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Do you really believe generics can continue to grow the market with no promotion, assuming Amarin were to cease its efforts?
With no ability to promote the CV indication, and with no DTC, how would the generics develop the US market in any meaningful way beyond where it is now?
Under your assumptions, what would you expect sales to be for Hikma at the end of 2021? At what rate do you think it will grow in the following years with no promotion of the CV indication? Do you think it will be "selling itself" for the CV indication by end of 2021?
Alternatively, what would you expect the sales to for Amarin, if they had exclusive control of the market, by end of 2022, with full promotion of the CV indication?
I would argue that HIkma would do much better owning most of the mature market beginning in 2023/24 than they would owning most of it beginning next year with no CV promotion thereafter. I don't think the exclusivity for Hikma in the near-term comes close to outweighing the value of a non-exclusive share of the fully developed market. They can only get that with Amarin's continued promotion of the CV indication.
Not exactly. I don't see the need for any agreement of any kind with the generics. They'll do whatever they do based on what will make them the most money. And keep in mind that it's not lost on any of the parties that what is at stake here is the market for a drug that will potentially be the best-selling of all time, so A LOT of careful thinking will be going into everyone's next moves. This will likely be the most important business decision anyone involved will ever make, and they know it.
Despite the legal setbacks, Amarin is still the key player here. The generics need Amarin to do its part if they're going to get what they want, and that part is to build the US market using their exclusive right to market Vascepa for the CV indication. If the generics "poke the bear" too hard by rushing into the market, they risk losing this monumental opportunity to make a lot of money for many years. So everyone involved, in my view, will be guided by purely economic realities, and that will effectively result in the same actions that a formal settlement would accomplish.
As a check on the overall investment thesis here, and setting aside the recent US litigation drama, I would just ask yourself what you think the global market for icosapent ethyl will be in 5 years. Then calculate what you think Amarin's share of that market will be. Then consider today's valuation of Amarin.
Happy to explain may take on this.
I used the term "joint venture" to capture the fact that both Amarin and the generics want the same thing. They all want to see the largest possible US market for Vascepa. The only way that happens is if Amarin continues a full-court marketing push based on the CV indication. If Amarin pulls back those efforts, everyone loses in the long run. If Amarin continues those efforts, with the informal understanding that generics remain out of the market until it's more mature, then everyone wins in the end. It's not the long-term exclusivity that Amarin had hoped for, but it gives them several lucrative years of de facto US exclusivity while they build their ROW business. The generics enter when the market is firmly established, at which point they each capture maybe $1B+ in annual revenues for what could be many years. The alternative is they enter now and they generate maybe $100M in annual revenues, with no legal ability to grow the market through promotion of the primary growth driver (CV indication), which Amarin controls exclusively.
Pay-to-delay agreements, where a generic is paid to stay out of a market they have rights to enter, are largely prohibited. When the generics prevailed in court, they won those rights.
I would agree that there are lots of stumbling blocks for other generics to enter the market, so I’m not concerned about a stampede of other competitors.
I think the likely universe of Vascepa and generic Vascepa marketers will be limited to Amarin/Hikma/Reddys/Teva.
I see no scenario where the district court’s decision gets vacated. But again, I don’t think it matters. In my view, if the generics want to maximize this opportunity, they’ll just wait until the market is fully developed, or at least until the adoption of Vascepa as a CV therapy has much more momentum than it does now. That’s how they will get the benefit of a large, established customer base, created by an intensive and prolonged marketing push by Amarin for the CV indication. You really have to think of Amarin’s efforts at this point as being an undocumented joint venture of sorts between Amarin and the generics.
I would expect the generics to wait at least two years before launching. If I were them, I’d wait until Vascepa is essentially selling itself based on a successful education campaign by Amarin. That’s not the case today, but it will be eventually.
They legally can’t pay them to stay out of the market. Additionally, any deal with one generic doesn’t block any others from entering the market. But I don’t think that matters. Putting myself in the shoes of any CEO of a generic company, I have a really hard time coming up with a compelling argument for launching anytime soon. Amarin still has very powerful leverage in their exclusive ability to promote the CV indication, as it’s that indication, and not >500 trigs, that will turn icosapent ethyl into a $10B+ market. If Amarin turns off their promotion engines tomorrow, the generics effectively lose most of that future CV market.
From the perspective of the generics, there is MUCH more value in staying on the sidelines for a while and rooting for Amarin to grow the CV market as quickly as possible, and then stepping in once that market is mature. Consider the value of inheriting a US customer base of, say, 10 million customers who will be buying your drug for the rest of their lives, versus simply grabbing a piece of today’s small customer base, with no ability to promote the primary indication.
Scenario 1: Generics launch now, with no ability to promote CV indication, and the real threat of Amarin ceasing US promotion, thereby limiting market opportunity to some portion of less than $1B.
Scenario 2: Generics hold off on launch, let Amarin grow market to $2B+ over next three years, then launch and grab majority of that fast growing market where the benefits of Vascepa have become widely understood.
Given that this is a lifelong medication, it would seem illogical for generics to not let Amarin fully develop the market before they swoop in and take the bulk of an established customer base who will be taking the drug for the rest of their lives.
If generics launch now, they forfeit most of that long-term opportunity. That seems like a bad business decision.
Tough day at the office for Jonathan Singer.
It would be hard to come away from today's oral arguments without diminished hopes for a reversal, given the negative slant of Dyk's line of questioning and Singer's fumbling of the Novo questions from both Dyk and Reyna. A better panel for Amarin might have made the difference, but we'll never know.
