World Patent Information 30 (2008) 139 143
www.elsevier.com/locate/worpatin
Twenty years of transgenic animals: Are some inventions SO
important as to NOT be entitled to full patent protection?
*
Michael Fuller
Nerac Inc., One Technology Drive, Tolland, CT 06084, USA
Abstract
Transgenic animals have been known for 30 years but the first transgenic mammal patent dates from 1988. This first patent, for the
Oncomouse which has been created to be susceptible to developing tumors, has generated large revenues for its licensee, DuPont. Equiv-
alent patents were only granted in Canada and Europe after litigation and amendment of the patent. DuPont has strictly enforced its
patent rights but this has led to debate over whether it is impeding research.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Transgenic animals; Transgenic mammals; Oncomouse; Oncogene; DuPont; Harvard mouse; Patenting organisms
1. Introduction carries the instructions for making the proteins necessary
to keep the organism alive and growing. Each segment of
April 12, 2008 marks the 20th anniversary of the first the organism s genetic material that codes for a protein is
patent granted on a non-human mammal. The patent called a gene. The cell contains its own machinery for read-
described a mouse carrying an activated oncogene sequence ing its genetic material and synthesizing proteins.
that led to its superhero-sounding name: Oncomouse. Over The concept of transgenic animals uses the cell s own
the life of the patent, the Oncomouse has certainly proved machinery to the scientist s advantage. The scientist creat-
to be super at generating licensing revenue for DuPont, ing the transgenic organism introduces a segment of DNA
which owns the patent and has licensed the patent strictly. that codes for a protein foreign to a host cell (called a
What effect did this patent have at the time it was granted? transgene) somewhere into the host cell. As the host cell s
And what effect has it had in the ensuing 20 years? This normal mechanisms for producing proteins from its gen-
article will discuss the status of patenting living beings ome (called translation) continue to function, the cells that
when the Oncomouse patent was granted, as well as the were inoculated with the foreign gene will also make the
details of the Oncomouse patent, and the effects the proteins encoded by the transgene, making the host organ-
Oncomouse patent has had on the patenting and commer- ism transgenic.
cialization of transgenic mammals. Two well-known types of transgenic animals are knock-
ins and knock-outs. A   knock-in organism has a trans-
2. Transgenic animal technology gene inserted into a specific portion of its genome, allowing
for over-expression of the transgene product.   Knock-
The idea of a transgenic animal originated in the 1970s. outs, by contrast, have had genes inactivated by insertion
All living organisms contain genetic material in the form of of mutated genes into the host genome.   Knock-ins and
DNA or RNA. This genetic material (called the genome)   knock-outs have been highly useful for studying diabe-
tes, cancer, heart disease, and other common maladies.
*
The insertion of the transgene into the host organism s
Tel.: [phone].
E-mail address: [e-mail] genome results in the vast majority of cells not containing
0172-2190/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.wpi.2007.11.002
140 M. Fuller / World Patent Information 30 (2008) 139 143
the transgene. However, for the process to be successful, mice, the best indicator of a compound s ability to cause
the transgene must be passed onto its progenitor cells. If cancer was an indirect measure called its mutagenicity,
only one generation of cells produced the transgene prod- discussed below.
uct of interest before dying, there would be no useful yield This system will test the carcinogenicity of a compound,
of product. rather than its mutagenicity. The original test for a com-
The first published transgenic animal was described by pound s ability to trigger mutations in genomic DNA,
Gordon et al. at Yale in 1977 [1]. Building on the work called the Ames test, involved treating bacteria with
of Jaenisch and Mintz [2], who showed that DNA placed increasing amounts of a compound until mutations were
into mouse blastocysts could be found in the resultant off- seen in the bacterial colonies.
spring, Gordon and his colleagues genetically transformed The transgenic animals could serve as sources of trans-
mice embryos by microinjecting DNA. Although only two formed cells, offering another avenue for testing com-
of the 78 embryos showed DNA sequences homologous to pounds. These cells could be induced or down-regulated
those injected (suggesting successful insertion of the trans- whenever an inducible promoter sequence was present
genic material), the experiment served as an enticing proof in the oncogene sequence.
of principle.
