[author: Andrew Williams]
Last week, in Pozen Inc. v. Par Pharmaceutical, Inc., the Federal Circuit affirmed the decision of the U.S. District Court for the Eastern District of Texas that two patents that describe treating migraines by combining two known drugs in a single dose had not been shown to be obvious or inadequately described, and that in addition to these patents being infringed by three separate ANDA filers, two generic drug companies were also found to infringe a third patent to a co-formulated tablets under the doctrine of equivalents. The Federal Circuit agreed that the prior art would not have provided a motivation to combine these two drugs to a person of skill in the art, and therefore could not render the patent invalid for obviousness. The Court also agreed that one of ordinary skill in the art would understand that the inventors had possession of packaging or instructions for the use of their tablet. With regard to infringement, the Federal Circuit agreed that Pozen did not need to show testing to establish that the limitation "independent dissolution" was met by the doctrine of equivalents. Finally, the majority held that even though "substantially all" was already a "fuzzy" term, it was still entitled to equivalents.
The reference drug product at issue in this case was Treximet®, which is a combination of sumatriptan, a 5-HT receptor agonist effective at treating migraines, and naproxen, a widely known non-steroidal anti-inflammatory drug ("NSAID"). Pozen markets Treximet® in partnership with GlaxoSmithKline, and holds three patents to the co-administration of these drugs. The claims at issue in this case include:
• claim 15 of U.S. Patent No. 6,060,499 ("the '499 patent"), drawn to therapeutic packages for dispensing one or more unit doses of sumatriptan and naproxen at specific concentrations;
• claims 11, 12, 24, 26, 27, 29, and 30 of U.S. Patent No. 6,586,458 ("the '458 patent"), drawn to pharmaceutical compositions in unit dosage forms which comprise a 5-HT agonist and a long-acting NSAID; and
• claim 2 of U.S. Patent No. 7,332,183 ("the '183 patent"), drawn to a multilayer pharmaceutical tablet in which "substantially all" of the 5-HT agonist is in the first layer, and "substantially all" of the naproxen is in the second layer, and in which the dissolution of the naproxen occurs independently of the other drug.
Three generic companies, Par Pharmaceuticals, Inc. ("Par"), Alphapharm Pty Ltd. ("Alphapharm"), and Dr. Reddy's Laboratories, Inc. ("DRL") (collectively "Appellants") filed three separate ANDAs to market generic versions of Treximet®. In turn, Pozen filed suit in the Eastern District of Texas. The lower court held a claim construction hearing, followed by a five-day bench trial in which the patents-in-suit were held to be valid and infringed, either literally or under the doctrine of equivalents. However, after the claim construction ruling and before trial, Pozen stipulated to a judgment of non-infringement of the '183 patent in favor of Alphapharm, and therefor Alphapharm's only interest in the appeal was the validity of the '499 and '458 patents.
Validity – Non-obviousness
The first issue related to the lower court's non-obviousness determination that the Federal Circuit addressed was whether the claims required "simultaneous administration" of the two drugs. Par pointed out that all of the claims recited the limitation "concomitant administration," and because the District Court construed this term to mean "[g]iven in close enough temporal proximity to allow their individual therapeutic effects to overlap," than the two drugs in the prior art need not have been administered at the same time. However, the Federal Circuit was not persuaded, because all of the asserted claims also contained the limitation "unit dose form," "unit doses," or "unit dosage form(s)," and all parties agreed that these terms meant "single drug administration entity(ies)." Therefore, irrespective of the fact that the claims had the broader term, the "unit dose" limitation necessarily limited the claims to "simultaneous administration."
Even though this claim construction issue would have been determinative for an anticipation allegation, a reference that discloses administration of two drugs, albeit not at the same time, could still render a simultaneous-administration claim obvious to one skilled in the art. Therefore, the Court analyzed each of the four cited references. Interestingly, most, if not all, of these references evidenced the actual administration of these two drugs to at least one patient in "temporal proximity" to each other. Nevertheless, because these references did not tout the advantages of the combination of these drugs, they could not be used as motivation to combine sumatriptan and naproxen. In fact, most of the references highlighted other factors for the patients' positive response. For example, one of the patients in one of the references was also receiving acupuncture, and the authors attributed this to the successful treatment of the patient's migraines. A second factor considered by the Court for at least some of these references was that they did not disclose the "efficacy limitations" recited in the claims. One could argue that the particular efficacy would be "inherent" in the co-administration of the drugs, but it is important to keep in mind that one skilled in the art would not have been motivated to combine these drugs to obtain this result without an explicit teaching. As a result, the panel agreed with the District Court that appellants failed to meet their burden to rebut the presumption that one of ordinary skill in the art would not have combined these two drugs in order to benefit from the longer lasting efficacy as compared to taking either agent alone.
Par also alleged that the '183 multilayer tablet patent was obvious in view of the '499 patent combined with the prior art or the knowledge of a person of ordinary skill in the art. Par argued that the prior art taught that naproxen has low solubility in the stomach, which would impede the dissolution of sumatriptan if co-administered, and that multilayer tablets were well known in the art. However, during prosecution, the Patent Office had allowed these claims even in view of similar art. Moreover, the fact that multilayer tablets were commonly used did not necessarily mean that Pozen's claimed dosage form of these two drugs was obvious. Par also alleged that the lower court used two different meanings of "independent dissolution" in its infringement analysis and its validity analysis, but the Federal Circuit failed to see the difference. Therefore, the Court concluded that appellants had failed to rebut the presumption of validity of these claims.
