Image by andylepp (via Flickr.com under Creative Commons licence)

“US Supreme Court rules that human genes cannot be patented” is the headline that millions of people around the world will be reading today, after the US Supreme Court issued its decision yesterday (13 June 2013) in the ‘Myriad case’.

However, the headline for the general populace is quite different to the take-home message for those in the biotechnology community and for patent attorneys in particular.  Whilst there is no doubt that some patents exist to human genes (although never in so far as they encompass a natural gene within a human being – a popular misconception in the press), patent attorneys have understood for a long time that patent offices, such as in the US and Europe, have not granted such broad patents for many years – the patentability requirements are simply too tough to obtain broad gene sequence claims in the modern era.  In fact, the results of ‘the human genome sequencing project’, which opened up the possibility for people to easily try to claim human gene sequences has, in fact, made that prospect far harder.  People have never needed to worry that ‘their’ genes might be patented by someone else.

In yesterday’s decision it was held that a naturally occurring DNA sequence is a product of nature and not patent eligible in the US, but a cDNA sequence is patent eligible provided it does not occur naturally.

So what would be a more realistic headline to this latest US decision?  Well, fortunately for all concerned, the headline is probably not so dramatic as that stated above!  We need to take a couple of steps back to understand the outcome of this latest decision.

The Boring Bit (or ‘the science’ as it is otherwise known)

The genetic make-up of a human being, which helps to determine all of our physical features and characteristics, is stored in ‘genes’ in each of our cells.  There are over 20,000 ‘genes’ in the human genome, which are arranged into far larger molecules known as ‘chromosomes’, of which there are 23 pairs in the average human cell.  Most genes determine and direct the production of specific ‘proteins’, which carry out important biological functions within our cells.

A gene is a complex chemical molecule, which is typically made up of thousands of DNA units (or ‘nucleotides’) joined head to tail in a specific sequence.  A natural gene, e.g. from a human, can be still more complex: containing long strings of DNA units that determine the sequence of a particular protein molecule (known as ‘exons’), interspersed with long strings of DNA units that are not represented in the final protein (known as ‘introns’).

In order for a gene to produce a protein, the DNA sequence of the gene must first be used as a template to produce a slightly different type of molecule known as RNA (or mRNA to be precise), and this mRNA molecule is then used as a template to produce the corresponding protein molecule.  It is during the mRNA phase in this process that the introns of a gene sequence are removed so that the protein sequence represents only the sequence of the exons.  Therefore, the sequence of a protein can be used to predict the sequence of the mRNA responsible for its production, which in turn can be used to determine the DNA sequence of the exons in a particular gene.  By contrast, no information on the possible sequences or locations of any introns in a natural gene can be gained from the protein or mRNA sequence used to produce the protein.

A DNA or gene sequence made up of just the exons of a natural gene, as would be achieved by producing an artificial gene sequence based solely on the natural mRNA or protein sequence is termed complementary DNA (‘cDNA’ for short).

I think that’s about enough of the science.

The Medical Break-through

Myriad (or at least its founding scientist) was the first to discover and identify the gene sequences of the BRCA1 and BRCA2 genes and their locations within the human genome.  Mutations in these genes are known to dramatically increase the risk of develop­ing certain types of breast and ovarian cancer.  In fact, as a result of certain mutations in these genes it seems that the chance of a woman developing breast cancer can be as high as 80%.  There has since been understandable interest in knowing whether an individual has any of these genetic mutations in advance of developing a cancer, and this has even led to woman taking the bold step to undergo pre-emptive mastectomies.  Angelina Jolie is a notable recent example.

Identifying these key genes allowed Myriad to claim gene and DNA sequences, as well as methods in which those sequences (or the resultant proteins) might be used, for example, in cancer screening.  This has allowed Myriad to control breast cancer screening across the US for many years.

It’s probably fair to say that had Myriad not discovered the BRCA1 and BRCA2 genes, there were probably several other scientists close behind who would have done so soon afterwards, but Myriad got there first and so were entitled to try to patent their ‘inventions’.

The Patents

Myriad have many granted patents in the US that relate to the human breast cancer genes BRCA1 and BRCA2.  The present decision relates only to a small subset of those patents (US 5747282, US 5693473 and US 5837492), and moreover, to only a small subset of the allowed claims in this subset of patents.  The patent claims at issue were specifically directed to DNA / gene sequences that encode for the BRCA1 and BRCA2 proteins, and to small fragments of those genes.

Claim 1 of the US 5747282 patent, one of the contested claims states “[a]n isolated DNA coding for a BRCA1 polypeptide, which has the amino acid sequence set forth in SEQ ID NO:2”.  In other words, this claim encompasses any isolated DNA / gene sequence which encodes for the BRCA1 protein sequence that is defined in SEQ ID NO: 2.  This protein sequence is a naturally occurring protein sequence and so the DNA / gene sequence claimed encompasses a natural BRCA1 gene, albeit in an ‘isolated’ state, i.e. outside of its natural environment in the human genome.  Claim 5 of the same patent states “[a]n isolated DNA having at least 15 nucleotides of the DNA of claim 1”.  This claim, therefore, is far broader than Claim 1, in that it encompasses any isolated small fragment (of at least 15 nucleotides) of a DNA / gene sequence encoding the BRCA1 protein sequence.