However, as an Amarin shareholder knows, nothing is a sure thing, so it's worth considering what rays of hope might exist for a surprise reversal. I can think of the following:
Dyk is clearly a strong Novo adherent, as demonstrated by his lead question, so there was probably zero chance of converting him on the major issues. But I think it's noteworthy that at every opportunity, Singer tied all the issues raised by Dyk and Reyna back to two very specific issues: 1) the DC's initial prima facie conclusion "bleeding into" subsequent secondary indicia analysis; and 2) the weighing of secondary indicia against each other. While Singer's weak responses to the Novo questions likely conceded that issue in the minds of Dyk (for certain) and Reyna (likely), the court's inclination on the other two issues were not so clear.
The "bleeding into" argument, which holds that even though the district court may have technically considered all four Graham factors before reaching a final legal conclusion with respect to the prima facie case, it's initial prima facie conclusion infected ("bled into") and effectively diminished/weakened the secondary indicia when using those indicia as a safeguard against hindsight. Singer offered examples of skepticism and long-felt need both being weakened to support that argument. None of the judges commented on that argument, so we just don't know if there's any traction there for a possible reversal. Singer was given the time to really lay out the theory, and then Reyna directed him back to a discussion of Novo, at which point Singer probably hit the low point in his legal career when he struggled badly to distinguish Amarin's case from Novo.
More importantly, in my view, is the issue of the weighing of the secondary considerations against each other. As I outlined in a prior post, the paragraph on page 69 of the district court's decision, which explicitly articulated the court's methodology for the weighing, would be the most vulnerable issue for a reversal. While Dyk seemed unconvinced by Singer's argument on the issue, suggesting that the district court didn't exactly weigh the indicia against each other, both Reyna and Hughes were silent on the subject. As I've said previously, it would take some linguistic gymnastics to argue that Judge Du didn't mean what she said about the weighing, so I think it's possible that Reyna and Hughes, with their silence, were agreeing with Singer's take on the issue. If so, a reversal or affirmation would come down to whether or not Reyna and Hughes found the erroneous weighing to be a severe enough procedural lapse to require a reversal. If there was anything positive for Singer in today's arguments, it was that he did do a very nice job of quickly summarizing the weighing issue at the very end of his rebuttal, and those were the last words the panel heard. That finale, I believe, underscores Singer's understanding of how important the weighing issue is to the chances for reversal.
It's also worth noting that there were several major topics that really didn't get addressed in any meaningful way today, including the significance of the Kurabayashi error, and the entire two population issue, so it would be a mistake to conclude that the panel's deliberations hinge entirely on the substance of today's oral arguments. That said, I think Amarin's bad luck on the panel composition makes a reversal, which are always difficult, that much less likely.
I’ve not sold out. I’ve been adding shares since the district court decision.
The tenor and substance of this board since the decision has kept me away. I won’t offer a detailed analysis of the last brief here, but will say that I believe Singer has given Amarin it’s best chance for a reversal. My expectation is that the infamous “weighing of secondary considerations” will offer the panel non-controversial grounds for reversal that avoid the philosophical disputes among the federal circuit. That said, I don’t think that one error, in isolation, necessarily guarantees a reversal, hence the importance of Singer’s arguments in support of the other issues (e.g. >500mg, Cyclobenzaprine citation, Kurabayashi, etc). In total, Singer’s arguments should give the panel adequate confidence that reversal is warranted.
Is it possible that the panel finds that, while errors were made, they do not warrant reversal? Yes. But I would be surprised by that given the facts at hand.
I’ll add that I also believe the following:
- ROW has been significantly undervalued
- GIA in Europe is best course for maximizing shareholder value
- a decision on the briefs is a possibility
- oral arguments will provide meaningful visibility into the court’s leanings (it will be the most important and dramatic 15 minutes of Amarin’s life. Can’t wait.)
Best of luck to all.
The reply brief from the generics was as expected. They went to great lengths to promote a narrative that relies on the impression that Amarin's case is weak on multiple points. However, for the generics there is no getting around the fact that central to the district court's finding of obviousness is a major procedural error that the appeals court will have no choice but to address. Setting aside the reply brief for a moment, it's illuminating to revisit the actual language of Judge Du's opinion as it relates to the law.
Here it is, in all its glory:
vii. Weighing These Secondary Considerations
The Court thus finds that the satisfaction of long-felt need and commercial success secondary considerations weigh in Plaintiffs’ favor, and the remaining secondary considerations weigh in Defendants’ favor. More specifically, the Court finds that Vascepa is a commercial success even though it has not yet turned a profit, and that there was long felt need for a single pill that reduced TG levels without increasing LDL-C levels. However, these secondary considerations are outweighed by the fact that the Court found Plaintiffs’ other proffered secondary considerations favor Defendants. Thus, at best, Plaintiffs have presented weak evidence of the existence of secondary considerations, which do not overcome the Court’s finding that all Asserted Claims are prima facie obvious. See, e.g., ZUP, 896 F.3d at 1373 (holding that “a strong showing of obviousness may stand even in the face of considerable evidence of secondary considerations”).
For the reasons discussed above, in view of all four Graham factors (including alleged secondary considerations), Defendants have proven by clear and convincing evidence that all Asserted Claims are invalid as obvious under 35 U.S.C. § 103.
