 So first of all, this was not my title. It was asked by the organizers. The title is, Is the recent patent case law good for precision that medicine? This is a hard question. And so let's start with my approach. When I was thinking about this question, I needed, first of all, to parse it. Number one, what do we mean by precision medicine? Number two, what is the relevant case law? Number three, how does this relevant case law affect precision medicine? And once we have that background, which I'm going to try to do it in two slides, number two, we need to look at the impact of these decisions and then assess how they affect the different stakeholders. Good for whom? So that's the approach. So what I propose to do here today to address these questions is to share results from a series of papers that we publish in Nature Biotechnology. There are six papers, five of them are empirical and one of them is a summary, and you have it in your packet. Now, after I do the background, this gives me for around two minutes per paper. So I'm going to go really fast. I'm going to do some interaction with the audience. So let's start. Question number one, what do we mean by precision medicine? What is the relevant recent case law? And how does it affect it? For the purposes of this talk, I'm going to think of precision medicine as tailoring of medical treatment to the individual characteristics of each patient. This is the National Research Council definition. In reality, whether we talk about precision medicine or personalized medicine, there is a spectrum of personalization. All the way from group, perhaps all the way to the individual, if it is truly personalized. And we can also talk about two types of precision medicine, explicit personalized medicine that uses relationships between different types of biomarkers and medical responses to determine diagnosis and guide treatment plans. So that's case law on biomarkers and on relationships is going to be important. Another one is implicit personalized medicine, sometimes called black box medicine. And this is where the relationship may not be explicit, but perhaps using machine learning, artificial intelligence, et cetera, it may come out. And so perhaps case law on algorithms may be relevant, too. So that's the starting point of precision medicine for the purposes of this talk. And it is quite mainstream. Well, what is relevant? This is the paper that you have in the packet of this series of six papers in Nature Biotechnology. It's a 2019 paper, and it is a summary type of article. It's the only non-empirical. And we address how does the emergent patent case law in the US and Europe affect precision medicine? I'll summarize it in one slide. I'll focus primarily on the US side of things, because they have been very significant changes. And most of you are probably quite familiar already with the European part. So precision medicine, PM is precision medicine. We discussed that either it is based on biomarkers, relationships, or some advanced algorithms. So if we are talking about biomarker-based precision medicine, and especially with classical biomarkers, many of which may be nature-based products, the immediate decision in the US Supreme Court is quite important, is core. So we are going to need to analyze that decision. If we are looking at a personalization by looking at individual responses to treatment derived from natural relationships and correlations, then value is key. And if we are thinking about that implicit personalized medicine using advanced algorithms, big data, artificial intelligence, the Alice US Supreme Court decision is quite important. So this is an overall mapping. So we are mapping the three key US Supreme Court decisions in 2012, 2013, and 2014, to these three areas of precision and personalized medicine. When you go to each one of these, there are things that we know, there are things that we don't know, and so we can think immediately. What is ineligible? The US Supreme Court decision set in, of course, in the US, what is excluded is isolated DNA. We know that. Isolated DNA, not eligible as a subject matter eligibility issue, 35 USC 101 in the US. What is eligible? CDNA as being quote unquote not naturally occurring. What is affected everything in between? From isolated DNA to CDNA, there is a gray spectrum, everything is affected, whether it is eligible or not depends on two inquiries. The significantly more test or what is different from nature. And that can affect both DNA products as well as other nature-based DNA products. So classical biomarkers are going to be affected. In mail, this is where you're personalizing to the patient perhaps and individual those response. Ineligible, relationships that exist in nature, apart from human action, this is based on excluding from the ability loss of nature. The first one was a subset of that products of nature. Eligible, we now know, post-media, the Vanda case, methods of treatment, affected everything in between, not the other two, including methods of detection and methods of diagnosis. And the same thing can be applied to Alice. Ineligible abstract ideas, algorithms, pure machine learning algorithms, eligible based on MFIS and MCRO, if the claim is directed to a practical application, improving our technology or the technical field. This is similar to the technical character and the technical effect, in some cases, inquiry in Europe, is everything in between affected. So with this mapping, our objective was less study, media, manual analysis, from an empirical standpoint, at different levels, to look at the impacts. And then based on those impacts, we can make some determination, are those good and bad, and by crew. So I'm going to handle the next two questions, the impact of these decisions and how this impact may affect different stakeholders as the guidance for the talk going forward, given that background. Does that make sense? OK. The methodologies that we use are empirical, and although they are all based on some sort of landscaping, they are very different when we are doing a broad-level impact, which is, what are the impacts before and after a case at the landscape level? These are like before and after pattern landscapes, that when we are looking at the claim level, how are the claims changing? This claim language was illegible. This now, if you amend it, becomes illegible. Does that