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Replies to post #279207 on Amarin Corp Plc (AMRN)
Du Quote Bench Order 3/30:___________________________________
Mori reports that triacylglycerols (TGs) “decreased significantly by 18.4% with EPA
(P = 0.012) and by 20% with DHA (P = 0.003).” (Ex. 1538 at 3.) A POSA would consider
this difference in triglyceride reduction “indistinguishable and of no clinical significance.”
(ECF No. 367 at 740:1-13.) A POSA would likewise recognize that Mori teaches that “4
grams pure EPA could reduce triglycerides by about 20 percent.” (ECF No. 371 at
1826:24-1827:5.)
Mori also reports that “[s]erum LDL cholesterol increased significantly with DHA (by
8%; P = 0.019), but not with EPA (by 3.5%; NS),” (Ex. 1538 at 3), “strongly suggesting
that these two Omega-3 fatty acids could have distinct effects on LDL cholesterol levels”
(ECF No. 367 at 740:1-17). In the Abstract, Mori summarizes these results as showing
that while “LDL, HDL, and HDL2 cholesterol were not affected significantly by EPA, . . .
DHA increased LDL cholesterol by 8% (P = 0.019).” (Ex. 1538 at 1; see also ECF No. 371
at 1827:8-11.) Mori concludes that “EPA and DHA had differential effects on lipids.” (Ex.
1538 at 1; see also ECF No. 371 at 1827:8-19.) Therefore, “a skilled artisan would
understand from Mori that DHA and EPA work differently.” (ECF No. 371 at 1829:6-8.)
552. A person of ordinary skill in the art reviewing these results would not have distinguished the LDL-C effects of EPA from those of DHA on the basis of these results. While the LDL-C increase was only statistically significant in the DHA arm, the person of ordinary skill in the art would have attributed the absence of a statistically significant increase in the EPA arm to (1) the study’s small sample size (19 patients in the EPA group and 17 patients in the DHA group) and (2) the difference in the baseline TG levels of the two groups, with the EPA group having a mean TG level 11% lower than the DHA group (2.01 mmol/L or 178 mg/dL for the EPA group versus 2.25 mmol/L or 199 mg/dL for the DHA group).
Problems w Mori(2000) which negate any value in evaluating AMRN patent
1. Baseline (N=19) TG level FOR EPA GROUP reported as 2.01 ± 0.19 mmol/L [x ± SEM]. Converting SEM to sd --> 0.19 * sqrt 19 = 2.01 ± 0.8282 [x ± sd]. 1.96 sd = 1.623. So 97.5% of group have a baseline TG < 3.633 mmol/L == 321.8 mg/dl.(ie expect >18.5 of 19 patients in the EPA group to have a TG < 322). Aren't the patents in question in patients with TG >500?
2. Post treatment decrease in TG levels 21.6% greater for DHA than EPA - so expect LDL-C to increase more in the DHA group. I don't know if it is proper to refer to the Friedewald equation, but LDL-C est as = TC- HDL-C - (TG/5) suggests that decreasing TG by 21% more could increase LDL-C by 4.2% more.
3. Post treatment LDL-C INCREASED in the EPA Group from 4.28 ± 0.19 [x ± SEM] to 4.46 ± 0.10 [x ± SEM] (+ 4.0%) while in the DHA Group from 4.27 ± 0.17 to 4.64 ± 0.10 (+ 8.7%). How do we know a 21% greater reduction in TG levels (by DHA cf EPA) shouldn't be expected to increase LDL-C by this amount over EPA? It seems to concur with the 4.2% expected above.
4. The paper compared the EPA group to the control and the DHA group to the contol - but not to each other. Converting to std dev gives a post treatment LDL-C range [x-sd to x+sd] of 4.024 - 4.896 for the EPA group and 4.248 - 5.052 in the DHA group. I think we would need to know the TG and LDL-C levels for each individual patient to know for sure, but I'd bet there would be enormous overlap between these 2 groups and some stats guru could prove.
1. Mori does not teach that DHA raises LDL levels MORE than EPA.
2. Mori does teach that DHA raises LDL level relative to a placebo group with greater than 95% probability. (or more precisely, you can reject the null with >95% percent probability, which is a slightly different, but more accurate statement).
Does Mori teach that EPA DOES NOT raise LDL levels relative to a placebo group? No. It teaches there is not 95% confidence that EPA raises LDL levels relative to placebo.
What is the probability, given the DATA in Mori that EPA raises LDL levels? One can easily compute this since they report the mean and SEM.
The answer is 87.38%
Or conversely there is a ~12.6% chance that EPA does NOT raise LDL levels given the data in Mori.
These probabilities can be changed by looking at data outside of Mori, of which there is some. But not in the right TG populations. Nor is Mori the right triglyceride population. So is it obvious? Well trying to be unbiased, w.r.t. LDL, I can maybe see an argument, though I tend not to agree. But with regards to ApoB and Kura, I do not see it. Combined, I do not see it.