The generics can say what they will, but the appellate panel will look long and hard at the above conclusory paragraph from the decision, as it represents not just major judicial error (as there is no basis in law for the "weighing" methodology), but error that very likely yielded a different finding (obviousness) than would have been reached had the error not been committed. The district court, notwithstanding the generic's desperate attempt to deny as much, clearly and erroneously assigned negative values to the "unproven" objective indicia in its calculation that yielded a finding of "weak evidence of the existence of secondary considerations". In effect, the evidence of secondary considerations was only rendered weak by the courts erroneous discounting of their value based on the flawed "weighing" methodology. If the erroneous "weighing" made them weak, what were they before? When the district court writes, ". . . these secondary considerations are outweighed by the fact that the Court found Plaintiff's other proffered secondary considerations favor Defendants. Thus, at best, Plaintiffs have presented weak evidence of the existence of secondary considerations, which do not overcome the Court’s finding that all Asserted Claims are prima facie obvious", the court is explaining exactly, in no uncertain terms, how it got to its obviousness conclusion, and that explanation provides the appeals court with a blueprint for the district court's error. This is not the inconsequential error that the generic's are attempting to pass it off as. It's a monumental error that was at the heart of the district court's obviousness finding.
Another interesting point from the district court's decision, related to Mori:
In the district court's language below, you can see that the finding of prima facie obviousness was based largely on the court's dismissal of Dr. Toth's testimony in support of non-obviousness. The court based that dismissal on three grounds that , we now know, can all be pretty easily refuted. First, the court claims that, based on Mori, Toth was wrong when he stated about the prior art that "all these treatments increased LDL-C in patients with very high triglycerides". Mori, as we now know per Bhatt's recent paper, showed exactly what Toth stated, that there was no statistically significant differential effect on LDL between the DHA and EPA groups. And the court's second dismissal of Toth's testimony, related to Von Schacky's interpretation of Mori, was also factually incorrect, as it turns out that Von Schacky was right in concluding that Mori showed no difference in LDL-C effects between EPA and DHA. And the third dismissal of Toth testimony is based on the very weak argument that anything from 1977 would, by definition, not be considered relevant to a POSA in 2008. Now, the issue of admissibility of the new Mori information to the appeals case takes on even more significance, as the statistically correct interpretation of Mori largely undercuts the district court's critical finding of prima facie obviousness. Add to that the fact that the district court, had it followed proper procedure for applying the four Graham factors, would likely have not reached a conclusion of prima facie obviousness, even given the dismissal of Toth's testimony, and you have the makings of a real dismantling of the district court's decision. But obviously, the big question here is if/how the correct Mori analysis gets into the appeal.
The Court therefore finds that Defendants established by clear and convincing evidence at Trial that all Asserted Claims are prima facie obvious. Plaintiffs arguments to the contrary are unavailing. Many of Plaintiffs’ arguments depend on the premise that POSAs as of March 2008 would not have expected that using a composition of purified EPA would not increase LCL-C levels. (ECF No. 379 at 22-23.) But this premise is not supported by the evidence. To explain, Plaintiffs primarily point to testimony from Dr. Toth to support this premise. But there are at least three issues with Dr. Toth’s testimony. First, he agreed under questioning that, as of “March 2008 [. . .] the prior art reflect[ed] that all these treatments increased LDL-C in patients with very high triglycerides.” (ECF No. 370 at 1574:1-1575:1.) But that cannot be correct, because Mori taught that EPA did not increase LDL-C levels like DHA did. (Ex. 1538 at 3.) Second, Dr. Toth testified that von Schacky contributed to his view that all TG-lowering therapies increase LDL-C levels. (ECF No. 370 at 1697:9-1703:7.) But as Defendants point out (ECF No. 378 at 26), von Schacky did not correctly summarize Mori. Specifically, von Schacky, citing Mori, wrote, “In more recent comparative studies, no effects of either EPA or DHA were seen on total cholesterol, HDL, or LDL levels.” (Ex. 1605 at 5.) But even Dr. Toth agreed on cross- examination that is not what Mori said. (ECF No. 371 at 1847:8-17.) Mori actually found that LDL-C increased with DHA, but not EPA. (Ex. 1538 at 3.) Third, part of Dr. Toth’s opinion, and Plaintiffs’ argument, is based on the Carlson reference from 1977. (ECF No. 377 at 43-44 (citing ECF No. 370 at 1577:22-25 and Ex. 1026.).) The Court is unpersuaded that an article from 1977 reflects the knowledge of a POSA in 2008. Thus, Plaintiffs’ argument, in part based on Dr. Toth’s testimony—that a POSA would have thought that both DHA and EPA would cause an increase in LDL-C in March 2008—lacks evidentiary support. The Court accordingly rejects this argument.
Lastly, as others have noted, the attempt by generics to claim that the district court, in its decision, was not stating that the court believed that the PTO was unaware of Kurabayashi when issuing the patents in suit, is ridiculous in light of the actual language below from the decision:
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.
So it's possible "unexpected benefit" could make its way into the appeals court's consideration of the district court's obviousness finding.
As for the issues of prima facie/rebuttal methodology and the related burden shifting, it will be interesting to see how Singer takes on the Novo v. Cyclobenzaprine citation showdown. The generics obviously are leaning heavily on convincing the court to look at this case through a Novo lens, and Amarin is banking on a Cyclobenzaprine perspective. I think it's fair to say that the generics mischaracterized Cyclobenzaprine in several key ways in their brief in order to encourage a Novo view, so I think Singer, who was winning counsel on Cyclobenzaprine, and who obviously knows this stuff better than anyone in the world, will have a strong response.
One thing about Cyclobenzaprine that is encouraging with respect to Amarin’s appeal is the aggressiveness with which the court dismantled the district court’s decision once the panel found it to be built on flawed facts and procedure. Amarin is similarly arguing that the district court was led down an erroneous path by the defendants, compounded by procedural errors, and if Cyclobenzaprine is any guide, Amarin can rest assured that the appellate panel won’t hesitate to blow up the district court’s decision if they find it similarly flawed. Given the facts of Amarin’s case, it’s not hard to argue that the errors here, both in number and import, exceed those of Cyclobenzaprine.
