Thank you ggwpq--an intelligent post
Some further musings
The Markman blog
was comprehensive but erred in my view in some points:
Quote: BOTH statements are not true IMO.
That said, this appeal suffers from certain obstacles that no one can do anything about. This case does not touch upon any major hot-button policy considerations in the fields of patent law or pharmaceuticals. Nor does Amarin marshal any, apart from possibly the Cyclobenzaprine issue. The Federal Circuit has affirmed the invalidity of scores of branded pharmaceutical patents in the past, and it will most likely continue to do so without concern that it will diminish investment in pharmaceutical R&D.
(2) Moreover, while Amarin does a very diligent job of detailing an inventor story, the patents do not really jump out as groundbreaking stuff. For all the talk about how surprising it was that pure EPA would not increase LDL-C in certain patients, that data is not in the patents themselves.
A situation of dangerous laissez-faire has arisen in the CAFC that threatens to ignore ad libitum the SCOTUS direction and prior precedent cases that support the Graham v. John Deere approach". "It requires considering all four Graham factors, including evidence of the fourth factor, secondary considerations, at once, before deciding the issue of obviousness.By so doing, it keeps the burden of proof on the challenger to prove obviousness by clear and convincing evidence, rather than transferring the burden of proof to the patentee to disprove obviousness using evidence of secondary considerations." SCOTUS
has mandated by prior judgements that the challenger's heavy burden of proof (by clear and convincing evidence) of obviousness not be transferred to the patentee--which has happened here due to lack of clear procedure and a judge Du who made horrific errors in her adoption of the "prima facie rebuttal approach". Analysis of all four Graham factors, including the fourth (secondary considerations) has become a nebulous and subjective exercise, subject to capriciously diverse interpretation across the spectrum of the CAFC bench.
Even assuming that a prima facie rebuttal
approach is correct, it ASSUMES that the prima facie evaluation was done in good faith (open mind) and with proper attention to scientific facts and analysis and avoiding fatal errors of interpretation (not done bu Du).
Defendants did not prove by clear and convincing evidence that the POSA would have been motivated to use substantially pure EPA as a treatment for severe hypertriglyceridemia, or that such a person would have reasonably expected to avoid a substantial increase in LDL-C using EPA in those patients. The prior art taught that every drug approved for lowering TG's in the severely hypertriglyceridemic — whether niacin, fibrates, or omega-3-fatty acids — raised LDL-C dramatically in that population, even though they did not have that effect when administered to patients with lower TG levels. The POSA attributed this increase in LDL-C to the way TG-lowering drugs were understood to work in the severely hypertriglyceridemic—enhancing clearance of the superabundance of VLDL particles to LDL. The POSA expected EPA to work the same way.
So this is the crux of why the Du's conclusion of prima facie evidence of obviousness was flawed
-- irrespective of what ensued in subsequent legal procedural error in terms of shifting burden of obviousness proof, and thereby weighting secondary factors (objective indicia) and using them to negate or reinforce an ab initio flawed prima facie obviousness assumption, as well as ignoring prior relevant case precedent and SCOTUS direction etc.. Two patient population arguments and their validity
is highly relevant--part from having biological evidence for plausibility it directs the therapeutic approach and differentiates Vascepa as THE drug that lowers Triglycerides without raising
LDL and lowering ApoB
the key atherogenic particle that in essence carries the RISK inferred in elevated triglycerides--for a good summary read this article: https://www.mayoclinicproceedings.org/article/S0025-6196(19)30678-0/pdf
This is why the Du misinterpretation of Kurabayashi data and infamous table is so disastrous, because it showed categorically the non-ApoB altering ability of EPA as administered in Kurayabashi's hands and in that population and using his EPA formulation.
Turning back to Mori et al
and the much cited, much ado about nothing (scientific) article. It need placing in temporal and scientific context.