Mori found
1. EPA treatment does not statistically significantly increase LDL (compared to placebo, olive oil). BUT there was an increase observed.
2. DHA does statistically significantly increase LDL compared to placebo.
Now if you want to claim DHA raises LDL more than EPA, you have to do a direct comparison. When this is done, there is no statistically significant increase.
So IMO, Mori ALONE does not teach, in an obvious way that EPA raises LDL levels less than DHA. But why not? Well the direct comparison fails the significance test, so you might assume that perhaps EPA treatment actually does increase LDL levels, but because of the small sample size, it failed to show up as significant. It is also POSSIBLE from Mori that it was the EPA versus DHA comparison that failed due to a lack of power, which would imply the EPA treatment raises LDL levels less than DHA treatment. Either option is possible, neither is "taught".
How could one decide between these options? Well, you could look at other studies, and if you found additional evidence that EPA does not raise LDL levels in a *similar* population, (this is another thorny issue -- good arguments can be made that the Mori population is NOT relevant to the MARINE indication) then you might reasonably conclude that DHA raises LDL while LDL does not. Is that obvious? No, I don't think so, certainly not from Mori alone. However, you can make the case that Mori DOES teach that DHA raises LDL levels relative to placebo, just not relative to EPA. There is some hint of the "right" path, that could then be gleaned by referring to additional literature.
Kura teaches there is no stat. significant difference between EPA and placebo. There is no other way to interpret those particular data that is not erroneous.plt.show()
We are finally in a position to test our null hypothesis,
?LDLDHA<=?LDLEPA?LDLDHA<=?LDLEPA
If we can reject this null, that is the p < 0.05, then Mori provides evidence that DHA raises LDL levels more than EPA does. If we cannot reject this null, the Mori does not provide such evidence.
The easiest way to test the null is to simulate the popluation means of ?LDLDHA?LDLDHA and ?LDLEPA?LDLEPA and then simply count how many times ?LDLDHA<=?LDLEPA?LDLDHA<=?LDLEPA.
In [41]:
#Simulate 1000 draws from each normal distribution
#and compute the fraction of the time the estimate
#for $ \Delta LDL_{DHA} <= \Delta LDL_{EPA} $.
mu_DHA = 0.34
sigma_DHA = 0.14
mu_EPA = 0.15
sigma_EPA = 0.13
test = [1 for x in list(np.random.normal(mu_EPA, sigma_EPA, 10000) - np.random.normal(mu_DHA, sigma_DHA, 10000)) if x >=0]
print(len(test)/10000)
0.1542
So p = 0.15 and we cannot reject the null hypothesis. This means there is not good evidence in Mori et al that ?LDLDHA?LDLDHA is greater than ?LDLEPA
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Statistical Flaws in a Key Piece of the Prior Art The fundamental problem, however, is that Mori et al.5 did not address the question of differential effects of DHA and EPA on LDL cholesterol levels. While providing comparisons of baseline and postintervention LDL levels based on a “general linear model” (which also incorporated the changes in the levels of the olive oil comparator), the authors did not report a test for interaction that would assess whether the 9 Electronic copy available at: https://ssrn.com/abstract=3618671changes in LDL cholesterol levels in the EPA and DHA groups were significantly different from one another. Stated differently, Mori et al. did not include a critical comparison necessary to determine if the effects of DHA and EPA on LDL cholesterol change were truly “differential”. In the Appendix we show one way in which this test could be conducted given the information available in Mori et al.5 Our result indicates that we could not reject the hypothesis of no difference in effect of DHA vs. EPA on LDL cholesterol at any reasonable level of statistical significance. It is noteworthy that the appropriate statistical test for the data analysis in the study by Mori et al.5 would be known by ordinary researchers in the discipline and does not require advanced knowledge of statistics. Another important consideration is the small sample size of the study of Mori et al.5 and the large number of different statistical tests conducted. Studies of this type are considered “hypothesis generating” and their findings are meant to suggest avenues for further research rather than provide definitive answers. In the case of the study by Mori 10 Electronic copy available at: https://ssrn.com/abstract=3618671et al.5, the appropriate statistical analysis indicated a null result, which taken at face value would not necessarily motivate further research.
Appendix Assuming that the conditions for a two independent samples t-test are met, and using estimates from Table 2 in Mori et al.5 as the mean changes with the corresponding standard errors, we can construct a test statistic: t = (Mean_DHA - Mean_EPA)/sqrt(SE_DHA^2+SE_EPA^2) For LDL cholesterol we have: 16 Electronic copy available at: https://ssrn.com/abstract=3618671t = (0.34-0.15)/sqrt(0.14^2+0.13^2) = 0.19/0.19 = 1.0, which would not be statistically significant at any reasonable level.
