appeals from denial of swimming or injunction motion in which the district court reached one issue likelihood of success on the merits has found its patent would likely be held invalid a trial we focused on a number of legal all over the place to to once a month likelihood of success at least it hasn't been shown well that we have to look at the course to dish reports opinion and what the district court concluded based on the review of that evidence the district court considered to fact that roche did not just claim monthly dosing with an effective dose of drug roche or claim to specific dose of the drug one fifty milligrams and i'd like to focus my argument on why that particular dose would not have  been obvious to a person skilled in the art under the appropriate legal standard and yes the fact no i just want to understand exactly what it is you think tragic and wrong first of all you're not objecting to the standard that when apply as it relates to pretty loyal to take untiring walk through that so there's no issue there crept around that's correct i in in your brief you argued that that place undue focus on an obvious try analysis and i can get to that in a minute are you now adding something pinions said that plaintiffs have failed to point out what it was that the inventors had invented what was the contribution here what was the big deal about the one fifty milligrams just the district court acknowledged that there had been  argument that it would have been unexpected that those would have been safe and effective we can get into that the legal error was that the district court over loved the evidence presented by roche of unexpected superiority of that the reason that disappear already would have been unexpected is because the clinical trial papers published before the filing date established in the court agreed with was some indication that i would work also there was indication that by works but did not provide as much benefit as a two point five the two point five was actually s properties to the by and the other issue with the five is that in the plume an area clinical trials in and where it's doesn't post menopausal women the drugs cause a very large honored cases that deal with that particular issue for example in great girl they focus on the fact that if you present evidence that let's say the five milligram dose would have been disfavored that's still relevant to consider it but i think the determining factor would be why was it the where there's a peer your results of cheat with the one hundred fifty milligrams dose and with those have been expected and this is why effective however the trial court based its conclusions on extrapolation from daily doses and we have that two point five those in the five s with a two point five was really the best five did not increasing the dose or doubling that those did not improve the efficacy of the drug therefore in the normal course of development of these drugs particularly with drugs that had gastrointestinal side effects like the bisphosphonates the art uses the lowest effective dose of the drug and this was taught in the scofield reference relied on vial district court and paragraph thirty of that reference to use the lowest effect of the which would be two point five milligrams the other clinical trial reference the court relied upon the recent reference in the use that two point five milligram dose in both rabbit and in response to clinical trial references said that the two point five milligram dose was the one that was going to be tested in phase three fracture reduction clinical trials and as we pointed out in our breaks roche received he considered all that happened and found it persuasive actually it doesn't say he considered the evidence of unexpected superiority your honor you're referring to i believe the discussion of page fifteen of the opinion  he doesn't say we pointed out what the magic bullet was if you will and that's what our unexpected superior our superiority argument goes directly to that when roche began to develop the monthly dosage they started from fracture reduction results that they had that weren't in the art with the two and a half milligram dose and with an intermittent world those that averaged eighty milligrams a month said in the conclusion that the two point five was better though for bone mineral density he also said in the conclusion that the five milligram dose had a higher incidence of gastrointestinal side effects so i think that the the the reason that the superiority of the one fifty milligram dose is important is because there was no reason to expect to be able to exceed the performance of daily continuous administration of the best dose that was known in the art two point five milligrams or for that matter the five milligram dose did not give you better results than two point five so doubling the dose with daily continuous administration did not improve results it increased the side effects by sixty four percent it resulted in women dropping out of the study because they could not tolerate the drug and  judge kessler did agree with us that the two point five milligram dose was a period so in developing monthly dosing we're looking at a dozen regimen once monthly that had not been tried before in the prior art there was one clinical trial we brought to the district court's attention concerning a sanofi drug to lucrative that was tested in monthly doses but they divided the doses over seven days giving it for the first week of the month with three weeks off and that was a clinical trial failure fail to reduce fracture risk so actually yes and human yes because the patents are directed to treating or preventing osteoporosis as weeks planes in the breach osteoporosis involves in post menopausal women involves the bone remodeling cycle getting so out of balance that bone starts to deteriorate and break down and ultimately leads to risk of fracture practical matter that may be t the main goal in treating us to oppress us is to put women on these drugs chronically in order to reduce the risk of fracture you're treating women who have probably already broken a backward step you're putting money into drugs to reduce the