From October 2016 to March 2017 the team is joined by Guest Kats Rosie Burbidge and Eibhlin Vardy, and by InternKats Verónica Rodríguez Arguijo, Tian Lu and Hayleigh Bosher.

Sunday, 15 February 2015

Personalised Medicines: a Presidential Initiative, inherent treatments, Mayo and Akamai

President Obama recently announced his ‘Precision Medicine Initiative’ in which $215 million dollars would be invested to ‘pioneer a new model of patient-powered research’ in which treatment takes into account a person’s ‘genes, environments, and lifestyles’, the aim being to choose the treatment which is most likely to be effective. Taking his cue from the White House, this Kat thought that now would be a good time to revisit this topic which he previously wrote about in 2012 (see Katpost here). That post complained about the direction the European Patent Office (EPO) was taking in assessing novelty of patient groups, making it more difficult to obtain patents for personalised medicine inventions. I also complained about the US Supreme Court decision Mayo making the situation difficult in the US. Since that post, things have got better in Europe and much worse in the US.

Why does personalised medicine matter? 

The terms ‘precision medicine’ and ‘personalised medicine’ are essentially interchangeable for most situations. The term ‘companion diagnostics’ is sometimes used to describe technology in this area. Personalised medicine is based on the realisation that, since patients form subgroups which respond differently to medical treatments, each patient should be given the treatment most appropriate for the subgroup to which he or she belongs. This approach is presently most advanced for cancer, where therapy is increasingly tailored to the type of cancer the patient has.
The President was good at choosing subgroups

We now know that many drugs only work in a subgroup of patients, and so they have a low efficacy when given to ‘all’ patients. That low efficacy can prevent a drug gaining regulatory approval and heathcare providers will also be reluctant to buy drugs which are ineffective in many patients. The development of companion diagnostics can solve these problems by allowing prediction of the subgroup in which the drug will work.

Problems in patenting personalised medicines

In Europe personalised medicine inventions will need to ‘fit into’ medical use claims. If, for example, we know that the subgroup in which the drug works has a particular genetic marker Z, then the claim can take the form below, which tends not to raise too many eyebrows at the EPO:
‘Drug X for use in a method of treating condition Y in an individual, wherein the individual has genetic maker Z’
However if patentability lies in a ‘new’ method of detecting a genetic marker that is already known in that disease context, then things get more complicated. Claims along the following lines need to be attempted:
‘Drug X for use in a method of treating condition Y in an individual identified as having genetic marker Z using [new method of detecting Z]’ 
‘Drug X for use in a method of treating condition Y, wherein said method comprises testing an individual using [new method of detecting Z] to determine whether the individual has genetic marker Z, and providing treatment if the individual is identified as having genetic marker Z’
The EPO Examiner was not convinced that
multistep medical use claims were allowable
Such claims are stretching the ‘medical use’ format a little, and whether they are allowed can depend on the factual scenario and the generosity of the Examiner.

Leniency at the EPO – is this due to the particular approach to ‘inherency’?

Decision T734/12 of May 2103 seems to represent the EPO’s present position on the matter. In this case the Board overturned the Opposition Division’s previous finding of lack novelty based on the Division’s approach there should not be an ‘overlap’ of the patient population defined in the claim with the population defined in the prior art. It now seems that an ‘overlap’ does not prevent a subgroup being novel, and clearly such a lenient approach is helpful in protecting personalised medicine inventions.

Some commentators have described this way of looking at the novelty of a patient population as ‘selection invention’ test. However this Kat disagrees, and believes that it comes about as a result of the EPO’s approach to inherency in medical treatment situations. Essentially, in most situations, the EPO will not view a medical treatment which occurs inherently in the prior art as being publicly disclosed unless the prior art explicitly mentions it. Those familiar with US practice will know that the opposite is true there: all inherent ‘medical treatments’ are assumed to be disclosed in prior art that describes administration of a drug to a patient. The EPO’s view means that the ‘inherent’ treatment of a subgroup is not disclosed by prior art describing giving the drug to ‘all’ patients. Though it is not relevant to the present situation readers may be interested in this ‘K’s Law’ post on inherency at the EPO.

