I AM INTERESTED IN ALL YOUR OPINIONS ON THIS DISSECTION OF THE KURABAYSHI ISSUE BY MARKMAN (Z SILBERSHER) It touches on the issues that we are discussing...dated 04-17-2020 https://www.markmanadvisors.com/blog/2020/4/17/amarin-response-to-comments-on-kurabayashi I will withold comment till others have expressedtheir thoughts. I reproduce it in entirety for convenience including the comments by our own R luther: Amarin: Response to comments on Kurabayashi. Zachary Silbersher
More on Kurabayashi . . .
The Honorable Miranda M. Du’s Bench Order found that it was not unexpected that pure EPA would reduce Apo-B because Kurabayashi showed a “statistically significant reduction in Apo B levels in the EPA group of 6.9%. With a p-value of < .001, EPA’s effects on Apo B were highly significant. In contrast, Kurabayashi reports a non-statistically significant 1.5% reduction in Apo B levels in the control group.” (Bench Order at 29, citations omitted).
The argument that Judge Du committed a clear factual error goes like this: Table 3 shows that the EPA group and the control group both experienced reductions in Apo B (6.9% and 1.5%, respectively). However, the p+ values for weeks 12, 24 and 48 are labeled “NS” (not significant.) Given that, Judge Du committed clear error when finding that Kurabayashi showed a statistically significant reduction in Apo B that was attributable to EPA. Since the reduction in Apo B between the EPA group and the control group (pure estriol) was not statistically significant, Kurabayashi could not have created an expectation that pure EPA would reduce Apo B.
As we discussed in our earlier post, one question is whether Amarin has preserved the right to make this argument on appeal. Several commenters have pointed out that Amarin’s pre-trial proposed findings of fact included argument to this effect. That may be so, and Amarin may have indeed preserved the right to challenge Judge Du’s interpretation of Kurabayashi on appeal. But there are a few caveats to consider.
First, to make that challenge, Amarin is still limited to the evidence in the record. Judge Du essentially adopted the generic’s argument regarding how to interpret Table 3 from Kurabayashi. That argument was included in the generics pre-trial proposed findings of fact. (See Docket 333 at paras. 418 and 422). Thus, Amarin was aware that the generics might make this argument going into the trial. Despite that, neither Amarin’s pre-trial nor post-trial proposed findings of fact appear to include expert testimony on why p+ values are the statistically-significant values rather than the p* values.
Amarin’s post-trial proposed findings of fact do not appear to raise this argument, and the proposed pre-trial findings of fact raise the argument, but do not appear to delve into the nuanced distinction between the p+ and p* values. For Amarin to delve into the p-values on appeal, it will theoretically need to point to some expert opinion. If it did not solicit expert opinion on this at trial—either in the form of direct examination testimony from Amarin’s expert (Dr. Toth) or cross-examination testimony from the generics’ expert (Dr. Heinecke)—then it may be limited in what it can rely upon. (You cannot introduce new expert testimony during an appeal.) Amarin may try to make that attorney argument on appeal, and perhaps the Federal Circuit panel will find Judge Du’s misinterpretation of the p-values in Table 3 as clearly erroneous as many of those following this case. That is not impossible. But without concrete expert admissions from the testimony at the trial, then it remains just that—i.e., something of a gamble.
There is another caveat to consider, which we discussed in the update to our earlier post. If we compare Amarin’s pre-trial proposed findings of fact with its post-trial findings of fact, Amarin appears to have dropped the argument challenging the generics’ interpretation of the statistical significance of the 6.9% reduction from Table 3 from Kurabayashi. If Amarin made a deliberate decision not to challenge Kurabayashi at trial on the basis that the generics were misinterpreting Table 3, it is questionable whether Amarin will choose to return to that argument on appeal. More to the point, if Amarin refrained from pressing that challenge at trial—most importantly, by refraining from cross-examining Dr. Heinecke on this point—then Amarin may not have sufficient testimonial evidence to mount this challenge on appeal. (This is another way of saying, if Amarin didn’t solicit and put this testimony in front of Judge Du before issuance of the Bench Order, it can’t really argue on appeal that Judge Du sorted through that evidence incorrectly.)
But if the generics interpretation of Table 3 from Kurabayashi was so clearly erroneous, then why did Amarin refrain from challenging it at trial? Presumably, the reason is because Kurabayashi was not the only prior art relied upon by the generics to show a reduction of Apo B from pure EPA. Dr. Heinecke also relied upon Grimsgaard and Nozaki. The tactical calculation may have been that it is not worth burning considerable time at trial challenging the hairy statistical conclusions of Kurabayashi when other prior art references taught or suggested the same thing. (The parties did not have unlimited time at trial to present their respective cases.)