chance that they're going to break their backs again and so it's critically important and there was testimony in the in the record of the health fracture risk reduction being required  at page two thirty three to thirty four and to thirty four to thirty seven indeed in order to bring in order to commercially developed a drug the f d a at this time and still today and reducing fracture risk and then you could you could bridge to that the first data available on russia's drugs that it would successfully reduce risk of fracture came after the filing date based on a road clinical study that proved a two point five milligram dose work continuously it proved that there was significant fracture reduction with an intermittent oral dose not the claimed able to go and develop the monthly invention up until the time growth started to work on monthly posting and it tested one hundred in a test of one fifty milligrams the normal course of research in new york would have been to start with arguments that mr ridout raised here where he and his brief work is that the district court didn't consider this issue and this is the outcome determinative to the obviousness analysis the district court has in fact considering those issues and he in fact ruled that judge has or has now ruled in concluded that the patent is invalid so we know that roche did not succeed on the merits so to me i don't understand why written business appeal is perhaps a better question for m there is a second patent the nine five seven patent that has not yet been held invalid formally but here before this court the only thing the only patent claim that roche identified as the representative patent claim that was going to appeal and those are the claim no one is the judge shows or has already found are invalid obviousness so i question whether if this stage there's really much for this court to do since judge why my order does not apply to the nine five seven padding as well because again that that was never argued separately and roche requested an opportunity to brief to judge chancellor you know they basically wanted another bite of the apple to try to don't know the exact i can't predict which i've shown is actually going to do but you know for all intents and purposes he has entered the judgment on the merits for the six three four patent so there's really nothing left to do in that case the sole reason why that center right it's like that is what they actually think was the error here because obviously in a preliminary injunction appeal the abuse of discretion standard is not just occasion for them to basically really argue all of the same things that they put in front of the district court  point five milligram daily dosing with all due respect roche's never put in any actual evidence that demonstrates that and in page forty three of their brief where they discuss this issue they cite t combined statement opposition to the statement of material fact but you know that statement that they put in that paragraph eight o nine they don't even put this before you're honest to say here 's the person in the prior art who said this is what we're going to expect here is a person who actually did look at the evidence and conclude either in the literature source of patent or in expert testimony that this is in fast and unexpected result there is no actual evidence of that so while i can certainly respect that the district court if actual evidence of unexpected results is put before zero nine two six he it actually it actually been reported that graham russell stated that he does not find it surprising and he does not find it surprising that a greater e is seen with one hundred fifty milligram dose than the two point five milligram dose and that far exceeds the total cumulative dose provided by the daily regimen you're gonna say these results  dose because the total those concepts when you look at the are as a whole particularly back of them the relevant timeframe that we're looking at here the total those kinds of those actually driving people to select two point five million for another two point five milligram daily dose as the placebo those two doses were the two point five milligram daily and the five milligram daily now mr dell suggested that robin says all these then things about the five milligram daily dose that in fact is not what the wrapping paper says other paper in fact found that both of those doses were effective and statistically significant relative to placebo and when it came to the side effects the raavan paper in fact she included in this is a page a one three three nine seven talks about the participants the two point five milligram group and the those who parted faded into place in the five milligram group none of these adverse events were considered serious none of the safety laboratory parameters and then it because if you're talking about today the reason why i mean aside from the second were generic companies but the reason why no one sees a need to go for some of these lower doses is based on what actually happened with some of the other drugs in this over time they expressed some concern about the two point five milligram dose and said you know what we want to go with the five milligram dose because that's where we think we've got the better efficacy a lantern ate the leading this fascinating than market that you daily doses that were selected for a lender an eight were five milligrams per day and ten milligrams per day the you know so when it came to the three drugs that are routinely in this class linked together th one of the doses that they identified was a thirty five milligram in bandra nato's which if you apply the dole the total those concepts that's a five milligrams per day dose so while i understand why mr wood l here wants to focus on just that one robin dos and what roche itself did when you look at the art as a whole there are actually multiple teachings that were guiding you towards the five milligram dose in preference to two point five milligram dose moreover  eighty three sixty two in the appendix he pointed out that if you looked at the restated for in the reef paper by the one month mark the patients had been given twenty