Building on Gordon s success, other scientists perfected
the technology further. In subsequent years, transgenic 4. Genesis of the Oncomouse patent
mice were created containing human globin genes [3,4];
rabbit globin genes; the chicken transferrin gene; and a Drs. Stewart and Leder applied for and received a pat-
functionally rearranged immunoglobulin gene. Palmiter ent on this technology in April 1988. The abstract of their
et al. took the technology a step further, creating a trans- patent (US 4,736,866) described   a transgenic non-human
genic mouse containing the rat growth hormone gene fused eukaryotic animal whose germ cells and somatic cells con-
to a heavy metal-inducible metalothionein promoter tain an activated oncogene sequence (namely a c-myc onco-
sequence (promoter sequences facilitate the translation of gene, claim 6) introduced into the animal, or an ancestor of
genes); a thymidine kinase gene fused to a metalothionein the animal, at an embryonic stage. The  866 patent specif-
promoter sequence; and the human growth hormone gene ically excluded humans from the scope of its 12 claims, but
fused to a metalothionein promoter sequence.1 otherwise was quite broad; it covered   any transgenic ani-
mal. . .that contains in all its cells an activated oncogene
3. Development of the Oncomouse that had been introduced into it or an ancestor at an
embryonic stage. Claim 2 discloses a chromosome within
In the late 1980s, Drs. Timothy Stewart from University the transgenic animal including an endogenous coding
of California, San Francisco, and Philip Leder of Harvard sequence that is   substantially the same as the oncogene
College successfully bred a mouse into whose genome they sequence, but that is inserted into the transgenic animal
had inserted an activated oncogene sequence by microinjec- genome at a site different from the endogenous sequence
tion. The activated oncogene sequence makes the mouse (claim 3), and that is controlled by a different promoter
susceptible to breast cancer by expression of the oncogene sequence than that of the endogenous sequence (claim 4).
sequences in mammary tissue. Transgenic mice that were The  866 patent also claims the use of an inducible (claim
susceptible to developing tumors were quite valuable for 5) viral promoter sequence (claim 7) to control transcrip-
many reasons: tion of the transgene, such as MMTV (claim 8) or RSV
(claim 9), or alternately, a synthetic promoter sequence
Because of the size of the mice and their hypersensitivity (claim 10). This would ostensibly allow for the non-infring-
to developing tumors, much less material would be ing use of a bacterial promoter sequence or some other
needed not only to test the potential carcinogenicity of non-viral promoter sequence (assuming it was not syn-
test compounds, but also to test their ability to treat thetic) in a similar transgenic technology.
tumors. This decreased the costs and time involved with While claim numbers 11 and 12 claim the use of a
basic research. rodent, specifically a mouse, as a host for the transgenic
The mice will develop the tumors faster because of their technology, the abstract immediately preceding the claims
predisposition to develop tumors. This also led to faster section also discusses the use of   any species for the trans-
and less expensive research. genic technology, such as a primate. Because of the com-
The information gained from testing compounds in plexity of the primate genome compared to a rodent
these mice should be more relevant to humans because genome, despite its usefulness because of its similarity to
both are vertebrates. This is important because, before the human genome, this technology would probably
require a substantial amount of effort to develop. In fact,
transgenic rats have only just recently been developed.
