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Yes, Ralphey, we had better worry more about killing all innovative drugs coming to the USA first, than worrying if the cost of generics will skyrocket.
Talk about demagoguery and emotional grandstanding:
IMO Kurabayashi was critical. Why? Let me count the ways:
(1) The patent was granted for ApoB lowering without elevation of LDL and then for TG>500. Therefore if you are going to invalidate the MARINE patents, you must show obviousness in the prior art for (a) EPA lowering LDL and (b) EPA lowering ApoB. The lowering of ApoB is thus a sine qua non for invalidation. Judge Du recognizes this in the concluding paragraphs of her judgement.
Jasbg
I concur with Marjac. The facts are crystal clear and obvious to see, for anyone who examines the court records, and pauses to question the validity of the HIKMA science. We do not underestimate the HIKMA lawyers, as they have proven themselves capable of the most nefarious dealings. We have been thumping the table for the gross injustice carried out at Nevada and at Appeals ever since and before our Amicus brief. Everyone on this board more or less understands the issues.
The issues are so clear cut, and so stunningly obvious, that the only thing a judge can do here is to say YES,( I will look into it in unbiased fashion) or NO ( I will deliberately disregard it despite significant evidence). It's not like it can be ignored. It demands an answer. The charge is a very serious one--in my book fraud by deliberate misrepresentation. This clear cut choice determines how Judge Du and the Nevada court will be themselves judged in future. Lady Law is either blindfolded or she is not. We shall see.
HK
Mike
I agree it seems small. Just saying that many offices are closed, doctors working remote, even the drug lunch indoctrination is sometimes virtual with the food dropped off delivery...
HK
Its the reality Raf, these third party payors and PBM's force/induce the pharmacists to toe the line and switch to generic, using financial "inducements" as blackmail for the consumer to seal the deal and take the generic. I prescribe Vascepa, they dispense generic IPE and if they can't get enough supply, substitute Lovaza...
I sent one now LB
There are different problems going on here to explain the scrip direction:
(1) January is conventionally a slow month. In a pandemic with virtual consults going on and lab work completion by patients reduced, there will be a slow down in scriptwriting.
(2) Assuming a V script is written there is the effect of pharmacy/payor pre-mandated switching to either gen IPE or Lovaza (this explains the rise in new scripts for both)
HK
Well stated Marjac
You are utterly missing the point. In this motion to intervene under a rule 60 petition, are not litigating the prior art again.
HK
Without Kurabayashi there is NO case for obviousness in the prior art for EPA effects on ApoB. We should also remember that we are not litigating the subtleties of the prior art in obviousness, we are litigating misrepresentation of crucial evidence by an expert witness and fraud on the court.
It is actually the Curfman paper and Greg Curfman is a deputy editor of JAMA Journal of the American Medical Association.
Authorship was Curfman, Bhatt, Pencina (Duke Biostatistician).
I fac=vor referring to it as the Nature biotechnology paper.
This is essentially what the HIKMA shysters did. They wove a web of lies into a tissue of seeming plausibility for Judge Du, all the time leaving out the crucial discussion of the comparative statistics between the two groups. Then, while articulating this falsehood, they illustrate it with a castrated Table 3 minus one critical explanatory legend that actually explains that NS all along the bottom row of comparative statistics means NON-SIGNIFICANT. They knew exactly what they were doing--this was no casual mistake of editing. Nor can it be excused by saying.."well we gave you the reference citation Judge"... it's like asking the poor judge to self learn quantum mechanics with access to the library of Congress. ..it all there, but who knows where?
HK
Every bit of exposure, discussion, and publicity this board can raise for our rule 60 justice efforts at other forums, will be crucial to getting fair play and not being swept under the carpet. Those on the board with access to other forums for discussion could help by doing so...
HK
Two summary excerpts from the District Court’s bench order:
(1)As explained above as to Defendants’ prima facie obviousness case, Mori found that EPA did not raise LDL-C levels, and Kurabayashi suggested that EPA reduced Apo B levels. (ECF No. 373 at 76-80, 246-47.)
