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North....
"From your mouth to God's ears"
Its nice to see you stepping up to the plate...I guess it all depends on what the generics think of Judge Du's "masterpiece." I'm not sure Amarin has the stomach for another go around in the Federal Court snake pit and I know that there are very few on this board that want two see "DU" two..."Revenge of the Death star"...
":>) JL
amarininvestor...
You, pd and card are wrong..Generics are not FDA approved for the R-I label...And one of the most important issues in the trial was the inducement issue and the judge ruled that if Generics attempt to write scripts for the R-I indication then they are indirectly inducing on Amarin's patents..
These same rules hold for the Drug plans...The generics can not legally convert Marine Scripts to R-I scripts and the drug plans are going to set Generic Vascepa at Tier 4 (the most expensive) because Generic Vascepa is only approved for the Marine label and is not approved for the R-I label..This is the same situation that Amarin faced all of last year...
The drug plan companies did not "discount" Vascepa because doctors were prescribing it "Off Label"...This is what everyone on the board was screaming about. The drug plans set the Tier at Tier four (the highest) because the only label Amarin had was the MARINE label and Lovaza and and generic Lovaza were both cheaper..And rules say Tier four if there is a cheaper alternative for a drug that has the same indication(s)..
I know this is complicated...but read it again..A common misconception is that "Generic" conveys priority...this is incorrect, "Price" conveys priority..most of the time the Generic is the cheapest..but in this rare case Generic Vascepa, is not the cheapest alternative because the drug plans know generic Vascepa can only be prescribed legally for the MARINE indication (Very high trigs) and can not be legally prescribed for the R-I indication..Also the implications here are that Amarin can sell Vascepa for the R-I indication...Has an FDA approval and valid patents...And since there is no competing drug which is a cheaper alternative...Amarin will be able to sell Vascepa at a lower Tier than the generics can...How does that sound?
":>) JL
card...
Quote..."Pharma dude explained it yesterday
Once a script reaches pharmacy, Vascepa script gets converted to generic.
Brand name rarely prescribed."
Pharma dud is wrong...Not going happen in this very special situation..Generics can only prescribe for the "Marine" indication. They have no FDA approval for the R-I CVD events label..If they prescribe for the MARINE label with the intent to get R-I via way of "Off Label" then they are infringing on Amarin's patents.
This means the generics are in the same situation Amarin was without the CVD Label expansion...and even if the generics try the off label end run...The drug plans will charge their patients "Marine" label prices which in this case are not the cheapest alternative. Tiers determine the out of pocket expenses for patients and tiers are determined by the price of the drug and not simply awarded on the basis of being a generic..In most situations the Generic price is the lowest so it receives the lowest Tier...But in the case of the Marine label Generic Vascepa will not be the cheapest alternative..Lovaza and generic lovaza have the same label as Generic Vascepa and are lower priced...So generic Vascepa will be Tier 4 and could cost patients up to $350/ month...Generic Vascepa expressly can not be prescribed for the R-I label by the federal court ruling...So Generic Vascepa will be Tier four since Lovaza and Generic Lovaza has the same label and will be cheaper than Generic Vascepa...
":>) JL
Meowza...
"Just a couple weeks ago, here were posts about insurers telling pharmacists to switch script from V to generic Lovaza."
True, but requires an explanation...Social Security and other drug plans have an enrollment period where customers can change drug plans..And that period begins in Nov nd caries through half of December..When this happened in 2019...the label expansion (to include the R-I CVD events) was delayed until late Dec..So the Drug Tiers for Vascepa did not include the R-I label, but only the Marine label...An the drug companies chose not to include the CVD event reduction indication...So they only included the Marin indication (Very high trigs ) and because of that Lovaza was also included as a trig lowering drug and was cheaper than V...So the drug stores were more or less requires to provide patients with the cheaper alternative. ie Laovaza...
This might not change until Nov of this year (the drug plan companies are bottom line focused..
That's the bad news..The good news is if the generics can only sell V for the Marine indication (and that is what the trial results say) Then even if the Generics want to sell V off label (for the CVD risk) the drug plans will require all scripts for V to be Tier 4 (up to $350/month) for patients..because the generics can only sell for the Marine indication according to the recent Federal Court trial. And if they try to sell off label for the REDUCE-IT CVD label...They will induce on Amarin...
So generics might want to game the system by going off label..This will not be permitted..
":>) JL
JDUR....
Wow..This is significnt shyt...This is prima facie evidence this bimbo should not be Judging trials. And not be making decisions costing people millions of dollars..
She is an embarrassment to the entire Federal Judicial system...But you got to give her credit in gaming the system...A highly praised talent in Saigon, my home town, years ago. If you don't know the answers then find someone who looks smart and copy off his test...
":>) JL
What a jumbata....
Hamoa...
Great post...I would think the first paragraph of your post is enough overrule her opinion...And she is simply too lazy to be a judge. It is clear she had made up her mind before the trial began..
Deciding issues in complicated medical subjects like the therapeutic benefits of Omega-3 by reading the literature is an almost impossible job...There a thousands of articles in the Medical and Nutritional literature and like fingerprints; no two are the same..The only thing that is really obvious is the R-I trial results..An FDA designed and proven clinical outcomes trial.
I understand FDA does not always get it right, but I would take their opinion over a lazy and non impartial Judge...Not only did she copy and paste but she did not even bother to learn the proper procedural format for a judge to express her opinion..
She is a disgrace...She already has one sanction on her short record..She should not be making decisions that effect thousands of people and hundreds of millions of dollars..
":>) Jl
I don't think this Federal court Judge has presented any cogent argument that Mori proves or predicts the clinical benefits of Vascepa...Mori was a small clinical trial published in a an Nutrional Journal along side Articles like "Fruit and vegetables: Think Variety: Go ahead Eat",,.."Use of the Term Vegetarian."or "Pomegranate Juice
Consumption reduces oxidative stress"...
Very few to these articles are peer reviewed.
