Optimising autoimmune treatment patent invalid: a ‘Law of Nature’ is not a law passed by Congress

By Peter Kerr 23/03/2012 8


By guest blogger Doug Calhoun

On 20 March the Supreme Court of the United States (SCOTUS) issued a decision unanimously allowing an appeal by the Mayo Clinic and declaring invalid two patents that a lower court had found Mayo to be infringing: (see here)

The background to the invention is described on the web page of one of the inventors: (see here)

In Yves Théoret’s own words:

‘[We study] the relationships that exist between concentrations of medications and their metabolites (medication transformation products) in plasma and blood cells, and therapeutic response, according to genetic characteristics of individuals or a given population (French Canadians, Amerindians, American Blacks, Asians). These characteristics (or polymorphisms) can translate into a deceleration or an acceleration in the enzymatic transformation of medication and/or an amplification or reduction in medicated response on specific tissue sites. By determining these various variables, it is possible to individualize and optimise therapeutic treatment while minimizing toxic effects.’

‘Our studies with thiopurines (6-mercaptopuirine or Purinethol; azathioprine or Imuran) administered to children have made it possible to validate this axiom. Thus, patients with an activity deficiency of a particular transferase enzyme (thiopurine methyltransferase) have higher concentrations of active metabolites (nucleotides of 6-thioguanine) and a higher percentage of therapeutic response than patients who do not have reduced enzymatic activity. The sex and age of the patient are also determining factors when it comes to the pharmacokinetics of the medication and therapeutic response. Facing the obvious impracticality of performing pharmacokinetics (measuring the concentration of the medication and its metabolites per unit of time) on all drugs administered to children with various ailments, we also study the possible relationships between the intensity of the drug dose (quantity administered per unit of time) and the therapeutic response as evaluated by various parameters (white blood cell count, gastric acidity, hepatic enzymes). Specialized software makes it possible to determine these relationships.’

In the words of the patents, the invention ‘provides a method of optimising therapeutic efficacy of 6-mercaptopurine drug treatment of an immune-mediated gastrointestinal disorder’ — the goldilocks level of dosage.

The SCOTUS decision (pages 5 and 6) focused on one representative claim (claims define the invention of a patent — the rest is background):

‘A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:
(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and
(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,
wherein the level of 6-thioguanine less than about 230 µmol per 8×108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject, and
wherein the level of 6-thioguanine greater than about 400 µmol per 8×108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.’

The decision then went on to analyse the claims. On page 11 it came to the conclusion:

‘… the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.’

Going back a step, SCOTUS was making a determination of whether or not the invention claimed was patent eligible – whether it fitted within the definition of an invention:

‘Any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof.’

It did.

But then SCOTUS went on (from page 2) to consider if it was nevertheless excluded under any of the three judge-made exclusions to patent eligibility: ‘phenomena of nature, mental processes and abstract intellectual concepts.’ It focused on the first of these exclusions. The balancing act it said it was performing was to exclude patents for the ‘basic tools of scientific and technological work’ – while at the same time recognising ‘that too broad an interpretation of this exclusionary principle could eviscerate patent law. For all inventions at some level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena, or abstract ideas.’

The premise (Page 8) on which SCOTUS came to the conclusion that the patents were invalid was:

‘Prometheus’ patents set forth laws of nature–namely, relationships between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm.’

This is a breathtaking extrapolation. Go back up and read Dr. Théoret’s first paragraph. There is a huge variability between people, based on their genetic make up, causing different rates of metabolising the thiopurines they are taking. The relationships are hardly ‘laws of nature’ within the meaning given in earlier SCOTUS decisions referred to in this one. Determining that a particular range of metabolites in the blood for a particular disorder is the goldilocks range is hardly going to pre-empt a ‘basic tool of scientific and technological work’.

What is a law of nature? One example is that nothing can travel faster than the speed of light (except maybe neutrinos between Geneva and northern Italy!). I think a definition most scientists could agree on is that it is an hypothesis that has not been disproved by so much experimentation that it is generally agreed to be correct. But remember the scientist’s lament, ‘a beautiful hypothesis – ruined by an ugly fact.’

SCOTUS justices generally deal with matters concerning the interpretation of the constitution. And a training in and understanding of science is not a prerequisite to being appointed. But a lack of understanding of science, or a wilful overlooking of what a law of nature is to a scientist, has led to this decision. And there is no appeal from here.