Moreover, Amarin clearly chose to distinguish Kuarabayashi on different grounds—namely, the study focused on the wrong patient population and the EPA group was also administered estriol. The former ground dovetails with Amarin’s distinctions of other primary prior art references, such as Mori and Hayashi. Thus, Amarin may have chosen to develop a larger theme at trial to distinguish much of the prior art at once. Having spent the time to develop the record of those distinctions during trial, that is likely the best record Amarin is equipped to return to on appeal. This strategy has traction and it may still save Amarin on appeal, as previously discussed.
There are other issues with Kurabayashi other than Table 3. One of the problems faced by the generics’ reliance on Kurabayashi was that the EPA group was not administered pure EPA, but rather EPA and estriol. Thus, Kurabayashi, on its face, does not disclose a reduction in Apo B from administration of pure EPA, which is what the patent claims require. That is why, to overcome this problem, the generics also argued in their post-trial findings of fact that the results of Kurabayashi show no “interaction or synergy” between EPA and estriol. (Docket 373 at para. 281). They were essentially trying to paper over the question of whether Kurabayashi would have anything relevant to say about pure EPA to a person of skill. Amarin clearly challenged the generics on this point at trial, as shown by citation to testimony solicited at trial within their post-trial findings of fact. (See Docket 374 at para. 580). Judge Du did not address Amarin’s evidence on this point within the Bench Order. Thus, this is a ground on which Amarin may choose to challenge Kurabayashi on appeal based upon testimony clearly developed at trial.
If Amarin does challenge Judge Du’s interpretation of Table 3 at trial, the generics are likely to double-down on the argument that the court’s focus on the 6.9% reduction was, in fact, the correct data point. The generics will argue that the claims do not require any comparison to placebo (more on that in the next section,) and to show prior art disclosed, taught or suggested a certain benefit (reduction of Apo B) does not require absolute certainty, only reasonable certainty. Put another way, the generics are likely to argue that even if Judge Du misread the significance (or non-significance) of the comparison between the EPA and control groups, it is irrelevant because the comparison to baseline is sufficient to defeat the showing that reduction of Apo B was truly unexpected. Indeed, Amarin itself repeatedly argued that the Marine study showed a reduction of Apo B based upon a comparison to both baseline and placebo. (See e.g., Docket 327 at 7). So Amarin itself relied upon a comparison to baseline to show the benefit.
This is a hairy issue. Even given that Judge Du may have misconstrued the p-values in Table 3, Amarin will have to weigh whether it is worth burning pages in its appeal brief to focus on this issue, especially given the other prior art in play and whether testimony was solicited on this issue at trial.
What about claim 8 from the ‘677 patent?
We received another comment about an alleged factual error by Judge Du that may be apparent on the face of the patents. Dr. Heinecke’s reply expert report, dated June 7, 2019, responds to Dr. Toth’s report (Amarin’s expert). In Dr. Toth’s report, he argues “that the difference between the EPA group [in Kurabayashi] and the estriol-only control group was not itself statistically significant.” (See Docket 234-12 at 201). In his reply report, Dr. Heinecke states, “none of the asserted claims as construed requires an actual comparison to a second patient in a control group.” (Id.). Yet, one of the asserted claims does appear to require exactly that comparison. Indeed, claim 8 from the ‘677 patent recites as follows: “The method of claim 1, comprising administering to the subject about 4 g of the pharmaceutical composition daily for the period of at least about 12 weeks to effect a reduction in apolipoprotein B compared to placebo control.” (emphasis added).
So, given this, the alleged error on the part of Judge Du appears to be as follows: Judge Du relied upon Dr. Heinecke’s interpretation of Table 3 from Kurabayashi, and in doing so, she erroneously focused on the reduction in the EPA group compared to baseline rather than the lack of statistical significance between the EPA and control groups. This error, the argument goes, is compounded by the fact that Dr. Heinecke incorrectly stated that the asserted claims do not require comparison to a second patient control group. In so doing, did Dr. Heinecke mislead Judge Du about the significance of the comparison between the EPA group and the control group?
The short answer is, it doesn’t seem so. The key phrase from Dr. Heinecke’s statement in his reply expert report is “as construed.” That phrase refers the Judge Du’s prior claim interpretations (otherwise known as “constructions”) that issued in the claim construction order. (See Docket 135). That order included Judge Du’s interpretation of the phrase “compared to”. (That phrase appears in many of the asserted claims, not just claim 8 from the ‘677 patent, but we will focus on the language of claim 8.) Judge Du found that though claim 8 recites “compared to a placebo control,” that comparison is not actually required by the claim. Put another way, Judge Du interpreted claim 8 from the ‘677 patent in manner that does not require a comparison to a placebo control group.
