What do dioxaborinanes and benzoxaboroles have in common? They both exhibit activity against fungi, and so Anacor failed before the Federal Circuit, which could not have been fun-guys…
| May 17, 2018
Anacor Pharmaceuticals Inc. v. Andrei Iancu, Under Secretary of Commerce for Intellectual Property and Director of the U.S. PTO; case number 17-1947
May 14, 2018
Before Reyna, Bryson and Stoll. Opinion by Bryson.
要旨:
本件は、米国特許庁審判部の無効審決に対する控訴事件であり、争点は自明性に関するものである。具体的には、既存の組成物を利用した新しい治療法の特許に関する。CAFCは以下のような判断を示した。まず、似たような組成物同士が一定の特性を共通に備えている場合、他の関連する特性においても共通していると推定するのが合理的である。また、組成物同士の構造上の類似性は、組合せの動機づけや「当該組合せの成功に対する合理的な期待」を評価する上で重要な要素である。類似の構造を備える組成物同士が類似の特性を持つこと、また、構造の類似性が特性の類似性を示唆することは、長年の実務慣行である。一方、化学の分野では予測できない結果も起こり得るので、構造の類似性が常に特性の類似性につながるとは限らない。したがって、自明性の判断は、しばしば、構造上の類似性と機能的な類似性との間に強い関連性があることが証拠によって証明されたか否かに依存する。本件では、Austin引例とBrehove引例とに開示された組成部には限られた構造上の類似性しかなかったのであるが、構造および機能の類似性に鑑みれば、無効という判断を支持する十分な証拠があると判断された。(中村剛)
Summary:
This is an appeal from a decision of the Patent Trial and Appeal Board in an inter partes review proceeding. The Board held all claims of U.S. Patent No. 7,582,621 (‘621 patent) owned by Anacor pharmaceuticals Inc., (Anacor) to be unpatentable for obviousness. The patent is directed to the use of 1,3- dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole is also known as tavaborole. When applied topically, tavaborole can penetrate the nail plate and treat an underlying fungal infection. Anacor appealed only one of the rejected claims.
The single claim of the ’621 patent that is at issue in this appeal is claim 6, which depends from claims 1 and 4. The three related claims recite as follows:
1. A method of treating an infection in an animal, said method comprising administering to the animal a therapeutically effective amount of 1,3- dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof, sufficient to treat said infection.
4. The method of claim 1, wherein said infection is onychomycosis.
6. The method of claim 4, wherein said onychomycosis is tinea unguium.
Tinea Unguium is the term for onychomycosis that is caused by a dermatophyte (fungi).
In 2015, the Coalition for Affordable Drugs X LLC filed a petition requesting inter partes review of all 12 claims of the ‘621 patent, and the Board instituted review and found the claims would have been obvious in light of the combination. Int’l Pat. Appl. No. PCT/GB95/01206 (Austin) and U.S. Pat. Appl. No. 10/077,521 (Brehove).
Both Austin and Brehove teach the use of boron heterocycles as antifungal agents that inhibit C. albicans, amongst other fungi. Evidence before the Board showed that C. albicans are known to be responsible for about 5% of all onychomycosis cases, whereas dermatophytes are responsible for about 90% of all cases.
Austin teaches tavaborole as one of a small group of oxaboroles (boron heterocycles that include a five member ring containing three carbon atoms, one oxygen atom and one boron atom) that were tested for antifungal activity, and discloses that tavaborole is highly effective in inhibiting a variety of fungi, including C. albicans.
Brehove teaches the use of boron heterocycles in a topical composition to treat onychomycosis. Specifically, two dioxaborinanes—boron heterocycles that include a six-member ring containing three carbon atoms, two oxygen atoms, and one boron atom—were determined through in vitro testing to have powerful potency against C. albicans. Brehove also reports the results of five in vivo tests, in which onychomycosis was successfully treated but the reference does not identify whether the onychomycosis was caused by C. albicans or some other microorganism, such as a dermatophyte.
In addressing claim 6, the petition referred to the in vivo tests of Brehove, which failed to disclose the cause of onychomycosis, which is more often than not caused by dermatophyte. In addition, the petition pointed out that tavaborole has a lower molecular weight than the Brehove compounds, and would therefore be expected to be more likely to penetrate the nail barrier at lower concentrations.
In Anacor’s reply, they argued that (i) a person of ordinary skill would not have combined the references because they concern structurally different compounds; and (ii) such a person could not have predicted activity against dermatophytes based on activity against yeast such as C. albicans. In support, Anacor cited an article “Segal” that reported a compound that was effective against dermatophytes but had variable and species-dependent effectiveness against different species of the Candida genus.
The petitioner also relied upon the Segal document, introducing the article during the deposition of one of their experts. In the deposition, the expert explained that the compound in Segal was effect against both dermatophytes and various Candida species, and so it would be understood that most antifungal drugs are found to be active against different strains over a broad spectrum of organisms.
Anacor also included declarations from several experts. One of the experts, Dr. Lane, cited two installments of a three-piece study by Dirk Mertin to support her view that one skilled in the art would not have expected the combination of Austin and Brehove to be successful. However, during the deposition of Dr. Lane, the petitioner introduced the third installment of the Mertin articles to challenge Dr. Lane’s testimony regarding the relationship between a compound’s molecular weight and its ability to penetrate then nail plate. Dr. Lane explained that she was aware of the third installment but she disagreed with the findings.
The petitioner also used this third installment of Mertin during the deposition of another Anacor expert, Dr. Ghannoum. Dr. Ghannoum relied on a paper by Nimura which teaches that some antifungals are effective against C. albicans but ineffective against dermatophytes. The petitioner challenged the expert testimony in that the third Mertin installment states that dermatophytes are usually more sensitive to antimycotics than yeast.
