drug the invention went against the conventional wisdom which was that controlled release formulation should be limited two or three times daily because it could not be reliably predict whether any particular drug it turned out surprising the scientists who were doing the work that way and i see the time it was absorbed through the colon less metabolife was formed then when i was absorbed through the small intes e it turned out that there's oxy metabolite is the cause of the principal side effect of my finding which is dry mouth and so the control at least formulation by allowing produce formation simply known to the artist and they can look them up in a textbook they are known things like a melting point or a boiling point they may be omitted from the path for some reason and the eight correct goes for a controlled release formula time it was not known in the prior art and indeed required experimentation and assessment now is just to determine this was conceded by miles over expert dr amador who testified that if he were to determine example the samples show that eighty to eighty percent or more drug is released you know under twelve hours but that i mean that is outside the ranges of our cap what that means is that bakewell reflects the conventional the critical determination of the three patent which is that slow release when you're at least over twenty four hours can produce a therapeutic benefit and there's nothing when the drug should be taking bakewell on its face it's simply discloses a controlled release formulation reflecting the conventional wisdom prior our quick release eight percent or more drug released in twelve hours it doesn't so it certainly i'm not suggesting includes the release rates that are in the path but not to the twenty four hours that is absolutely correct but the drawn roughly the bands on the pad which are a linear release for twenty four hours so the patient gets the benefit of steady constant dosing for twenty four hours bakewell reflects quick release most of the drug is a play is released in the first eight twelve hours which is the conventional wisdom that because a lot of absorption cannot be relied upon it's critical to get most of your drug released in the first eight to twelve hours that's the critical difference between them that's the critical difference between the invention and examples three and four when he experimented with after the three five five he discovered that he obtained different release rates ending on whether the patient was taking the drug in a fit of fasted and likewise after the three five die and finland a commercial product called cistern c r was introduced that has that package instruction that sets up at the end his patient question conditions could produce the slow release rates of the three five five that argue that is simply not insist the patient the reason it's not just a patient is because this court element of the missing element is inherent or necessary under normal or usual operating condition and what that is saying correctly and wisely a matter of policy is that if an invention has been made i hear we have one taking off and simply practicing the fire or unaware of the subsequent discoveries of the car right you know might or might not take it on an empty stomach they might or might not appreciate the benefits of linear release because there's simply nothing in bakewell that instructs one of them is utterly happenstance to turn bakewell into a useful in  if sister and sister in a subsequent discomfort let's assume they were specific claims in bakewell and they discovered that it could be taken out empty or full stop but are you suggesting that even in that instance it wouldn't be in here in tory or to tory because anticipation because it's a subsequent discovery i'm not and i'm not understanding the arguments you seem to be making ok based on a subsequent discovery if you turn out even possible candidates for control one day release through the colon actually titan is not among them and seventy percent of all his efforts fail so high risk uncertain exercise teaches to the contrary as the patent office record recognized the teacher's faster allee's it simply doesn't do it the the text here i wasn't talking about the time release i was talking about and the question is what's happening are you getting any predictable reliable release or are you just getting occasional small unpredictable erratic release and that's the problem that's why devices like make well emphasized the first twelve hours if you want the benefits to happen which are linear release constantly over time you need predictable reliable rapid absorption and therefore passing for twelve hours through the colon and want to expect the drug that is released from the drug or be absorbed through the client wall and that is what the art said repeatedly was highly unpredictable variable uncertain not something i want to scale and you actually count on and that's the reason the controlled release formulations were directed towards what shorter timelines but there was there was seven referenced and reliable i'm not sure whether seven fifty seven does that or not i will agree that the art reflected that there were a handful of compounds that could be absorbed through the it for twenty four hours what was going to happen are you going to get twenty four hours of linear benefit or we're going to get to read it in blood stream and juan doesn't really addressed that at all  says is here's my carrier here's my pill choir she says you can put santa anything reliably for twenty four hours the next step is is that any release in the g l in terms of releasing drugs which doesn't get to the next say question ok now you've created a pill that you can control its release rate is that doing any good or is the judge just accumulating in the c very careful in looking at the art keep separate the element of technology for drug drug formulations which is a very active and sophisticated are and the separate question of whether these very number apparatus number three be true testing the morello formulations released in vitro under the claims of the patent and therefore meet the claims and put infringe court accepted the was found insufficient for purposes of infringement i think the infringement errors are many and cannot be corrected on appeal but i respectfully ask that the case be remained in district court to the fact finding the issued a very careful fifty seven page opinion she found they failed to prove infringement she found that the patents were invalid based on the prior let me turn first to infringement this affects the mylan products this is a princip infringement argument is that each and every claim has in it an express quantitative limitation as to either the percentage or the milligram amount of oxy butin that is released at the end  four hours eight hours fourteen hours and twenty four hours judge healy