And who is the winner? The Mayo Clinic:

Although it is a non-profit organisation, it brings in handsome sums of money and any premium it might have had to pay for the Prometheus diagnostic kits will hardly make what it charges its patients any cheaper.

And the losers?

Prometheus Laboratories will now lose its exclusivity in marketing the diagnostic kits used to carry out the patented method. The patents were due to expire in seven years time, so its investment in commercialising the invention will have to be recouped in competition with suppliers who have contributed nothing to getting the science from the lab to the market place.

But the real losers are Ste-Justine’s hospital (the French language children’s hospital in Montreal — my home town) and the taxpayers of Quebec who fund the public health system that Ste-Justine’s is a part of. They will lose the royalty income stream the patents were generating.

And where does this leave the Myriad Genetics gene patents appeal pending before SCOTUS?

One commentator has speculated that SCOTUS will refer that case back to the appeal court that held the ‘gene’ claims to be valid. But in 2011 SCOTUS referred Mayo v Prometheus back to them — and the CAFC did not change its mind.

Watch this space.

~ Doug Calhoun
IP Mentor


8 Responses to “Optimising autoimmune treatment patent invalid: a ‘Law of Nature’ is not a law passed by Congress”

  • You appear quite scathing of the verdict. As far as I can tell the invention is a method to measure patient levels of active metabolite(s) and adjust the drug dose or dose-rate accordingly to stay in a pre-defined band of drug concentration. Seems like a no-brainer to me, but there is probably a lot more to it.

    From a quick look on the Prometheus website the “kit” consists of shipping (refrigerated) the blood samples to Prometheus who will then measure the metabolites by HPLC (quantitative HPLC, no less!). Again, not much to it; anybody could do that.

    Although none of the nine justices may have a scientific background one would think that these people are intelligent enough and capable of logical reasoning. They would have heard the arguments from both sides, sought clarification when necessary, and came to a unanimous decision.

    The commentator could be quite right; the share price for Myriad Genetics has plunged about 11% since the verdict. No doubt it will bounce back or at least recover some of the losses next week.

  • There’s 2 aspects, a) laws of biology compared with laws of nature (in general physics)
    b) to what extent Prometheus advanced the state of the art

    Firstly, laws are just our imperfect model of reality. Before the periodic table came along, the weights were used until Mendeleev sorted it by attribute. Then chemists could predict the missing elements. System biology at moment is imperfect, the metabolic regulatory network is complex. As far as I can tell (they must have paid their patent lawyer by the syllable) they measured it and used the numbers to set a dwell point (homeostatis or equilibrium). Court didn’t reject it on grounds of not novel nor inventive. But the element by element dissection showed that once you assumed the metabolic rate was inherent/natural, the rest of the steps were obvious. My personal opinion is that the judges were wise to be cautious because if the 20 year monopoly was granted, there would be less incentive to actually look for the missing gaps, ie a suboptimal solution.

    Secondly and this goes to the heart of the patent system. How much innovation is deserving of a monopoly? The fundamental problem is that the statutory period of protection is not matching the economic life. Complex or insightful leaps should deseve more whilst trivial tweaks or combinations not so. Going back to your example, if Prometheus added several steps, then yes that may be taking advantage of the (imperfectly understood) laws of biology but that was gained through empirical measurement. Whereas if they added undertook all the activity (mere labor?), would that quality as essential act of invention?

    I’d have to go back to the fundamental issue. Is the policy of the patent office (as judged by the highest and supposedly brightest) to improve the useful arts/sciences? In this case, apparently not sufficiently. I can give you the example of nanotubes v graphene. Nanotubes were novel and heavily patented and as a result, breakthroughs/progress has been comparatively less frequent than ripping off a layer of graphite using sticky tape. The number of advances using the hexagonal structure is truely amazing (eg using atomic microscope to mimic the effects on a metal). So whilst the judges may be imprecise in setting exactly where the bright line for subject matter may be, the direction of pulling back (at this stage) was probably correct.

    I feel sorry for the suffers an any situation but if the goal is to treat the masses, then the average cost should be reduced through more OPEN R&D. Losing the patent stream is a side issue as that comes from a levy on all other suffers. I’d give you a counter-example, if all the stricken victims pooled together funds for a bounty on diagnostic kit, the benefits to be accrued to all, would that be a solution?