(2)Further, while the Patent Office found that a decrease in Apo B was an unexpected benefit constituting a valid secondary consideration, the Patent Office’s examiner did not consider Kurabayashi. (Id. at 246-47.) Where “the PTO did not have all material facts before it, considered judgment may lose significant force” See i4i, 564 U.S. at “Thus, the Court finds that the unexpected benefits secondary consideration does not weigh in favor of finding the Asserted Claims nonobvious.”
Bouf,
It was open to AMRN to argue this point to the court when the generics filed their proposed findings. But we don’t know why they did not. It was also open to AMRN to argue the point on appeal that the trial court decision was based on an erroneous interpretation of the K table.
“The only thing necessary for the triumph of evil is that good men should do nothing.”
Burke
sts
A similar problem on a smaller scale is CA and MA not allowing manufacturer coupons or discount programs if a generic is available for any indication - that violates AMRN IP too - and makes it much more expensive for patients.
To be fair she twisted what Toth said--and Toth could only say what counsel directed or lead him to say in questioning...
HK
Thank you for the clarification:
Wherever there is strife there is HIKMA:
While the obvious choice was to reference Colcrys, Hikma (through it US agent West-Ward Pharmaceutical Corp.) chose the approved combination product Col-Probenecid (colchicine 0.5 mg and probenecid 500 mg, ANDA 084729; Watson Laboratories) as the listed drug for their single-ingredient colchicine product, Mitigare. This allowed them to rely on the FDA’s previous findings of safety and effectiveness for colchicine (in combination with probenecid) while circumventing the exclusivity periods and patents associated with the single-ingredient Colcrys product. To bolster the application, Hikma utilized published literature to support the efficacy of single-ingredient colchicine products. Additionally, Hikma conducted a handful of previously-agreed-upon safety studies to investigate potential drug-drug interactions. Taken together, the application provided sufficient safety and efficacy data to be granted FDA approval.
Strategic Listing
The FDA has consistently given applicants room to maneuver in their choice of listed drug to rely upon for approval of a 505(b)(2) application. Most importantly, at this time, there is no requirement that an approved pharmaceutical equivalent be cited as the listed drug. Instead, an applicant can make the determination, based upon their planned development program, of which product will best support and fill the information gaps in their application. In fact, Camargo has experience with gaining 505(b)(2) product approvals without listing a drug at all.
Totally in agreement
Good news Kiwi--you got three times the mRNA dose as the Pfizer vaccine and still did well. Kudos
HK
For those afraid to take the Pfizer (or any other) Covid vaccine
https://www.nejm.org/doi/full/10.1056/NEJMoa2035389?query=RES
PREPARE-IT
https://clinicaltrials.gov/ct2/show/NCT04460651
PREPARE-IT is a study "with a simple, pragmatic, and universally applicable strategy with IPE at high doses intended to reduce infection and subsequent morbidity and mortality among subjects at high risk of infection due to SARS-CoV-2".
IPE could also be useful at pre-hospital and hospital stages due to its potential anti-inflammatory and antiviral effects. High-level exposure and infection risk among health-care providers, as well as the fundamental need for their active role under the current pandemic, make the search for tools to reduce or avoid infection, or its clinical manifestations, a priority.
Eight,
I respect your experience and you may, in the end, be proven right. I have spent many an hour wondering why a person of integrity who aspires to judge like Solomon, could not admit a simple error of judgment, without an axe to grind. But the answer to that question stems from the study of the human ego and its voracious exercise of power at all cost. Sad, that it epitomizes people at the very top of our legal system. This shame is equally shared by a man of science, who is also at the top of his chosen profession. Neither of these facts prevented one from uttering a blatant falsehood, and the other from accepting it after it was pointed out and yet others from complicitly covering it up afterwards. We all want restitution but our motivation is truly higher. Righting a wrong is about the pursuit of Truth, and for men and women of principle, there can no higher endeavour. So whether we lose or win, we must pursue the Truth irrespective of the outcome. We are about to find out if the Nevada court has any moral backbone. The answer will leave history in no doubt on how to pronounce on the ethics of our legal system.