having worked and had als insisted she interpreted that release to be released that you had to prove how does it release in people in the human g i tract that claim construction is not challenged on appeal when we got to trot it was judge keeley's opinion makes clear alza failed to offer any evidence any competent evidence showing what was the actual quantitative release of the milan product inside the human g i tract instead dance to arguments dance by its counsel which are repeated in their briefs here to this court regulatory approval the curves show the appearance in the bloodstream of oxy i think this judge jr's pointed out this is after release absorption metabolism distribution is a result that is the result of all these fundamental competing processes going on it for f d a purposes the only things they care about their only two parameters they care one to you how high is the c max the second one is let's look at the total area under the current over a full sixty hours if you were with them i think it's eight percent to one hundred twenty five percent for f d a regulatory bioequivalence is judge acutely correctly found that there was no factual support for that argument and the argument looking merely at these curves and you know trying to make a comparison does not provide any specific information about witnesses at trial said you know i'm in charge of this area you know if i can chart run either fast enough or slow enough i could give you any kind of relation one in these in vitro tests with judge healey found correctly so  to mimic something that's going on in the human body in fact in our brief following page thirty four we have a chart we show all the different tests when you run on different standardized tests and they vary all over the lot although i think all that one out of eight or ten tests show nine infringement when you use the in vitro both our expert dr amidon analysis expert dr far testif that you can not use in vitro testing to determine in vivo release just standing by themselves cannot be done the only way you can do have some use like that is where you then he's going to make calculations and show from the blood plasma data what it really means going on inside the body at the last minute they just said doctor he never appeared at trial in response we called dr amador w data on top of the you know most of the in vitro test which all fall well below the claim patients they are all consistent and they all show non infringement but i think the important thing is here it's not harper to prove no of technical information make that show on the show the burden was on you and your pals when you were trying to prove infringement what kind of test can you run and make measurements to show  body you run it through a complex program which will that help complete and take out the elements of exclusion so logic has how do you how do you know what's going on inside the body how do you know how much of a of a sudden she's been released in any point in time because the patient is taking it you're taking blood samples every two four hours you are running through the computer against a separate task which puts an i v dose directly into the bloodstream so that data which we got at her deposition we showed that it was if anything it's considered at all it proves not infringement let me go on to the marella reference which is the first round the judge really found dr pepper us at trial transcript five ten this is not in the joint appendix this is one of those things got left out accidentally but in trial transcript five ten dr pepper this was specifically asked what he used them or other formulations and use routine experimentation that will give you something that comes within the claims of the three five five he said yes but i don't and so you're saying that even though morel itself fails to disclose specific therapeutic amo that that boy is filled by that line no i'm talking about release rates i go on and i will now address your honor the question of the special therapeutic amounts which is the only argument that have in their brief against what they said was missing in the road that it doesn't somehow tell you the five milligram ten milligrams and fifteen milligrams amounts that appear in some of the clips but not all the claims claim one has no no amounts and your disclaimer that argument your honor is incorrect as the record evidence shows a rebel specifically teaches using a there are beautiful affective amount the basic question is and that there was a standard there are few to the effect of amount that was well known to those skilled in the art would be a total daily dose between five milligrams and twenty milligrams and i refer the court specifically tablets or a five milligram tablets given two to four times a day but simple arithmetic that is everything within the range five milligrams of this and up to twenty milligrams at the other we also put in where it states that the adult therapeutic dose starts at quote two point five milligrams twice or three times daily and increase according to the response to a maximum of twenty milligrams daily unquote once again this is exactly what their expert admitted everyone anyone skilled we are knew that the standard daily dosage that you would use for a patient it varies from  be somewhere between five up to twenty milligrams and that fully includes five ten fifteen milligrams amounts that are recited in some of these claims often wherever share arguing at all that the total amount of  wrong one skilled in the earth knows it's going to be between five and twenty milligrams and that was well known you don't write these plans to put in for every drug everything that is there you you know perfectly you don't put into the papists the stuff that is well known which in the case of oxygen is that the five to ten milligrams is i'm sorry five to twenty milligrams is the standard dose let me just do very quickly on beige wall they said that the critical difference on age wall is that it goes too fast dissolves too fast that's based on in vitro tests under conditions pavel's fifty education is permitted which we would fail it does not five through two thousand and seven he was went through i'm sorry to house and five through two thousand and seventy four and the exhibits that he we went through with that we went through literally two dozen references where he went back to address the state of the art of clonic absorption trench heard his testimony it was unimpeached it was on rebutted as a one nine hundred ninety five one of ordinary skill in the art would have point even if the court finds that the milan product is not afraid three fifty five half this court still leaves to reach the invalidity issues presented here because of the impacts analysis that i think choir's that the judge's finding about business before we start with the one pact the one patent teaches everything the three fifty