While one might be concerned that panel composition will be determinative here based on the panel’s collective views on prima facie obviousness theory, I would think that regardless of the panel composition, it will be very difficult for any panel to give the district court a pass on the multiple errors that appear to be irrefutable, and which were, in combination, determinative with respect to the obviousness finding (e.g. weighing secondary considerations against each other; Kurabayashi “not considered”; misreading of Kurabayashi results; “unaware of Mori”, etc.).
This excerpt from the Cyclobenzaprine decision is illuminating as it relates to concerns here about panel composition:
* * * * *
“After the district court found that Mylan and Par proved the asserted claims obvious, it considered Cephalon's proof of objective considerations of nonobviousness to determine whether Cephalon's proofs were sufficient to “rebut” that obviousness determination. Specifically, the district court considered Cephalon's evidence of the failure of others to make the patented invention; ?longfelt but unsolved needs fulfilled by the patented invention; ?commercial success of the patented invention; ?and unexpected results produced by the patented invention. See Graham, 383 U.S. at 17–18, 86 S.Ct. 684; ?Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1369 (Fed.Cir.2007). The district court found Cephalon's evidence insufficient to rebut Mylan's and Par's showing. The district court erred, however, by making its finding that the patents in suit were obvious before it considered the objective considerations and by shifting the burden of persuasion to Cephalon. In doing so, the district court contravened this court's precedent requiring that a fact finder consider all evidence relating to obviousness before finding a patent invalid on those grounds, and the court imposed a burden-shifting framework in a context in which none exists.
1.
The premature nature of the court's obviousness finding is apparent. Before it reached the objective considerations, the district court stated that the claimed PK profile “would have been obvious to one of skill in the art at the time of the invention” and that “a person of ordinary skill in the art would have been motivated to take a group of known elements to create an extended release version of cyclobenzaprine, and [would have had] a reasonable expectation of success in doing so.” It was not until after the district court found the asserted claims obvious that it proceeded to analyze the objective considerations, or what it called the “secondary considerations.”
2.
The district court's error is understandable because this court has inconsistently articulated the burden of proof applicable to an obviousness defense in district court litigation. It was error nonetheless.
In Stratoflex, Inc. v. Aeroquip Corp., we held that a fact finder in district court litigation may not defer examination of the objective considerations until after the fact finder makes an obviousness finding:
It is jurisprudentially inappropriate to disregard any relevant evidence on any issue in any case, patent cases included. Thus evidence rising out of the so-called “secondary considerations” must always when present be considered en route to a determination of obviousness· Indeed, evidence of secondary considerations may often be the most probative and cogent evidence in the record. It may often establish that an invention appearing to have been obvious in light of the prior art was not. It is to be considered as part of all the evidence, not just when the decisionmaker remains in doubt after reviewing the art.
713 F.2d 1530, 1538–39 (Fed.Cir.1983) (citations omitted). Many subsequent cases have expressly followed Stratoflex's directive that courts consider all objective evidence before reaching an obviousness conclusion. See Ruiz v. A.B. Chance Co., 234 F.3d 654, 663 (Fed.Cir.2000) (“Our precedent clearly establishes that the district court must make Graham findings before invalidating a patent for obviousness.”); ?Cable Elec. Prods. v. Genmark, Inc., 770 F.2d 1015, 1026 (Fed.Cir.1985) (quoting Stratoflex, 713 F.2d at 1539) (“The opinions of this court have suggested that evidence on these secondary considerations is to be taken into account always, ‘not just when the decisionmaker remains in doubt after reviewing the art.’?”); ?Simmons Fastener Corp. v. Illinois Tool Works, Inc., 739 F.2d 1573, 1575 (Fed.Cir.1984); ?(“The section 103 test of nonobviousness set forth in Graham is a four part inquiry comprising, not only the three familiar elements (scope and content of the prior art, differences between the prior art and the claims at issue, and level of ordinary skill in the pertinent art), but also evidence of secondary considerations when such evidence is, of course, present”); ?Richardson–Vicks Inc. v. Upjohn Co., 122 F.3d 1476, 1483 (Fed.Cir.1997) (holding that “we must consider all of the evidence under the Graham factors before reaching our decision”); ?Rockwell Int'l Corp. v. United States, 147 F.3d 1358, 1366 (Fed.Cir.1998) (following Richardson–Vicks?); ?and Kan. Jack, Inc. v. Kuhn, 719 F.2d 1144, 1150–51 (Fed.Cir.1983) (finding that a district court's consideration of commercial success complied with “the basic requirement that all evidence touching the obvious-nonobvious issue be fully considered before a conclusion is reached on that issue” (citing In re Sernaker, 702 F.2d 989, 996 (Fed.Cir.1983))).
While many panels of this court have adhered to Stratoflex's directive, some instead have spoken of the obviousness analysis in terms of a “prima facie” case which must then be “rebutted” by the patentee. Under that framework, a court inquires whether the party challenging validity has proven a “prima facie” case of obviousness, based only on reference to the patent and the proffered prior art, and only then considers objective evidence, asking whether such evidence is sufficient to overcome the prima facie case.3
Despite this language, however, those cases should not be interpreted as establishing a formal burden-shifting framework. This is so for a number of reasons. First, a review of those cases indicates that in none was the placement of the burden with respect to evidence of objective considerations, or the timing of the fact finder's consideration of that evidence, determinative. See supra n. 3.