While Judge Du’s interpretation may seem counter-intuitive, it was an interpretation that was actually pressed and put forth by Amarin, not by the generics. Indeed, Judge Du’s construction of the “compared to” language was, at the time, technically a win for Amarin and a loss for the generics. By contrast, the generics argued that to infringe claim 8 from the ‘677 patent (and other claims with similar “compared to” language) would require a doctor to essentially conduct a clinical trial each time he or she treats a patient to therefore satisfy the “compared to placebo control” limitation. Judge Du found that to be an absurd result.
In the big picture, this was a good result for Amarin. Had Judge Du agreed with the generics on this particular dispute, rather than agreeing with Amarin, then Amarin would never have been able to prove infringement of the patents. The generics’ proposed labels do not instruct physicians to assess a reduction in Apo B through comparison to a placebo group. On this basis alone, the generics would have been able to show no infringement on summary judgment, and there never would have been a trial.
This is not an uncommon dilemma that arises within patent litigation. If you are the patent-holder, and you stake out a construction of the patent claim that is too broad, it may make it easier for you to show infringement, but it may simultaneously make it easier for the defendant to show invalidity. By contrast, if the defendant stakes out a construction that is too broad, it may sweep in more prior art and make it easier to show invalidity, but simultaneously open up the door for the patent-holder to more easily show infringement. Threading this needle, and choosing your constructions carefully, is where cases are won and lost.
And so, Dr. Heinecke is not necessarily incorrect when he stated in his reply report that the asserted claims “as construed” do not require comparison to a placebo group. Indeed, he references Judge Du’s claim construction order in his report at Docket 234, paragraph 197.
APRIL 17, 2020 COMMENTS (10)Newest First Newest First Subscribe via e-mail Preview POST COMMENT… R. Luther 3 months ago · 0 Likes
Z. Silbersher - Thanks for your response. A few points in reply:
1) I did not suggest that Judge Du's possible errors of fact include any citation of Dr. Heinecke's expert report. I pointed out his report only for purposes of illustrating the Defendants' interpretation of the claim construction for claim 8 of '677, as I think it's relevant to the ultimate question of whether or not Kurabayashi is determined to have taught a POSA at the time that EPA + estriol lowered Apo B.
2) Would you agree that if Defendants' characterization of the "compared to placebo" claim construction - that it does not require any comparison to an untreated group - is accepted by the appeals court, then the court would have to conclude that Kurabayashi did, in fact, teach that EPA + estriol lowers Apo B?
3) Would you agree that if the appeals court were to find that claim 8 of '677 DID require a comparison to an untreated group, then the court would have to conclude that Kurabayashi did NOT teach that EPA + estriol lowers Abo B?
4) Is it your understanding that Amarin agrees with Defendants' characterization of the court's construction of the "compared to a placebo" language, that it does not require any comparison to an untreated group or subject? Can you cite anywhere in the trial record where they concede that point?
5) Reading Judge Du's claim construction order for the "compared to placebo" language, do you personally interpret it as eliminating any requirement of a comparison to an untreated group?
6) Would you agree that Judge Du rejected Defendants' proposed construction and endorsed Amarin's proposal that no construction was necessary, and that the plain and ordinary meaning of "compared to placebo", as would be understood by a POSA, was accepted by the court?
7) When you read the excerpt below from Amarin's Opening Markman Brief, an argument that Judge Du wholly accepted, would it be your understanding that Amarin is proposing that:
a) any comparison to a placebo or control group would be irrelevant to a POSA in determining the effect of EPA + estriol on Apo B levels in a subject
or
b) a comparison to a placebo or control group would be important to a POSA in determining the effect of EPA + estriol in determing the effect of EPA + estriol on Apo B levels in a subject
From PLAINTIFF'S OPENING MARKMAN BRIEF:
I. “compared to placebo control” and “placebo control”
Claim Term: “compared to placebo control” Amarin’s Proposal: "compared to not administering treatment" Defendants’ Proposal: "compared to a subject who is administered a placebo and not concurrently administered a pharmaceutical composition comprising ethyl eicosapentaenoate"
Claim Term: “placebo control” Amarin's Proposal: "not administering treatment" Defendants’ Proposal: "a subject who is administered a placebo and not concurrently administered a pharmaceutical composition comprising ethyl eicosapentaenoate"
As discussed in Section E above, a person of ordinary skill in the art would have readily understood the plain and ordinary meaning of the “compared [to]” terms within the context of each claim, such that a construction is not necessary. In addition, “placebo control” is a well understood term in clinical research. (Miller Decl. ¶ 98.) As Dr. Miller explains, a skilled artisan would understand the term “placebo control” in the claims to be the counterpart to the individual being treated, i.e., an individual who is not administered treatment. (Miller Decl. ¶ 98.) Plaintiffs’ proposed construction properly reflects the plain meaning of the term “placebo control” as “not administering treatment.”