In all likelihood unless this article was identified using a Medlars Study it is very unlikely a medical doctor or researcher was aware of the article. Judge Du makes a very serous error when she assumes that everyone agrees with Mori. Physicians who are interested in the effects of Omega 3s are not only unlikely to be aware of Mori. But there are many other articles scientific or otherwise whose results vary with those of Mori.
Studies on Omega-3s vary widely in their findings and measurements..That very few if any physicians or others have any certainty as to the accuracy of any of them. For example in 2018 the year the R-I trial results were reported a major article in JAMA (Peer Reviewed) stated there was no proof that fish oil or Omega-3s Reduced the risks of Heart disease..
This is a list of references from one study on Krill oil// measurements not much consistency of opinions..
Bioavailability
Among the seven papers, four studies reported data on bioavailability and digestibility of EPA and DHA from KO and FO.26,27,29,31 In one of the studies, the same amounts of FO or KO, but different amounts and structural forms of EPA and DHA (TG versus PL), were used in the experiments,29 while in two studies, different amounts of FO and KO, but similar doses of EPA and DHA were used in the experiments.26,27 Tou et al31 examined the effects of different sources of n-3 PUFAs.
Tillander et al29 used a high-fat diet model and fed the mice with similar doses of KO and FO for 6 weeks. The content of EPA and DHA was lower in KO compared to that in FO, but both groups showed significantly increased plasma and liver PLs of EPA and DHA compared to controls. No difference in increase of EPA and DHA was seen between the FO and the KO groups, which indicates that KO may have a higher bioavailability compared to FO.
Vigerust et al26 used a high-fat-diet transgenic mouse model expressing human tumor necrosis factor (TNF) and fed the mice with similar doses of EPA and DHA from KO and FO for 6 weeks. In the plasma, EPA and DHA significantly increased in both groups compared to controls. The increase in plasma EPA and DHA between the two groups did not differ, suggesting that the bioavailability is not dependent on the structural form of EPA and DHA. Batetta et al27 fed Zucker rats with similar doses of EPA and DHA for 4 weeks, and they reported that plasma EPA and DHA were higher in the FO and KO groups compared to the levels in the corn oil, (CO) group. In the study by Tou et al,31 Sprague Dawley rats were fed a high-fat diet consisting of different marine oils, all containing different amounts of EPA and DHA, for 8 weeks. They measured the digestibility using the formula [(fatty acid intake – fecal fatty acids)/(fatty acid intake)] ×100 and showed no significant difference in EPA digestibility among rats fed the different marine oils. The DHA digestibility was higher in SO- than KO-fed rats. There were no significant differences in DHA digestibility in rats fed MO or tuna oil (TO) compared to SO- or KO-fed rats.
Plasma lipids
Among the seven studies, five studies reported the effects on plasma lipids.25–29 In two of the studies,25,29 the authors used the same amount of FO or KO, containing different amounts and EPA and DHA, in the experiments. Tillander et al29 found no differences in plasma lipids between the FO and the KO groups after 6 weeks. However, within the FO group, total plasma cholesterol, cholesterol ester, free cholesterol, TGs, and PLs were significantly reduced compared to the same in controls. In contrast, Wistar rats fed the same amount of FO and KO for 1–6 weeks showed significantly decreased plasma TG and total cholesterol compared to controls, but these effects seemed to be more pronounced after KO intake compared to FO intake.25 The reason for this discrepancy may be that Tillander et al29 used mice on a high-fat diet and not lean rats, and moreover, the amount of oil differed between the two studies.
In three of the studies, similar amounts of EPA and DHA from KO and FO were used in the experiments, and the dose of EPA and DHA was similar between the experiments.26–28 Vigerust et al26 did not observe any significant difference between the effects of KO and FO on plasma lipids, but KO significantly reduced plasma TG compared to controls, suggesting that KO is more effective than FO in lowering plasma TG. However, LDL cholesterol was significantly reduced in the FO group compared to controls, thus suggesting that FO is more effective than KO in lowering plasma LDL cholesterol. Total plasma cholesterol, free cholesterol, and HDL cholesterol were however significantly reduced in both groups compared to controls, but no differences between KO and FO were observed. These data are in line with the results of Batetta et al,27 who showed that KO and FO significantly reduced LDL cholesterol compared to control. In contrast, Burri et al,28 who fed mice for 12 weeks with similar amounts of EPA and DHA, did not see any changes in plasma lipids in any of the groups. These conflicting results may be due to the longer period of supplementation and probably because the mice were lean and not fed a high fat diet, as was done by Batetta et al27 and Vigerust et al,26 respectively.
Inflammation
Vigerust et al26 did not observe any substantial difference in levels of proinflammatory cytokines between treatment groups. Batetta et al27 compared the effects of KO and FO on ectopic fat and inflammation in obese rats. Lipopolysaccharides significantly increased the release of TNFa from all three groups; however, the increase was higher in the control compared to FO- and KO-treated groups, with no difference between these two groups. In these obese rats, KO also seemed to have a more pronounced inhibitory effect on the endocannabinoid system compared to FO, which is in accordance with the results of the human study by Banni et al.20
Ierna et al30 used an arthritis-induced mouse model to show that clinical arthritis score and hind paw swelling were significantly reduced in the KO group compared to controls. Mice fed the KO also had lower infiltration of inflammatory cells into the joint and synovial layer hyperplasia when compared to control. Thus, in this mouse model, KO seems to be more efficient compared to FO, in the treatment of arthritis. KO did not modulate the levels of serum cytokines, whereas consumption of FO increased the level of interleukin (IL)-1a and IL-13.30 Tou et al31 observed no significant effects on the Series-2 prostaglandins, thromboxane B metabolites, and markers of oxidative stress when rats were fed different marine oils.