HK
Devotion to this Truth is the sole justification for our existence. All our activities should be centered in Truth. Truth should be the very breath of our life.
MK Gandhi 1927
There isn’t a sane biostatistician in the world who would analyze Kurabayashi or Mori the way Heinecke did.
All the MD superstars and legal hot shots contracted by Amrn couldn’t point that out?!!
Well said Marjac
Lizzy
I think the PREPARE-IT design is much better thought out in comparison to the endpoints chosen by the COLCORONA investigators. The endpoint of Covid "hospitalization" has to be concretely defined (it may be a soft endpoint driving most of the trial benefit and what if a positive endpoint is a patient who got seen and discharged from the ER after a positive nose swab PCR test-- was that a visit or a hospitalization). Better would have been some ascertainment of Covid serological or PCR RNA positivity before and after colchicine Rx and/or a record of significant Covid diagnosis positive illness eg Fever O2 desaturation, clinical or radiographic pneumonia) Incidentally, Dr Tardif is a REDUCE_IT investigator and a paid consultant to Amrn.
You can sense that in the two contrasting interview viewpoints--Tardif is clearly annoyed at being challenged by what he perceives a stupid interviewer and counter punches with some classic Gallic hauteur and condescension (brilliant entertainment):
https://beta.ctvnews.ca/local/montreal/2021/1/27/1_5283839.html
https://beta.ctvnews.ca/local/montreal/2021/1/27/1_5283839.html
https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:0b0f64b4-0654-4d45-9b35-ba5e4efff609
Milkshake followed by a lab test followed by a prior auth for Vascepa/Vazkepa. I like it!
Eight,
IMO, It is not "new evidence" neither is it a request for further debate about previously arbitrated prior art. In plain fact, what this represents is overlooked fraud on the court by misrepresentation. It should be every bit as compelling to a judge as an evidentiary gatekeeper, as evidence tampering or contamination. To dismiss it for reasons of failure to raise previously, or as "new evidence" would be to debase our legal system to a new level of unscrupulousness motivated by party politics. Fraud is fraud whether undiscovered by any of the parties, judge, plaintiffs or defendants. The burden of the law is to detect it and expunge it from evidentiary influence, and not dismiss it because no one mentioned it before?
HK
In the COLCORONA trial, the main benefit was in reducing hospitalizations for covid related illness, there was a stated reduction in mechanical ventilation and death but the CI's were widely spread/ overlapping zero, and the exact statistics for their significance are not expressly stated -- so for these endpoints--our conclusions have to be tentative.
One other note of irony. Colcrys was brand name starting 2009 and then became an authorized generic from the brand name manufacturer Takeda in 2015. Colchicine had been used and sold in the US for many years but had not been reviewed by the FDA for safety and efficacy. The manufacturer of Colcrys submitted an application for review to the FDA in 2009, and they were awarded a three-year exclusivity period (meaning they were the only ones who could market Colcrys in the US). It cost pennies on the dollar prior to 2009 then became wildly expensive and then came down somewhat in price. Now 30 pills even with a discount card in the US will cost you between $57-73, whereas Takeda Colcrys (the "authorized generic") in Canada sells for $26 for 60 pills more than half less! See any parallels with Vascepa and Amarin?
HK
Lizzy,
When it comes to Reducing Inflammation to reduce CV risk and CV events many roads lead to Rome: witness the disparate mechanisms but positive CV outcomes trials from inflammation reduction: CANTOS (canakinumab--Il-1 beta inhibitor); COLCOT and LoDoCo2 (colchicine: inhibition of tubulin polymerization and alteration of leukocyte responsiveness ) and REDUCE-IT (Vascepa: unknown mechanism). All these drugs mower markers of systemic inflammation like hs-CRP. Vascepa's mechanism in ameliorating Covid illness (and possibly preventing covid infection) may be related not just to its anti-inflammatory effects but its effect on cell membranes which are the last barrier preventing cellular viral infection. All the tested anti-inflammatory Covid Rx strategies published so far, including the monoclonal antibodies to spike protein (eg Bamlinivimab, casirivimab and imdevimab) all work better in the mild-moderate Covid scenario and all bets are off in severe disease...Worth noting that in LoDoCo2 where 0.5 mg colchicine was administered daily, in an approx 5500 pt trial followed for 29 months mean duration a 31% RR reduction with an NNT of 36 was noted--impressive. But there was a 10-11% drop out from side effect intolerance or other issues, for those on colchicine.