By proposing that “placebo control” be construed as “a subject who is administered a placebo and not concurrently administered a pharmaceutical composition comprising ethyl eicosapentaenoate,” Defendants appear to be attempting to add a requirement that a clinician also administer a placebo. This attempt is misplaced and conflicts with how a person of ordinary skill would understand the claims in the context of the patent and prosecution history.
A skilled artisan would have understood the claims to be referring to a comparison between the subject undergoing treatment and a subject who is not administered treatment. (Miller Decl. ¶ 98.) Indeed, this understanding is consistent with evidence-based medicine, in which clinicians rely on clinical trials to provide information concerning the effects of the drugs that they use to treat patients. (Miller Decl. ¶ 98.) Thus, a person of ordinary skill in the art would understand “compared to placebo control” to mean “compared to not administering treatment.”
Markman Advisors 3 months ago · 0 Likes
R. Luther -- Thank you for your numerous comments. I do not share your views on your “construction” of Judge Du’s construction of the “compared to” language. But it is really irrelevant. If Amarin were to pursue this theory on appeal, it would have to take into account that claim 8 from the ‘677 patent is only one of the ten asserted claims. Seven of the other asserted claims do not recite reduction of Apo B as a limitation whatsoever, and the other two claims that do require reduction of Apo B do not require a comparison to placebo. At trial, Amarin argued that reduction of Apo B was an unexpected benefit for the purpose of showing all ten asserted claims were not obvious. (An unexpected benefit can save the validity of a patent claim even if that benefit is not itself recited in the claim.)
Dr. Heinecke’s statement in Docket 234 where he references the claims, “as construed,” is from his reply expert report. Judge Du did not cite to Dr. Heinecke’s expert report, or to that particular sentence from his report, in the course of rendering her findings on Kurabayashi. (That would be unusual if she did.) Thus, even if Dr. Heinecke was purportedly wrong with regard to how the court construed the “compared to” language, if Judge Du did not explicitly rely upon Dr. Heinecke’s construction of her construction, then that does not give Amarin much purchase to argue it is reversible error. Put another way, the claim constructions are legal conclusions that were decided by Judge Du herself. It would be very difficult, and not very persuasive, for Amarin to argue that Judge Du committed reversible error because she erroneously relied upon a medical expert’s opinion on the proper interpretation of one of her own legal conclusions.
But I would like to go back to the larger question, which was raised in your comments as well by numerous commentators. Even if we assume that the Federal Circuit finds that Judge Du erroneously overlooked that Table 3 states there was no statistical significance between the EPA group and control group, the next question is whether that error is a reversible error. There has been a lot of diligent work identifying errors within Judge Du’s factual analysis. But not all errors of fact necessarily lead to reversal. If the Federal Circuit can still determine, on a de novo basis, that the patents are obvious, even after correcting the factual errors, then Judge Du’s decision will be affirmed.
The generics will argue that nine of the 10 claims do not require comparison to placebo. (They will argue the same for claim 8.) They will argue that even if Judge Du misread Table 3, Kurabayashi nonetheless showed a statistically-significant reduction of the EPA group compared to baseline. They will argue that is sufficient to show that it was not unexpected among persons of skill in 2008 that pure EPA could reduce Apo B. Amarin itself did not argue that the unexpected benefit was a reduction of Apo B compared to a placebo group. (See Post Trial Brief at 26). Amarin itself relied upon the reduction to baseline in the Marine study to tout this benefit.
The tougher question here is whether a comparison to baseline alone is, in fact, sufficient. By itself, perhaps it is sufficient because a reduction to baseline is itself a reduction. (This is where Amarin would need to have solicited expert testimony at trial to support its argument that comparison to baseline is not sufficient. Without that testimony, its job is harder.) Nevertheless, Amarin will also point out that Kurabayashi also concluded that there was no statistically significant difference between the two groups. That is important because that suggests that the reduction of Apo B to baseline was not necessarily attributable to EPA. And if it wasn’t attributable to EPA, then Kurabayashi cannot speak to whether the reduction of Apo B was, in fact, an expected or unexpected benefit.