  • drllaw

    I agree with your observation that natural “laws” are an imperfect model of reality – and indeed when you get into quantum mechanics and the mathematical equations describing the interaction of the smallest particles or the cosmologists’ theories of multiple universes – they cause us to reconsider what we mean by reality.

    But that was not what was at issue here. The judge said he was trying to define the line between excluding the “basic tools of scientific and technological work” while at the same time avoiding so broad an exclusion that it would “eviscerate patent law”. He observed that “all inventions at some level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena, or abstract ideas.” What I was criticising was that the decision shifts the boundary too far and does eviscerate patent law. The invalid claim did not prevent anyone from carrying out all diagnostics tests for any ailment. It only prevented one test for a limited range of auto-immune diseases from being carried out without authorisation.

    And the court deliberately refused to consider whether the claims were novel or obvious in spite of being urged to do so by the (neutral) lawyer representing the US government point of view. It stated that to do so would render section 101 (of the US Patent Act) meaningless. The judge had dissented on this ground in a previous case and was determined to make his hobby horse the prevailing law.

    Your second question, “How much innovation is deserving of a monopoly?” is not one that is asked by any patent law in any country. The criteria under which patent applications are examined are: novelty, obviousness, usefulness and is it a “technology” that is patent eligible. As a result patents are (and always have been) granted for incremental steps in innovation – and just occasionally for fundamental breakthroughs.
    It is not the role of a patent examiner to pick winners.

    The patent system is inefficient because a patent application has to be made before the invention has been described or worked in public. And the invention must be described and claimed with the understanding of the inventor and attorney at the time the application is filed. It is easy to be wise in hindsight and recognise that an invention is a breakthrough after the rest of the world does – but those drafting patent applications don’t have the luxury of hindsight. If an invention proves successful commercially, improvements will be patented separately. But each new modification must meet the same patentability criteria as the original.

    The patent system is a one size fits all system – and patent term is set at an arbitrary 20 years for all types of technologies. For a minor breakthrough in electronics technology that may be too long, but for a new drug that has to go through 10 –12 years of clinical testing to prove it is safe it may be too short.

    As medical technologies become more complex, big pharma is moving more and more to the open source model. But open source does not mean free to all. It means that big pharma companies are willing to license or buy in new medical technologies from the best researchers – technology transfer. Patents are the currency of technology transfer. The availability of patents means that researchers like those of Ste-Justine’s hospital can fund at least a part of their research through licensing of patents to companies with the resources to commercialise them. And the companies that do commercialise are incentivised to do so because of the time limited exclusivity of the patents being licensed.

    There is no free lunch and there is no free health care. There is a lot more clever unused research than there are diagnostic tests or safe drugs that are not available to the “masses”. No government is itself in the business of providing a commercial diagnostic service or of being a drug company, and there is no viable alternative to patents to incentivise companies to do so.

    Your suggestion that stricken victims be charged a levy leaves out the connection of how such a levy would incentivise a company to get the approvals and manufacture kits so that they are available for general diagnostic testing.

    You might well ask whether venture capitalists would see the absence of any patent protection as an incentive to invest in a new start up. Then you might see what the patent system is meant to incentivise.

  • I find I am not alone in my observation that SCOTUS made a “breathtaking extrapolation” by considering the determination of an optimal level of metabolites to be a “natural law” in its decision. This post by Robert R. Sachs makes the point more eloquently and in much greater depth than I did:

    http://www.patentlyo.com/patent/2012/03/punishing-prometheus-the-supreme-courts-blunders-in-mayo-v-prometheus.html

    And for patent law trainspotters who want an equally eloquent explanation of how SCOTUS ignored its own judicial precedents the same author has posted a chapter 2:

    http://www.patentlyo.com/patent/2012/03/punishing-prometheus-part-ii-what-is-a-claim.html

  • > It is not the role of a patent examiner to pick winners

    I accept your point that the exercise of patent office power is limited in scope, but I was trying to look at the wider policy issues (more suited to refactoring the legal framework). As the highest court in the US, the fact that the decision is unaminous (as was prior) is perhaps a signal that society is wanting a pause.