We are all by now familiar with Table 2 of the Mori article
cited in the Du Judgement as supporting prima facie obviousness of EPA not raising LDL). This was a double-blind, placebo-controlled trial of parallel design, 59
overweight, nonsmoking, mildly hyperlipidemic men
who were randomly assigned to receive 4 g purified EPA, DHA, or olive oil (placebo) daily while continuing their usual diets for 6 wk. We see from Table 2
which I attach that the 19 patients in each arm had an average TG level of 178 mg/dl
NOT even close to 500 mg/dl. It is true that the EPA had no perceptible change on LDL c/w DHA that increased it, while both reduced TG's by 18-20%. Purified eicosapentaenoic and docosahexaenoic acids have
differential effects on serum lipids and lipoproteins, LDL particle
size, glucose, and insulin in mildly hyperlipidemic men Mori et al Am J Clin Nutr 2000
However, let us now consider another MORI paper (Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension, Am J Clin Nutr 2002;76:1007–15
) written in the year 2002
(2 years later). Here the same author Mori in conjunction with Woodman et al study 39 men 12 postmenopausal women with diabetes and hypertension and baseline Triglycerides of 119-154 mg/dl
and what did they find? [b]EPA and DHA BOTH lowered triglycerides by 19% and 15% respectively BUT NEITHER CHANGED LDL CHOLESTEROL from baseline compared with olive oil control
So we have Mori studying "normal middle aged males" and shows differential LDL changes with TG lowering in ONE population then then he studies middle aged men (mostly) /postmenopausal women with diabetes and HTN and MILD hypertriglyceridemia (average TG at baseline =119-154 mg/dl)
For reference here is the population studied by Bays et al in the MARINE TRIAL:
It is clearly evident EVIDENT that even in the mildly hypertriglyceridemic population DIFFERENTIAL LDL effects were seen in normal males vs. Diabetic males/postmenopausal women ...what then can a POSA of circa 200-2002 discern...nothing at all...we needed larger better powered studies in clearly defined levels of hypertriglyceridemia
which is what the MARINE trial provided in 2011. Here we see EPA providing the profound TG lowering without raising LDL and IMPORTANTLY the apoB lowering that is the key to risk reduction and which is NOT shown by the Kurabayashi study of middle aged moderately hypertriglyceridemic (150-400 mg/dl) menopausal women. In this study, treatment with BOTH estriol estrogen and EPA (Epadel) showed c/w control estrogen, a statistically significant 8% reduction in LDL and a 16% reduction in Triglycerides WITHOUT
a statistically significant reduction in apoB:
I conclude that NOTHING Mori published disclosed a jot about the LDL TG behavior of a population like MARINE with severely elevated TG's and the novel findings of powerful TG lowering WITH LDL neutral effects and significant ApoB reductions is what rightly pushed the USPTO examiner to recommend the granted MARINE patents to Amrn. In critical contrast Mori's data was confined to a TOTALLY DIFFERENT POPULATION WITH ENTIRELY DIFFERENT LEVELS OF TRIGLYCERIDES AND THE LIPID EFFECTS WERE SO DIVERGENT IN DIRECTION IN BOTH HIS STUDIES THAT BETWEEN 200-2011 NO POSA COULD HAVE CONCLUDED ANYTHING FROM THE DATA
This is why the two population argument is both critical and holds water The second Woodman/Mori paper should be brought out by Singer at Appeal argument to show this critical point.No POSA would ever come to a conclusion of prima facie obviousness when confronted with this data.
Finally Mori concludes in a further paper in 1999 that he believes DHA is the promising compound for lowering BP and HR:
REFERENCES: https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:e7dd2fd6-0458-476f-a205-b716c28484c5 https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:2a387396-bb58-4455-8fd3-56cc416299ed https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:8b337776-d2b2-4d7b-9fd8-124e02b57ae8 https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:50c062d7-3929-466e-9d3a-f87df6e622e7 https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:2fc581eb-d884-4ff1-a486-a8ecac428c07