Download BRCA 1 and BRCA 2 CASE

2013
Marek Vácha
BRCA 1 AND BRCA 2 CASE
http://www.nybooks.com/articles/archives/2013/mar/07/can-they-patentyour-genes/?pagination=false
http://www.nature.com/news/the-great-gene-patent-debate-1.11044
http://www.genome.gov/19016590
BRCA
 BRCA 1 is a tumor suppressor gene
 In the patent law of 1793, Congress defined eligibility partly
in language that Jefferson provided and that remains at the
heart of the statutory code (USC Title 35, Section 101) for
the subject.
 According to the statute, patents could be
obtained for “any new and useful art”—the
word was replaced in 1952 by “process”—
“machine, manufacture, or composition of
matter [Jefferson’s phrase], or any new and
useful improvement…[thereof].”
 During the following two centuries, these
exclusions from patent eligibility came to be
explicitly articulated in a body of federal court
decisions holding, for example, that
 natural elements taken from the earth, even
if they had to be chemically isolated from
other substances, did not constitute
patentable subject matter under Section 101,
if only because they were not new.
Discovery or Invention?
 Thus products of nature such as the naturally
occurring elements in the periodic table or
the creatures of the earth, being neither new
in the world nor made by man, were taken to
be ineligible for patents.
 So, tacitly, were
 laws of nature,
 natural manifestations,
 abstract ideas,
 thought.
Patent on Adrenalin
 1911: patent on adrenalin, which a
chemist had isolated from the body,
purified, and produced in concentrated
form
 having been extracted, purified, and thus
made useful, the adrenalin “became for
every practical purpose a new thing
commercially and therapeutically.”
Patent on a GMO
 1980: a landmark case that allowed
patents on a genetically modified
bacterium—they had “markedly different
characteristics from any found in nature.”
 Patent and Trademark Office (PTO)
 1980s: the PTO began issuing patents
on DNA—not DNA in the body, which was
indisputably a product of nature—but on
three different versions of DNA isolated
from the body.
 cDNA
 isolated fragments DNA
 the whole of the raw DNA in a gene.
BRCA 1 and BRCA 2
 1990: a geneticist at
Berkeley announced that
her laboratory had tracked
the location of BRCA1 to
somewhere on
chromosome number 17.
 A transatlantic race then
ensued to find the exact
position of the gene
 major competitor was Mark
Skolnick, a geneticist at the
University of Utah and a
cofounder of Myriad
Genetics.
Mark Skolnick
BRCA 1 (1994) and BRCA 2 (1995)
 Skolnick and his colleagues won the race in
1994, finding BRCA1 and isolating it from the
rest of the DNA and the tangle of protein that
form chromosome 17.
 In 1995, Myriad’s scientists also identified
and isolated BRCA2, which resides on
chromosome number 13.
 Shortly before November 1995, the ICR team found a
mutation from one of their breast cancer families that looked
as though it might very well sit in the BRCA 2 gene. Within
two weeks of the sequence being available, they not only
confirmed this mutation but found five more.
 There was no doubt: they had found the gene. Mike moved
fast to publish the group´s discovery in Nature, while keeping
it secret even from his collaborators until the last possible
minute.
 But despite his efforts, enough information about the
discovery reached Skolnick to enable him to locate the gene
himself and bang in a patent application – the day before the
ICR paper came out in Nature.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science, Politics, Ethics and
the Human Genome. Gorgi Books, London
 In 1994, Myriad, applied for patents on both
 the isolated DNA that makes up the BRCA1 gene
and also
 on a set of diagnostic tests to detect its presence.
 In 1995, it did the same for the isolated
DNA of BRCA2.
 In 1997 and 1998, the PTO awarded a total
of seven patents on the two isolated genes,
various DNA fragments within them, and the
diagnostic tests to find them.
 Myriad’s patents extended to all three types
of DNA extracted from the two BRCA genes.
 the patents give Myriad exclusive rights to
conduct diagnostic tests on the genes.
 Women who test positive using Myriad's
gene test, BRCA Analysis, have an 82
percent higher risk of breast cancer and 44
percent higher risk of ovarian cancer in their
lifetimes.
 Myriad Genetics filed for and received a
patent on the BRCA1 and BRCA 2 genes,
and this patent gave the company a
monopoly on diagnostic uses of these
discoveries.
 Myriad has aggressively protected its patent
right by posing legal challenges to any other
laboratory that has tried to offer testing.
 As a result, all competing diagnostic efforts
for BRCA 1/2 in the United States have been
driven out of business.
 Although Myriad has offered a test that is
highly accurate, the absence of any
market competition has kept the price
quite high (about $ 3 500), placing it
outside the reach of many individuals who
would like to have the information.