The disastrous situation in the US

We still do not know what the full impact of the Mayo decision will be in the US, but it is clear that this decision is potentially very far-reaching and is presently causing difficulties in examination of inventions relating to diagnostics. The diagnostics and personalised medicines industry is having to cope with the tremendous uncertainty of not knowing what is patentable in their area. The recent Interim Guidance on defining eligible patent matter (see Katpost here) provides little information about how the United States Patent and Trademark Office (USPTO) will assess eligibility of a claim to a diagnostic based on a natural correlation. This Kat notes how in the Mayo decision the Supreme Court took a very strict position, not wanting the development of future ways of measuring the metabolite to be inhibited by a patent claim. If that principle does become relevant to assessing the eligibility of diagnostics inventions, clearly the scope of protection that can be obtained will be severely curtailed. A patent could then only cover use of the known specific techniques to measure a correlation. In fast-moving fields where new assay techniques are being continuously developed the real term of effective protection could then be quite short.

The Mayo decision had caused mayhem
In June 2014 the US Supreme Court decision in Akamai found that direct infringement by a single party had to occur before ‘inducement’ of infringement could be found (see Katpost here). This reversed the previous finding of the Federal Circuit that inducement of infringement could be found where different parties had performed different steps, but taken together all the claimed steps had been carried out. In the case of personalised medicines the diagnostic and treatment steps will often be performed by different parties, and so this makes it harder to find infringement of claims in which diagnosis and treatment are defined as two separate distinct steps.

The ethics of personalised medicines

Soon after the President’s initiative was announced ‘The New Yorker’ posted this article about a case where a young girl was misdiagnosed by a genetic test as having the very serious condition DiGeorge syndrome. It raises the issue of whether doctors, patients and relatives are ready for the information that genetic testing will bring. This Kat wonders about the implications of having ‘treatable’ and ‘non-treatable’ patient groups defined by their genetics, and making decisions on whether to treat people based on tests which are not yet 100% accurate. Readers interested in knowing more may want to see this article on the ethical, legal and regulatory issues around personalised medicines.

16 comments:

Anonymous said...

"‘Drug X for use in a method of treating condition Y in an individual identified as having genetic marker Z using [new method of detecting Z]’ "

"Such claims are stretching the ‘medical use’ format a little"

They are not stretching the claim, but ridiculing it. There is no novelty in the medical use. The use of the drug in the specific, identified, patient sub-group is already known.

It would pain me to see the EPO grant such a claim and I would put it down to incompetent examination practice, yet again, if they have done so.

If the USPTO are rejecting equivalent claims then good for them, event though a method of treatment claim would be more amenable to such practice.

Can the Kat post an EP granted example?

I also have to sat that the dismay expressed by the Kat in not getting desired claims granted is simply another example of the 'it's not fair on biotech' position.

The inventor of the new assay has added nothing to the therapy over and above providing a new (alternative, possibly improved) assay. They will benefit commercially from this as much as is 'worthy' by virtue of sales of their assay/screening service. Such will be adequately protected by the patents available for the assay.

Suleman Ali said...

Thank you anon at 19:08 for the interesting comment. In the US one could get a method of treatment claim that referred to an initial diagnostic step followed by a therapy step. I would refer to T1020/03 and say that in general EPO practice allows a medical use equivalent to any method of treatment claim. I believe in cases, such as the present, where it becomes difficult or impossible to do so then that is unfairness towards a particular technology area. The inflexibility of the medical use claim should not be the determinant of what activities can be protected.

I agree that whether or not known therapies should be covered by a personalized medicine claim is an arguable point. I would say that we already have the situation where medical use claims can refer to using known drugs in new patient groups or in new administration schedules. So it does not seem unreasonable to allow claims where the person to be treated has been selected by a new diagnostic method.

Anonymous said...

Thank you Suleman Ali for your incisive and thought-provoking discussions of modern pharmaceutical patent law!

We are getting awfully close to the Galenic exception that is still present in national patent laws of a number of countries; in the UK, S.60(5)(c) PA1977.

I have been waiting for recognition of this feature that is so gaining in importance with modern diagnostics and personalised medicine.

I am quite convinced that this is the next barrier to total patent monopoly in the pharma field that we shall see lobbying against. I feel confident that this last vestige of the general public's protection against all-encompassing rights will disappear as well. Everything else is now permitted, such as second medical use, extension certificates, prolongation of term if it works on children, etc., etc. Is the overall cost to a society with a national health system really lower with private development of drugs rather than directly society-funded development in university environments?