1
These first attempts at creating transgenic animals were not commer-
Soon after receiving the  866 patent in 1988, Drs. Stew-
cialized as extensively as the Oncomouse, perhaps because, as   proofs of
art and Leder granted an exclusive license to DuPont, who
principle, it was more technically feasible to start with genes that were
easier to manipulate and insert into the mouse genome. had funded their research. Later, Harvard College applied
M. Fuller / World Patent Information 30 (2008) 139 143 141
for and received two additional patents derived from the the Commissioner of Patents, stating that transgenic mice
transgenic mouse technology: US 5,087,571, related to a were patentable subject matter.
method for culturing cells originating derived from a trans- The Canadian Supreme Court reversed the Federal
genic animal; and US 5,925,803, related to an Oncomouse- Court of Appeal s ruling, holding that   higher life forms
based screening system. Their patent protection through did not qualify as patentable subject matter, neither as
these three patents does not expire until 2016 [5]. composition of matter nor as manufacture. Instead, the
Transgenic animals were well-known in the art at the Court left it to the Canadian legislature to change the pat-
time Drs. Stewart and Leder applied for their patent (see ent laws to allow for patenting of transgenic animals and
infra for a list of prominent transgenic animals that pre- other   higher life forms. Ultimately, Harvard College
ceded the OncoMouse). But none had apparently been able was forced to amend their application to remove their com-
to develop a transgenic mouse worth commercializing, and position of matter claims on transgenic mice in order to
therefore worth patenting, until the   Harvard mouse, as it receive their patent, which it did on October 7, 2003.
became known,2 came along. It has been a similarly bumpy ride for the Oncomouse in
Europe. Harvard College filed their European patent appli-
5. Science can create living organisms but can they be cation in 1985. The EPO rejected this application in 1989
patented? on the grounds that animals were not patentable. On
appeal, the Board of Appeal held that animal varieties were
At the same time the technology of transgenic organisms not patentable, but animals were patentable. The Board of
was taking wing, the patenting of living organisms was Appeal weighed the value to society of a means for deter-
becoming a touchy issue in patent law and science since the mining possible cancer treatments versus the pain or dis-
Supreme Court heard the Diamond v. Chakrabarty case. In comfort caused to the mice, and determined that the
Diamond, the Supreme Court held that a microorganism former outweighed the latter [6]. The application finally
genetically engineered to ingest oil (as a way of mitigating matured into a patent in 1992, after which it was opposed
oil spills) was patentable subject matter under 35 USC by 17 parties, including Greenpeace. At the end of these
ż101, which states only that a   new and useful process, opposition proceedings in November 2001, the EPO held
machine, manufacture, or composition of matter will be that the patent must be limited to transgenic rodents con-
entitled to a patent. Writing for the majority, Chief Justice taining an additional cancer gene [7]. The opposition deci-
Warren Burger made his now-famous statement that patent sion of November 2001 was then appealed, but the patent
law extends to   anything under the sun, made by man. was upheld (albeit in amended form) in 2004 [5].
Therefore, even though these bacteria were living organisms,
the mere fact that they were   made by man made them 6. Ripple effect of the Oncomouse patent
potentially patentable.
While the patenting of the Oncomouse was relatively DuPont licensed the rights to this patent for $6 million in
straightforward in the United States,3 DuPont has had dif- 1988. Soon, Fortune magazine would name the Oncomouse
ficulty receiving patents from other patenting authorities. the   Product of the Year [8]. The fact that the granting of
The Canadian Oncomouse patent finally issued in 2003 the Oncomouse patent had broadened the scope of patent-
after the rejected version of the application was amended ability from Diamond v. Chakrabarty (which permitted the
to conform to Canadian patent law, by removing the por- patenting of modified bacteria) to now cover mammals,
tion of the patent that claimed the transgenic mouse as a led to a boom in life science patenting in general between
composition of matter. When first submitted, the Commis- 1989 (when DuPont first announced their intent to commer-
sioner of Patents rejected the Canadian Oncomouse patent cialize the Oncomouse) and 1999, US research universities
application on the basis that transgenic mice were not pat- alone received over 6000 life science patents [9]. Just within
entable subject matter. Canadian patent law, as codified in the realm of transgenic animals, there are now transgenic
the Canadian Patent Act, states that an invention is any sheep, goats, chickens, and pigs. Transgenic animals are a
new and useful improvement in an art, process, machine, source of insulin, growth hormone, blood anti-clotting fac-
manufacture, or composition of matter, but the Commis- tors, and human protein-enriched milk from cows. Addi-
sioner of Patents did not feel that transgenic mice (as tionally, there are   knock-out transgenic mice that are
  higher life forms ) qualified as a composition of matter. missing genes of interest, to help understand the functions
On appeal, the Federal Court of Appeal, using logic similar of the proteins encoded by those genes [10,11].
