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Federal Circuit Finds Treximet Patents Non-Obvious And Infringed

Posted in 103; Doctrine of Equivalents; Federal Circuit Decisions

In Pozen, Inc. v. Par Pharmaceutical Inc., the Federal Circuit upheld the district court’s determination that the patents at issue were not invalid as obvious and were infringed by the subject Abbreviated New Drug Applications (ANDAs). Comparing this case to In re Droge, I cannot help but wonder how much the procedural posture impacted the Federal Circuit’s decisions. While the court reached opposite determinations as to obviousness, in each case it affirmed the decision on appeal.

The Patents At Issue

The three patents at issue—U.S. Patent 6,060,499, U.S. Patent 6,586,458, and U.S. Patent 7,332,183—each relate to methods and compositions for treating migraine using a 5-HT agonist and a long-acting, non-steroidal, anti-inflammatory drug  (LA-NSAID). 

Pozen listed the patents in the Orange Book for Treximet®, a combination product comprising naproxen (an LA-NSAID) and triptan (a 5-HT agonist).  Par and the other appellants wanted to market generic versions of Treximet®, and made Paragraph IV certifications against the patents. Pozen then sued for patent infringement

Non-Obviousness

The ’499 and ’458 patents were challenged over prior art references that disclosed the use of various drugs (alone and in combination) to treat migraine, including sumatriptan and NSAIDs. However, the Federal Circuit credited the district court’s determination that none of the references taught or suggested that the simultaneous administration of a 5-HT agonist and an LA-NSAID would have a particular therapeutic benefit, or would achieve the improved efficacy observed with the claimed combination (e.g., unexpected results).

The ’499 and ’458 patents also were challenged over “two patient records from the Henry Ford Clinic in Detroit, Michigan.” These records were asserted to show that “doctors prescribed a daily dose of naproxen as a prophylactic treatment, and sumatriptan for treating acute migraines.” In upholding the district court’s determination of non-obviousness over this evidence, the Federal Circuit noted testimony from one of the doctors that “he did not recall ever prescribing or giving a patient sumatriptan and naproxen simultaneously,” and that the records “do not suggest that it produced longer lasting efficacy or reduced migraine relapse.”

The ’499 and ’458 patents were challenged over another patient case study, but that reference did not clearly disclose the simultaneous administration of sumatriptan and an NSAID, and in any event did not indicate that the therapy was effective.

(The ’183 patent also was challenged as obvious, but the Federal Circuit opinion does not provide a very detailed discussion of that issue.)

The Federal Circuit concluded:

We agree with the district court that the prior art would not have provided one of ordinary skill with motivation to combine sumatriptan and naproxen in order to benefit from longer lasting efficacy as compared to when either agent is taken alone. Appellants failed to rebut the presumption of validity afforded issued patents by clear and convincing evidence.

Written Description

Asserted claim 15 of the ’499 patent was challenged on written description grounds. Claim 15 depends from claim 5:

5. A therapeutic package for dispensing to, or for use in dispensing to, a migraine patient, which comprises:
(a) one or more unit doses, each such unit dose comprising:
(i) a 5-HT agonist and
(ii) a long-acting, non-steroidal, anti-inflammatory drug (LA-NSAID);
wherein the respective amounts of said 5-HT agonist and said LA-NSAID in said unit dose are effective, upon concomitant administration to said patient of one or more of said unit doses, to reduce migraine relapse or produce longer lasting efficacy compared to the administration of said 5-HT agonist in the absence of said LA-NSAID or the administration of said LA-NSAID in the absence of said 5-HT agonist, and
(b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of migraine.

15. The improvement, method, or composition of claims 1, 2, 3, 4, 5, 6, 7, or 8, wherein said 5-HT agonist is sumatriptan, said LA-NSAID is naproxen and the unit dosage form is an oral unit dosage form comprising sumatriptan in an amount greater than 15 mg, and naproxen in an amount greater than 200 mg.

Par asserted that claim 15 was invalid because “therapeutic package,” “finished pharmaceutical container,” and “said container further containing or comprising labeling directing the use of said package in the treatment of migraine” were not described in the specification.

The Federal Circuit found no clear error in the district court’s determination that these embodiments were adequately described. For example, the district court had noted that the skilled artisan would have understood that the “pharmaceutical dosages [described in the specification] are administered to a patient in containers or packages with labeling and inserts with dosage instructions.” The court also noted that “the FDA requires container labeling and information for prescription pharmaceutical products.” The Federal Circuit therefore agreed that “[t]he ’499 patent specification meets the written description requirement because the specification describes the invention in such a way that it is understandable to a person of ordinary skill in the art.”

Infringement

Par challenged the district court’s determination that claim 1 of the ’183 patent was infringed under the doctrine of equivalents. The court’s analysis focused on two aspects of the claims, highlighted below.

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.  

Independent Dissolution

In accordance with the specification, the district court construed the ‘independent dissolution” limitation as meaning 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.”

The district court found infringement under the doctrine of equivalents based on Pozen’s expert’s testimony “that Par’s ANDA product was specifically formulated to achieve complete and independent dissolution,” and Par’s representations to the FDA that “the sumatriptan and naproxen in its ANDA product dissolves completely and independently from each other.” Par challenged this finding because there was no proof that its product would exhibit the dissolution profile required by the claim construction, e.g., dissolving “in about the same time (± 10%) it would take for either of the active agents to achieve dissolution when taken alone.” In rejecting this argument, the Federal Circuit noted that “[u]nder the doctrine of equivalents analysis Pozen need only show that the ANDA products performed the same function in the same way to achieve the same result,” and did not have to show that the specific dissolution test was satisfied.

Substantially All

The district court construed the “substantially all” limitation as meaning 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.”

According to the Federal Circuit decision, “[i]t is undisputed that the first layer of Par’s ANDA tablet ‘contains 100% of the tablet’s sumatriptan, along with 15% of the tablet’s naproxen, with the remaining 85% of the naproxen in the second layer.”

The district court found infringement under the doctrine of equivalents, noting that “absent more limiting language in the intrinsic record” the doctrine of equivalents can be applied to find infringement where the accused value is insubstantially different from the claimed value.

On appeal, Par argued that “substantially all” is a “fuzzy” quantitative limitation that is not entitled to any range of equivalents. The Federal Circuit disagreed, noting that “the claim construction pulls directly from the specification to give the term ‘substantially all’ a quantitative definition,” and that “the doctrine of equivalents is not foreclosed with respect to claimed ranges.” Moreover, the court found that Pozen never had taken the position that the range “should be an absolute floor.” Thus, the Federal Circuit stated:

Under the doctrine of equivalents a tablet layer with 85% of the agent can be fairly characterized as an insubstantial change from a tablet layer with 90% of the agent.

 (Judge Clevenger dissented from this aspect of the decision.)

The Importance Of Procedural Posture

In this post-KSR era, it can be difficult to obtain patents directed to combination therapies and combination pharmaceutical products, even when the invention is supported by unexpected results. Here, Pozen not only obtained  three patents, but also successfully defended them from Par’s challenges. Nevertheless, reading the Federal Circuit opinion, it is not hard to imagine the court reaching a different decision if the district court had viewed the evidence in a different light. In that way, this case underscores the value of a favorable district court decision, especially if you have a close case.