affect the business methods? Does it affect the scope of protection? Prosecution level, what happens inside the USPTO, for instance? Does the prosecution time gets much longer? That type of questions. And are there significant wider impacts or side effects or ripple effects? So it's a total of work that we did on media at the general level, claim level, prosecution level, other impacts, as well as major analysis. I'll summarize five papers really quickly. All of these have debates. The first one, media. Remember, this was a naturally occurring DNA segment. It's a product of nature and not patent-illegible because it has been isolated. But CDNA is patent-illegible because it's not naturally occurring. So you have some scholars that will say, well, like Charco, it now seems clear that gene patterns are not only that, but most sincerely that. And then you have other scholars that say, well, it would be a mistake to think that. What a surprise. Why are reasonable minds disagree? Let's look at the data. We can keep debating for a long time. Let's look at the data. So the first question, the media resulting in a reduction of gene-related patterns in general, beyond isolated DNA. We address this in the immediate impact on gene patterns in natural biotechnology 2016. And so let's do it and let's have some interaction from the audience. This is the general gene-related patterns up to 2015. At this point, I think Michael in the audience wrote an article in Nature Biotech also, the end of an error, thinking that maybe this will go down. What do you think in the audience? Do you think that gene-related patterns from 2005 to 2013, when the media decision came, went down to indicate this, stay the same or number three up? Yes, it can be analog. So up, yeah. Some people have been reading the papers, others don't. So they went up. They went up and now the media decision comes in 2013. And the question is, does it affect other beyond, does it have an impact? Impact on applications beyond isolated DNA. What do you think? See, impact? Oh, look. These are like the students not really participating. Huh? Yeah. OK. Actually, no impact beyond isolated DNA on general patent activity. Applicants keep applying. But let's look at now, what about isolated DNA? Isolated DNA was a big issue in the US in the media decision, right? It received quite a lot of press. There are maybe thousands of patents here. Who owns your genes, et cetera? You can look at the number of general patents here. We are talking about thousands per year. What about isolated DNA? Do you think that there are many of those or few of those? Many, few, few. Yeah. So actually, there were already quite a few of them by 2005. You think they went up or down after 2005? Actually, it went down. And then the decision comes. And it keeps going down. But at the same rate that it was already down, maybe the decision didn't have an impact. Maybe it didn't have an impact on the amount of activity. And maybe they had looked that these were very few patents and perhaps linking at the priority dates. So maybe they will not have much term. Maybe they will think it through differently. And furthermore, are there additional side effects? There are two colors there. Blue is small entities, black are large entities, and that's a proportion. What happened to small entities as defined by 37 CFR? They disappear, right? So same rate, but disappearance. So is there any indication that the patent system was already self-correcting prior to immediate? That you don't have a competitive advantage now. Somehow, because I selected DNA subject but illegible here, but not in the US. Does the data tell us anything of what will happen if the US Supreme Court decision had reached the opposite decision in 2013? So we explored that question. And to explore that question, we mapped all these patents by the priority date. And what you see is in the US, the priority peak in 1999. Why is that? I mean, you see the number of applications in 2013 were very, very few. Most of the applications were claiming priority back to 13 years earlier. Why is that? It was because the standard of novelty and non-obviousness 35 USC, 102 and 35 USC, 103 in the US, or inventive step, was already taking care of the issue. What was novel in the 90s, it is not novel in 2013. Does that make sense? So perhaps they were correcting a problem that didn't need any correction at all. It was a good question to decide 20 years ago, but not in 2013, perhaps. Furthermore, you can see in Europe where the law has not changed, also these patents are not being granted. There is a shift in the priorities, but these patents are not being granted. So we have done also the analysis for Europe. So that's the first debate. Second debate. Well, fine. But this still has a profound impact. Patent applications maybe continue to be filed, but the claims are different. And others may say, actually, is of little practical importance because you can draft the claim language to get around media. To study this, and what do you think? Has it been easy for attorneys? What do you think, easy or hard? Most people think easy. So we have Lionel saying easy. Awesome. So we have an authority here. We answered this question, addressed it, in this article in 2017, after media, what makes a gene patent claim markedly different from nature. And we were studying claims of applications that were submitted prior to media. Then media come along and examiners and applicants need to amend the claims. And so that's a test as to what transform subject matter in illegibility into subject matter illegible and the type, are you able to amend? Complex methodology to look at this at the claim level, look at the paper. It actually, at that point, it was not easy. 79.2% of the patents containing isolated DNA claims were either abandoned, the whole patent, or those claims all canceled. Only 18.6% were amended. Okay? Now, having the benefit of this paper and the transformations, perhaps now it's easy. We don't know, but at the time, this indicator was not that easy. We evaluated in all those cases where there was that transformation from ineligible to eligible, what was the amendment that was successful in overcoming the 35-USC 101 rejection based on the exclusion of products of nature based on media, and we categorized it in eight classes. In some cases, it went to CDNA. In others, so