Myriad also have many claims directed to cDNA sequences for various mutated BRCA genes and to various medical diagnostic tests.

While in force, this suite of patents has given Myriad the exclusive right to isolate BRCA1 and BRCA2 genes, and to use these sequences in diagnostic tests.

The Law

The decision relates to the issue of ‘patentable subject-matter’ – Section 101 (§ 101) of the US patents act.  In other words, does a particular type of discovery overcome the first hurdle towards a potentially valid patent, i.e. can it be an ‘invention’.  This decision does not address other key determinants in patent validity, such as novelty and inventive step, which are the issues more commonly tackled by patent attorneys and their clients in biotechnology.

§ 101 states:

“[w]hoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title”.

In the past this has been broadly understood to mean that ‘everything under the sun’ is potentially patentable in the US.  However, there have always been exclusions to patentability, which fall under the “conditions and requirements” specified in the rule above.  These exclusions prevent the patenting of laws of nature, natural phe­nomena and abstract ideas: things that constitute the tools of scientific progress and development and which it are deemed important to preserve for all to use.

The question addressed in the decision at hand is whether gene sequences should be considered a ‘natural phenomenon’ and, therefore, subject to such an exclusion.

The Decision

The US Supreme Court ruling comes after a line of previous decisions by lower courts in the US, but does not dramatically overturn the previous decision of the Federal Court.

During the case, it was accepted that Myriad did not create or alter any of the sequence information in the BRCA1 and BRCA2 genes.  Myriad’s contribution (insofar as the patents relate to BRCA1 and BRCA2 gene sequences) was simply to identify the genes and their locations in the human genome, enabling them to be isolated and ‘used’.  However, as a result they were granted patent exclusivity on the natural gene sequences in isolated form.

To cut to the chase, the Supreme Court decided, first, that “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated”, and second, that “cDNA is patent eligible because it is not naturally occurring”.

Therefore, the decision confirms that an isolated gene or DNA sequence that is identical to a corresponding gene or DNA sequence occurring naturally is not patentable in the US (even if it does have a very useful application in science or medicine); irrespective of whether it was particularly difficult or clever to identify or isolate the gene in the first place.  As a result, Myriad lost some the contested claims including the two highlighted above.

However, provided the isolated gene or DNA is modified in some way from the corresponding natural gene sequence, in principle (subject to other patentability requirements, novelty, inventive step etc.), the isolated sequence is patentable.  A cDNA gene is not generally identical to a counterpart natural gene, because whereas a natural gene may have introns, a cDNA gene does not.  This modification was considered sufficient to meet the patent-eligibility criteria.  However, it is not quite so straight forward.  Some natural genes may not have introns.  More significantly, some cDNA sequences that may be claimed in a patent relate to (short) fragments of gene, and these fragments may fall squarely within a single exon of a natural gene, meaning that no introns have been removed.  Such cDNA sequences would now appear to represent a natural phenomenon and, therefore, be excluded from patentability.

It is important to note that this decision did not have any effect on the patentability of method claims that might use gene sequences, of new applications relating to gene sequences, or of claims to modified (genetically altered) gene sequences.

The Conclusion

This is a common sense decision.  It is not a thunderbolt out of the blue that is going to turn the world of patents on its head or bring multinational biotechnology corporations to their knees.

It is in part a victory for the public, because finally there is confirmation that a natural gene cannot be patented; and this will no doubt help to bring additional medical methods to the marketplace sooner, which will be a good thing for all of us.

However, it is also a partial victory for the biotechnology industry and Myriad in particular.  Most importantly, Myriad’s patent claims to cDNA sequences have been protected, and this is extremely important.  The alternative decision on the patentability of cDNA sequences would truly have sent a shock-wave across the biotechnology industry.  Fortunately, this has been avoided.  Also, Myriad’s patented method claims are also protected, and this is a core part of their business.

We wait to see how much impact this decision will have: perhaps very little.  There will be other biotechnology companies more affected by this decision than Myriad, because all US patents directed to natural gene sequences will now be open to attack.  Myriad, on the other hand, has already enjoyed many years of exclusivity on the BRCA1 and BRCA2 genes based on these patents.  In fact, the contested patents were filed in the period of 1996 to 1998, and are due to expire naturally at the end of their 20 year term over the next few years.  So despite the dramatic headline, the result is certainly of less consequence.

A far less interesting but more suitable headline would be:

“US Supreme Court finally brings clarity to the patentability of gene sequences”.

Michael Moore   14 June 2013

“DNA Representation” Image by Andy Leppard- Andylepp (via Flickr.com under Creative Commons Licence)