teaches except it does not specifically mention ox you time specifically it teaches three release rate within the scope of the three fifty five that teaches that you can formulate almost any something like this this is a linear release and one teaches that you can formulate an extraordinarily broad range of drugs to achieve that and among the drugs that want teaches you can use to get this kind of for at least rate are muscle relaxants and your unary tractrix and has been already observed to this court oxy the time it had been around for decades as a well known muscle extended release formulation now also says yes but the person wouldn't do that because the person ordinary schoolie are would accept conventional wisdom that oxycontin wouldn't absorb in the therapeutic is an important word in that context i'm the evidence at the trial it was clear that an oral drug reaches the large intestine the colon in about four to four and a half hours twenty four hour therapeutic formulation additional absorption would purse some way into the large test you simply can't have a twenty four hour therapeutic formulation without kalani absorption moreover the evidence during the milan  that a person aboard mary schiavo would not be discouraged by what aliza calls the conventional wisdom and would use want to formulate an oxy time in formulation with a reasonable expectation that it would succeed not simply that it was obvious to try that there was a reasonable expectation it would succeed that finding is not clearly erroneous and as it really doesn't make an argument that it's clearly rose there was ample evidence to support the trial judge's conclusion and it should be a fur now let me direct your attention to the baseball anticipation  the reason i submit why this court has adopted the inherited to sufficient doctrine and we're court and the reason why the court does not require the inherent characteristic of the prior art to be known to persons of ordinary skill in the yard turns on a very fundamental proposition of patent law and that is that the public may not be deprived of the right to practice the prior art with its terms under normal forseeable usual circumstances the reason why big t the united states after the issuance of the three fifty five patent it would infringe now the maxim which as a who says that what infringes if later intic earlier in fact reflects this fundamental proposition of patent law you cannot be a patent simply cannot stop the public from practicing the prior art under normal circumstances in every iteration if later well then always anticipate ever and ever saying with respect to the entity inherited by anticipation that you ought to be certain that you know that you're  invalidating the right path they should have and if situation in which the thing that's being claimed always was occurring at some earlier stage all is edged in that that's their argument but i'm suggesting that that is great a restriction on the bill of the of the public to practice the prior art baseball teaches the particular formulation with a specific purpose of treating on t v time for the specific purpose of treating out to be timed with twenty four hour therapeutic formulation so a person reading baked wall and let's assume that they will have expired license can see that and say that's a great idea i'm going to use that to treat my urine or your neary and continence patients that party has the right to practice it with fed patients with fast patients then the three fifty five happened comes with oil and they say we've got to stop doing that because at least when administered too fast and patience you're going to infringe the claims of our pat that's right but the conclusion is that three fifty five patent cannot stand in a sense  impoverish the public domain the public has a right to practice big wall with patients on an empty stomach with patients who have just finished breakfast and anything in between and effects are to remove existant knowledge from the public domain or to restrict free access to materials already available this court in the atlas powder case applies only when under every normal and foreseeable circumstance the characteristic expressed because the public is entitled to practice the prior art under any normal foreseeable circumstance  in the public is entitled to practice the bakewell examples in accordance with their terms which are not limited to fast food or fish therefore the the subsequent part three fifty five patent cannot prevent the public from practicing  ball in accordance with its terms but it doesn't say what terms or it doesn't limit the terms and i'm saying that as long as the circumstances are normal foreseeable and there was no dispute that that was the case it is the commonest thing in the world for patients to take a prescription drug on an empty stomach well done it therefore it is foreseeable the judge the trial judge found an else it doesn't dispute that it is entirely foreseeable that somebody practicing the testimony there's a high degree of scientific belief that absorption from the colon i psec question of the articles we've looked at so far haven't said anything like that answer we have not looked at any particular statements like that correct and there aren't any and fact with the prior art in fact reflects his doctor i am an ons own article from right team ninety six the absorption of drugs from the gastrointestinal tract is very complex and often not well characterized many factors affect the extent and rate of drug absorption they include p k a c l u ability stability diffusive a t city salt surface area vertical size crystal for me goes on and on and we prove or claim that we can't be faulted for not having evidence you can't think why you came here the evidence we did have should have been sufficient to meet the burden of proof the evidence we did have was designed to mimic the release of bloodstream in vitro testing me i have to call didn't test the ethical to test an unapproved drug in humans you need approval from the institutional review board an informed consent is a general matter scientists do not like or approve human testing for litigation purposes and when you compare doing human testing for litigation purposes with the additional complexity we have drugs that we received in the mail from  litigation and certainly tested approved drugs that sponsor subject against the same strict i r b approval and informed consent when you're trying to get approval to have a drug prescribed for treating patients it's a completely different set of circumstances in which both control the drug and also now are doing it for science not litigation but that's the undisputed evidence and i think it's the same test done by the same party proving the same release rates i think it double standard was in play and the double standard went the wrong way were entitled to the lower burden on infringement i think