulin, while Lilly was making insulin via a fusion protein. UC
surrendered coverage for expression via a fusion protein during
of the claims in the USPTO. The Federal Circuit also dealt with issues
jurisdiction, venue and enforceability (lawsuits were filed in both
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
as vectors, since viruses are good at getting their DNA into cells.
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
of the virus. In January, Nature Biotechnology (15 January 1997, page
reported that a group of scientists in France has developed an
adenovirus shell, a dodecahedron made of adenovirus penton bases using
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,
"Vectors and methods for gene transfer to cells", being sought by GenVec
(Rockville, MD), which provides a chimeric adenovirus coat protein,
differs from the wild-type coat protein by the introduction of a
amino acid sequence.
There have been a fair number of PCT applications involving
over the past few years. Some combination of all these technologies
result in useful gene delivery vectors in the years to come.
A few weeks ago, Transkaryotic Therapies (TKT - Cambridge, MA) and
Marion Russel (HMR - Kansas City, MO) asked the Federal District Court
Boston to dismiss Amgen's (Thousand Oaks, CA) erythropoietin (EPO)
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
of EPO to date has only been for FDA testing purposes, for activities
TKT has contracted with HMR to commercialize and market.
TKT is arguing that under the Waxman-Hatch Act (35 USC 271(e)(1),
is no infringement when a drug is made "solely for uses reasonably
to the development and submission of information" to the FDA. Amgen has
also asked for declaratory relief, asking for an infringement
whenever and whoever markets TKT's version of EPO.
Nice article in the July 1997 issue of Genetic Engineering News,
by Chester Bisbee, a Boston area biotech lawyer (508-475-5264).
The July 4th issue of Science reports that researching are upset
DuPont with regards to their policy dealing with their patented
mice (CreloxP mice). DuPont is insisting that researchers using the
acknowledge the company's rights to the animals, share any money that
be made on discoveries from the technology, and distribute the animals
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.
NIH is talking with DuPont, protesting the company's restrictions. Dr.
Varmus (the NIH official trying to get the PTO to explain its EST
will be meeting with DuPont this summer and people believe compromise is
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
developed a congenital birth defect test for Down's Syndrome based on
levels of hormones in pregnant women. He immediately applied for and
a patent (at the time, UCSD declined to patent his discovery). He then
a company, the Biomedical Patent Management Company, which recently has
sending letters arounding the country to laboratories asking for as much
$9 per test - which often is the net reimbursement level for doing the
and threatening an infringement lawsuit if a license isn't taken.
Dhuey, a lawyer in San Francisco, is representing BPMC.
The patent is controversial for a variety of reasons. First,
are upset in general over the patenting of what is essentially
of natural phenomena of the human body. Robert Merges, a law professor
the University of California in Berkeley is quoted after reading Dr.
patent, "This does seem a little like patenting Newton's law of
Second, Dr. Bogart's test by itself is of limited value. His
uses one hormone, human chorionic gonadotropin, HCG, but is limited
it has a high false positive rate (identifying normal fetuses as having
Down's syndrome). A few years after his discovery, other scientists
his technique, using HCG plus Alpha fetoprotein, a protein, and Estriol,
hormone. This triple screen rapidly became popular. When in 1990,
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
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
nonprofit group a percentage of royalties if it disclosed which labs
the country participated in a quality assurance program it conducts for
screening. This would let the lawyers know whom to sue for
The foundation rejected the offer.
Yet faced with a lawsuit, the foundation settled. Even for patents
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
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
it may go too far under the patent laws".
Letters of notice of infringement have been mailed out, with some
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
May 15th Nature (page 221) reports on squabbles over patents
DNA chips, which allow solid state sensing of gene products. Since
state etching techniques allow very small surface and volume areas to be
defined and electrically accessed, DNA chips can allow the parallel
of thousands of DNA sequences.
In 1989, the European Patent Office awarded a patent to Ed Southern
the University of Oxford (inventor of the non-patented and very popular
Southern blot process) for using oligonucleotide arrays as testing
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
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
specifications are insufficient to support the claims of existing scope.
While lawyers for Southern and the University of Oxford (which
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
amended claims of narrower scope), they argue that the techniques are
Both sides seem willing to reach a compromise agreement. Which would
be nice for Affymetrix, which later this year will be facing complaints
the Northern District Court of California for infringing two 1993
on DNA-chip technology held by another California company, Hyseq, which
also challenging Southern's patents.
Sometime ago I reported on an exchange of letters between the NIH
the PTO on the confusion surrounding the patenting of ESTs. My last
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
and sent a letter to Lehman asking him to explain his vagueness. Stay
NATIONAL ACADEMY OF SCIENCES
2101 CONSTITUTION AVENUE, N.W.
WASHINGTON, D.C. 20418
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
patents granted for DNA sequences do not unfairly impede research and
innovation in biomedicine and biotechnology. I write on behalf of the
of the National Academy of Sciences (NAS) to express our concern. I will
make this letter and subsequent correspondence public to advance the
The NAS Council discussed your recent correspondence with Dr. Harold
Varmus at its last two meetings. It found your reply of April 2
but was puzzled about how to interpret the following sentence from your
"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
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
underlying patent claims, and how it will determine appropriate claim
The Council's concern stems in part from the central importance of
about DNA sequence in modern biology. Your sentence quoted above implies
the main concern is about the subsequent patentability of full length
if EST patents issue. Blocking future patents is one concern, but it is
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
cooperation between laboratories and centers--within the United States
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
if only partially explored, resource of enormous potential value. It
be sad indeed if patent policies diminished the pace of discovery or
of practical applications; yet patents that allow an early group of
who have disclosed little new knowledge to constrain the actions of
investigators threaten to do just that.
The main use of ESTs is to find genes that in turn lead to proteins
nucleic acid products), which could themselves lead to therapeutics or
targets for drug development. We are concerned about patents that can
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
DNA sequences in question that can be implemented without substantial
developmental research. We are encouraged by sensitivity to this issue
your letter to Dr. Varmus, but the equivocal sentence quoted above
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
applicants have supplied a sufficient enabling disclosure for these
Disclosure of DNA sequence alone is plainly insufficient to enable
to use an EST for any of these purposes. Data about the exact
site from which a DNA fragment arose are needed for mapping; data about
expression in a particular tissue or physiological state are needed for
tissue typing or diagnosis; and data about polymorphism among
needed for forensic uses. Inventors should be required to include the
data at the time of initial patent application to satisfy the
an enabling disclosure.
The perceived threat of EST patents is based in part on the
of the research community with patents on other research tools,
transgenic animal patents and related site-specific recombination
Some of these patents on research tools that lie far upstream of product
development are being used to "reach through" and extract rights to
discoveries. This complicates the commercialization of biotechnology
inventions, but more importantly it also hinders research into the
of disease, because access is limited to only those institutions willing
abide by the restrictions. Initial licensing of the Harvard oncomouse
Patent 4,736,866, assigned to Harvard and licensed to E. I. DuPont de
and Company) raised this concern years ago, and DuPont's licensing of
patent on site-specific recombination (US Patent 4,959,317) raises it
Similar use of EST patents could be devastating to the study of human
and disease by limiting access to the finite set of human genes. Our
is that patents are being used in ways that create obstacles to
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
potential difficulties that can arise for research when USPTO issues
patents on research tools.
In summary, we urge you to exercise caution and restraint in
patent law standards to ESTs and in determining the appropriate scope of
Bruce Alberts, President
On behalf of the Council,
National Academy of Sciences