When does a prior art disclosure of a concentration range of a medicament render obvious the use of a species that falls within that range, when that same use was also known in the prior art? After all, common sense should dictate that if the same drug were used in the prior art at a different concentration, and the claimed concentration was part of a previously disclosed concentration range, than the claimed use at that concentration should have been obvious. The Federal Circuit came to such a conclusion last week in Galderma Laboratories, L.P. v. Tolmar, Inc., when it determined that if the claimed concentration falls within a prior-art disclosed range, the burden shifts to the patentee to present evidence of non-obviousness. However, Judge Newman, in dissent, complained that the majority distorted the burdens of proof and production, and ignored the presumption of validity. She warned that this opinion forecloses patentability for a large number of improvement patents, which will lead to disincentives to the developments of such improvements. "The losers," she concludes "are those afflicted with disease."
This was a Hatch-Waxman case involving Galderma's Differin® Gel, 0.3% drug product, which contains 0.3% by weight of the retinoid adapalene as the active ingredient, and which was approved for the treatment of acne. This composition was covered by several Orange Book listed patents, including U.S. Patent Nos. 7,579,377, 7,373,181, 7,834,060, 7,838,558 ("the '558 patent"), and 7,868,044. Claim 5 of the '558 patent is representative:
5. A topically applicable pharmaceutical composition comprising 0.3% by weight of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid (adapalene) relative to the total weight of the composition, effective for the treatment of acne, formulated into a topically applicable, pharmaceutically acceptable medium therefor, said composition being in the form of a topically applicable, pharmaceutically acceptable aqueous gel comprising at least one carbomer gelling agent and wherein the sole anti-acne ingredient is adapalene.
Before the invention that led to this drug product, Galderma marketed and sold Differin® 0.1% Gel. In fact, the only difference between these two formulations, other than the concentration of the active ingredient, was the use of "poloxamer 182" in the prior art composition, and "poloxamer 184" in the 0.3% product. Galderma had asserted that this newly claimed composition was not obvious because a dose-dependent increase in side-effects would have a taught away from the claimed concentration. This is because the prior art had shown that higher concentrations of adapalene were unduly irritative to acne-ridden skin.
Tolmar filed an Abbreviated New Drug Application ("ANDA") seeking approval to market a generic version of this composition. In turn, Galderma sued Tolmar in the United States District Court for the District of New Jersey. The lower court ruled against Tolmar after a bench trial on the merits. The only issue appealed by Tolmar was whether the asserted claims were obvious because they claimed "nothing more than the use of an old compound for a known purpose in a concentration that falls within a range disclosed in the prior art as preferred for that purpose."
One of the primary explanations provided for the Court's reversal of the lower court holding was a perceived misallocation of the burdens between the parties. As the basis of its obviousness rejection, Tolmar cited to three pieces of prior art, two patents by Shroot, U.S. Patent No. 4,717,720 ("the Shroot '720 patent) and U.S. Reissue No. RE34,440 ("the Shroot '440 patent), and the Differin® 0.1% Gel Data Sheet. According to the Federal Circuit, the District Court had improperly "framed the obviousness inquiry as requiring Tolmar to provide motivation in the prior art to triple the concentration of adapalene from 0.1% to 0.3%." Instead, the Federal Circuit rephrased the question as "whether there was motivation to select the claimed 0.3% adapalene composition in the disclosed range." As a result, in cases like this (where the claimed invention falls within a range disclosed in the prior art), "the burden of production falls upon the patentee to come forward with evidence that (1) the prior art taught away from the claimed invention; (2) there were new and unexpected results relative to the prior art; or (3) there are other pertinent secondary considerations." In dissent, Judge Newman thought the Court was ignoring the presumption of validity of the patents-in-suit, and instead was presuming "that the prior art established invalidity," and placing "the burden of establishing patentability based on 'secondary considerations'" on the patentee.
In finding that the patentee could not establish that prior art taught away from the claimed invention, the Court accepted the lower court's factual findings. Specifically, the lower court had found that the prior art taught away from a concentration of 0.3% because of a dose-dependent increase in the side-effects of the drug. The prior art and the expert testimony had shown that when increasing from 0.03% to 0.1%, there was increased irritation on the faces of patients with acne, such that it would have taught away from tripling the concentration of adapalene to 0.3%. In addition, the lower court had found that the prior art taught the optimal concentration of adapalene for the treatment of acne was 0.1%. The Federal Circuit, instead, explained that a reference does not teach away if it merely expressed a general preference, but did "not criticize, discredit, or otherwise discourage investigation into the invention claimed," citing Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314 (Fed. Cir. 2009). Because the art cited by the parties did not mention 0.3% adapalene compositions, it did not teach away from this concentration.
