pharmaceuticals versus sandoz which is related in part to get a research and development versus milan we asked the parties to come prepared to discuss the effect of the supreme court opinion status on this particular case in general as to how the court should treat that that opinion and then especially in this case if there's a particular concern or issue with this case then we'd milligrams were tested five milligrams at different toasting dosing frequencies had been tested and indeed fifteen milligrams twice per day was described as quote well tolerated and demonstrated benefit on some of the points that's appendix twenty three nine zero and tell itself the record reflects was considering a number of options when it decided the two forty milligram three times per week including fifty milligrams once or twice a week and that's seventy five when you refer to large scale studies where you're referring to look phase three trials so the fact is though the options that were available to a person of ordinary skill in the art at the time were literally infinite it necessary or appropriate for limiting the scope of the art for purposes of what would be considered an obvious to try alison indeed that's exactly the kind of of reverse reasoning that this court rejected in honeywell versus mexico the fact that  had been tested is not a reason to let the universe twenty and forty is a reason to expand the universe to consider other testing testing whether doses the testing of other methods of administration and that's exactly why it took some inconsistent and again the title really we let me go back to a statement you just made you said that the twenty was the optimal dose but there is there is certainly evidence in the record that forty had the advantage of faster on forty milligrams three times a week when forty milligrams is being dose every day that's two hundred eighty milligrams per week the dozing regimen here is only one hundred twenty milligrams per week that's less than one hundred forty milligrams per week that was it the twenty milligrams every day so that district court is simultaneously saying well there's an advantage to early dosing but there's also an advantage to pursuing a dosing amount that on a per week basis in settling this centrally similar to what had been previously approved by the f d a those two don't exist in the same world they're inconsistent and there's nothing in the record it gets back to the fundamental unknowns about well these are the specific question of balancing the well i mean you have certain advantages for the forty milligram you have certain advantages to the every other day and why is that not simply a matter of deciding that you will balance off the the advantages by going to something  like forty every other day or alternatively forty three times a week which is pretty close to forty every other day so just breast i think that involves assuming and basically making the very kind of sort of inherently contradictory rationale of this court criticized in cycle and supreme because it assumes you know more about how this drug works then the prior art actually reflects and indeed there  of the clinical results that tell you something about how it works in that you understand something about onset of efficacy you understand something about side effects why isn't it reasonable to say with respect to the competing clinical outcomes that you're trying to balance the advantages and disadvantages of various dosages and dosing regiments so just right you don't know that there's early onset with dosing forty getting other advantages that comes with less frequent than daily why isn't that a reasonable way to look at that at the question well i think two things to address and first even if you think that it is even if you think that it might be going to start with that five hundred reference and it is it is purely hindsight indeed the whole concept of close prior is a hindsight driven concept under that under the grand factors for deciding whether or not there were unexpected results not why does a person  we're very close so so statistically even even and tight table five so statistically there's no significant indication that alternate is worse in terms of side effects correct but just right and i guess an answer  current two thousand and eight study as well as in the flecker study and your honor asked about the flanker study it did have a statistically significant because reduction in drop outs with the twenty milligram every other day versus the mi twenty milligram daily and of course that's a big point of the product which here the concern is are patients going to be adhering to their medication and the hearings is do you take it and if you don't take it are you going to stay complain on it and so that was the problem with  related more to frequently crude it is your honor ok it is related although dr fox testify on his direct examination that if you reduce a severe reaction such as the collateral if you reduce the frequency of that reaction you reduce the severity and you improve the tolerability and so again the goal is improved tolerability and that's the motivation to go from every other day regimen or a daily regimen to something that is three times a week  their motivation to do that is what dr greene testified in the district court credit is was that patients were more compliant and had better hearings when they took their drug monday wednesday friday they knew every day of the week what they were going to take and they got their weekends off and that makes sense daily in that study and then just scored her a lot of actual argument about this from both sides experts and the district court credited dr greene and violence expert on this court and also asked a question of starting with twenty versus forty and i believe my colleague answered that there were many doses in the art there were many doses in the arthur studies he referred to in the cohen study and if you want to look at that that they are very small do through two thousand and eight in the prior to do two thousand and nine it was still unclear what the lies so there are plentiful trials studying twenty milligram dosing and forty milligram dose in and those are the predictable identifiable choices that the district it rejected that twenty milligrams was the optimal dose that is a finding the court made at age twenty seven three twenty nine it rejected the reason to use it the court the court made factual findings from which the only conclusion one can draw is that all of these claims are obvious the court found both that persons of steel in the art would be motivated to use a for dose would be motivated to do that three times a week and would have a reasonable expectation of success the clearest statement of that is in at the end of the court's opinion after it's considering the then the objective considerations of concludes on a forty seven both that the forty milligrams three times a week would be motivated to be used and would be expected to succeed and that it would expected to dr green testified at eighty four eight six to seven and the district court i don't dr green's credit dr green's testimony that in the context of this drug which works on the immune system one would not look  one would instead look to the clinical studies and the clinical studies here showed and gave one a person of skill we are the motivation to use and reasonable expectation that it would work forty milligrams three times a week for the reasons that my colleague four where the judge concluded the fact that the p k profile was unknown because in relevant here ga is an immune modulating drug that is not necessarily measurable in the bloodstream and even if it is measuring the levels in the blood does not indicate anything about the effect of the drug on the patient our expert dr fox testified that instead persons of skill in the art would look to the clinical studies and in fact that clinical studies were strong evidence that no one was deterred no one  deterred from the fact that they didn't know exactly how this drug works from testing and using it in patients less than every day and forty milligram dose was about the obvious to try point that day that that because this was only one dose off your honor that that would provide adequate motivation and then that can cause it was itself then later confirmed by the forte study and and studies that came after  data there is no data showing that this is going to be efficacious once you introduce a seventy two hour gap then while there was plenty of testimony to the district court that explained why it was that that having a constant activity need and you've now got a seventy two hour gap that's being introduced nothing in the prior teaches that and the district court it never finds you will look at this opinion in vain to find a reasonable expectation when you've introduced the seventy two hour gap what the district court does isn't obvious to try to assess that's the only analysis it does and the defendants don't even defend it they didn't say a single word about it either one of them until they got a question can't just simply say that there is a reliable basis for extrapolating again it doesn't matter whether there's p p p the fact that there wasn't the fact that you wouldn't perhaps be indicative meds or worse what you would need is something like those arranging clinical studies and here of course you have the invention in which you are simultaneously adjusting to different parameters you're changing the dosage now you're changing the dosing frequency and there is nothing not one single thing in the prior to suggest that if you change both of those that you can have a reasonable expectation of success the data certainly that they point to doesn't support and doesn't identify that it doesn't give a basis for the gaps in for the changes that are made and that is why the district court ultimately falls back on obvious to