Second, even panels that have used the “prima facie” and “rebuttal” language generally have made clear that a fact finder must consider all evidence of obviousness and nonobviousness before reaching a determination. For example, in Iron Grip Barbell Co. v. USA Sports, Inc., while the panel did hold that “there is no objective evidence to rebut the strong showing of obviousness based on the prior art,” 392 F.3d 1317, 1325 (Fed.Cir.2004), it also cautioned that, in “determining the question of obviousness, inquiry should always be made into whatever objective evidence of nonobviousness there may be.” Id. at 1323 (quoting Vandenberg v. Dairy Equip. Co., 740 F.2d 1560, 1567 (Fed.Cir.1984)). In Transocean Offshore Deepwater Drilling, Inc. v. Maersk Contractors USA, Inc., while the panel observed that, “f all of the factual disputes regarding the objective evidence resolve in favor of [plaintiff], it has presented a strong basis for rebutting the prima facie case [of obviousness],” the panel stated, “[t]o be clear, a district court must always consider any objective evidence of nonobviousness presented in a case.” 617 F.3d 1296, 1305 (Fed.Cir.2010). And in WMS Gaming Inc. v. International Game Technology, while the panel stated that “[t]he objective evidence of nonobviousness may be used to rebut a prima facie case of obviousness based on prior art references,” it also stated that “[t]he consideration of the objective evidence presented by the patentee is a necessary part of the obviousness determination.” 184 F.3d 1339, 1359 (Fed.Cir.1999). Thus, a reading of these cases that permits a fact finder to reach a conclusion of obviousness before considering all relevant evidence, including evidence of objective considerations, would not only conflict with Stratoflex's directive that objective considerations are “to be considered as part of all the evidence, not just when the decisionmaker remains in doubt after reviewing the art,” 713 F.2d at 1538, but would ignore their actual holdings.
Next, the Supreme Court has never imposed nor even contemplated a formal burden-shifting framework in the patent litigation context. It has, instead, required that all evidence relevant to obviousness or nonobviousness be considered, and be considered collectively. In Graham, the Court stated that “[s]uch secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented,” along with the scope and content of the prior art, the differences between the prior art and the claims at issue, and the level of ordinary skill in the pertinent art. 383 U.S. at 17–18, 86 S.Ct. 684. Notably, the Court did not characterize the objective factors as after-the-fact considerations or relegate them to “secondary status.” The Court, rather, indicated that the objective considerations have broader applicability, noting that, “[a]s indicia of obviousness or nonobviousness, these inquiries may have relevancy.” Id. The Court recently reaffirmed this approach to objective considerations when it described the obviousness inquiry as “expansive and flexible” and noted that Graham “invite[s] the courts, where appropriate, to look at any secondary considerations that would prove instructive.” KSR, 550 U.S. at 415, 127 S.Ct. 1727. And, in i4i, the Court reaffirmed both the scope and placement of the burden of proof in these circumstances. 131 S.Ct. at 2245 n. 4.”
For anyone interested in a more complete understanding of the issues at hand in Amarin’s appeal case, and of how the appellate panel will be thinking about this case, I strongly recommend that you read the Cyclobenzaprine decision in its entirety. Cyclobenzaprine was Singer’s case, with uncanny overlaps with Amarin’s current appeal, and the decision explains in clear language how the relevant precedents will be applied by the court. As you read the decision, it’s quite clear where and how you can substitute the facts of Cyclobenzaprine with the very similar facts of Amarin v. generics.
https://caselaw.findlaw.com/us-federal-circuit/1608878.html
There is nothing in your explanation that doesn’t make sense. Despite that, I do think that the generics are still likely, in their reply brief, to rely heavily on the “someone with trigs of exactly 500 mg/dL” argument, arguing that they need only show that such a subject would be likely to respond to EPA therapy in a manner similar to a subject with trigs under 500 mg/dL in order to prove obviousness. They will argue that the language of the claims simply doesn’t require that they consider what happens in a mechanistically differential respect as you go higher than 500 mg/dL, and that, per testimony at trial, there is nothing biologically significant that happens at exactly 500 mg/dL that doesn’t happen at, say, 450 mg/dL.
But I just don’t think that the appellate panel or Singer will spend Singer’s 15 minutes of oral argument time getting into the weeds of this subject, as I think the hindsight issues, as argued so effectively by Singer in the opening brief, negate the significance of the prior art entirely, as they powerfully demonstrate that when you properly apply the secondary considerations to a preliminary impression of prima facie obviousness, you find that the initial impression of obviousness is overcome by clear evidence of non-obviousness (‘long-felt need’ and ‘commercial success’, at a minimum, and very possibly ‘unexpected benefit’ when Kurabayashi gets dismissed from obviousness consideration due to yet another irrefutable district court error).
The district court’s errors of fact and procedure are simply too glaring and impactful for the appellate court to simply overlook. As Singer stated so succinctly, “That can’t be the law”.
Regarding the generics' response to Amarin's opening brief, which is due next week, I think it's highly likely that the generics will focus on the district court's agreement with their argument that the prior art had only to make EPA treatment without LDL increase obvious as it applied to a subject with triglyceride levels of exactly 500 mg/dL. Judge Du concurred with the generics' argument that it would be error to find the patents in suit valid based on arguments related to what had historically happened to LDL levels in severely hypertriglyceridemic patients treated with triglyceride lowering therapies.
As Judge Du wrote in her decision:
"Critically, in view of the claim language, obviousness is proven as long as there was a reasonable expectation that 4 g/day of 96% purified EPA would achieve the claimed effects (i.e., not cause an LDL-C increase) in patients with triglycerides of exactly 500 mg/dL. “It is a long-established rule that claims which are broad enough to read on obvious subject matter are unpatentable even though they also read on nonobvious subject matter.” In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1281 (Fed. Cir. 2015) (quotation omitted). Thus, to prove obviousness, Defendants do not need to prove that a skilled artisan would have reasonably expected success in achieving the claimed effects in patients with triglycerides above 500 mg/dL, much less substantially above that level."