to that employed by the US Supreme Court in Diamond
v. Chakrabarty, sided with Harvard College and reversed 7. Licensing the Oncomouse patent
Since the transgenic mouse patent was granted, DuPont
2
The transgenic mouse described in the  866 patent will be called the
has gained some notoriety for the severity of its licensing
  Harvard mouse and   Oncomouse interchangeably throughout this
agreement for anyone wishing to use the Oncomouse. Crit-
paper.
3
ics of the agreement say that its stringency with respect to
Interestingly, no parties have attempted to invalidate the Oncomouse
patent during its term, despite its obvious money-making ability [5]. how the Oncomouse may be used unnecessarily and
142 M. Fuller / World Patent Information 30 (2008) 139 143
improperly impairs research by scientists afraid of the con- should be more readily available for research. After all, the
sequences of unknowingly violating the terms of the agree- basis of patent law is to share innovations with the public so
ment, especially when dealing with a company with the that useful technologies may continue to be developed.
financial and legal resources of DuPont. Indeed, agreements DuPont continues to act under the doctrine that, as the
with Massachusetts Institute of Technology, the University owners of the patent, it is allowed to exploit that patent
of California system, and the Memorial Sloan-Kettering within the limits of the law as it sees fit, and that the com-
Cancer Center have been delayed or cancelled outright, pany is not totally restricting access to the Oncomouse.
ostensibly due to the terms of the Oncomouse licensing Much as the USPTO is willing to grant expedited review
agreement [12]. DuPont would probably reply that it is for patent applications falling into certain classes (such as
merely protecting its intellectual property rights as strictly counter-terrorism or energy), some form of special review
as would any other holder of an extremely valuable patent.4 should also be considered for patents falling into certain
In fact, DuPont has gone so far as to pressure institutions important classes (such as treatment of cancer or heart dis-
using knock-out mice to sign one of their licensing agree- ease) to impose certain restrictions on patents upon issue.
ments, arguing that, because of the breadth of the language By so doing, patentees are still allowed to exploit these pat-
in their patent, knock-out technology falls within the ents commercially, while not impeding the   progress of the
Oncomouse patent boundaries.5 Whether their claims are useful arts  as has been suggested by some to be the case
indeed as broad as they argue (and it is highly debatable with the Oncomouse licensing agreement. One possible
whether a mutated, inactivated transgene in a knock-out change would be to offer a greater incentive to inventors
mouse is the same as an activated gene in the Oncomouse) within these disciplines, such as extended patent terms
misses the big picture: there are few companies with the (such as those offered for drugs requiring regulatory
financial resources to litigate with DuPont, when licensing approval prior to marketing), to offset the patent holder s
the Oncomouse patent (or even developing their own trans- ability to fully exploit their patents commercially. Congress
genic mice) would probably be much more cost-effective. needs to take the first step, by acknowledging that this is a
Perhaps in response to this criticism, DuPont entered into problem and addressing it with appropriate legislation that
a Memo of Understanding with the National Institutes of would empower the USPTO to act accordingly.
Health (NIH) with respect to NIH s use of the Oncomouse
in 2000. The NIH is allowed to use the Oncomouse for
References
research purposes for free; in exchange, DuPont is allowed
to restrict the NIH s ability to transfer Oncomouse materials
[1] Gordon Jon W, Scangos George A, Plotkin Diane J, Barbosa James
to non-profit and for-profit institutions. For-profit institu-
A, Ruddle Frank H. Genetic transformation of mouse embryos by
tions receiving Oncomouse materials from the NIH must
microinjection of purified DNA. PNAS 1977;77:7380 4.
pay license fees to DuPont on top of whatever fees they [2] Jaenisch Rudolf, Mintz Beatrice. Simian virus 40 DNA sequences in
DNA of healthy adult mice derived from preimplantation blastocysts
may already be paying NIH for the use of the materials.
injected with viral DNA. PNAS 1974;71:1250 4.