milligrams per day every other day for a total accumulated dose of two hundred forty milligrams then had at the end of a mind patients who had been given only seventy five milligrams over the course of a month he said when you looked at that two hundred forty milligram data you so much better results with the patients who had had that larger dose in comparison to the ones who have had the seventy five milligram dose and what that signals to you is that you are not at the top of the dose response curve if you rely on just that two point five milligram dose so quite the contrary the art in fact is not teaching towards a two point five milligram dose there were very serious reasons that would have caused a person of ordinary skill in the area to avoid the two point five milligram dose but in the end i think that from the perspective of the obviousness analysis it really significant results relative to placebo and if you apply either dose in the total those concepts it's our position that you get two obvious doses so any five milligrams once a month and a hundred fifty milligrams once a month and if what you're doing is you're following the teaching and suggestion and motivations in the art particularly is dictated by the tone of those concepts you don't have an unexpected result to select the one hundred fifty milligrams result that is in fact where the art is taking you explained there was that the reason that the superior effort to see one hundred fifty milligrams was so unexpected was because of a property of banter that was not known in the prior art it wasn't even known to roche before they started experimenting with it it's an issue that i i didn't get into today frankly because it's so technically dense but it involves the concept of arithmetic extrapolation from a daily dose to a monthly dose assuming that and something you need to know about this fascinates is that when a minister orally they are very poorly absorbed less than one percent drug gets in you take an oral it's like a stone going through the body very little gets absorbed if you're going to assume that you can do arithmetic extract relation to a monthly dose thirty times stat then you have to make an assumption about what extended up to fifty milligrams much struggle and your native only stands up to eighty but roche case up to fifty when you start increasing the dose above fifty and particularly when you get to  hundred fifty milligrams the actual absorption of the drug is super proportional it's much more than you would have expected just from multiplying thirty times a five milligram dose this is covered first to clinical trial data that was submitted to the f d a so the actual evidence is there defendants didn't know in their opposition break that they had moved to strike that evidence and prevent wrote from relying on it the district court decided you could not have expected super superior results with the one thing milligram dose because they would have no basis to expect that increasing the dose to one fifty would also increase the absorption rate of the drug that wasn't known in the art and that's very clearly covered in the dye photostat the ration that was submitted in the appendix here and also called for the attention of the different court in our in our brief blast on the on the issue of the summary judgment there are key patents and suit we're here only focused on the plenary junction decision and the court's rapture now but we did have oral argument subsequent to the appeal briefing in judge summary judgment decision he has withdrawn its reliance on the spoke field reference he's now relying on a different combination and an obvious to try analysis he still is not considered our evidence of unexpected that relevant to the claims to treating osteo paralysis and we explain that we did not bring that in a claim construction hearing because the parties had submitted a joint statement agreeing to a definition of osteo process that included that the disease includes an increased risk of fracture so we have extensive briefing before the court now on a claim construction issue on the relevance of fracture reduction advocacy and i think that may explain summary judgment as to the nine five seven patent and the judge's reconsideration of the question of whether fracture reduction efficacies should be looked at in the summary judgment context because remember judge opinion that he saw evidence of some uncertainties in the field and summary judgment to recognize that there was a lot of uncertainty about or at least disputed evidence about whether fracture reduction could have been reasonably predicted but he decided that that evidence need not be looked at because in his six thirty court opinion he does not understand why fracture reduction was a telephone conference with the district court judge we thought he was in a hurry to enter summary judgment on the ny pipe seven pattern to close the case out and we thought by now we would have been appealing from entry or final judgment apparently we've raised some issues in the supplemental briefing that have given the court something to think about what do you think we should be ruling on this appeal or should we hold intending for what i ask is the court rule on whether it is necessary for the different court to consider the evidence of this unexpected superiority of that magic bullet one hundred fifty milligrams thus because again a page fifteen in the p r i opinion the judge only refers to the other argument of if it would have not been expected or it was unexpected that that those would be say an effective that's a different argument from it was unexpected that it was actually going to be subpoena or ear to the best those of this drug that was  brief here they did not put those paragraphs of the di fotis declaration in front of judge chancellor during the preliminary injunction hearing and when it came to the summary judgment hearing judge shows were specifically says that page forty of his ruling at oral argument roche raised the contention that the non linear bioavailability of abandon it was an unexpected result this reading this is page forty of judge has lawyers summary judgment opinion