[MUSIC] So welcome back everybody. And today we'll be talking about patenting small molecules and compounds. So small molecules and compounds as we can imagine are very important if you want to move into the pharma business or you want to work into the pharma business, and. Why we need to have a special lecture about this, is because small molecules have some important differences in the way you can actually patent them. And that mainly has to do with novelty. So during this lesson, or this lecture, we'll be talking about the novelty of small molecules, which will be this first we talk about the doctrine of equivalence. Then we have a lecture about pro-drugs, drugs, and metabolites: what can can be patented and what can not. This is going to be a very important lecture because it is very, very critical into the farmer business. And then we'll finally close with a special case on natural chemicals which brings us back to the concept of discovery versus invention. So the requirements for patentability. So as for other, many other, patents as for other patents small molecules have to show to posses the key requirements of industrial patentability that we have seen in the previous lectures. Basically, our molecule has to have an industrial application. Can it be used for industry? Can we have some benefits? Can we use it? Can we produce it? Can we sell it? Can we do something with it? Yes, if it has it and all is good, we can process to the patent, and most importantly it has to be novel. So we have to have our novelty, which goes with any patent, with any invention. So, therefore, the compound is novel If, and here I'm saying if, for normal patents or normal inventions, novelty would be defined as is it equal or is it identical to something else? If it is identical, it is not novel, if it is different it is novel. For chemical compounds, we have some different Notions and we explain why later. So first of all, is novel if the structure, name or formula have not been explicitly mentioned, described, or presented, or made available in prior art, and that means explicitly. It has to be really explained how it's, what the structure is, what the name is, and what the formula is. Really clear there. It is novel if we take a non-novel compound, so something that existed and we put the functional change int he structure and we basically change activity or we kind of change the function of this molecule. So basically we can take something that exists already, non-novel, we make a change and that change results an increase in activity, in longer storage room capabilities, in lower side effects, in better kinetics whatever. Any kind of functional change that this new molecule and give to an already existing molecule that would be considered novelty. And finally, as for anything else, the change is non-obvious to the person skilled in the art. Again, we get back into the non-obviousness of our invention. And we should remember, and I'm sure you still remember, who this person skilled in the art is. So finally, novelty for chemicals is not straight forward. Concept, like if it used for other inventions, so basically, what I want to say is that contrary to other inventions and fields, a chemical compound will be considered as prior art only if, not only is formula and structure if presented or is available. But also if there is a clear description on how this particular compound can be synthesized or prepared or created or purified or basically generated. So this means that let's say you have your formula or your invention formula. And another chemist, I will just draw something simple like this, everybody knows it, but this is my new invention, behold, I have my new invention, I call it the Fred chemical. Fred chemical, and I know exactly how to produce it, how to prevent it. And if I want to do a novelty search, or if I go to a conference or something, and I see in bold on a piece of paper or in a cartoon, Mickey Mouse, somewhere I get exactly the same structure within there drawn there. If it were a normal invention field, like non chemicals, that could be prior art, like the example we saw in the first lecture with and balls and the Donald cartoon. But in terms of small chemicals, this guy here that would be maybe drawn in another cartoon would not be prior art because other than the structure, we also need to have exactly how this guy's named, how it is prepared, how it is synthesized, how it is produced. So, because and only then that particular chemical compound join a Disney Cartoon will be prior art. Otherwise it would be the chances of finding the same thing would be too random, too high to basically keep novelty. So this is the point, and this is what we say here is that other than having the name of the structure of the drawing present in the prior art. We also need to have all the explanation of how this particular compound is produced and prepared and synthesized for it to become prior art for your invention. And that's a very important point because, naturally, as we all know, pharma companies are leading on the idea of finding that particular compound that will make me my drug and that will give me some profit I can use for more research and for the things we're not getting done. But the point is that where is novelty and how can we use this novelty to basically bring our compounds to market. So let's use real life example that is kind of emblematic of this particular field. And let's go back to the 50s when all these new drugs regarding antipsychotics and mental health drugs are starting to be produced and we have here the example of Chlorpromazine, which is one of the very first compounds used for schizophrenia. It was very popular, but it resulted in very unpleasant side effects. So pharma companies started working on how we can do better, and in 1959, Clozapine came into the market, which is a derivative from Chlopromazine. We can see we have a change here, the original one has group here. Here we have a different group, so that's the change that we have, and we have another change here. And basically, this structure, which could be very similar to the previous one. If you look at it, this structure basically had the same, almost the same effect in terms of therapeutic effects, but really decreased the side effects of the initial clozapine. However, this compound itself has it's own side effects which kind of lead sometimes to death of the patient, because of the suppression of white blood cells. In some particular patients, Clozapine was removed from the market and more studies were done. And it was later reintroduced some years later with the condition of performing weekly blood tests for each patient that was taking this drug. Which actually became very costly and very messy for the patients, because every week he needs to take a blood test, so it was becoming pretty hard to cope. But still, it was a very good compound because of the activity. We come to 1996, where Eli Lilly came out in the market with Zyprexa, which is a kind of market name for the compound called Olanzapine. And it became initially a massive commercial success because the side