DuPont is also entitled to   reasonable quantities of any
[3] Wagner. PNAS 1981;78:5016.
materials resulting from Oncomouse-based research, thereby
[4] Stewart et al. Science 1982;217:1046.
supplementing any DuPont research efforts. While some
[5] See Wikipedia s Oncomouse page at http://en.wikipedia.org/wiki/
researchers feel this Memo of Understanding has made the Harvard_mouse.
[6] See Bioethics and patent law: the case of the oncomouse, available
Oncomouse more available for non-profit researchers, other
at http://www.wipo.int/wipo_magazine/en/2006/03/article_0006.html.
institutions have contested DuPont s use of the MOU [10,11].
Note that this same rationale was applied to a transgenic mouse for
hair loss (by Upjohn in 1992), and the EPO Board of Appeal held
8. Conclusion
that these mice were not patentable.
[7] See European Patent Office limits Harvard s  oncomouse patent,
available at http://www.epo.org/about-us/press/releases/archive/2001/
The Oncomouse patent has certainly proved to be a
07112001.html.
lucrative acquisition for DuPont. However, some research-
[8] Murray F. The Oncomouse that roared: resistance and accommoda-
ers would argue that the tight control that DuPont main-
tion to patenting in academic science, page 3. tains over the Oncomouse patent has hindered cancer
fmurray/www/papers/THE%20ONCOMOUSE%20THAT%20ROA-
research to a degree, and that such an important technology RED_FINAL.pdf>.
[9] See F. Murray, The Oncomouse that roared, at page 7, citing Owen-
Smith and Powell, 2003.
4
Chip Murray, head of intellectual assets for DuPont is quoted as [10] See Transgenic animals: their benefits to human welfare, by Endang
saying,   We know we have a very important property, and it is in our best Tri Margawati, available at http://www.actionbioscience.org/biotech/
interests to get it as widely used as possible. And despite the MOU with margawati.html.
NIH, Murray admits,   We are still trying to make the most return on our [11] See also http://www.gsk.com/research/about/about_animals_roles.
original investments in the OncoMouse portfolio. Our strategy [with html for a pro-transgenic industry perspective.
respect to exploiting the Oncomouse] has not changed [13]. [12] See of Transgenic Mice and Men, by Peter Shorett, citing the San
5
Arguments by DuPont as to the breadth of their claims have probably Francisco Chronicle, June 3, 2002 article titled   OncoMouse breeds
helped limit the scope of later oncomammal patents by applicants controversy: Cancer researchers at odds with DuPont over fees for
unwilling to contest DuPont in court, as well as deterring the development patents, available at http://www.sfgate.com/cgi-bin/article.cgi?file=/
and patenting of other related transgenic animals [9]. chronicle/archive/2002/06/03/BU116161.DTL&type=business.
M. Fuller / World Patent Information 30 (2008) 139 143 143
[13] Ongoing battle over transgenic mice, available at http://www.the- Michael is a USPTO-registered patent attorney working for Nerac as a
scientist.com/article/display/14847/. Project Analyst. Michael wishes to thank his beautiful family for their
support Rita, Zachary, Emma, and Claire.
Michael Fuller was born in Baltimore and lived
throughout the United States before attending
Tulane University in New Orleans. He spent more
than 15 years researching neurodegenerative dis-
eases such as Huntington s disease (at the Mary-
land Psychiatric Research Center, under Dr.
Robert Schwarcz) and Parkinson s disease (at
Guilford Pharmaceuticals, under Dr. Joseph
Steiner). During that time, he has also completed
his MS in Pharmacology from UMAB, and his
JD (cum laude) from University of Baltimore.