    Judges can (and do) opine on novelty and inventiveness (with help of experts and peers) and protect products accordingly .. see

    http://ipkitten.blogspot.co.nz/2012/03/vegf-trap-eye-trapped-by-genentech.html

    > The patent system is a one size fits all system – and patent term is set at an arbitrary 20 years for all types of technologies. For a minor breakthrough in electronics technology that may be too long, but for a new drug that has to go through 10 –12 years of clinical testing to prove it is safe it may be too short.

    I totally agree, elsewhere I’ve pointed out that one of the problems with software patents is that the legal protection is longer than the economic life. This mismatch is creating a gap for NPE to exploit. I also agree with you that high complexity products deserve consideration for extension … provided they meet a societal bar of usefulness. The courts implicitly acknowledge this by granting extensions if new markets/uses found for the same invented molecule.

    > suggestion that stricken victims be charged a levy leaves out the connection of how such a levy … incentivise
    NO … I was pointing out that the current royalty rate (collected from kits sold to other victims as per your comment “lose the royalty income stream the patents were generating”) is EQUIVALENT to a levy. And I’d note the incentive is not for the company but for the sufferers to BAND together. There’s a lot of talk about crowd-funding nowadays. There are still issues with free-riding but why not offer a collective bounty for ANY firm to pass through the stagegate process? Take a look for example at an intriguing use for old “drug”

    http://scienceblogs.com/pharyngula/2011/05/dichloroacetate_and_cancer.php

    Now whilst a BigPharma may not want to touch this (though history shows otherwise) I can think of other approaches that may want to undertake the development (eg nanopills http://www.sciencedaily.com/releases/2012/03/120316145755.htm). Not everything needs to be a drug, sometimes value can accrue to a new delivery pathway.

    > capitalists would see the absence of any patent protection as an incentive to invest in a new start up
    NZ has no software patents … now a real question is does this hinder the dynamicism of local ICT industry (cf Xero)? If so I will concede your point.

  • “I also agree with you that high complexity products deserve consideration for extension … provided they meet a societal bar of usefulness. The courts implicitly acknowledge this by granting extensions if new markets/uses found for the same invented molecule.”

    The patent term in New Zealand is limited to 20 years. The courts here have no power to extend that term for any invention under any circumstances. Until the law was amended in 1994 the patent term was 16 years – but the Commissioner of Patents or the court could extend the term for up to another 10 years if the invention met the “societal bar for usefulness”. NZ patent 178949, for lead rubber bearings that seismically isolate buildings to protect them from earthquakes, was extended for 9 years for a total term of 25 years. (The absorbers proved their worth in the Canterbury earthquakes – Christchurch Hospital sits on them and was able to continue to provide services throughout.)

    The patent policy of successive NZ governments has been governed by the belief that because 90% of patents are granted to foreigners, the benefits will flow overseas. Therefore they are to be discouraged as much as possible. The previous government (prior to 2005) started a policy review of whether a patent term extension should be reinstated under the new legislation, but terminated it early, stating that they considered that the 20 year term was adequate. The current government has not changed the provision. One of the items on the table in the TPP talks is an American proposal that would require the law to again open up the possibility of a patent term extension. Because the talks are being held in secret we have no idea what the outcome might be.

    The article about DCA as a possible cure for a type of brain cancer illustrates a consequence of the government’s policy of putting a chill on patents. That policy overlooks the government’s innovation policy that encourages researchers it funds to generate IP and get a return on the government’s investment by licensing or selling that IP. As “Raven” points out (in the comments to the PZ Meyers post you provided the link for) the discovery of a new use for DCA could have been protected by use patents and could still attain exclusivity under the US “orphan drug” laws. The Patents Bill in NZ prohibits “use “ patents for newly discovered uses of drugs such as DCA. So NZ researchers are limited in how they can transfer technology in the area of personal medicine (where useful research is being done here) – because of the protectionism behind its patent policy – go figure!

    “NZ has no software patents … now a real question is does this hinder the dynamicism of local ICT industry (cf Xero)? If so I will concede your point.”

    I think I should turn that statement around. (The assertion that NZ has no software patents is dependent upon what you mean by “software patents”.) Software related inventions have been patented in NZ for nearly 20 years. This does not appear to have hindered the dynamicism of the local software industry.