Taking this a step further, this is why the debate over the “synergy” between EPA and estriol is very important, as discussed in my post above. Technically, that “synergy” issue will likely to be the focus of this dispute if Amarin goes down the Kurabayashi path for the appeal. In other words, even if Federal Circuit understands that Judge Du committed factual error in reading Table 3, Amarin most likely still has to win on this “synergy” point in order to win reversal, at least as regards Kurabayashi.
Andrew Fleischman – Thank you for your comment. Please see my comment above in response to R. Luther, where I attempted to address your comment as well.
David Shirley – Thank you for your comment. I addressed your questions in an earlier post, here.
R. Luther 3 months ago · 0 Likes
Corrected version of previous comment, correcting some Plaintiff/Defendant confusion.
I looked a little deeper into the trial docs and did find one reference by Defendants to claim 8 of '677 claim construction, in their Post-Trial Findings of Fact.
Defendants state the following:
"The additional limitation, “to effect a reduction in apolipoprotein B compared to placebo control,” was also known and obvious in view of the prior art. For the same reasons discussed above for claim 5 of the '929 patent and claim 14 of the '715 patent, a skilled artisan would have reasonably expected that purified EPA would reduce Apo B in view of Kurabayashi, which taught a statistically significant, 6.9% reduction in Apo B in patients who were treated with over 96.5% purified EPA. This result was compared to a placebo control (i.e., the “control group”), in which there was no significant change in Apo B. DX 1534 at 3, 5. In any event, as discussed above, the Court’s construction of the term “compared to” does not require an actual comparison to a placebo group. (ECF No. 135 at 12.)"
This is interesting in a couple of ways. First, Defendants confusingly acknowledge the statistical insignificance of the Apo B reduction comparisons between the EPA + estriol and estriol-only groups when they reference the reduction from baseline in the EPA + estriol group, and that is was “compared to a placebo control (i.e., the “control group”), in which there was no significant change in Apo B." To clarify what they're saying there (which I suspect they intentionally made confusing) is that the reduction in the EPA + estriol group WAS compared to a placebo group. What they conveniently leave out is that the comparison showed no statistical significance between the two groups. They do however, manage to mention that the reduction in Apo B in the placebo group showed no significant change. Interestingly, they then immediately add the statement, "In any event, as discussed above, the Court’s construction of the term “compared to” does not require an actual comparison to a placebo group. (ECF No. 135 at 12.) So even though they omitted the fact that the comparison between the two groups showed no statistical difference, they tack on the same disclaimer that Heinecke used in his response to Toth, which is that, based on Defendants interpretation of the claim construction (i.e. "as construed"), a comparison isn't required. They then cite to Judge Du's Claim Construction Order. (Based on how Defendants crafted the above statements, it's little wonder that Judge Du misunderstood the meaning of Table 3. Especially considering that Defendants used the cropped version of Table 3 in their filings, which omitted the key that explained the meaning of the p+ values that showed the difference between the two groups to be not significant. Defendants’ language above, which evades mention of the results of the comparison between the two groups, suggests that their use in other filings of the cropped version of Table 3, which graphically did the same thing by omitting the key explaining the p+ values, was not accidental. If it was on purpose, that strategy seems to have worked, as Judge Du appears to have simply copied the Defendants’ entire Kurabayashi argument (including cropped Table 3) directly into her decision without commentary, and not checked their Kurabayashi assertions against the full text of the study that was submitted previously to the court. Her faulty of reading of that table, clearly articulated by her finding of "statistically-significant differential effects reported between the EPA and control groups" is maybe the single most important fact of her entire decision in light of the possibility that the addition of "unexpected benefit" to secondary consideration would have been the difference between obviousness and non-obviousness.)
The problem for Defendants here in citing to Judge Du's construction is that it DOES NOT eliminate a comparison to an untreated group from the claim, as I've outlined here previously. In her order on this issue, Judge Du roundly rejected Defendants attempted construction of the claim 8 and embraced Plaintiff's construction, which simply specifies that practitioners can refer to study results as a means of setting expectations for what the treatment's effect would be on a control or placebo group relative to the treated group, rather than ridiculously conducting a trial for every individual patient (which was the construction that was proposed by Defendants).