Collins, F., (2010) The Language of Life. Profile Books LTD. London, GB. p. 199
 January 2001: The PTO issued “Utility
Examination Guidelines” to clarify the
criteria that patent claims on DNA would
have to satisfy.
 products of nature can become eligible for
patents if they had “markedly different
characteristics from any found in nature.”
 2001, PTO: cDNA, which is made by
scientists outside the body, differs
markedly from the DNA inside it.
 So does the raw DNA extracted from the
body, whether the whole of a gene or a
fragment of it.
 when it is chemically disentangled from its
chromosomal housing it becomes a new
composition of matter.
 2005: 4,382 human genes (~20% of the
total number in our genome) are covered
by patents or other intellectual property
claims.
„BRCA CASE“: Defendants and Plaintiffs
 Defendants
 Plaintiffs
 the Myriad Genetics
 medical geneticists,
Corporation
 Patent and Trademark
Office (PTO)
 the University of Utah
Research Foundation
 pathologists
 advocates for women’s
health
 biomedical
researchers
 genetic counselors
 several women with
breast cancer or at risk
for it.
 May 2009:
 Plaintiffs contended that
 BRCA DNA—and by implication all
human DNA—should not be eligible for
patents as a matter of law
 Myriad’s enforcement of its patents interfered
with the progress of science and the delivery
of medical services.
 The plaintiffs contended that the patents should never have
been granted on either the DNA or the tests
 Myriad’s diagnostic methods boiled down to comparing the
base-pair sequence in the DNA taken from a patient with the
sequence in a version of the gene that will dispose the
person to cancer.
 the comparison did not require any particular process but
only the act of looking at one sequence and seeing whether
or not it matched the other.
 The “claim” was therefore to abstract ideas and thought and
as such was excluded from patentability.
Plaintiffs:
 the raw DNA and the cDNA forms embodied
the same sequences of cancer- disposing
base pairs—the same defining genetic
information—as did the native genes.
 The extracted raw DNA differed in material
composition only trivially from the native
version.
 It was no more transformed from the
natural DNA than was gold upon removal
from a stream bed or the yolk after
separation from the rest of the egg.
Myriad
 The patents gave Myriad a virtual lock on
research and diagnostics on the workings of
the BRCA1 and BRCA2 genes because,
 such research and diagnostics required analysis and
manipulation of the DNA in isolated form.
 Myriad reserved to itself the performance of all
diagnostic analyses of a patient’s DNA that might
be disclosed to her.
Myriad
 The legal argument in favor of patenting is
that the gene being patented is not being
claimed in its natural state, but is a product of
experimental investigation in which the gene
has been spliced into a recombinant DNA
vector, sequenced, and analyzed.
 The United States Patent and Trademark
Office has chosen to accept the argument,
based on an analogy with chemical patents,
that this is „composition of matter“
appropriate for patent protection.