Biological effects
In four studies, the aim was to understand biological effects of KO and FO by studying gene expression levels and protein activity in the liver.25,26,28,29 Ferramosca et al25 fed the same amount of FO and KO to rats and both oils significantly reduced the hepatic activity and expression of the mitochondrial tricarboxylate carrier. They also observed that FO and KO significantly reduced the activity of enzymes catalyzing de novo lipogenesis compared to the activity in controls. Tillander et al29 used quantitative polymerase chain reaction (PCR) to study changes in hepatic gene expression after KO and FO supplementation. FO mainly increased the expression of genes involved in fatty acid metabolism, while KO specifically decreased the expression of genes involved in isoprenoid/cholesterol and lipid synthesis.
Vigerust et al26 showed that KO significantly increased the mitochondrial and peroxisomal fatty acid ß-oxidation, as well as the overall carnitine turnover in the liver, which can explain the TG-lowering effect of KO seen in this study. Thus, it seems that KO has a greater potential to promote lipid catabolism. By the use of quantitative PCR, Vigerust et al26 showed that both KO and FO downregulated specific hepatic target genes involved in de novo lipogenesis and genes involved in cholesterol import and synthesis compared to the control-treated groups.
Burri et al28 also fed mice with different amounts of FO and KO to maintain the content of EPA and DHA similar in the two groups to evaluate the efficacy of KO and FO administration on gene expression profiling in liver. Long-chain n-3 PUFAs derived from KO downregulated the activity of pathways involved in hepatic glucose production as well as in lipid and cholesterol synthesis. The data also suggested that KO increases the activity of the mitochondrial respiratory chain. Long-chain n-3 PUFAs derived from FO modulated fewer pathways, even if the content of EPA and DHA was the same as KO, and did not modulate key metabolic pathways regulated by KO. FO also upregulated the cholesterol synthesis pathway, which was the opposite of the effect mediated by KO.
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Discussion
Studies on the bioavailability of EPA and DHA from KO and FO in humans and animals are limited and their interpretation is difficult, as different amounts of EPA and DHA have been used, duration of intervention differs among the studies, and different study groups have been included. Two human studies that are included in this review – one postprandial study and one intervention study – used the same amount of EPA and DHA from KO or FO, and they both show that the bioavailability of EPA and DHA from KO seems to be higher than from that from FO.19,21 This strengthens the hypothesis that there is a difference between the bioavailability of PUFAs from KO and FO. In contrast, Laidlaw et al24 showed that similar amounts of EPA from PL KO and TG SO resulted in the same increase in whole-blood EPA, suggesting that there is no difference in bioavailability of DHA from FO and KO. The problem in comparing these studies is that one study analyzed whole-blood fatty acids, while the two other studies used plasma PLs and plasma RBCs. In future studies, the same amount of EPA and DHA from KO and FO should be compared in plasma PLs, RBCs, and whole blood. If possible, adipose tissue biopsies should also be taken to study whether the fatty acids from KO and FO are differently incorporated into adipose tissue, as shown in the animal study by Tou et al.31 In animals, one study29 also indicates that KO may have a higher bioavailability compared to FO; however, another study indicates that bioavailability is not dependent on the structural form of EPA and DHA.26
The doses of KO and FO, type of study subjects, and duration of the studies showed very limited effects on lipids and inflammatory markers in human studies. Most of the studies did not see any effects between the groups. In one study,19 total cholesterol and LDL cholesterol increased following intake of KO and FO compared to controls, while Bunea et al23 showed reduction in concentration of total cholesterol and LDL cholesterol by KO and FO, as well as reduction in TG by KO. KO (at most doses) was more efficient than FO in reducing glucose and LDL cholesterol, whereas high-dose KO was more efficient in reducing plasma TG than FO.23
In the future, better-designed clinical studies are warranted to gain insight into the beneficial health effects of KO compared to FO. The animal studies show that there is a very small difference between KO and FO when it comes to health effects. KO seems to be more efficient in reducing the concentration of plasma TG, liver TG, and endocannabinoids, compared to FO, in animal studies. No adverse effects were reported.
Because KO and FO differ in their structural form, this may influence the incorporation of EPA and DHA into cells, resulting in different biological effects. KO also contains the antioxidant astaxanthin that protects the unsaturated bonds in the fatty acid from oxidative damage, which may influence the biological effects of KO. The possible biological difference between FO and KO was studied in animal models using gene expression analysis.25,26,28,29 EPA and DHA possibly regulate the activity of transcription factors by acting as ligands for the peroxisome-proliferator-activated receptor alpha (PPARa) or influence the activity of sterol regulator element-binding protein 1-c (SREBP1c).32,33 Consequently, these fatty acids have the ability to control transcription factor activity, which in turn regulates gene expression. Many of the beneficial health effects of EPA and DHA may be linked to their role of regulating expression of genes encoding proteins involved in transport, uptake, and storage of lipids, as well as enzymes involved in metabolic pathways and processes. The results from the studies included here show that FO upregulated the cholesterol synthesis pathway, which was opposite of the effect mediated by KO. KO also regulated more metabolic pathways than FO because glucose, fatty acid, and lipid metabolism pathways were affected by KO in some studies, and the same biological response was not seen with FO. This difference in biological effect may be caused by the different structure of PLs in KO and TG in FO.
In humans, it is also possible to perform biological studies using peripheral blood mononuclear cells (PBMCs), which are readily available, and FO has previously been shown to be able to modulate gene expression in these cells in human trials.34 PBMC gene expression analysis in human dietary intervention studies with FO and KO can be a powerful tool to understand the underlying molecular mechanisms of the effect mediated by these oils on lipid metabolism and inflammation in humans.
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Conclusion
Studies suggest that there may be a difference in the bioavailability of EPA and DHA after intake of KO and FO. However, more human studies designed to compare the effect of KO and FO are needed to conclude if the bioavailability of EPA and DHA differs between KO and FO. Furthermore, it is also necessary to document beneficial health effects of KO with high-quality human studies and to investigate whether these effects differ compared to the effects observed after regular fish and FO intake.
":>) JL
FDA Marine Label..