Based on the above theory, the findings of Mori, for example, were found by the district court to argue for obviousness. The fact that Mori was conducted on a non-severely hypertriglyceridemic population was not found to be relevant, as the results only had to be applicable to a 500 mg/dL subject. In Judge Du's view, the trial testimony supported the notion that a trig level of 500 mg/dL was a somewhat arbitrary designation related more to pancreatitis risk than LDL levels, and therefore, the Mori results could reasonably be applied to a subject with triglyceride levels of 500 mg/dL. The effects of triglyceride-lowering treatments on subjects with higher than 500 mg/dL would simply be irrelevant to a determination of obviousness, as Judge Du stated clearly in her opinion.
The above is important as it lays at the foundation of the district court's obviousness finding, and it undercuts Amarin's argument that any prior art not powered for severely hypertriglyceridemic populations was irrelevant. Based on Judge Du's perspective on this issue, none of Amarin's >500 mg/dL arguments held any merit at all. Hence her obviousness finding.
For this reason, I believe the >500 mg/dL argument is not Amarin's best hope for reversal, as the district court's decision indicates that the court had logical (albeit debatable) grounds for dismissing Amarin's >500 mg/DL arguments. It's not that Judge Du didn't understand the >500 mg/dL argument, she simply didn't find it at all relevant based on her legal theory.
However, none of the above diminishes the importance of secondary considerations in this case. Regardless of the extent to which the prior art suggested obviousness, the fact remains that for many years, despite the claimed obviousness of the solution to this long unmet need, no one was motivated to use this "obvious" solution to solve the problem. In my view, how the secondary considerations were applied to protect against hindsight will be the focus of the appeals panel. The district court's errors of fact and procedure with regard to the application of secondary considerations are vivid in this case, and were clearly determinative with respect to the obviousness finding. Singer did a masterful job of arguing the secondary consideration points in the opening brief, so I think Amarin will go into the oral arguments with a very strong hand. I would expect the appeals panel to quickly zero in on the secondary consideration issues with their questioning, which will back the generics into a corner from which their only escape would require that the panel overlook serious district court errors.
[In the upcoming generics' reply brief, they will likely argue that the district court's decision was sound based on the above theory. This would allow them to dismiss any challenge based on >500 mg/dL arguments. They'll also likely dismiss any claim that there was anything inappropriate about the district court's prima facie finding of obviousness, citing precedent. And regarding the claims of factual errors on the part of the district court, I would expect the generics to dismiss any "minor" factual errors (e.g. USPTO Kurabayashi consideration) as being insignificant in the face of overwhelming evidence of obviousness.]
I stepped away from iHub for a few weeks, as it seemed there wasn't much constructive or thoughtful discussion of Amarin going on here. Conspiracy theories and ad hominem attacks are not for me, nor do I think they're relevant to serious issues of concern to Amarin shareholders.
Regarding Singer's brief: As expected, I think it's the strongest brief Amarin could have possibly hoped for. They got their money's worth. Singer captured the district court's errors of procedure and fact in an accessible, exceeding well-structured net of logic, and while I don't think it's necessarily checkmate, he's definitely got them on the run.
The plot definitely thickened today with the publishing of the JAMA paper addressing the statistical issues related to Mori. It would be wildly naive to think that paper is the result of a few docs standing around and saying, "Gee, it seems like maybe that Mori study was misinterpreted. Let's publish a paper."
The publishing of that paper is undoubtably a strategic move by Singer, and there is no way the findings of that paper will not make it into the appeal arguments. The prohibition of the introduction of new evidence on appeal is not the rigid restriction that some make it out to be. There are many, many ways new evidence makes it's way into an appeal, and Singer knows how to do that probably better than anyone in the world. Additionally, evidence that was not available at the time of the trial (which the JAMA paper purportes to disclose) is treated differently than known evidence that a party could have presented at trial but did not. Furthermore, parties are free to present new evidence in briefs or oral arguments on appeal. It's just up to the discretion of the panel of appellate judges to then apply, or not apply, any prohibition of new evidence. Application can also be made to the court to submit a post-deadline amicus brief, with the court having the option of allowing the late brief provided the opposing party is given adequate time to respond.
In any case, I think the JAMA paper, coming from such an unimpeachable source, and striking at the very heart of the district court's decision, is significant to the appeal case in ways we probably don't yet know. It certainly will weigh heavy on the generics as they plot their next moves.
I guess my bottom line is that, notwithstanding the traditional handicapping of chances of success on appeal, I'd much rather be in Amarin's shoes right now. And I do think there's more intrigue to come. Anyone who thinks Amarin management and counsel are sitting on their hands waiting for oral arguments would be very mistaken.
The court can allow late filing of an amicus brief, provided defendants are given adequate time to reply.
Well, one October night in 1977 I was sitting with my dad behind home plate in Yankee Stadium. It’s Game 6 of the World Series with the Dodgers, Yankees leading the series 3-2. In the previous game, Reggie Jackson had hit a home run in his last at bat, connecting on the first pitch.
In Jackson’s first at bat in Game 6, he takes four straight balls for a walk. In his second at bat, he swings at the first pitch and sends it over the right field wall. So two swings, two home runs. Next at bat, first pitch, he hits a line drive over the right field wall. That’s three swings, three home runs. In the eighth inning, he comes up and, on the first pitch again, hits a home run over the center field wall. In four consecutive swings between the two games, he has hit four home runs to clinch the World Series.