It all began when the chemical industry realised that their originally lofty ideals about their contribution to science and the patentability of methods only, could very advantageously be replaced by a product protection. Society at large does not understand what it permits -- it does not understand patent law.

Kind regards,


George Brock-Nannestad

Anonymous said...

What if the patient does not accept to be genetically tested for the treatment, will the pharma companies force him to do it in order to be treated?

Anonymous said...

Suleman, it s not unfairness It is simple application of the law. The invention is an assay. The law allows protection for the assay. When you clients invent a new tin whistle, do you bemoan the fact you cannot have a monopoly over the QE2 because the ship's captain has such a whistle?

On second thoughts, I don't tink you need to answer that one.

George, you are clearly ignorant of how the pharmaceutical industry works and have no interest in encouraging the development of new therapies.

"lofty ideals"? Yet not so lofty that you can still look down on them.

Anon. The patient can certainly refuse to be tested before taking a life-saving medicine. No, of course the pharma companies will not force such testing. You watch too many stupid films and read too many conspiracy theories dreamt up by the likes of George. If they do refuse to be tested, which is at the request of their doctor, the doctor probably will not be ale to prescribe the medicine. This is not, as you no doubt believe, the result of bullying evil pharma companies. It is in fact a decision made by the organisations responsible for purchasing the drugs out of your taxes or insurance payments, who don't believe in wasting money on drugs that do not work in everyone, but only those who having a specific 'marker'. This is not simply genetic, but can be a measure of a specific phenotype.

Feel free to ignore your doctor's advice and suffer which is your right.

Does anyone else have any other ignorant comments they want addressing?

Suleman Ali said...

In response to George, I agree we need debate on what rights to give to people. However the public has no interest in knowing about patent law, and so a real debate will not happen soon. My personal position is that we need to operate in the free market monopoly-based system we have and to try to protect everyone as best as possible. The benefit of having a 'private' sector in research is that individuals can make choices about risks and the public won't need to bail them out when they fail. Big pharma is increasingly funding small biotech companies and taking the risks of doing so.

Anon at 00:11, I agree there are difficult situations. If someone does not want to be genetically tested, do we deny treatment? Does society have the right to test everyone to discover what drugs would work on them? I don't know

Anon at 8:29, the 'law' changes. Self-opposition used be allowed, transgenic plants used to be unpatentable, some Boards held that medical use claims could not be limited by administration schedules. And patent law must be responsive to the needs of all technology sectors. The invention here is not an assay. It is a better way to give treatment. The therapy might not get regulatory approval and might not be commercially viable without the new diagnostic means, and so arguably claims that cover therapy are justified.

Anonymous said...

To Anon@0011 (a little more patiently than anon@829). Genetic testing is just a new form of diagnosis. If a patient refuses to let a doctor diagnose them, the doctor is going to struggle to give them to correct medicine.
I suspect your worry is because genetic testing sounds like it will reveal personal information. Certainly in the real-world current applications, it won't. They are testing the patient's tumor to see what mutations the tumor has (and so which pathway/antigen to target). These mutations would not be found in the rest of the body and so reveal nothing (for the pedantic, ok some tumor-driving mutations will be in the germline - I personally wouldn't find that more revealing to the doctor than anything else). Could you be treated without having the tumor genetically tested? Given the balance of benefit to side-effects, it could be perfectly reasonable for treatment to be refused for your own good, if it were suitable only for a sub-population. But the younger generations understand genetics, and I can't see this being any more of a problem than those who refuse conventional diagnosis.

Anonymous said...

To follow up on my last post (as I think real world examples make it feel less intimidating). A big breakthrough right now is blocking the PD1 pathway for some tumors. In short the PD1 pathway is an immune system feature that allows the body to "exhaust" immune cells that it no longer wants to respond. Some tumors use this system to prevent the immune system from attacking them. If you block the PD1 pathway your own immune system can attack the tumor. BUT blocking the pathway is a pretty big thing to do, it'll affect the whole immune system, so it's a good idea to make the tumor in question is actually using PD1, so they test it (hence personalised medicine). So in answer to anon, why would a patient refuse the test? You wouldn't want the powerful drug if the test were negative...

Anonymous said...