Quote...VASCEPA is an ethyl ester of eicosapentaenoic acid (EPA) indicated as an
adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe
(≥500 mg/dL) hypertriglyceridemia. (1)
Limitations of Use:
•The effect of VASCEPA on the risk for pancreatitis in patients with severe
hypertriglyceridemia has not been determined. (1)
•The effect of VASCEPA on cardiovascular mortality and morbidity in
patients with severe hypertriglyceridemia has not been determined.
Is the court not aware that FDA does not accept blood markers as sufficient proof of therapeutic benefit..Since Mori addressed no clinical condition but was solely an exercise in measuring the change in lipids caused by DHA and EPA...How could Mori be considered predictive or obvious. It seems the FDA does not accept MOri as being obvious on any clinical condition..Read the marine label above..I can not find the part that says Vascepa cures any disease...I guess the FDA does not keep up with the legal system..
":>) JL
Quote:...
"This is only if the Appeals judges don't use the prima facie method (but use the traditional Graham approach instead), right?"...
I'm not a lawyer but I believe the Harvard Law prof..Said no prima facie. could even be mentioned..Compared Du's inappropriate use of prima facie to "Assault with a deadly weapon" as far as procedure is concerned..
I understand that the appeal has been handicapped as a even money shot..But I believe the fact we will be using Covington gives us some added points in DC....I still think the the notion that Mori contains enough real factual information to confirm obviousness is incorrect..
I would like to ask the company if I could speak to the Amarin lawyers on that subject..I may be full of sh;t and off the reservation, but so far I think the reasoning behind Mori is scientifically in error...Basically the notion that Vascepa's MOA is lowering trigs; is incorrect. In reality...EPA's MOA is lowering Systemic Inflammation...And the notion that trig lowering has any effect on other diseases is incorrect... Even though EPA did lower Trigs and and did not increase then the LDL to the extent DHA did..Mori noted that DHA (and not EPA) increased the LDL particle size and that would have indicated DHA would have an additional benefit. because larger LDL particle are less atherogenic than small particles.
So far the the Judge's non scientific opinion on Mori is IMO very flawed.
I would compare the Judges view of Mori to be like the belief of "Ether" before Einstein's Theory of Special Relativity..Also I compare this to Monot and Murphy being awarded the Nobel Prize in medicine for their discovery that folic acid deficiency caused Pernicious Anemia..Tuns out their research was flawed and Pernicious Anemia was actually caused by Vit B12 deficiency
":>) JL
Dude...
The PTO does make mistakes..Everyone makes mistakes. The point here is the Company or its resident experts need to inform the PTO of the mistake so the PTO can correct it..
Du seems to have an agenda here as she used the PTOs negative slant and ignored the extenuating circumstances. In my opinion she has broken the cannon that requires her to be objective and not insert her own preferences at the cost of objectivity and truth..I think she should be sanctioned.
Her actions are deceitful..Amarin needs to make a complaint about her strange way of thinking and should demand a new trial..and not in the 9th district.
":>) JL
Dude..
Quote: "If the patent office decided it was obvious from the beginning based on prior art then I see it as extremely difficult for Amarin to argue against the USPTO base decision."
I know you are a pharmacist but not a clinician or a medical scientist..
So answer me this.. How many patients with Acute Pancreatitis were treated in Mori...Ans zero...
When is the last time the FDA signed off on a drug which had treated no patients that had the disease. .ans..Never.
The Marine indication specifies only patients at risk for Acute pancreatitis...So how can any information from Mori be anything but an inference since the the drug was not used to treat pancreatitis..
Mori was simply an exercise in measuring lipid levels subject to DHA vs EPA..Conclusions such as Du's opinion it was obvious..Obvious what?..a first year med student would understand that was just someone shooting her mouth off.
":>) JL
Actually the PTO made a factual error and that can be proven..They do make mistakes and this is a complicated situation...I understand that PTO originally considered Mori as Obvious...But they are in error..and they can go back and fact check it..This error has just not been explained before.
":>) JL
James..
I hope my post can be understood...The judge has a simplistic view of how trigs are related to clinical conditions..She thinks High trigs are like a poison..So she thinks obviously lowering the trigs will get rid of the poison and since Mori showed both EPA and DHA lowered trigs then they should "obviously" be used to treat Pancreatitis..EPA would be preferred because it has the added benefit of not raising LDL...Actually the n-3s do not work by that simplistic MOA...DHA actually lowers trigs on a mg basis more than EPA does..But no one has suggested DHA as a stand alone for Acute Pancreatitis..
and more to the point EPA and not DHA is more effective at lowering CVD event risk because it and not DHA can interact with the Eicosanoid receptors which are on all cells save Red Blood Cells...and the Eicosanoid receptors are the main determinants of Systemic inflammation..Not the trig levels..
":>) JL
Judge Du is wrong and Mori is not predictive..ie. not Obvious..
Du may be skilled in the art of being a judge, but she is not skilled in the art of pathophysiology...and she has omitted a couple of steps on the way of going from A to C...and that can get you in deep trouble in medicine..
To be obvious in the Marine indication (treating or preventing Acute Pancreatitis)..You would have to show more than the fact EPA lowered Trigs and did not raise LDL-C . You would also have to show that lowering trigs would prevent or cure acute Pancreatitis..Mori was just a series of observations made on how DHA and EPA effected blood lipids..And that does not prove that lowering trigs cures or prevents Acute Pancreatitis. The Marine label does not say Vascepa will prevent or cure Acute Pancreatitis...because there is no proof that it will...This is not the FDA being fussy..This is a true fact..
What The judge does not know is that high trigs are mainly caused by elevated Systemic Inflammation..Trig levels are controlled by a mechanism which is similar to the way the body controls Blood sugar..Only it uses different molecules..Patients in T2DM have elevated Blood sugar not because they eat too much sugar..But because the hormone that lowers blood sugar, Insulin is not as effective as that of non T2 diabetics..and they require more -insulin because they have Insulin Resistance (IR) and IR is caused by elevated Systemic Inflammation (SI)
High trigs are caused by a mechanism which is less well known, but is similar to the way Blood sugar is handled by the body..Trigs are lowered not by Insulin but by another hormone (S) Called Fatty Acid Synthase (FAS) ..and FAS is also made less effective by elevated SI...This is what creates the paradox that elevated trigs are a marker for CVD event risk..But lowering trigs by many drugs does not result in decreasing CVD event risk...The increased CVD event risk in those with elevated trig is due to the elevated SI...Drugs like Niacin or fibrates will lower trigs..but they do not effectively lower CVD event risk because they do not lower SI..
