Replies to post #262361 on Amarin Corp Plc (AMRN)

[ggwpq]

HDG, below is the link for MARINE patent:

https://patents.google.com/patent/US8293728B2/en?oq=8293728

Under Non-Patent Citations, it listed the Kurabayashi's paper. Can we assume USPTO Examiner had at least considered Kurabayshi? So the Examiner is aware of the Kura paper and still approve the ApoB reduction patent.

However Du said "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.) 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, its considered judgment may lose significant force[.]” See i4i, 564 U.S. at 95. Thus, the Court finds that the unexpected benefits secondary consideration does not weigh in favor of finding the Asserted Claims nonobvious."

[mc1988]

Applicant was able to overcome the above 103 obviousness rejection by showing: … The prior art is either silent or teaches that there is no statistically significant change in Apo-B levels when patients with TG levels less than 150 mg/dl or between 150-499 mg/dl are treated with either 96% pure ethyl-EPA or a mixture of ethyl-EPA and DHA

The bolded "prior art" above does not necessarily refer solely to Kurabayashi, but let's assume it does. I checked Kurabayashi (Kurabayashi, T., et al., "Eicosapentaenoic acid effect on hyperlipidemia in menopausal Japanese women." Obstet Gynecol 96:521-8 (2000).) Copy here https://sci-hub.tw/https://www.sciencedirect.com/science/article/pii/S0029784400009881

and in Table 3 of that paper (page 525), the difference is statistically NOT significant.

Notice that under Table 3 the legend distinguishes between:
- P of differences in changes over time, vs
- P of intergroup differences

You might have misinterpreted P of differences in changes over time in the EPA group being statistically significant as "Kurabayashi teaches differently: ss changes in Apo-B exist". What I'm reading from Table 3 of Kurabayashi is that there is NO statistically significant changes in Apo-B between the Control group and the EPA group.

As a confirmation of my point, page 523 of the Kurabayashi paper contains a description of the findings:

The changes in serum levels of apolipoproteins from baseline to week 48 are shown in Table 3. The apolipoprotein A-II level in the eicosapentaenoic acid group significantly decreased from baseline to week 48, and there were significant differences between the two groups at weeks 12 and 24. The apolipoprotein B level in the eicosapentaenoic acid group was significantly lower at week 48 compared with the baseline level, but there was no significant difference between the groups. The atherosclerotic index of the eicosapentaenoic acid group decreased significantly from baseline to week 48. In the eicosapentaenoic acid group, the level of lipopro- tein(a) significantly decreased from baseline to week 48. The difference in remnant lipoprotein cholesterol was not statistically significant.

[circuitcity]

Quite:
—
Applicant was able to overcome the above 103 obviousness rejection by showing: … The prior art is either silent or teaches that there is no statistically significant change in Apo-B levels when patients with TG levels less than 150 mg/dl or between 150-499 mg/dl are treated with either 96% pure ethyl-EPA or a mixture of ethyl-EPA and DHA

Kurabayashi teaches differently:_ ss changes in Apo-B exist.
—
Hdg,

Can we say we have established per mc1988 that Kura did not reach us there is ss apoB reduction with epa, instead of e + epa (not epa + e either,seems to me more focus on e for this study)

Kura trial base line trig: 150 - 400, study group: 1800mg epa + 2mg e, purity 99.8%
Control group: 2mg e only?

I am wondering where re those number coming from in PTO quote: 150, 499 and 96%. He gave no reference, maybe you can find them. Thanks a lot for doing this by the way.

[Eagle2002]

Hi, I just wanted to add that Kura is also referenced in '715 patent, not just '728.

https://patentimages.storage.googleapis.com/a8/f7/57/0a377d21c2d3a2/US8318715.pdf

On the other hand the following language is accurate:

The prior art is either silent or teaches that there is no statistically significant change in Apo-B levels when patients with TG levels less than 150 mg/dl or between 150-499 mg/dl are treated with either 96% pure ethyl-EPA or a mixture of ethyl-EPA and DHA

Kura did not teach anything about EPA in mono therapy. If anything, Kura teaches the combination of EPA and estradiol. (Du makes an extrapolation about synergies and says that the Kura paper "suggests" there is no interaction; I find that unbelievable BTW). So Kura does not teach anything about mono therapy. (on top of this folks in this board have highlighted the fact that there is no stat significant change between groups).

So in essence there are 2 factual mistakes:
1) 715 patent - Kura paper is cited and therefore considered

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. (pg 66) of ruling


2) Kura establishes there is no statistically significant difference between groups

The apolipoprotein B level in the eicosapentaenoic acid group was significantly lower at week 48 compared with the baseline level, but there was no significant difference between the groups