First I have to say I am glad that you looked at the images. Sincerely. And I don't mind gentle digging, but this is potentially some tricky stuff.
OK, you got me worried. Real worried. Maybe MSB's patents have a Problem (with a capital p-value). To be clear, unfortunately because, well Reg, I have to restate an important fact which is that the the figure you are looking at and I showed you is not from a granted patent it is from a patent
application. This is not a quibble its important because Mesoblast is in the process of trying to get that patent application turned into a patent and that is something that quite naturally is a current project - with current back and forth between Mesoblast and the patent offices.
This slide from the recent Bell Potter presentation perhaps offers context -
What I want you to see in this short diversion on that slide is Silviu stating or showing (under forward looking statement protections probably) that
"US patent exclusivity for use of mesenchymal precursor / stromal cells for all indications, and for acute GVHD specifically, provides a major commercial barrier against potential competitors". Well if Mesoblast could get a US Patent GRANTED in which the definition of mesenchymal precursors effectively included all cells from which a mesenchymal stem cell could be derived INCLUDING iPSCS (making iPSCS fall into the definition of mesenchymal precursors) then that would indeed be a problem for companies like CYP in my opinion because they'd have to get around the dumb stuff up by the patent office examiner in allowing for too broad a definition. And that could be both expensive and time consuming. But that hasn't happened yet. Just as in my opinion the FDA haven't stuffed up yet neither have the US PTO on this front.
But in my opinion Silviu in that slide is laying it on - and in my opinion Otherperspective was swallowing and repeating with elaboration beyond what Silviu said.
MSB does have a granted patent - and is applying for more.
Last year on the 21 of November MSB did get a USPTO granted patent entitled "Mesenchymal Stem Cells Expressing TNF-alpha receptors". (US 11821004 B2) I went through the patent office database available online, just public stuff, to see what the series of exchanges between MSB and the examiner had been - I saw how, afterwards, I wasn't aware, hadn't seen any notice of patent announcements by MSB which I think would have been price sensitive, in my opinion, happening on that date, so I saw the initial claims being back to be more modest in scope.
But nonetheless that granted patent relates to TNF-alpha handling - so it does contain some useful specific information about what amounts to a core part of MSBs potency matrix as presented as far back as ODAC. So August 2020 public domain stuff.
Now about this patent application entitled "A composition comprising mesenchymal precursor or stem cells and their use" US 2023/0398154 A1 Pub. date Dec 14, 2023. If you (anyone) plugs those key words into google patent you will see a page of what looks like the patent claim as well as links to a variety of different pdfs for a variety of different patent offices amongst which are the WO (world office) and the US. Because the claims / application process is further along in the US the claims have been more cut back then they have in the WO pdf. This is important (in my opinion) there are no claims still standing in the US version of the pdf that actually refer to IL2Ralpha, thought there is a claim, specifically 16 still in the WPO version.
Why does that matter - well the US patent office is apparently not granting claims over IL2Ralpha yet, the WO still has them in, perhaps I put to you because the US patent examiner is not keen on giving a patent over something that is not yet proven to work. (See above slide "Upon FDA approval patent term may be extended up to 5 years to 2037"). Me again - both the FDA and the US PTO have in my opinion a duty to behave like professionals and not grant either patents for stuff that hasn't been shown to work yet on the evidence presented or in the FDA's case BLAs for products that haven't satisfied the requirements of having at least one adequate and well controlled trial and a validated potency assay.
I don't really doubt Silviu would like to get both a BLA and a wide blocking patent - wide enough to preclude companies iPSCS derived MSC producing companies from using TNF R1 markers and IL2Ralpha inhibition in their potency assays if he could get it. IF.
although I'm not a physicist, or even a biostatistician, I'm going to have a crack at solving this one by doing nothing more than using a technique which I call 'looking at the pictures you posted'. Good that's what I wanted.
Ahem...OK, I just looked.
First - Spearman's rank correlation coefficient or rho (r) has the little p-value calculated & displayed below it on the first diagram. It's written right there underneath it, viz: [figure]
Yup
Second - Coefficient of determination (R2), which just for the heck of it I'm going to call 'R Squared', has the little p-value calculated & displayed on the second one. Also printed right alongside it, viz: [figure]
Yup
You're not going to believe this, but I have discovered that these things - Spearman's rank correlation coefficient & the Coefficient of Determination are actually two (2) different things.Of course I believe it. Wikipedia has two separate entries and everything but going on the similarity of your sentences with those in Wikipedia you already know that.
Amazing. Huh.Well, no. As you say two different things. But ... well see below.
Apparently there is something to this statistics gig, after all. I'm a little curious - does anyone actually use statistics thingies over on your CYP stock?Well I'm just a shareholder and a not particularly pleased one, but yes. That was for Reg and co's benefit though wasn't it.
Both these measures are effect size measures, apparently.
Ok.
I understand that Spearman's rho, for example, represents the degree of correlation of the data after data has been converted to ranks. It's said to capture the strength of relationship, you know, when one is assessing how well the relationship between two variables can be described using a monotonic function. Intuitively, the Spearman correlation between two variables will be high - like 0.76 - when observations have a similar rank between the two variables, and low when observations have a dissimilar rank between the two variables. Whereas I heard some biostatisticians think the Coefficient of Determination is the proportion of the variation in the dependent variable that is predictable from the independent variable(s). Go figure. Well I don't mind going to figure, but I think you've kind of missed my point - whether MSB is presenting data to the FDA to get a BLA as it was at ODAC in 2020 or whether MSB is presenting exactly the same data to the US patent office in both cases (IT IS IMPORTANT ANY READER RECOGNIZE IT IS EXACTLY THE SAME DATA - you should look at the pattern of 11 dots and also note the y and x axes are measuring the same things) so why would they use different statistic? Were they wrong in their choice of statistic to the FDA in the first place so they are having another go with another statistic?
And even more importantly why are there no new data points? Three and a half years later there are still only 11 data points in which only 11 specific patients blood at first treatment and at 28 days is available to be compared with the batch of cells that reduced IL2Ralph in vitro (so at release test time), could not MSB have added more data points from EAP data ?
Phaedrus if you look at para [0224] ".... The observed inverse relationship is significant using either th Spearman or Hoeffding coefficient measurements"
Hoeffding - there's another one - so, why doesn't MSB just choose use one statistic (the most appropriate one whatever they think that is and say why ) rather than a swag of them when its all relating back to exactly the same data set of 11 lonesome looking patients?
Look, it's a simple mistake. Anyone could have made that mistake. Anyone.I know you are having a gentle dig at me that's okay. I don't actually see a mistake on my part yet - the statistics are different and the data isn't so the question is still why on that score in my mind.
So in similar spirit I'll reply - anyone includes you, me and it includes Silviu, Eric and Philip and even sets of those acting together in preparing to present compelling data to the FDA for a second time it seems.
TD
R. The patent application claims as they currently stand in the work in progress between MSB and the patent examiner do not even reference IL2 - though the older less examined version at the WO in the pdf at claim 16 (use google patent search to see the pdfs) show that was what MSB originally intended to include if they could.
MSB is trying to patent something (a part of a potency assay) that they haven't demonstrated actually works.
(20min delay)