Judge Du's construction of "compared to" for this claim is well-captured in this excerpt from her Claim Construction Order:
"Defendants rely on the example in the specification of the ‘728 patent wherein the practitioner considers four measured values, specifically the “lipid parameters of at least one subject who is administered AMR101 both before and after a treatment period, and the lipid parameters of a control subject both before and after the treatment period.” (Id. at 37.) However, this construction of the term would require that a practitioner of the method “conduct a clinical trial every time he treats a patient,” a seemingly absurd result. (ECF No. 113 at 17.) At the Hearing, Plaintiffs relied on Allergan, Inc. v. Sandoz, Inc., No. 6:11-cv-441, 2013 WL 13141188 (E.D. Tex. Mar. 28, 2013), to argue that the clinical trials required for VASCEPA®, which are in the intrinsic evidence, would also be available to a POSA on the labeling of the product, and this data would provide a POSA with enough context to appreciate how to perform a comparison. By performing a comparison between what happens when the treatment is administered and versus what would otherwise happen to a second subject, "compared to" merely "defines the magnitude of the lipid effect or the avoidance of undesirable lipid effects" and not the specific method advocated for by the Defendants. The court agrees and finds that the clinical data in the intrinsic record supports Amarin's view of the terms plain and ordinary meaning."
R. Luther 3 months ago · 0 Likes
I looked a little deeper into the trial docs and did find one reference by Plaintiffs to claim 8 of '677 claim construction, in their Post-Trial Findings of Fact.
Plaintiff's state the following:
"The additional limitation, “to effect a reduction in apolipoprotein B compared to placebo control,” was also known and obvious in view of the prior art. For the same reasons discussed above for claim 5 of the '929 patent and claim 14 of the '715 patent, a skilled artisan would have reasonably expected that purified EPA would reduce Apo B in view of Kurabayashi, which taught a statistically significant, 6.9% reduction in Apo B in patients who were treated with over 96.5% purified EPA. This result was compared to a placebo control (i.e., the “control group”), in which there was no significant change in Apo B. DX 1534 at 3, 5. In any event, as discussed above, the Court’s construction of the term “compared to” does not require an actual comparison to a placebo group. (ECF No. 135 at 12.)"
This is interesting in a couple of ways. First, Plaintiff's confusingly acknowledge the statistical insignificance of the Apo B reduction comparisons between the EPA + estriol and estriol-only groups when they reference the reduction from baseline in the EPA + estriol group, and that is was "compared to a placebo control (i.e., the “control group”), in which there was no significant change in Apo B." To clarify what they're saying there (which I suspect they intentionally made confusing) is that the reduction in the EPA + estriol group WAS compared to a placebo group. What they conveniently leave out is that the comparison showed no statistical significance between the two groups. They do however, manage to mention that the reduction in Apo B in the placebo group showed no significant change. Interestingly, they then immediately add the statement, "In any event, as discussed above, the Court’s construction of the term “compared to” does not require an actual comparison to a placebo group. (ECF No. 135 at 12.) So even though they omitted the fact that the comparison between the two groups showed no statistical difference, they tack on the same disclaimer that Heinecke used in his response to Toth, which is that, based on Plaintiff's interpretation of the claim construction (i.e. "as construed"), a comparison isn't required. They then cite to Judge Du's Claim Construction Order. (Based on how Defendants crafted the above statements, it's little wonder that Judge Du misunderstood the meaning of Table 3. Especially considering that Defendants used the cropped version of Table 3 in their filings, which omitted the key that explained the meaning of the p+ values that showed the difference between the two groups to be not significant. Plaintiff's language above, which evades mention of the results of the comparison between the two groups, suggests that their use in other filings of the cropped version of Table 3, which graphically did the same thing by omitting the key explaining the p+ values, was not accidental. If it was on purpose, that strategy seems to have worked, as Judge Du appears to have simply copied the Plaintiff's entire Kurabayashi argument (including cropped Table 3) directly into her decision without commentary, and not checked their Kurabayashi assertions against the full text of the study that was submitted previously to the court. Her faulty of reading of that table, clearly articulated by her finding of "statistically-significant differential effects reported between the EPA and control groups" is maybe the single most important fact of her entire decision in light of the possibility that the addition of "unexpected benefit" to secondary consideration would have been the difference between obviousness and non-obviousness.)
The problem for Defendants here in citing to Judge Du's construction is that it as it DOES NOT eliminate a comparison to an untreated group from the claim, as I've outlined here previously. In her order on this issue, Judge Du roundly rejected Defendants attempted construction of the claim 8 and embraced Plaintiff's construction, which simply specifies that practitioners can refer to study results as a means of setting expectations for what the treatment's effect would be on a control or placebo group relative to the treated group, rather than ridiculously conducting a trial for every individual patient (which was the construction that was proposed by Defendants).