Collins, F., (2010) The Language of Life. Profile Books LTD. London, GB. p. 199
Plaintiffs:
 Myriad’s policy enabled it to charge prices
for the tests that put them beyond the
reach of some women.
 It also prevented patients from obtaining a
second diagnostic opinion from an
independent laboratory.
Plaintiffs:
 DNA is not just another chemical.
 Even in isolated form, it embodies the gene’s
natural repository of genetic information and its
ability to express laws of nature.
 genes are not only special natural products;
each is also unique in its composition and
function.
 No one can invent another BRCA1 or BRCA2 any
more than someone can devise a different hydrogen or
oxygen..
 March 2010, Judge Sweet struck down Myriad’s
patents on the isolatedBRCA DNA and the
diagnostic methods that Myriad used to
determine whether a patient possesses the
genes herself.
 the isolation of the BRCA DNA, in whichever
form, did not alter its “essential characteristic”—
the sequence of base pairs that made it a carrier
of genetic information.
 Myriad’s BRCA DNA was thus not eligible for a
patent as a new composition of matter
Court of Appeals
 July 29, 2011, a three-judge panel of the
court partially reversed Judge Sweet by
upholding Myriad’s claim that
the BRCA DNA is eligible to be patented.
Court of Appeals
 August 16, 2012, a Court of Appeals panel,
composed of the same three judges who had dealt
with the case the year before, affirmed Judge
Sweet’s ruling against the patentability of Myriad’s
diagnostic methods, finding them tantamount to a
law of nature,
 but overturned his decision once again. The panel
held that cDNA itself is patent-eligible because it is
markedly different from the DNA in the body,
 they ruled that the other forms of
isolated BRCA DNA, whether the fragments or the
whole of the gene, are also eligible to be patented.
Plaintiffs:
 the isolated BRCA DNA is fundamentally
the same in structure and function as
the DNA in the body.
 It is no more a human invention because it
had been isolated from the chromosome
than was
 a kidney taken from the body,
 a limb removed from the tree, or
 a mineral or plant extracted from the earth.
Plaintiffs:
 James Watson:
"Life's instructions
ought not be
controlled by legal
monopolies
created at the
whim of Congress
or the courts."
John Sulston
 „My first response is that the genome
sequence is a discovery, not an invention.
 Like a mountain or a stream, it is a natural
object that was here, if not before we
were, at least before we were aware of its
existence.“
 „You can´t ever say that you own a gene,
because then you´d be owning one of my
genes as well.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science, Politics,
Ethics and the Human Genome. Gorgi Books, London
 Anyone who wants to make a better
mousetrap has to invent around existing
mousetrap patents.
 You can´t invent around discovery; you
can only invent around other inventions.
Defendants
 Venture capitalists would be reluctant to
invest in a small biotechnology firm if there
was no secure patent protection
 On September 25, 2012, the plaintiffs
asked the Supreme Court to review the
Court of Appeals’s August decision and on
November 30 the Court accepted the
case, confining its review solely to the
fundamental question of whether genes
are patentable…
 If the court decides that the patents are
invalid, that ruling would reverse more
than 20 years of precedent, during which
companies and academic researchers
have patented thousands of genes.
 November 2012
 The Supreme Court agreed to decide
whether human genes can be patented
 Myriad shares fell as much as 9 percent after
the Supreme Court agreed to hear the appeal
 cca more than 4,000 of the roughly 22,000
genes in the human genome have U.S.
patents.
 January 25, 2013
 For the second time, the US Supreme
Court has agreed to hear a lawsuit that
challenges patents on
the BRCA1 andBRCA2 genes...
Questions remain...
 Are genes part of our collective heritage
that should not be patentable at all?
 Should the isolation and purification of
genes from their natural state be a
sufficient basis for a patent?
 should the applicant be required to
demonstrate a use for the discovery?
Francis Collins
 „Recognizing these principles, my own
laboratory and that of Lap-Chee Tsui
insisted that the discovery of the CF gene,
in 1989, be available on a nonexclusive
basis to any laboratory that was interested
in offering testing.
 Many legal scholars have pointed to this
as a better example of how to ensure
public benefit.
Francis Collins
 Furthemore, I donated all my own patent
royalties from the CF gene discovery to
the Cystic Fibrosis Foundation, to support
further research into treatment. As director
of HGP, I took further steps to discourage
unwarranted gene patenting, insisting that
all information about the human DNA
sequence be placed immediately in the
public domain.“

Collins, F., (2010) The Language of Life. Profile Books LTD. London, GB. p. 201
Francis Collins
 The information contained in our shared
instruction book is so fundamental and
requires so much further research to
understand its utility, that patenting it at
the earliest stage is like putting up a
whole lot of unnecessary toll booths on
the road to discovery.

Collins, F., (2010) The Language of Life. Profile Books LTD. London, GB. p. 201
HUMANE GENOME
John Sulston
 Patents (or so I had always believed) are
designed to protect inventions. There are
three essential criteria for an invention:
 it has to be novel (no-one has published the
idea before)
 useful (in that it could be developed for
commercial or other uses) and
 non-obvious
 The ESTs met none of these criteria
John Sulston
 There was no „invention“ involved in
finding them, so how could they be
patentable?
 Yet the 1991 patentn application claimed
exclusive rights not only to the ESTs, but
to the whole genes they represented and
even the proteins encoded by these
genes. It was crazy.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science, Politics,
Ethics and the Human Genome. Gorgi Books, London
EST
 = expressed sequence tag
 A unique stretch of DNA within a coding




region of a gene that is useful for
identifying full-length genes and serves as
a landmark for mapping.
krátká sekvence cDNA
délka 500 – 800 nukleotidů
je komplementární k mRNA
EST je tedy část exprimovaného genu
 When Craig announced at a public briefing
on genome research for the US Senator Pete
Domenici in July 1991 that the patents had
been filed, Watson burst out that the
movewas „sheer lunacy“, and said he would
be „horrified“ if it were true that random bits
of sequence could be patented. He argued
that there was no invention involved,
asserting that the automation of sequencing
meant that the work could be done by
„virtually any monkey“.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science, Politics,
Ethics and the Human Genome. Gorgi Books, London
 Despite these protests in February 1992
the NIH added a further 2 375 ESTs to the
patent application, although this time they
dropped their claim to the proteins
encoded by the genes they represented.
 Their action set off a fresh round of criticism.
Berg spoke for many when he said, „It makes
a mockery of what most people feel is the right
way to do the Genome Project.“