So there was really nothing "Obvious about Mori...The judge just made an assumption...EPA lowered trigs...trigs are bad..lowering them should obviously be a good thing..it turns out lowering trigs might indeed be a good thing if it was done by lowering SI...But Mori did not go into detail about how Omega threes make these blood lipid changes..and at present time twenty years after Mori..Most physicians know elevated trig increase CVD event risk..But don't understand just lowering trigs does not guarantee you will lower the CVD event risk..or Acute Pancreatitis
The real benefits of EPA emanate from its ability lower SI by its effects on the Eicosanoid receptors..Something that Mori did not comment on..and was only recently confirmed by the R-I CVOT
Hope this makes sense to you..
":>) JL
Beachboat...
Thanks for posting...
":>) JL
I believe Amarin will come out of this and if you were not margined out you will have a good chance to recoup your losses..
Here is my reasoning..Amarin getting gored might be enjoyable to some of the other drug companies. But make no mistake about it..This legal "leger de main" by which the court transfers Amarins discovery and profits to an entity outside the USA has to be a wake-up call for the rest of the drug industry and they need a war council to find out how to stop this clearly criminal activity..
Here is the deep dark secret of drug development..No drug that comes to market can pass a rigid patent trial. Drug design does not develop in a vacuum. There has to be some "prior Art" that suggests the drug might have some clinical effect..Otherwise who would consider spending millions or billions on developing the drug..The very history of medicine was mainly driven by what I call the Peanut butter and Jelly method...It goes like this You have this disease and no one understands it. No one knows what will cure it..So you line up a hundred monkees and you feed them different things if the one that gets peanut butter and Jelly gets better then you run a trial of hundred other monkees and give them P&J if they get better then you have your cure..Simply put every drug that is started on the FDA marketing process (with the exception of designer drugs) has some history of its interaction with diseases or physiology...Drugs are not pulled out of thin air..
Perfect example is the COVID-19 virus...The drug everyone is looking at is Chloroquine CCQ) and HydroxyChloroquine...HCQ...CQ has been used in medicine to treat Malaria since 1945...Malaria causes parasites to develop in the cytoplasm of red blood cells these are called "plasmids " and these share some similarities to Virus and CQ inhibits entry of Plasmids into the cytoplasm and interferes with their production..
Should CQ not be used for the Virus because it was noted to be effective in a condition tht bears some similarity to malaria..
The fact some obscure guy in Australia decided to find out exactly (or almost exactly) how EPA and DHA affected other blood lipids 20 years ago should have absolutely no effect the fact that purified EPA in sufficient dosage could cut the risk of CVD events 25% or more.. Shoehorning in the Marine indication which is a ruse to rob Amarin of its long and expensive R-I trial whose results were definitely not obvious, is a scam..Either that or Judge Du is the stupidest person ever to become a judge..
The patent issue needs to go the way of the DoDo Bird and the passenger pigeon...Out of here.. and so does Judge Du...Who should seek a new occupation..I see her fighting forest fires in California next to Nancy and Bernie..
":>) JL
lab...
Be my guest if you think they're worth it...
I will be interested in the Feedback..
":>) JL
goamrn...
I am not a lawyer..and do not know the answer to that question..
":>) JL
jomama...
Thanks for posting...This is a case of government bait and switch.The rationale for granting the patent was spelled out clearly by the examiner in the PTO...Read..Quote.. "The Examiner then spent more than three pages specifically discussing the evidence of objective indicia supporting the Examiner's ultimate conclusion that the claims were patentable."
So Judge Du had it all explained to her..that the evidence here was not the highest quality ever recorded..But the benefits of Vascepa as a therapeutic was so substantial that these considerations revolving around the patent were more important than the history of the drug.
Judge Du just flushed all the PTO's careful explanation down the toilette as she flaunted her own agenda..Which I guess is anti capitalism. And I guess she would like to see the American drug industry go down the drain and maybe end up in Vietnam or India..Because if this charade continues and is allowed to stand..Then you can say good bye to the Drug industry in the USA. Nobody is going to risk the time and money required to go through the USA FDA marketing process. Look out for your drugs to be made and developed in India or Vietnam.
":>) Jl
PS.. the Mori trial was no big scientific event..It was not read or cited by American physicians...It was very small (59 patients) was of short duration several weeks not reported in a medical journal..but in a Nutritional Journal...It was never fact checked or peer reviewed..Nutritional Journals are not very reliable..I am not suggesting the trial was never actually done (Mathematicians might want to checkout the P numbers) but I can say there have been some totally fabricated papers regarding the benefits of Krill Oil Results that did not conform to the Friedewald equation..
":>) JL
ilove...
Nice post...If you want to learn something about India..Then read "White Tiger"...It will not increase your confidence in having your drugs made in India...
Thanks Judge Du...
":>) JL
This guy HDG
He posted that my daughter who is lawyer (just out of law school) did not make an full analysis of the patent trial..Means that she has no respect for me (quote Your daughter not answering tells me everything I need to Know)..He (HDG) knows nothing about my relationship with my daughter). My daughter did not feel qualified to give an opinion other than a brief note earlier..Patent law is very Niche. And they have their own Bar..Also my daughter having recently passed the New York bar has just recently obtained a job with a big firm in Albany...and she is low man on the totem pole...Currently New York is in lockdown and her entire law firm is practicing from home,,and billings are down and my daughter needs to work hard as she would be one of the first let go..So she needs to do her job and does not have the option of researching this patent issue...
The guy is classless and delights in putting everybody else down so don't get too worried about it..He can't help it..