Is there anything to be gleaned from that night? Well, in that moment, Reggie Jackson did exactly what he was paid to do. Some people are just gifted with the ability to meet a moment by rising to a singular level of excellence. It’s not luck. It’s some special combination of talent, preparation, and focus. In Jonathan Singer, Amarin has acquired their Reggie Jackson, and he’s approaching the plate.
Setting aside the understandable angst of the many shareholders here who continue to ride the Amarin roller coaster, I can't think of a more intellectually exciting moment than next week's filing of Amarin's opening appeal brief. The leading pharma litigators in the world will be stepping up to the plate for Amarin with the stakes being tens of billions of dollars and, more importantly, millions of lives. Searching the history of the pharmaceutical industry, it would be hard to come up with a more important legal document than this opening brief, as it will lay out a legal argument that will determine whether a breakthrough therapy for the leading cause of death in the US will be quickly promoted and delivered to as many Americans as possible, or whether the therapy's full-court launch will be limited to the rest of the world.
As a kid I was lucky enough to attend several historic sports events where the pre-game air in the stadium was truly electric with anticipation of what was about to unfold, and I have to admit to having the same feeling this weekend. The only difference being - this is not a game.
Fish & Richardson is great choice of counsel by Amarin. None better for this.
Amarin’s opening brief should be a doozy of a read. Let’s see what lines of argument they zero in on. Procedure, factual errors, MOA (>500 trig), Kurabayashi results, etc. We’ll know soon.
My response to Markman blog post this morning:
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 Apo 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.”
Thanks. Corrected.
Apologies for that.
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."
Thanks. Corrected
It’s still there. Go to markmanadvisors.com, click on “blog” in drop-down menu at top right.
The language of the actual patent claim is superseded by the court’s construction of the claim for the trial. See my earlier posts for excerpts from the court’s claim construction order. But you are correct given the fact that the court’s construction of the claim preserved the original intent.
Another comment I posted today to Markman blog.
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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 between 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 would still 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.
Yes, should read “Defendants’ . . .”
Below is a corrected version of my previous post. Only change is “Defendants’ torturously literal interpretation of the original language” replaces “Plaintiff’s torturously literal interpretation of the original language.”
* * * * *
Below is my comment in response to Markman's Zachary Silbersher's blog post today.
* * * * *
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.
To save people the trouble, below are the relevant excerpts from three key documents in the trial record regarding the claim construction issue. The first excerpt is from the final Claim Construction Order from the court, the second is Amarin's Opening Markman Brief, and the third is the Defendants' Responsive Claim Construction Brief.
From the court's CLAIM CONSTRUCTION ORDER:
E. “Compared To”
While the parties state that they rely on the “plain and ordinary meaning” of “compared to,” both parties have different views of what this plain and ordinary meaning is. The claims containing these terms are: claims 1, 5-8, 12, 14, and 19 of the ‘728 patent; claims 1, 4-10, and 17 of the ‘715 patent; claims 1, and 6-9 of the ‘677 patent; claims 1, 6-10, and 15-18 of the ‘652 patent; claims 1, and 6-10 of the ‘920 patent; claims 1 and 4-8 of the ‘446 patent; claims 1 and 6-9 of the ‘399 patent; claims 1, 2, 5- 14, 18-22, and 26-29 of the ‘335 patent; claims 11 and 14-17 of the ‘560 patent; claims 8 and 11-14 of the ‘650 patent; and claim 1, 4 and 5 of the ‘698 patent. (ECF No. 89 at 29 n.20.)
Plaintiff's Proposed Construction: No construction necessary; Plain and ordinary meaning
Defendants' Proposed Construction: Claim limitation and not merely a statement of intended result or effect; Plain and ordinary meaning
Plaintiffs argue that the plain and ordinary meaning of “compared to” is that the claimed effect can be compared to “the expectation if the subject did not receive purified ethyl-EPA. (ECF No. 89 at 31 (emphasis added).) By contrast, Defendants argue that “compared to” requires that a practitioner make an actual comparison with another subject or population and thus that the person practicing the method of treatment make specific measurements. (ECF No. 102 at 35-36.) The Court agrees with Plaintiffs as to the plain and ordinary meaning of “compared to” and finds that the term is not a claim limitation as indicated by Defendants.
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.
12
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.”
From DEFENDANTS' RESPONSIVE CLAIM CONSTRUCTION BRIEF
E. “Compared to . . .”
Defendants’ Proposed Construction: Claim limitation and not merely a statement of intended result; Plain and Ordinary Meaning
Amarin’s Proposed Construction: Plain and ordinary meaning
Exemplary claim language (’728 patent, claim 1)
1. A method of reducing triglycerides in a subject...comprising: administering orally to the subject about 4 g per day of a pharmaceutical composition...for a period of 12 weeks to effect a reduction in triglycerides without substantially increasing LDL-C compared to a second subject having a fasting baseline triglyceride level...
The plain and ordinary meaning of “compared to” requires the practitioner of the method to make a comparison between subjects or groups, such that the clinical effects may be observed and measured. Amarin argues, however, that construction is not necessary and that the plain and ordinary meaning of “compared to” means that the claimed effect can be compared to “the expectation if the subject did not receive purified ethyl-EPA, as described in the specification, prosecution history, and available clinical trial results.” (Amarin’s Br. at 26.) Amarin’s argument is nothing more than an attempt to read the “compared to” limitation out of the claims for purposes of establishing infringement. Under Amarin’s construction, a skilled artisan may simply prescribe the pharmaceutical composition to one subject, then compare the effect of that drug to an “intended lipid effect” or an “expectation” of what would have happened if that subject had not received the drug. Amarin’s reading of the claims is contrary to the plain language of the claims, the specifications, and statements Amarin made during the prosecution of its patents.