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science, Politics,
Ethics and the Human Genome. Gorgi Books, London
 The US Patent Office roundly rejected the firs
application in August 1992, but the NIH
ppealed against the rejection and applied for
patents on another 4 448 ESTs.
 After the election of Bill Clinton as US President in
November 1992 Healy resigned (the NIH head is a
plitical appointment and she was a Republican
appointee). Her replacement, the highly respected
cancer researcher and Nobel prizewinner Harold
Varmus, decided not to pursue the patent issue
any further and withdrew all outstanding
applications in early 1994.
 Not until 2000 did the Patent Office
produce a set of guidelines that tightened
up the definition of „utility“ to prevent
people giving uses as vague as „a gene
probe“ in their applications.
 It is still permissible to patent a gene
sequence as long as you can show how it
might be used to diagnose diseases, for
example.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science, Politics,
Ethics and the Human Genome. Gorgi Books, London
John Sulston
 The goal of the genome project, as I saw it, was
to provide as much information as possible that
could be freely used by everyone, public and
private, to adfvance our understanding and
develop new treatments.
 I didn´t have a problem, and still don´t, with the
companies protecting their rights to the
inventions they sell – drugs or diagnostic kits, for
exemple – but I thought there was a real danger
if they were able to gain exclusive rights to the
information contained in the sequence itself.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science, Politics,
Ethics and the Human Genome. Gorgi Books, London
 In 1994, Merck funded a massive drive to generate ESTs
and place them in the public databases, where they would
be freely avilable to all.
 Bob Watersoin and Rick Wilson received a grant from Merck
to generate 4 000 ESTs a week for two years, starting in
January 1995
 by doing this, Merck not only gave the entire research
community, public and private, free access to valuable
genomic data; it also made those sequences (and possibly
the whole genes from which they came) much more difficult
to patent.
 Once the sequences had been in the public domain for a
year they could not be patented

and it would be tough for any company to identify the most
promisisng genes out of so many and understand their function in
such a short space of time
Rok 2000
Clinton-Blair
http://jnci.oxfordjournals.org/
content/92/8/594.full
JNCI J Natl Cancer
Inst (2000) 92(8): 594597.doi: 10.1093/jnci/92.8.59
4
Clinton – Blair Statement
 On the day of th stataement CBS Radio News
reported that Clintona adn Blair had agreed to
„ban patents on individual genes“, following an
easrly morning White House press briefing.
 That proved to be the last straw for an already
jumpy and still overvalued stock market.
 The Nasdaq, the index of biotechnology and
other high technlology stocks,k suffered the
second biggest fall in its history, more than 200
points.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science, Politics,
Ethics and the Human Genome. Gorgi Books, London
„The good guys won“
 any constraints
 no patents filed on the raw sequences
 no licenses
 no documents to be signed
 all you need is an internet connection
 we produced a sequence, put it in the public
domain and made it impossible for any
individual or company to control access to it.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science,
Politics, Ethics and the Human Genome. Gorgi Books, London
 The guidelines on patenting genes in the US have recently
been clarified to give a somewhat tighter definition of utility –
the use must be „substantial, specific and credible“
 The European Patent Directive, approved by the European
Parliament in 1998, accepts that a sequence or partial
sequence of a gene is eligible for a „cmposition of matter“
patent once it has been replicated outside the human body –
say, copied in bacteria as we do for sequencing. This
argument has always seemed to me absurd. The essence of
a gene is the information – the sequence – and copying it
into another format makes no difference.
 It is as though I took a hardback book that you had written,
published it in paper-back, and called it mine because the
binding is different.

Sulston, J., Ferry, G., (2003) The Common Thread. A Story of Science,
Politics, Ethics and the Human Genome. Gorgi Books, London
SUPPLEMENT
(NON-MANDATORY FOR THE TEST)
June 13, 2013


Justices, 9-0, Bar Patenting Human Genes
Human genes may not be patented, the Supreme
Court ruled unanimously on Thursday.
 After
the ruling, at least three companies and two
university labs said that they would begin offering
genetic testing in the field of breast cancer.

http://www.nytimes.com/2013/06/14/us/supreme-court-rules-human-genes-may-not-be-patented.html
June 13, 2013

Held: A naturally occurring DNA segment is a
product of nature and not patent eligible merely
because it has been isolated, but cDNA is patent
eligible because it is not naturally occurring
 cDNA
is not a “product of nature,” so it is patent
eligible under §101.

http://www.supremecourt.gov/opinions/12pdf/12398_8njq.pdf
June 13, 2013

“The Supreme Court got it exactly right,”
 “It’s
a great decision for patients, it’s a great decision
for science, and I think it’s a great decision for the
biotechnology industry.” (Eric Lander)

It is often said that patents cover 4,000 human
genes, or about 20 percent of all human genes,
meaning the decision could have a large impact.