you have, look at the paper. Looking now at before and after, perhaps now it is straightforward or more straightforward to do this. But as of 2017, where we did this, it was hard. Especially, you were a small entity. Those that were successful had significant resources. Okay, next. Okay, so you looked, it does not affect at a high level. Perhaps it was not a problem at all because you have the no-obviousness. You look at the claims, it's actually hard or it was hard to transform ineligible into eligible, but surely this was intended as a narrowly crafted decision. Taking isolated DNA out and leaving everything. What do you think? Is it narrow, a surgical strike, or broad? Narrow, broad. Narrow, okay, Microsoft's narrow, we have somebody broad. So this was the title. Was the media decision a surgical strike on isolated DNA patterns or does it have wider impacts? We analyze, this is a prosecution level. You cannot answer this by doing a pattern landscape or by just looking at the claims. You need to go into the correspondence within the office. We analyze 14,000 USPTO correspondence documents. Effectively, every case where media was the basis of a rejection, as well as then the responses, and then we categorize. How many of those isolated DNA was at issue versus now other nature-based products? Surprisingly, in 85% of the cases, it does not have to do at all with isolated DNA. So although perhaps it was intended as a narrowly crafted decision, and there is language there, including the Amicus Braves as well as in the Supreme Court, the way it is being used by examiners right now is perhaps unintended. So notice, isolated DNA was not a problem. You create a decision for isolated DNA. It was not a problem because of no obviousness. You create a decision for isolated DNA, and the examiners are using it for all other things except for isolated DNA. That's myriad in three slides. Mayo. Mayo wins by having been termed as the worst patent decision in the history of the US Supreme Court, radically limit threatens the availability of patent production for the most blah, blah, blah. Quite a lot of controversy. We wanted to say, is this okay? I need to hurry up. So Mayo, what is the impact on Mayo? We analyzed it in another literature article. In this case, 72,000 documents. What did we find in Mayo? Yeah, if you get a major rejection, the allowance rate is quite low, 27% approximately. And in order to, is it possible to overcome the rejection to satisfy your CO1 rejection? Yes, but it requires resources. You need to do several rounds of prosecutions, require for continuing examinations. Again, large law firms are going to be in good shape. Small law firms were not in such a good shape. What we saw, however, is that the traditional 101 subject material eligibility rejections that in the USPTA used to be around 10% was now over 50%, which means on a matter of substantive law, you don't know what is eligible or not eligible, increase legal uncertainty, increase procession costs, and substantially lower protection of small entities, now crafty drafting, because in a paper that is coming actually on Monday in nature of biotechnology, one year after Banda, our diagnostic patterns transform into methods of treatment to overcome major various reactions. So this is a situation where we analyze patent applications that were filed as methods of diagnosis, which is difficult now to obtain a patent for, but if you transform them into a method of treatment, it is easier. And so type A claims are methods of diagnosis as file and VR methods of treatment. These are applications file. By the time they mature and they got allowed, methods of diagnosis became methods of treatment. Is that what we want, crafty drafting? Alice, Alice is just financial, abstract ideas, software, business method, does it potentially impact biotech, precision medicine, even medical devices? We analyze it. Of the three, it has the most significant impact. Over 200,000 office action documents citing Alice. And even when you go to the most hardware oriented inventions, like medical device, medical instruments, diagnosis, there are thousands of issues related to Alice, okay? So that's a summary. It is very interesting that significant difference in two periods, 2014 to 2018 and beyond 2019 in the allowance rate totally different based on the USPTO guidance. Did the US Supreme Court intended that actually the law was going to be determined by the director of the USPTO and who is in the office? So to recap, and we do not have time to do the European comparison, we saw media decreasing, but that was already going before. It looks like the system had self-corrected in non-obviousness, has been difficult to draft around. It has now been used actually, not in isolated DNA, but in other nature-based products based on the thinking of the USPTO. Significant legal uncertainty, more rounds of prosecution and crafty drafting just to get it through. So, good or bad? Well, you can consider public versus private entities, small versus large entities, investors, maybe good for law firms during the prosecution, takes longer, but how does this translate to innovation and ultimately the patient? So just a few conclusions. Based on our results, we can say that there has been a de minimis impact on isolated DNA patterns. The system had already been self-corrected, meaning if the US Supreme Court decision had reached the opposite decision, it was eligible, what you will see will be pretty much the same, which is what happens in Europe. Two, significant negative impact on legal certainty, higher legal uncertainty during prosecution and post grant. Even those that survive prosecution because the USPTO guidance changes, are they valid or not? Is that good or bad? Negative impact on the scope of claims, the scopes are narrower. If they involve classical biomarkers, digital biomarker or digital biomarkers based on algorithms and relationships, at least a major. Minileimal impact, however, on large entities. The ones that are fine are large entities, with sufficient resources to prosecute applications in an environment of high legal uncertainty. Negative interpret in small entities, working in biotech, higher prosecution times, more cost, decreased proportion of small entities actually receiving this. Of course, more difficult to assert. It is easier to evaluate the patterns. Thank you.