Validity – Written Description
Appellants also alleged that claim 15 of the '499 patent lacked an adequate written description because it contained the limitations "therapeutic package," "finished pharmaceutical container," and "said container further containing or comprising labeling directing the use of said package in the treatment of migraine," all of which were added during prosecution, but none of which appear in the specification. The Federal Circuit, however, did not take such a narrow view of the requirement of 35 U.S.C. § 112, ¶ 1. Instead, what is required is that the specification reasonably convey to a skilled artisan that the inventor had possession of the invention. Moreover, a person comes to the patent with the knowledge of what has come before. Therefore, because it was well known in the art that pharmaceutical dosages are administered in containers or packaging with labels and inserts containing instructions, such information need not be explicitly disclosed in the specification.
The slightly troubling aspect of the Court's decision is that it appears to have taken the position that because the use of packaging or instructions would have been obvious at the time of filing, such information need not have been included in the specification. Unfortunately, what is missing from the decision is why these limitations were added in the first place. If they were added to overcome cited art, it would be somewhat inconsistent to say that the other prior art can provide the support for the new limitation being used to distinguish the invention. Nevertheless, appellants did not make such an argument, so any potential inconsistency was not in front of the Federal Circuit.
Because the Court affirmed the lower court's finding of validity of the '499 and '458 patent claims, and because apparently none of the three defendants challenged the finding of infringement with regard to these two patents, the injunction preventing all three ANDA filers from making or selling their respective products would have been maintained based solely on these patents. Nevertheless, Par and DRL appealed the finding that their respective ANDA products infringed claim 2 of the '183 patent multilayer tablet patent under the doctrine of equivalents. Pozen had stipulated to a judgment of non-infringement of the '183 in favor of Alphapharm, and so it had no interest in this part of the appeal
The following is a reproduction of claims 1 and 2 of the '183 patent:
1. A multilayer pharmaceutical tablet comprising naproxen and a triptan and, wherein: a) substantially all of said triptan is in a first layer of said tablet and substantially all of said naproxen is in a second, separate layer; and b) said first layer and said second layer are in a side by side arrangement such that the dissolution of said naproxen occurs independently of said triptan.
2. The tablet of claim 1, wherein said naproxen is in the form of naproxen sodium at between 200 and 600 mg.
Par and DRL first challenged the finding of infringement with respect to the "independent dissolution" limitation. The parties had agreed that this limitation required that "[d]issolution of naproxen . . . and triptan from the multilayer tablet occurs in the same amount of time ± 10% as when the same amount of naproxen . . . and triptan are given separately." Both Par and DRL complained that no evidence was presented at trial demonstrating that the comparison as required by the claims was ever undertaken. The District Court, however, found the required evidence in the FDA filings of these two companies, as well as the expert testimony. The Federal Circuit took it a step further, noting that under the doctrine of equivalents, Pozen was not required to show an actual comparison. Instead, Pozen only needed to show that the ANDA products performed the same function in the same way to achieve the same result as the claimed element. This, of course, begs the question of how you can show the same result without testing, but the Court nevertheless concluded that Par and DRL presented no basis for setting aside the finding of infringement.
In addition, Par and DRL challenged the finding of equivalents to the claim term "substantially all." This term was construed consistent with the specification to mean that "at least 90%, and preferably greater than 95%, of the total triptan present in the tablet is included within one distinct layer and at least 90%, and preferably greater than 95%, of the naproxen present in the tablet is included within a second distinct layer." Par formulated its tablet to avoid infringement, putting only 85% of the tablets naproxen in the second layer. Conversely, DRL formulated its tablet to have only 85% of its sumatriptan in one of the layers. Par argued that the word "substantially" was "fuzzy," and itself was already being used to capture values lower than 100%. Therefore, it argued, the claims should not be found to encompass equivalents of equivalents. DRL argued that the scope of equivalents was already within the scope of the claim, and therefore the District Court had erred in granting a range beyond this. The majority pointed out, however, that the doctrine of equivalents is not foreclosed just because a range is claimed. As such, the change from 90% to 85% could be fairly characterized as an insubstantial change. Moreover, the Court did not find that the District Court had erred in finding that the ANDA products had the same function of having "separate, distinct layers of sumatriptan and naproxen," that they achieved this function in the same way, by creating physical barriers, and that the result was the same -- separating the naproxen from the sumatriptan.
Judge Clevenger dissented with respect to this finding. He noted that the District Court never directly addressed the issue whether a layer with 85% was an equivalent to a layer of 90%, and preferably 95%. Instead, he believed that the lower court skirted the numerical equivalents issue by only asking whether the accused product had the equivalent of a second layer with substantially all of the required ingredient. He, therefore, would not have affirmed this finding.
Pozen Inc. v. Par Pharmaceutical, Inc. (Fed. Cir. 2012)
Panel: Circuit Judges Newman, Clevenger, and Wallach
Opinion by Circuit Judge Wallach; dissenting-in-part opinion by Circuit Judge Clevenger