In a number of the asserted claims, the Effect Steps recite administering EPA-E to effect a reduction, or without effecting an increase, “compared to” the lipid parameters measured at baseline or in a placebo or control group. The concepts of reduction and increase have no meaning if only one measurement is taken, or if no comparison is made. In order to observe, for example, the claimed reduction of triglycerides, or the accompanying absence of increased LDL- C, the practitioner of the method must perform a comparison to effects observed in another subject or population. If the essential comparison is not performed by the person practicing the method of treatment, then there is no infringement under Limelight Networks, Inc. v. Akamai Techs., Inc., 134 S.Ct. 2111 (2014).
The specification discloses that the person practicing the method of treatment makes a comparison. The exemplary embodiment of the MARINE trial, as summarized in the Examples section of the specifications, discloses essential comparison steps to be performed by the practitioner while practicing the disclosed method.
A multi-center, placebo-controlled randomized, double-blind, 12-week study with an open-label extension is performed to evaluate the efficacy and safety of AMR101 in patients with fasting triglyceride levels ?500 mg/dL. The primary objective of the study is to determine the efficacy of AMR101 2 g daily and 4 g daily, compared to placebo, in lowering fasting TG levels in patients with fasting TG levels ?500 mg/dL and ?1500 mg/dL (?5.65 mmol/L and ?16.94 mmol/L).
***
The primary efficacy variable will be the percent change in fasting TG levels from baseline to Week 12. A sample size of 69 completed patients per treatment group will provide 90% power to detect a difference of 30% between AMR101 and placebo in percent change from baseline in fasting TG levels, assuming a standard deviation of 45% in TG measurements and a significance level of p<0.01. To accommodate a 15% drop-out rate from randomization to completion of the double-blind treatment period, a total of 240 randomized patients is planned (80 patients per treatment group).
(Amarin’s Br. at Ex. 4, ’728 patent at 13:26-34, 16:41-50 (emphasis added).) As disclosed in this specification, the primary objective of the exemplary method is to compare the efficacy of EPA- E with a placebo. (Wharton Decl. ¶63; Amarin’s Br. at Ex. 4, ’728 patent at 13:29-34.) The practitioner accomplishes this objective by considering at least four measured values—i.e., 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. (Amarin’s Br. at Ex. 4, ’728 patent at 15:34-36; Wharton Decl. ¶63.) As discussed above, the claims reciting that administration of EPA effects a change in lipid parameters are enabled by this exemplary method, and were drafted to capture it.
Below is my comment in response to Markman's Zachary Silbersher's blog post today.
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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.
These are salient points as they relate to the public welfare implications of Amarin's potential loss of exclusivity. They would certainly be on the mind of the appellate panel as they consider the case through the lens of the important role patents play in encouraging innovation. They're also relevant to a scenario where the appellate court encourages both sides to pursue a settlement (which the court will do), and the sides agree to settle on the condition that the district court's decision is vacated. Such a vacatur is permitted only in cases where the benefits of doing so to the two parties, the judicial system, and the public welfare are found to outweigh any harm to the public welfare caused by the removal of judicial precedent (i.e. the restoration of an invalidated patent).
I’m not sure I’m getting your point. To be granted an expedited appeal, Amarin will need the Federal Circuit to agree that Amarin, and the public, will suffer significant and irreversible hardship if the case is not expedited. Amarin’s most compelling argument, in my view, will be that there is a long list of things they will now be delaying as a result of the uncertainty created by the district court’s wrongful (in the company’s view) invalidation of the company’s patents, and the consequences of those delays will be measured in significant negative impacts on both the company and public welfare.
I don’t think distinctions between R-I and high trig indications are very relevant to the argument, as all indications for Vascepa apply to the harm to public welfare argument. And while the economic impact of a delay on the company seems to be your primary focus, I do think the public welfare argument will be heavily emphasized by Amarin in their motion.
She does.
Not really. The decision will be made based on the strength of Amarin’s argument that the circumstances require an expedited appeal, not on the merits of their case.
I would expect Amarin to argue that Vascepa is a life-saving medication, and that the stripping of their market exclusivity by the district court is hampering it’s roll-out, resulting in significant negative impact on public welfare, measured even in lost lives, in the midst of a national health crisis.
Based on the appeal timetable suggested by Thero on Monday’s call (summer), Amarin is most likely filing an Emergency Motion for Expedited Appeal. If so, it should show up on PACER in the next few days, and should include new counsel. They’ll argue that because of extraordinary circumstances they should be granted an expedited appeal.
A district court decision can be vacated post-trial under certain circumstances, particularly in cases where a post-trial settlement is conditioned on vacatur. (Hartford Cas. Ins. Co. v. Crum and Forster Spec. Ins. Co). However, such post-trial vacatur is appropriate only in exceptional cases where it is determined that some combination of benefits to the settling parties, the public interest, and the judicial system, outweigh any possible harm to the public interest derived from lost precedent.
The Eleventh Circuit in Hartford “embrace[d] the equitable nature of the Supreme Court’s Bancorp
inquiry.” It weighed “the benefits of settlement to the parties and to the judicial system (and
thus to the public as well) against the harm to the public in the form of lost precedent.” According to the
court, the “scales decisively [tipped] in favor of vacating the” district court’s orders."
Settlement is definitely still possible. Generics face some very tough business challenges (well documented here and in recent conference call) despite the district court win, and a settlement, even one that pushes a generic launch out 5 years or more, would likely put them in a stronger position than where they are now given Amarin's ability to both impede an at-risk launch and control level of demand in the market.