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Page 1
Genetic testing in the wake of the Australian and
US decisions re Myriad’s breast cancer patent
Jacinta Flattery-O’Brien, PhD
BRCA 1 protein
Zinc finger
Serine cluster domain
Isoforms (>1800 aa)
BRCA 1 gene on Ch 17 (43Mb)
Hundreds of mutations in BRCA1
Some variations carry 80% risk of
breast cancer
BRCA 1
An Australian problem
• Myriad startup established in US in 1994
• “Complete” Patent Application BRCA 1 lodged 1995
• Exclusive license to Genetic Technologies in Australia to conduct
breast cancer susceptibility tests BRCA-1 and BRCA-2
• In 2008 GT attempted to charge licensing fees
“genetic scanning on potential cancer victims has stopped in all
publicly funded laboratories, potentially placing many women’s lives
at risk”.
• GT backed down... too late...
Attempts to exclude gene
patents
• Inquiry by the Senate's community affairs committee into the
patentability of genes and other biological material
- recommended no exclusion of genes or biological materials
• Private members bill to exclude genes and biological materials from
patentability 2010
- rejected by the Senate Committee
Cancer Voices Australia v Myriad
Genetics Inc. [2013] FCA 65
(single judge)
• Invention means any manner of manufacture …. within section 6 of the
Statute of Monopolies1623
• Manner of manufacture = an artificially created state of affairs with
economic utility (NRDC v The Commissioner of Patents (1959) 102 CLR
252)
• Inconsistent with NRDC for a person whose skill and effort culminated in
the isolation of biological material not to be rewarded by the grant of a
patent.
• Decision in favour of Myriad
“Naturally occurring DNA and RNA as they exist in a cell are not within
the scope of any of the disputed claims and could never, at least not until
they had been isolated, result in the infringement of any such claim”.
D’Arcy and Myriad Genetics [2014]
FCAFC 115
(Full Federal Court – 5 judges)
• The Court considered
– patentability boundaries must encompass the development of
science and technology and human ingenuity;
– human intervention that creates an artificial state of affairs that
has some discernible effect is essential;
– expressions such as “the work of nature” or “the laws of nature”
are not found in the statute; nor are they useful tools of analysis.
• Unanimous decision in favour of Myriad.
D’Arcy v Myriad Genetics Inc [2015]
HCA 35
Nettle Gageler Kieffel French Bell Keane Gordon
Are Myriad’s claims in substance directed to a molecule or to “information”?
Australian Patent 686004
Claim 1: An isolated nucleic acid coding for a mutant or polymorphic BRCA1
polypeptide, said nucleic acid containing in comparison to the BRCA1 polypeptide
encoding sequence set forth in SEQ.ID No:1 one or more mutations or
polymorphisms selected from the mutations set forth in Tables 12, 12A and 14 and
the polymorphisms set forth in Tables 18 and 19.
High Court decision
• Unanimous: claims not directed to a “manner of manufacture” i.e. claimed
nucleic acids are not an “artificially created state of affairs”.
• Claims directed to “information embodied in the arrangement of
nucleotides” and “this information is not made by human action”.
• The fact that the invention lay at the boundaries of what constitutes a
manner of manufacture coupled with the breadth of the monopoly defined
by the claims, raised the risk of a “chilling effect” on legitimate innovative
activity and risked an unwarranted de facto monopoly impeding the
activities of legitimate improvers and inventors.
• cf. Centre for International Economics: “Patents play a key role in
promoting innovation and the public-private partnerships required to bring
new human gene-based medicines and diagnostics to market.”
Extension of HC decision to
exclude cDNA from patentability?
• Majority: “Used in that sense, the information stored in
the sequence of nucleotides coding for the mutated or
polymorphic BRCA1 polypeptide is the same
information as that contained in the DNA of the person
from which the nucleic acid was isolated. [...] The
product is the medium in which that information resides.
That characteristic also attaches to cDNA, covered by
the claims which is synthesised but replicates a naturally
occurring sequence of exons.”
Patent Office Guidelines
• When the substance of the claimed invention is genetic information
that was not “made”, claiming of the invention as an isolated product
does not confer patent eligibility.
• High Court not concerned with “gene patenting” generally
• NO findings re probes, vectors, methods of production and methods
of diagnosis.
• NO general rule that isolated natural products or their derivatives are
excluded from patentability.