Judge Du's construction of "compared to" for this claim is well-captured in this excerpt from her Claim Construction Order:
"Defendants rely on the example in the specification of the ‘728 patent wherein the practitioner considers four measured values, specifically the “lipid parameters of at least one subject who is administered AMR101 both before and after a treatment period, and the lipid parameters of a control subject both before and after the treatment period.” (Id. at 37.) However, this construction of the term would require that a practitioner of the method “conduct a clinical trial every time he treats a patient,” a seemingly absurd result. (ECF No. 113 at 17.) At the Hearing, Plaintiffs relied on Allergan, Inc. v. Sandoz, Inc., No. 6:11-cv-441, 2013 WL 13141188 (E.D. Tex. Mar. 28, 2013), to argue that the clinical trials required for VASCEPA®, which are in the intrinsic evidence, would also be available to a POSA on the labeling of the product, and this data would provide a POSA with enough context to appreciate how to perform a comparison. By performing a comparison between what happens when the treatment is administered and versus what would otherwise happen to a second subject, "compared to" merely "defines the magnitude of the lipid effect or the avoidance of undesirable lipid effects" and not the specific method advocated for by the Defendants. The court agrees and finds that the clinical data in the intrinsic record supports Amarin's view of the terms plain and ordinary meaning."
Sanjay Srivatsa 3 months ago · 0 Likes
As R. Luther states: "The key here IMO is the way Judge Du worded her court order, which demonstrates a clear error that does not require expert testimony to refute (it is a fact clearly delineated in the Kurbayashi paper). She initially points to the statistically significant difference in ApoB from baseline in the EPA group early on in the court order. But then in forming the basis of her opinion, she goes on to state “in light of the statistically-significant differential effects reported between the EPA and control groups, a POSS would have attributed the reduction in ApoB to EPA”. THIS IS DAMNING IN FAVOR OF CLEAR FACTUAL AND INTERPRETATION ERROR BY JUDGE DU.
R. Luther 3 months ago · 0 Likes
Further to my prior comment, just as the study results within the Vascepa label would "provide the POSA with enough context to appreciate how to perform a comparison", so would the Kurabayashi results have been available to a POSA at the time to provide context for performing a comparison. But because there was NO statistically significant difference in Apo B reduction in the two Kurabashi study groups, as was acknowledged by Dr. Heinecke, Kurabayashi provided NO context for a comparison. The court's construction of claim 8 of '677 requires "a comparison with what would happen when the treatment is administered versus what would happen otherwise", and from Kurabayashi, a POSA at the time would have learned only that there was NO statistically significant difference between what would happen to the Apo B levels of a subject taking EPA/estriol "versus what would happen otherwise." Or, using Judge Du's own words from her Kurabayashi findings in her decision, there was no "statistically-significant differential effects reported between the EPA and control groups." Given that fact, it can be concluded, under the court's construction of claim 8, that Kurabayashi taught a POSA at the time nothing with respect to Apo B reduction, notwithstanding Dr. Heinecke's erroneous interpretation of the court's construction as not requiring a comparison of Apo B reduction in the EPA/estriol group with anything at all in order to render claim 8 of '677 obvious.
With regard to whether Amarin can argue this on appeal, it's important to note that throughout the trial, Amarin repeatedly referred to the court's claim construction on this issue as requiring a comparison with an untreated subject or group, which is consistent, I believe, with the court's understanding of the construction. And, as far as I'm aware, at no point during the trial, other than in Heinecke's response to Dr. Toth's report, did Plaintiff's challenge Amarin's characterization of the construction or advance Heinecke's theory that claim 8 does NOT require a comparison to an untreated group or subject.
Now why does this all matter for the appeal? I think it becomes important if, during any consideration of Kurabayashi, Defendants' were to claim that even if Judge Du mistakenly interpreted Table 3 of Kurabayashi to indicate a statistically different effect BETWEEN the EPA+estriol and estriol-only groups, which appears to be the case, the court's construction of claim 8 still would not require a comparison to an untreated group (Heinecke's theory), and therefore Kurabayashi still would have taught that EPA+estriol reduces Apo B. Under the proper interpretation of the court's construction, such a conclusion would be incorrect.
So to the extent Kurabayashi is important to the appeal, this subtopic could be meaningful. Given what appears to be the possibility of multiple errors of fact related to Kurabayashi (e.g. Judge Du's apparently erroneous claim that Kurabayashi was not considered by USPTO examiner; Judge Du's apparent misinterpretation of Table 3 data; Kurabayashi's use of something other than purified EPA (i.e. EPA + estriol), when claims require a mono-therapy of purified EPA), the issue of Heinecke's interpretation of the claim construction could become relevant.
R. Luther 4 months ago · 0 Likes
(Below is corrected version of my previous comment. Only change is “. . . Defendants’ torturously literal interpretation of the original language” replacing “. . . Plaintiff’s torturously literal interpretation of the original language.”)