    The patent ban is for “computer programs”. If you read through all the draft guidelines, submissions and the final “Explanatory note” at:

    http://www.med.govt.nz/business/intellectual-property/patents/draft-guidelines-patents-involving-computer-programs/examination-guidelines

    you will see that after 34 years of trying to distinguish between a patent claim for a computer implemented invention and a patent claim for a “computer program as such “ (in Europe and in the UK), there is still no real consensus. This means that there will be ongoing uncertainty as to whether or not a software related invention (such as the Fisher & Paykel Smartdrive) can be patented in NZ.

    The debate is not just about software developers. NZ companies Fisher & Paykel (Appliances and Healthcare), Airways New Zealand, Intergen, Air New Zealand and Thermal Chemistry have all made submissions to MED, concerned that their ability to patent their computer implemented inventions will be adversely affected by the uncertainty that would be created by the amendment to the Bill.

    The concerns expressed by the advocates for the ban are based on the experience with NPEs in the USA. The US patent office issues between about 4,000 to 5,000 patents per week. In contrast IPONZ issues about 4,000 to 5,000 per year. There have been mass aggregators of patents in the US because there are masses of patents to aggregate – over 2 million according to one estimate I read recently.

    But that is not the case in New Zealand. None of the submitters to the select committee that considered the bill gave evidence that they had ever been sued for patent infringement – they just feared they might be. The select committee did not weight up the consequences of its recommendations upon NZ entities that do try to patent software related inventions. Nor were they told about (or bothered to consider) the innovation policy promoting tech transfer of the results of government funded research through the medium of IPRs.

    That is what annoys me.

  • For more comments from the patent community insiders on this case see:

    http://www.ipwatchdog.com/2012/04/12/insiders-react-to-supreme-court-prometheus-decision/id=22988/

    The comments that reflect the commercial reality of the decision are those of Brian Stanton:

    “For better or worse, medicine is a business. Long gone are the days of the general practitioner’s little black bag and a doctor arriving at your child’s bedside.”

    “The more we push through Hamlet’s “thousand natural shocks that flesh is heir to” the greater the need for more efficient diagnoses and treatments. Mayo v. Prometheus highlights these needs but the Court’s finding belies means of fulfilling them. In denying patentees’ short-term reward for their medical efforts, they continue to reject that medical technologists require economic return. Altruistic motives aside, navigating the valley of death that lies between research and applications that benefit society requires resource concentration that has been most efficiently applied through the IP system.”

    “In patents, the name of the game is the claim. In Prometheus, the Court impugned the claims as in-artfully drafted and insufficient to evidence the hand-of-man (so long held as the gold standard of patent eligibility). The researchers efforts at defining clinical benchmarks has been denied economic reward for the limited time promised by the Founders. In nullifying the first step in clinical application of medical discoveries, the Court denies the economic realities of modern medicine. Nine persons in need of medical attention seem to have set back access to efficient treatment at the very moment that we face a crisis in providing even basic remedies.”

    In other words, just because it is medicine does not mean it is a free lunch.

  • The journal Nature Biotechnology has published a paper by Jeffrey L. Fox on the Mayo v Prometheus decision of the US Supreme Court. The first paragraph can be viewed for free at:

    http://www.nature.com/nbt/journal/v30/n5/full/nbt0512-373.html

    The rest of it is behind a pay wall of US$32 for non-subscribers.

    The key conclusion that Fox came to was:

    “By undercutting IP clarity for analytic tests, the Prometheus ruling may lead some companies to favor a strategy of trade secrecy in lieu of patenting as they scramble to continue leveraging costly R&D programs.”

    As an example of how companies might use secrecy instead of patents, the article goes on to suggest that Myriad Genetics now has a large proprietary database of the results of the breast screening tests it has carried out so far. Even if its patents are held to be invalid its database gives it a large competitive advantage. The trade secrecy model may set the template for biotech businesses and drive out smaller innovative companies.

    Theses conclusions bring to mind the warning in the GM Royal Commission Report, Chapter 10, paragraph 117:

    “The economic benefits of intellectual property systems are generally considered to be positive. Removing biotechnology developments from coverage by patent or property rights systems would not necessarily have the effect that opponents to such applications want. New inventions or ideas would probably be kept as trade secrets or ‘know how’, and, in the absence of the disclosure required by patents and PVRs, be held even more tightly. Not allowing New Zealand inventors and investors to protect their work under an IPR would leave them in an invidious position against the rest of the world. It would also place New Zealand in breach of its obligations under major trade agreements.”

    The opponents of gene patents and the patent system in general should be careful what they wish for.