In its final decision, the Board acknowledged that “there are obviously structural differences between the dioxaborinanes of Brehove and the benzoxaboroles of Austin” and that it is recognized that “small structural differences can cause different biological actions and activities.” Nonetheless, the Board was persuaded by the petitioner’s experts that the combination of the structural similarities and the similar activity against C. albicans would have led a person of ordinary skill in the art to combine the references. In support of that conclusion, the Board cited evidence that included Segal, Nimura and Mertin (e.g., the Board noted these articles showed the compounds therein do have activity against both dermatophytes and C. albicans even if the activity is less against one than the other).
On appeal, Anacor first argued that the Board violated due process and the procedural requirements of the Administration Procedure Act by failing to provide Anacor with adequate notice of, and an opportunity to repot to, the grounds of rejection ultimately adopted by the Board. Specifically, Anacor argues the Board abandoned Brehove in light of Segal and Mertin, and in doing so adopted a new theory without giving Anacor proper notice. CAFC rejected Anacor’s argument.
CAFC held that the Board’s final written decision was based on the same combination, Austin and Brehove that the petition proposed. Regarding, Segal and Mertin, the CAFC held there is no blanket prohibition against the introduction of new evidence during an inter partes review proceeding, in fact, the introduction of new evidence in the course of the trial is to be expected and, as long as the opposing party is given notice of the evidence and an opportunity to respond to it, the introduction of such evidence is perfectly permissible under the APA.
Anacor argued that Segal, Mertin, and Nimura “surfaced for the first time in Petitioner’s Reply,” but the CAFC held that is not so. Rather, Anacor discussed both Nimura and Segal in its patent owner’s response and related submissions, and that Anacor spent three pages of its patent owner’s response addressing Segal. As for Mertin, the first two installments in Mertin were first introduced and addressed by Anacor. The third installment was introduced by the petitioner during the deposition of Anacor’s experts and was then referred to in the petitioner’s reply. But the third installment did not come as a ‘surprise’ to Anacor. As noted, Dr. Lane admitted she was familiar with the article.
Next, Anacor argued that the Board improperly shifted the burden of proof by requiring the patent owner to disprove obviousness. In particular, Anacor contends that the Board failed to require proof from the petitioner as to the mechanism of action that would lead to the conclusion that tavaborole would kill both C. albicans and dermatophytes, and that the Board did not explain why the evidence that dermatophytes are usually more sensitive than yeasts to antimycotics applies to tavaborole.
The CAFC held that in substance, Anacor’s argument is not that the Board shifted the burden of proof to Anacor, but that the Board improperly relaxed the burden on the petitioner to prove its case. That argument, however, does not suggest that the Board shifted the burden of proof to Anacor, but instead is directed to the question whether there was substantial evidence to support the Board’s finding of obviousness. As to that issue, the Board found sufficient motivation to arrive at the combination of Austin and Brehove, and the CAFC agreed.
In its third argument, Anacor challenged what it referred to as the Board’s “conclusion that the compounds of Austin are ‘structurally similar’ to the compounds of Brehove.” Anacor contends that the compounds are structurally dissimilar, and that a person of ordinary skill in the art would have expected that even small structural differences between tavaborole and the Brehove compounds would result in significant differences in their chemical and biological properties.
The CAFC held that Anacor’s argument is premised on the misapprehension that the Board viewed structural similarity as a binary factor—either present or absent—and that the Board found it was present in this case. The CAFC held that this is not an accurate characterization of the Board’s assessment of the issue of structural similarity.
Specifically, the CAFC held that the Board did not regard the structural similarity between the compounds of Austin and Brehove to be sufficient proof, by itself, that tavaborole would be likely to have the same functionality as the compounds in Brehove. The Board correctly acknowledged that there “are obviously structural differences between the dioxaborinanes of Brehove and the benzoxaboroles of Austin,” but it concluded that “the combination of the structural similarities and the similar fungicidal activity against C. albicans would have led a person of ordinary skill in the art to combine Brehove’s method of treating onychomycosis using Austin’s tavaborole instead of [Brehove’s compounds].”
The CAFC noted that this case does not involve a patent on a new chemical compound. Where the patent is directed to a new treatment using a known compound, it is reasonable to assume that similar compounds that share certain common properties are apt to share other related properties as well. Further, the CAFC held that to be clear, they recognize that structural similarity is an important factor in assessing the motivation to combine and reasonable expectation of success. It has been long recognized that chemical compounds with similar structures often have similar properties and that similarity in properties can be inferred from structural similarity. At the same time, the CAFC notes that their cases recognize that the chemical arts are unpredictable and that similar structures do not always result in similar properties. Thus, the obviousness inquiry often depends on whether there is evidence demonstrating a nexus between structural similarities (or dissimilarities) and functional similarities (or dissimilarities). In this case, although there is only limited structural similarity between the compounds disclosed in Austin and Brehove, the CAFC concluded that, in light of the combination of the structural and functional similarities between the compounds, substantial evidence supports the Board’s findings and the so the CAFC affirmed.
Take-away:
- Structural dissimilarity is not sufficient by itself if the compound is known and there is similarity in function.
- Obviousness inquiry often depends on whether there is evidence demonstrating a nexus between structural similarities (or dissimilarities) and functional similarities (or dissimilarities), and so during prosecution this ‘nexus’ should be attacked rather than simply relying upon structural dissimilarities (if the compound is known and there are common structures shared).
- Always best to upfront address all known art.