State-mandated generic substitutions should be made illegal (unless they conform to the skinny label indication where applicable) by Congress, IF they wish to retain the carve out basis of H-W legislation.
Good summary ...I liked this finishing piece of prose:
No obvious explanation can explain the apparent discrepancy between the remarkable benefit of EPA in REDUCE-IT and the total lack of effect in STRENGTH. In fact, the lower limit of the 95% CI of STRENGTH (0.90) is not compatible with the large effect size suggested by REDUCE-IT. Although the two trials used completely different formulations, containing different amounts of EPA, indirect comparisons of pharmacokinetic (somewhat higher EPA levels in REDUCE-IT), and pharmacodynamic (similar 20% reduction in triglyceride levels) data of the two trials offer limited insight to explain qualitatively different clinical results. The hypothesis of untoward effects of the mineral oil used as control in REDUCE-IT seems untenable in light of the FDA review of the data. It should be emphasized that, in contrast to traditional drugs, no molecular target has been characterized to explain the potential benefits of omega-3 FA, something that has limited the scope of Phase 2 dose-finding studies, that should provide a pharmacodynamic basis for the choice of the optimal dose(s) for Phase 3 studies. In fact, the mechanism(s) of action of icosapent ethyl in reducing importantly major vascular events remains largely unknown. These considerations perhaps explain why the omega-3 FA field has progressed by trial and error (more error than trial) during the past 20 years and suggest that light at the end of the tunnel might just be the futility train of STRENGTH.
It's a huge opportunity, to put it mildly, as obesity and diabetes burgeon in every part of the world, TG and remnant lipoprotein elevation associated CV risk is multiplying. I believe it affects >30% of the population in either of the primary or secondary R-IT indications. Not just Europe..think about SE Asia, Middle East, China and South America...same problems.
I included Russia for comparison :
Sleven,
This is a very broad indication and further, there is no age limitation (just"adult"), just statin pretreatment (doesn't even say max tolerated) and TG>150 --fits more than 60% of the patients walking into my clinic every day...
HIGH CV risk is the following:(1) Anyone with a prior CV event --includes myocardial infarction, stroke, limb ischemia/gangrene etc..(2) Anyone with evidence of established CV disease eg found by CT or Ultrasound (3) Anyone with diabetes and 0e of any of the following: " Diabetes, hypertension, smoking, family history, positive ABI less than 0.9, etc...here is the full list:
Men ≥55 years of age and Women ≥65 years of age;
• Cigarette smoker or stopped smoking within 3 months before Visit 1;
• Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic) or on
antihypertensive medication;
• HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women;
• Hs-CRP >3.00 mg/L (0.3 mg/dL);
• Renal dysfunction: Creatinine clearance (CrCL) >30 and <60 mL/min;
• Retinopathy, defined as any of the following: non-proliferative retinopathy, preproliferative retinopathy, proliferative retinopathy, maculopathy, advanced
diabetic eye disease or a history of photocoagulation;
• Micro- or macroalbuminuria. Microalbuminuria is defined as either a positive
micral or other strip test (may be obtained from medical records), an
albumin/creatinine ratio ≥2.5 mg/mmol or an albumin excretion rate on timed
collection ≥20 mg/min all on at least two successive occasions; macroalbuminuria,
defined as Albustix or other dipstick evidence of gross proteinuria, an
albumin/creatinine ratio ≥25 mg/mmol or an albumin excretion rate on timed
collection ≥200 mg/min all on at least two successive occasions;
• ABI <0.9 without symptoms of intermittent claudication (patients with ABI <0.9
with symptoms of intermittent claudication are counted under Secondary
Prevention Risk Category)
Based on this broad label Vazkepa is a keeper.
Can someone post a link if they are able to get into this site
thanks
HK