":>) JL
I hope everyone here understands what just happened...This SB Judge just took a portion of the PTO's words and used them to destroy us..She didn't have to uncover Mori..this obscure O-3 paper that was buried in a Nutritional Journal back in 2000...
No she did not dig this up with diligence and hard work..She simply used the PTO examiners original words and citation which was the basis for the first rejection..On second consideration the PTO considered the fact that this issue effected an umet major need and other secondary considerations which made PTO decide to grant the patent..
Of course she did not include the patent office secondary considerations because it did not suit her agenda...This opinion of hers is covered in slime and a real stab in the back by a slimeball that is as lazy as she is crooked..
Welcome to the new America...
":>) JL
Quote (tucaman) "But it was brought up before that Generics may be preferred regardless of price." Not true..cheapest price is is given first choice..Why would a generic many of which are suspect be rewarded if it cost more..Read the Tiering rules...eg..Tier 4 where there is a cheaper substitute for the same indication..Its not about rewarding generics (particularly when USA dollars are going to foreign lands) its about saving patients money by reducing healthcare cost.
For example Vascepa was Tier 4 before the recent FDA label expansion because according to the then label the drug was only indicated for very high trigs and there were drugs that lowered very high trigs..e.g. Lovaza and generic lovaza and they were Tier 1 and Tier 2 because they were cheaper and also lowered very high trigs..
":>) JL
What is POSA ???
Ars longa, vita brevis....
This is the opening of the real Hippocratic oath which has been modified in these modern times to the millenial version...
The real version began Ars longa, vita brevis...Translated Art is long. Life is short...Art in this case is used in the form of "the Art of War"...Art being long means the subject material in medicine and is complicated and nuanced and can not be simply divided into Obvious and non Obvious...The law on the other hand according to Aristotle's definition of the law as "Reason free of passion" Implies that the law should not be complicated but based on "reason" ie "obviousness" and this is where medicine and law diverge...
The law tries to contain obviousness within a room whose walls are reason and logic and these walls are useful in most situations..but they are not capable of confining medical issues...Regardless of the egos of lawyers and judges..
Mori does not make predictions..Go read the paper. If Mori really provided the information that Judge Du argues it does; it would have changed the entire medical landscape...There would have been no reason to run ANCHOR, MARINE or even the R-I trial...Why if Mori had the shining light that answered every question regarding Omega-3s and made all their benefits obvious why did FDA make Amarin do these trials...Amarin could have simply gone to FDA and claimed their drug would work by citing Mori...Of course there would have been a long line of companies ahead of them..Mori was run 20 years ago..and only this judge twenty years later has recognised the obviousness..She should immediately be put in charge of the COVID-19 pandemic strategy as her intellect is so far above the rest of us mortals..
This whole issue is legal nonsense and if this goes forward..I think it puts the entire drug approval process at risk...You would have to be crazy to risk millions or billion of dollars and years to develop new and important therapies that can be taken away from you by some ignorant judge citing some crazy reasoning...This is a watershed issue..and the legal system has to get its head out of its ass..If they let this go there could be terrible repercussions
":>) JL
MateoPaisa...
Ever consider the possibility you are ignorant...
You really think Judge Du is doing the right thing here? and don't pull my chain byu telling me you are long this stock...
":>) JL
alm...
I am rethinking this...There are two issues here..The first is the how EPA effects other lipids...An issue that Mori partially addresses...The second issue is how EPA effects CVD event risk and Mori does not address that issue. Mori was a pure lipids study with no pretense of evaluating CVD or any other benefits..
So Mori might be germaine as far as the MARINE indication...ie very high trigs..but it says nothing about the REDUCE-IT indication which is reducing CD event risk..I can not speak as lawyer because I am not a lawyer..I can only speak as a clinical physician and a medical scientist..Mori says absolutely nothing about EPA's effects on CVD or any other medical condition it only addresses serum lipid levels..
The point being the real value of Vascepa lies in its ability to lower CVD and other clinical risks. Even so..Mori does not render Obvious the fact that lowering trigs without increasing LDL will benefit those with very high trigs The most obvious case is lowering very high trigs, in the 500 mg/dl.. to decrease the risk of acute pancreatitis.but the FDA does not agree with Judge DU and the last time I checked the Marine label it says there is no proof that Vascepa will provide clinical benefit those with very high trigs.
FDA as the leading clinical drug authority must have thoroughly considered Mori in determining the label and it is clear they do not think Mori makes it obvious that EPA will be beneficial for treating high trigs. .As I am not a lawyer Judge DU is not a doctor or a medical scientist and if she were she would understand..assuming something is obvious in medicine can be very dangerous..The history of medicine is rife with ideas that seemed obvious and turned out to be wrong...Medicine and physiology are far away from mathematics...if you are trying to get from A to C in medicine making an assumption on B can be very dangerous. That is why the FDA requires these long expensive trials...because FDA does not rely on "Obvious"...In the 1500s it was obvious cauterising amputation stumps would save lives..Phlebotomy almost killed George the third...though it was the obvious choice of his doctors at the time..Minot and Murphy were awarded the Nobel Prize in Medicine for their work in establishing the Folic Acid
deficiency cause Pernicious Anemia...Later William Castle proved the Pernicious Anemia was actually caused by Vit B-12 deficiency. Castle never got a Nobel Prize.
An old statement in medicine...one that Judge Du does not know because Judge Du is not an MD or a medical scientist is the statement "The questions in Medicine never change...Only the answers do..
As I have posted before.. regardless of the legal definition of obviousness. Medicine and medical science seldom lays things out in the neat rows that the law would have you believe...Organic life forms and biology..the very definition of "living" is defined by the high level of complexity more than any other factor...And this is something I learned from Jerry Lettvin..a Nobel prize winner and a very bright guy. Complexity does not go hand and hand with Obviousness...Quite the opposite..