Suleman, yes of course the law changes. This is completely separate from your example of perceived unfairness. Firstly, I presume you accept that the law as it stands does not cover your example? This being so in spite of the interpretation of the law by the EPO. Also remember that this is not a change of law.

Your issue revolves about your own interpretation of the invention. You say the invention is not an assay. I disagree. I assume when you draft your cases for your client you do try and protect 'the assay'?

Anonymous said...

I have a client that makes ambulances. They are the sole supplier to the NHS and they have a 100 year contract that the NHS cannot get out of (some sort of PFI initiative). I am just drafting a patent application for them on a new comfy-driver's-seat adjustment means.

Does the Kat recommend I include some reaching-through claims (I think that's what my chemistry colleagues call them) to the drugs used for treating a patient who has been delivered to hospital in an ambulance comprising the comfy-driver's-seat adjustment means?

Anonymous said...

To anon at 10:19. I was patient enough in responding to the anti-pharma comment. It was not a comment from a 'concerned citizen'.

Anonymous said...

To Anon at 10:53, I must warn your client that they will be infringing my screwdriver patent, which relates to the use of any old bog standard screwdriver for making such things as ambulances.

I am also a biotechie specialist and I have a patent on a method for making a screwdriver operator and the ultimate things made by such an operator using said patented screwdriver. Data was provided in the application as filed for the missionary position, although the drawings didn't photograph well from the back of the door of the public toilet. Something to do with all that blue light.

James Wagner said...

Dr. recommends I get screened for A using new patented screening process and old test. I go take both. Screening company A gets back to me first and says good news you don't have A, but unfortunately you have condition B and we have a reach through claim for B. Come to our licensed clinic and get the cure for only 10x normal prices.

The day later old test results come back and tell me no A but B.

Is treating me with old drug for curing B now prohibited for the life of the assay patent? Even through old assay also identified the presence of B?


Anon at 10:10, targeted screening of a tumor for whether there is mRNA indicative of the activation or non-activation of a particular patent doesn't reveal much about a patient, agreed.

However, given trends in the speed and decreased cost of genome scanning I would expect your entire genome to be sequenced by your health care provider at some point for each individual within the next 10-40 years.

Suleman Ali said...

To anon of 10:25 I don't see any clear legal reason why one cannot have a diagnostic step in a medical use claim.

To anons of 10:53 and 13:15, yes there is a possible reach-through issue here, if the claim recites a new way of diagnosing that will not be reflected in a 'structural' difference in the patient, and so arguably medical use groups should only be able to recite patient limitations which are reflected some way in the patient, rather than in the history of the test that was used.

To James, yes, very interesting point. Where a genetic marker is specific for an ethnic group and there is a medical use claim which defines a patient group using the marker then some people have argued this is discrimination against the ethnic group.

Anonymous said...

Some people may have argued it is discrimination, but that doesn't mean it is.

The fact that said arguments may come from said ethnic group may raise the profile of the argument, as happens commonly in many areas. However, that still does not make it discrimination.

There are numerous examples where products (drugs or other things) are sold directly to an ethnic group. EOne simple example is make-up. Black women have a different colour to their skin than white women (so I'm informed) which means that certain colours of make-up products are more suitable for one than the other.

Anyone who watched the recent Apprentice series (UK) will know that one product line was being developed for stockings of different skin tones for the benefit of women having those skin tones.

As for drugs, it is very well known that there are many differences between different races that result in the need for different treatments.

So, as I said, some may argue it is discrimination, but it is not.

James, you misunderstand the purpose of screening for a marker. An example can be found here:

http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/8/co-receptor-tropism-assays

Anonymous said...

Following my post at 00:11.
Thanks to those who took the time to put some more arguments than just "ignorant pharma hater".

Imagine the situation where person A is tested in order to determine the treatment. Then, the doctor tells A that the whole family should be tested in order to prevent risks. Then A discovers some unknown before things about his family...

Like this guy: http://www.vox.com/2014/9/9/5975653/with-genetic-testing-i-gave-my-parents-the-gift-of-divorce-23andme
And a bit more material:
http://techonomy.com/2015/01/brca-journey-fear-information-imperils-genetic-testing/

Of course, anyone can dismiss the scepticism as stupid, but that will not stop it from existing.

Anyway, I am very interested to see how the case law develops.

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