Judge Newman pointed out, however, that the lower court had determined that the evidence as a whole had taught away from increasing the concentration of adapalene above 0.1%. She meticulously walked through the art cited by the lower court. For example, the Shroot patents were found to provide a broad disclosure regarding adapalene, but provided no motivation or suggestion to select 0.3% for the treatment of acne. An article by Verschoore (1991) had shown the results of a Phase II clinical trial in which adapalene was tested on the faces of acne patients. This trial showed the increase in irritation in moving from 0.03% to 0.1%, and the expert testimony had suggested that those skilled in the art would understand that the irritation would significantly increase as the concentration increased. These findings were confirmed in a paper by Alirezai (1996), in which it was found that despite no patients treated with 0.03% adapalene having had "severe burning," 13% of patients treated with 0.1% adapalene did. Finally, the Allec (1997) article discussed 0.1% as being the optimal concentration of adapalene, balancing efficacy with safety and potential for compliance (patients tend not to be compliant when their skin is burning). Judge Newman pointed out that the other articles cited by the majority as suggesting that concentrations above 0.1% adapalene might be well tolerated either involved healthy patients, the use on less sensitive body parts, or with patients suffering from skin problems that does not make the skin as sensitive as acne. Judge Newman complained that the Court did not generally disagree with the findings of the lower court, and yet it substituted its own judgment for that of the lower court's without considering the prior art as a whole.
The lower court had found that it would have been unexpected that 0.3% adapalene would have been comparably tolerable as the 0.1% concentration in view of the prior art. However, the Federal Circuit again criticized this approach, in this case because the unexpected nature of the results should be "'different in kind and not merely in degree from the results of the prior art,'" citing Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317 (Fed. Cir. 2004). The differences in percentage, the Court explained, are differences in degree, especially where the skilled artisan is capable of adjusting these percentages. Judge Newman disagreed. She pointed out that the District Court considered the issue, and concluded that a difference in degree occurs when an "invention is merely a continuation of a trend previously described in the prior art." Instead, here, the invention achieved a difference in kind because it discontinued the trend that was seen from 0.03% to 0.1%. Judge Newman did not believe that clear error had been shown, and chastised the panel majority for discounting or ignoring the lower court's finding.
It seems in almost every Hatch–Waxman case that commercial success can be assumed, because otherwise, why would the ANDA filer seek to market a generic version of the drug. The panel majority dismissed such an argument, however, because of the lack of nexus with the patent claims. In perhaps the strongest statement on the subject that the Court has made, the Federal Circuit stated that "[t]he mere fact that generic pharmaceutical companies seek approval to market a generic version of a drug, without more, is not evidence of commercial success that speaks to the non-obviousness of patent claims." Apparently, all a generic company needs to do is make a profit selling a generic version of the drug. However, in this case, Tolmar could have chosen to seek approval of only the 0.1% version of the drug. Instead, by seeking approval of the 0.3% adapalene gel, it must have recognized its success.
The Federal Circuit also did not think that commercial success was demonstrated for the patented invention because the 0.3% adapalene gel was already blocked by the Shroot patents. The assumption that makes this secondary consideration work is that if a commercially successful invention was obvious, it would have been brought to the market sooner. However, when there are other barriers to entry, such as blocking patents, this logic breaks down. Therefore, as the Federal Circuit put it, in such a case as this, the commercial success is of minimal probative value. Judge Newman disagreed. She pointed out that the Differin® 0.3% gel quickly gained market share, despite the fact that the overall market was declining. Customers preferred this version over the 0.1% gel, she observed, which is exactly why Tolmar is seeking to market it. However, Judge Newman appears to ignore the majority opinion's criticism regarding blocking patents. It may be true that the market preferred the 0.3% gel, but no one other than Galderma could have sold it at the time.
In the end, the majority did not find that Galderma had presented evidence sufficient to demonstrate that the claimed concentration not obvious. Therefore, the Court reversed the finding of validity. Judge Newman, instead, would have focused on the presumption of validity and the allocation of the burden of production and proof, and would therefore have affirmed the lower court's validity determination.
Galderma Laboratories, L.P. v. Tolmar, Inc. (Fed. Cir. 2013)
Panel: Circuit Judges Newman, Bryson, and Prost
Opinion for the court by Circuit Judge Prost; dissenting opinion by Circuit Judge Newman