effects were very lower compared to the other on there, the other drugs that are on there, and efficiency was very good as well, so it became a very strong and very commercial success for Eli Lilly And as we see here with the 7th biggest selling drug in 2006. So you can imagine the markets of this particular drug, how much money was coming out from this. And actually, this was the intention of a lot of competing companies, which then tried to investigate the structure of philanthropy inside domestic literature. And they decided that they had the ground for suing or going against the patent, against Olanzapine, because they claim that there was no novelty in their drug. So the Olanzapine was not novel compared to the prior art, which was prior art defined from Eli Lilly itself. So basically they tried to suit, on the first instance they won their suit in Germany. The law suit in Germany where the German Federal Patent court deemed Olanzapine not to be novel because they said they found out that, or they deemed that Olanzapine had been described in previous documents from Eli Lilly. And therefore, they kind of cancelled, they annulled the patent from Olanzapine. So that kind of gave some time for those companies to start producing their own product, because there was no more patent for it. However, in 2009, very important thing, the German Federal Court of Justice decide tor reverse this initial decision and deemed Olanzapine to be another compound. So that basically reinstated a patent from Eli Lilly closing again to market for a big company. So basically we can see that the same country, Germany, first decided to nullify a patent claiming that the drug or the compound that was described on that drug was not novel because of prior art. But then later on, the same country with the Federal Court of Justice, decided to reverse this, and that deemed Olanzapine, or that compound, to be novel, and therefore they said. So, why is that? So, let's start from the beginning we're in 1974 where Eli Lilly kind of put down a provisional application in 1974 where it described this generic Markush model, we have Markush formula. Which this is a formula that encompasses a certain number of compounds that can be used for the schizophrenia drug. And if you look at this formula here and you look at all the possible change in the one can make in the R1, R2 here and here. And we come up with a list of 10 to the 19th possible compounds that can be derived from this. Later on, Eli Lilly wrote a patent or kind of fight for a patent from compounds derived from this initial formula here where they focused basically on this particular compound here called flumezapine and some others. And this one was specifically described in terms of name, structure, how to produce it, how to synthesize it, how to create it and everything, but there was never a mention of flumezapine itself. Like here there was never a mention of flumezapine. In this particular region a certain group of compounds were described in terms of names and some other compounds were described in terms of being synthesized. And flumezapine was one of those so they wrote a pattern for this guy for this flumezapine, never mentioned of olanzapine itself. And that's basically the patents together with two papers from Eli Lilly's chemistry departments, two scientific papers that came out that never mentioned Olanzapine. Those were the grounds for the competing companies to somehow suit Eli Lilly on the patent, and saying that it wasn't novelty. And why did he say they're like novelty? So here we look at flumezapine on the left, which is the one from the patent that was considered as being prior art, and this is olanzapine, which is the drug. And we see that the only difference that we have is basically in here, either difference, difference, nowhere fluoride group. That goes away. And according to the old jury in Germany or according to the source of the competing company, this change was not enough for causing novelty, and therefore olanzapine Was not novel compared to flumezapine. And that's why the German court first agreed with. But then Eli Lilly was able to prove that this change was first of all a big change in terms of activity of the compound that this change was never mentioned specifically in the patent or in any other documentation. This change was enough to change the activity of the molecule. And that also it was not obvious to this person skilled in the art, so basically the mash to show that there was non-organis in this change in terms of changes in activity. And that is why in 2009 the Supreme Court in Germany deemed Olanzapine from being novel because of these complete differences by just putting substitution and allows the patent to come back. So basically here we show that because of one change which is deemed not to be obvious, which was not described, and that changes completely or that changes significantly the activity of the drug even though the two molecules are very similar. They can be deemed as being novel and, therefore, Olanzapine can be considered novel and patentable compared to Flumezapine. So in summary, while Olanzapine could have been deemed not to be novel, and because it's very similar to the model that come out from the provisional in the patent, and it has never been, but it still has never been described or named or enabled in any prior art, so it was never specifically mentioned or. Therefore Olanzapine was deemed to be novel and the patent was reinstated in 2009, it was very important. And following this, the German rules on novelty were then brought closer in harmony with those of the European Patent Office which would have not consider that as being a non novel compound because of its root. So basically in Germany came close to European patent office rules in terms of novelty. So these shows are just one case, first of all, can make changes in the common law. And now we see how one single modification in a compound can lead to a complete either patent war, as we've seen this way, or can lead to completely different drug and completely different activity of a non-molecule. And that will cause novelty and patentability of the chemical. If you want to read more about this particular case, which I find it very interesting and kind of it's very well described in the literature because a very classical We have this link here, which is a very interesting read. You can go through the various texts, especially in terms of the seizures of the Germans in Germany. And we have this document from the patent office in London and Munich. The PDF I have put available in the course pages here in Courserum, and it's very interesting reading in terms of the history, in terms of what are the documents that were used for prior art. What were the ideas of the competing companies and some thoughts about the judges and the lawyers in terms of the various items referring to novelty referring to referring to non obviousness and how the case was covered. So those are very interesting reads and will give you very good ideas, or be your understanding on the novelty of chemical compounds for this part. [MUSIC]