Patent ineligible subject matter
• Isolated naturally occurring nucleic acid molecules
whether:
– DNA or RNA
– Human or non-human
– Coding or non-coding
• Claims to the following are excluded where they merely
replicate the genetic information of a naturally occurring
organism:
– cDNA and synthetic nucleic acids
– Probes and primers
Patent eligible subject matter
• Isolated naturally occurring material other than gene
sequences
• Recombinant or isolated proteins/microorganisms
• Pharmaceuticals and other chemical substances
• Methods of treatment and diagnosis
Method of diagnosis claims NOT challenged in Myriad
What does this mean for
pathologists?
Genes involved in a patented method of diagnosis of one
disorder may be used for diagnosis of another disorder
Note:
• Research exemption
• Actions in course of obtaining regulatory approval not an
infringement
Methods of diagnosis using genetic testing are patentable in
Australia
- exercise care when using patented methods
- consider patent protection for your methods of
diagnosis
United States vs Australia
Subject matter Patent eligibility in US Patent eligibility in
Australia Isolated naturally occurring gene
sequences
No No
Isolated naturally occurring gene
sequences having modified
nucleotides
Yes Depends whether the
modification contributes to the
working of the invention
Codon optimised gene
sequences
Yes Yes
cDNA Yes No
Interfering RNA molecules Yes Yes
Isolated naturally occurring
proteins
No Yes
Isolated micro-organisms No Yes
United States
Mayo Collaborative Services v
Prometheus
• Use of thiopurines to treat intestinal autoimmune
diseases such as Crohn’s disease and ulcerative colitis.
• Problem:
– The way each individual responds to thiopurines
varies markedly
– Difficult to determine an appropriate therapeutic dose
– Easy to administer either a toxic or a sub-therapeutic
dose
Mayo v Prometheus
Prometheus invention (personalised medicine)
– Administer an amount of thiopurine drug to a subject;
– Check the blood concentration of the metabolite 6-thioguanidine;
– Adjust the dose of thiopurine administered to attain a 6-
thioguanidine concentration of between 230 - 400pmol per 8x108
red blood cells
– The amount of drug metabolite, rather than the drug
administered, was key to successful treatment.
Court: “nothing significantly more than an instruction to apply applicable
laws when treating patients”
NOT patentable!
United States
Ariosa Diagnostics, Inc. v.
Sequenom, Inc. (Fed. Cir. 2015)
• Pregnant women’s blood contains large amounts of
cell-free fetal DNA (cffDNA).
• cffDNA can be used to determine a number of fetal
characteristics and abnormalities, e.g. Down Syndrome.
• Eliminates the need for amniocentesis and chorionic villus
sampling, which incur risks to both mother and child.
Claims US 6,258,540
• 1. A method for detecting a paternally inherited nucleic acid of fetal
origin performed on a maternal serum or plasma sample from a
pregnant female, which method comprises amplifying a paternally
inherited nucleic acid from the serum or plasma sample and
detecting the presence of a paternally inherited nucleic acid of fetal
origin in the sample.
• 24. A method for detecting a paternally inherited nucleic acid on a
maternal blood sample, which method comprises:
removing all or substantially all nucleated and anucleated cell
populations from the blood sample, amplifying a paternally inherited
nucleic acid from the remaining fluid and subjecting the amplified
nucleic acid to a test for the paternally inherited fetal nucleic acid.
Arguments
• Sequenom: methods are patentable as they define novel
uses of a natural phenomenon rather than the natural
phenomenon itself.
• Ariosa: the method does not "add enough" to a natural
phenomenon (the existence of cffDNA in maternal blood) to
render the claims patent eligible.
• The District Court agreed with Ariosa and stated that
Sequenom needed to invent novel ways of detecting cffDNA.
US Federal Circuit
• Using methods like PCR to amplify and detect cffDNA was well
understood, routine and conventional activity in 1997.
• The method amounts to an instruction to apply routine, conventional
techniques when seeking to detect cffDNA.
• The method of detecting paternally inherited cffDNA is not new and
useful (????).
• The only new and useful subject matter was the discovery of the
presence of cffDNA in maternal plasma or serum.
• The existence of cffDNA in maternal blood is a natural phenomenon.
Begins and ends with a natural
phenomenon?
• What comes out of the method is an artificially-enriched
substance that, unlike the naturally-occurring cffDNA
can be used for many diagnostic purposes.
• The method ends with a substance that is anything but a
natural phenomenon.
Comparing Mayo and
Sequenom
• Prometheus” every step of method had been performed
in the prior art; the only new aspect in those claims was
the therapeutic ratio, which the Court found to be a
"natural law."
• In Sequenom the inventors claimed something not
done before, ie detecting cffDNA in maternal blood for
diagnosis.
The big picture
• Methods of diagnosis are now very difficult to patent in
the United States
• Question: should diagnostic methods, genetic testing
methods in particular, be patentable?
• What is the purpose of the patent system?
• To encourage innovation?