I would strongly disagree with your analysis of the claim 8 of '677 construction issue. In Judge Du's claim construction order regarding the "compared to placebo" construction, her final construction in no way eliminates a "comparison" from the claim. Her decision on the construction was simply a rejection of Defendants' attempt to avoid infringement via an "absurd" proposed construction under which every practitioner would be required by the claim to conduct a study to compare treated subjects to a placebo control group. In order to avoid such an absurd construction, Judge Du accepted Plaintiff's alternative construction that replaces "compared to a placebo group" with "a comparison with what would happen when the treatment is administered versus what would otherwise happen", agreeing with Plaintiff's argument that any POSA would understand the "plain and ordinary" meaning of "compared to a placebo group". Amarin pointed out, and Judge Du agreed, that the results of the clinical trials required for Vascepa "would also be available to the POSA on the labeling of the product, and would be "intrinsic evidence" that "would provide the POSA with enough context to appreciate how to perform a comparison." In the case of Kurabayashi, the results of the estriol-only group represent the same " intrinsic evidence" that would be available to a POSA to help the POSA "define the magnitude of the lipid effect or the avoidance of the undesirable lipid effects".
So what happened here is that Judge Du rejected Defendants' "absurd" construction and accepted Plaintiff's practical solution that offered a construction that preserved the intent of claim 8 while avoiding Defendants’ torturously literal interpretation of the original language. But make no mistake, the original requirements of claim 8 remain the same under the court's construction; that is, the claim still requires that the efficacy of the treatment be confirmed by a comparison to an untreated group.
R. Luther 4 months ago · 0 Likes
I would strongly disagree with your analysis of the claim 8 of '677 construction issue. In Judge Du's claim construction order regarding the "compared to placebo" construction, her final construction in no way eliminates a "comparison" from the claim. Her decision on the construction was simply a rejection of Defendants' attempt to avoid infringement via an "absurd" proposed construction under which every practitioner would be required by the claim to conduct a study to compare treated subjects to a placebo control group. In order to avoid such an absurd construction, Judge Du accepted Plaintiff's alternative construction that replaces "compared to a placebo group" with "a comparison with what would happen when the treatment is administered versus what would otherwise happen", agreeing with Plaintiff's argument that any POSA would understand the "plain and ordinary" meaning of "compared to a placebo group". Amarin pointed out, and Judge Du agreed, that the results of the clinical trials required for Vascepa study results "would also be available to the POSA on the labeling of the product, and would be "intrinsic evidence" that "would provide the POSA with enough context to appreciate how to perform a comparison." In the case of Kurabayashi, the results of the estriol-only group represent the same " intrinsic evidence" that would be available to a POSA to help the POSA "define the magnitude of the lipid effect or the avoidance of the undesirable lipid effects".
So what happened here is that Judge Du rejected Defendants' "absurd" construction and accepted Plaintiff's practical solution that offered a construction that preserved the intent of claim 8 while avoiding Plaintiff's torturously literal interpretation of the original language. But make no mistake, the original requirements of claim 8 remain the same under the court's construction; that is, the claim still requires that the efficacy of the treatment be confirmed by a comparison to an untreated group.
Andrew Fleischman 4 months ago · 0 Likes
The key here IMO is the way Judge Du worded her court order, which demonstrates a clear error that does not require expert testimony to refute (it is a fact clearly delineated in the Kurbayashi paper). She initially points to the statistically significant difference in ApoB from baseline in the EPA group early on in the court order. But then in forming the basis of her opinion, she goes on to state “in light of the statistically-significant differential effects reported between the EPA and control groups, a POSS would have attributed the reduction in ApoB to EPA”.
This proves that Judge Du misunderstood what that there was no differential between groups, only compared to baseline. And that she used this as a key point in making the decision of obviousness. This iOS not an instance in which she chose to believe Heinecke over Amarin experts since Heinecke agreed there was no differential effect. This was simply a mistake. There is no question from a legal standpoint that clear errors like this are fair game for argument on appeal and it’s even possible a judge Du doesn’t appreciate the error and upon correction it would change her own opinion.
David Shirley 4 months ago · 0 Likes
Thanks for your insight Mr. Silbersher. Coming back to the following on page 66 of the Judge's Final Verdict: "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." Is this not factual error that can be argued? The Patent Examiner DID consider the Kurabayashi study (even though not cited) and used that to show obviousness of the Apo B reduction ("“the PTO did not have all material facts before it, its considered judgment may lose significant force[.]” To me she is obviously saying A (he didn't examine this prior art so the court can overrule the patent since not examined) when in reality it was B (the examiner did examine the prior art in his decision to approve patent). Appreciate your input. Best, David