The fact Mori determined the effects of EPA and DHA on other blood lipids in a narrow range...does not render any clinical benefit Obvious it only speaks to changing lipid levels and God knows how controversial that whole subject is..Is Judge Du in the least bit aware of all the conflicting Meta analysis..Surrounding Omega threes..Doesn't Judge Du wonder why FDA made Amarin conduct a multi year multi million dollar trial to determine if Vascepa had any meaningful benefit on CVD..And prior to the reported results of the trial..90% of cardiologists at the 2018 Annual Scientific Meeting of the AHA has serious doubts about Vascepa and expected the trial would show no significant clinical benefit..Is Mori really more important than R-I...Is that what Du and the lawyers think...That is insanity...
":>) JL
Hamoa....
Thank you for your opinion...This seems well considered. Non legally the entire consideration of obviousness seem to be subjective. And would be hard to be defined. At MIT in the sixties a favorite expression was "it is intuitively obvious." And that expression was used frequently in situations where proving something rigorously would have been very difficult...
What was obvious to the Indian mathematician Ramanujan. Might not be understood by mathematicians in this century. My point here is obviousness depends heavily on the subject material. And one size does not fit all.
Marjac..brings up the the HCQ (hydroxy Chroroquine) and Azythromycin trial in Marseille run by Dr. Raoult...The trial results were trivial: based on very few numbers..but the interpretation of the results differ widely among clinicians...So are these results Obvious...Apparently not...the same numbers mean different things to learned doctors..I read Mori and I would say that almost anyone including lipidologists would have trouble separating all the differing changes in lipids and what the balance between what actions were beneficial and and which were detrimental. And I am very knowledgeable about the effects of n-3s ..More so than 97% of clinicians...So does Mori really represent some important piece of the n-3 puzzle..You could easily poll 100 clinicians and not a single one of them would be able to give you accurate rendition of the trial...For God sakes it was not even presented in a medical journal..The FDA certainly did not give any consideration to Mori..They probably never heard of him or his famous trial...And now we have the legal profession exhuming the corps long ago dead and buried, and claiming....
He was the professor and the pioneer..And all credit should be given to his insights and observations...and oh by the way why was not this explained to Amarin before they spent all the money and ten years of setting up and doing the trial...If this is what the law thinks is fair and equable then we should not even have the law...This is just meddling and thievery..State sponsored...You lawyers should be ashamed of yourselves..You clearly do not know right from wrong..
":>) JL
north4000
Are there no cruise ships that you can get on for a long trip?
":>) JL
ilovetech...
I agree...Obviousness would preclude (eliminate) the need for ANCHOR, Marine and ultimately R-I. If the FDA thought everything was obvious then why did Amarin have to run ANCHOR and then Marine. If FDA thought all of this was obvious..
Seems Judge Miranda DU was smarter by half than the FDA and way smarter than the PTO...
":>) JL
G..
Quote..."Does not make any sense." Won't be the first time..
What I am suggesting and maybe it is not possible is Amarin going into the generic business and sell a generic Vascepa..That way they could potentially obtain the lowest price for Vascepa and get the lowest Tier designation...Which is based on the lowest price...
Is there a possibility they could do this or are there better strategies..
":>) JL
ilove...
Thanks for posting...Mori is a farce and Du is a hooker.
I love Steve R...even though I'm a guy...Great post...
":>) JL
Strategy (2)....
"Find a dog that will eat a dog."
The next plan is if you can not beat then then join them...Right now Amarin is a Biotech/BP in more or less "no man's land"....
If Generics are your biggest worry...Then why not become a generic..(Yes I know...Going to be warehouses of red tape and and pools of regulations)..But Amarin is use to that..They eat and drink regulations..
Amarin has a big advantage over the other drugs because they are the Brand and their manufacturing and producing suppliers are already FDA approved...Keep the Brand...but make a generic and sell the generic for less than the other generics can..Beat them at their own game...
File for an ANDA with FDA and become a player...Right now the generics have an early lead, but Amarin is still selling brand Vascepa enough to pay the bills..Then get into the generic game and undercut them...
Hell the very thought of Amarin doing that might be enough to scare the generics into settling..
":>) JL
Adding to Raistthemage...(1)
The Vascepa situation has always been a volume one...What we use to call
"Fast nickels beat slow dimes"...That means the money is made not by increasing the profit margins, but by selling more drug...Right now the key to beating the competition (the generics) is to beat them at their own game...
As far as drug sales...Amarin and the world in general will become more and more aware of the benefits of Vascepa..The hurtle Amarin needs to get over is the generics...It is often repeated that generics get favored Tier pricing...but that is not what is mandated by state laws..there is no magic to being a generic...The laws mandate the lower tier goes to the least expensive form of the drug...So Amarin's solution at present is OBVIOUS..(but it takes some creative thinking.)
Step one...(the Raistthemage gambit).....Amarin (before appeal decision) Threatens to make TEVA the "Authorised Generic" that grants TEVA rights to Amarin's suppliers and Amarin endorses TEVA as their Authorised Generic..TEVA can then produce Vascepa at lower price than the non authorised generics making their fore' into the US market not profitable..So Amarin offers Reddi and Hikma a choice to take a payoff (settle) or inherent a USA market that would be dominated by TEVA...
Part 1...::>) JL
Sluice...There have been several trials involving EPA and DHA since 2000 they include the Lovaza trial which ended with a CLR...There was a trial finished in 2018 I believe it was STRENGTH...It was not very strong..Presented right before the R-I results...None of these address the obvious patent issue..Ie they were obvious...
The judge Du Laid out her interpretation of what was obvious and it is not determined by how effective the drug is...But rather if you started with DHA and noticed the LDL-C was increased you could as others had done before add a statin to the mix to lower the offensive LDL which was related to using DHA,,(DHA increases LDL-C)...Or you could use another omega three EPA which has the effect of counter acting the LDL-C increase caused by DHA...This was the judges the judges rationale for citing Mori...Mori was a lousy study from a design standpoint and was published in an Australian Nutrition Journal..It was three groups of 49 yo slightly obese men who were treated with
1) Olive Oil the trial measured a number of blood lipid markers
which included trigs, LDL,three types of HDL as well as DHA and EPA levels
2) DHA platelet counts and LDL-C particle size..all measure in three separations Olive oil, DHA. and EPA...This measured the how these three lipids effected the other lipids...Even though this was a very loosly
3)EPA designed clinical trial that did not measure the effect on CVD events it did give some idea how the the omega threes acted n other lipids..Even though very few doctors read this article very few ever heard of it...Dr. Du used this to show that EPA acted on Trigs and did not raise the LDL-C and she used this obscure paper to prove EPA did not increase LDL-C when it lowered trigs and that was why Vascepa's actions were obvious..
":>) JL
ttt'
Marjac...
I was going through the trial transcripts and around pages 54 -58 there is considerable description of what is considered the legal definition of Obviousness....Some of this information seemed quite repetitive and such as adding and subtracting EPA or DHA were not intuitively obvious. The question of whether adding a statin to DHA which is known to raise LDL-C can mimic the effect of EPA if what you are trying to do is to lower trigs and not raise LDL-C..Zo according to the legal definition Adding EPA to DHA should be obvious if you are looking for the DHA statin result...I'm not sure that is true...
Here is the question..Mori was an obscure trial run 2000 in Australia and published in a non medical journal..A nutritional journal, not a peer reviewed journal and one which was very unlikely to be read by clinicians in USA or Europe...The plain fact however despite not being a well designed trial and one that might have been not published in the USA...Measured the effects of EPA and DHA in separate arms of the trial (19 patients in each arm)..nonetheless the results were that EPA alone did lower Trigs and did not increase LDL-C which would theoretically lower CVD event risk...and in the DHA arm.. DHA alone lowered Trigs but did increase LDL-C which would increase CVD event risk over the EPA arm risk...The study did not comment on the benefits or detrimental effects of the separate Omega -3s...and there was no attempt by the study to measure anything except the different effects on blood Lipids by the two omega-3s....
This article frames the basic argument for obviousness because it was shown in this obscure journal that EPA could lower Trigs and not raise LDL-C....
Does the existence of a fact or a principle anywhere in the world guarantee the obviousness of a fact or a principle.Regardless of the fact that very few people are aware this information exists...Which seems to be her argument.
":>) JL
smarter..
I don't have all the answers to your very good questions...Amarin's lawyers here from Covington..top litigation firm in the USA..The fact this Federal judge failed to listen to their arguments make me very suspicious that she had a hidden agenda..
Her decision is so patently convoluted and wrong that there are only a number of possibility..She was on drugs...She was being paid off...she is not intelligent enough to be making decisions that result in wins and losses in the billions..and she has no right being the judge in this case.
To reverse the PTO opinion on the obviousness of the 889 trig and LDL patent issue she would need clear and convincing evidence the PTO made an error...
What is the error I do not believe the PTO used "Mori" a trial reported in an Australian nutritional journal...Not peer reviewed or probably even known about by most members of the medical profession. Mori is vague involving 59 mildly obese males ages about 49yo and morbidities not clear...The 59 were divided into three groups so that only 19 0f the enrollees were on EPA..Nineteen more on DHA and the rest on olive oil. The stated purpose of the study was to determine if EPA and DHA had different effects on blood lipids..The trial ran for six weeks..Results: Fifty-six men aged 48.8 ± 1.1 y completed the study. Relative to those in the olive oil group, triacylglycerols fell by 0.45 ± 0.15 mmol/L (˜20%; P = 0.003)( aside the measuring of trigs in clinical medicine is trig levels in Mg/DL) so this study is little confusing) in the DHA group and by 0.37 ± 0.14 mmol/L (˜18%; P = 0.012) in the EPA group (both EPA and DHA lowered trigs DHA slightly more than EPA). Neither EPA nor DHA had any effect on total cholesterol. LDL, HDL, and HDL2 cholesterol were not affected significantly by EPA, but HDL3 cholesterol decreased significantly (6.7%; P = 0.032)( this is important because the author does not emphasize that EPA would be expected to raise LDL and the author completely overlooks this) and does not ignore EPA the fact EPA did lower HDL3 which would likely increase CVD event risk according to thinking in 2000 . Although HDL cholesterol was not significantly increased by DHA (3.1%), HDL2 cholesterol increased by ˜29% (P = 0.004).(again the author notes that DHA increased LDL cholesterol by 8% (P = 0.019).because it was thought at that time that HDL-was good cholesterol and that would be a positive for DHA. Adjusted LDL particle size increased by 0.25 ± 0.08 nm (P = 0.002) with DHA but not with EPA. In this case larger ldl particle sizes is known to decrease CVD event risk. EPA supplementation increased plasma and platelet phospholipid EPA but reduced DHA. DHA supplementation increased DHA and EPA in plasma and platelet phospholipids. Both EPA and DHA increased fasting insulin significantly. EPA, but not DHA, tended to increase fasting glucose, but not significantly so.
Conclusions: EPA and DHA had differential effects on lipids, fatty acids, and glucose metabolism in overweight men with mild hyperlipidemia
It is clear from this article the author summing up would have concluded that DHA and not EPA would obviously have cut the risk of CVD events more than EPA would.
":>) JL
LBL...
I like most of your posts...but I think you are going about this the wrong way...The real problem is the Judge and she made a very bad call here...So bad that it can be explained to practically everybody and they can understand it..Rather than going into hibernation we need to fight against this blight of a judge. Right now IMO we should be making hay while the sun is shining...The generics are still a couple of years years at least away until they can attack the US market..
We need to discredit the judge and get her ruling reversed and that should not be that difficult..This judge has a bad record..and maybe it is not just stupidity..Bug if it is she needs to go and her opinion needs to be overturned and should be..The first stop..The PTO..I am sure they would be interested in her opinion on the obvious issue..and their take on it..Then I would contact the FDA..I know we have haters here..but the FDA is one organization that can straighten he out...Would they do it ..Time will tell
I favor the "find a dog that will eat a dog" strategy for this problem...
":>) JL
l...
Absolutely correct..Facts only...educational not confrontational...
":>) JL