In re Brimonidine Patent Litigation: Reviewing Nonobviousness Determinations

By Jason Rantanen

In re Brimonidine Patent Litigation (Fed. Cir. 2011) Download 10-1102-1103
Panel: Bryson (author), Dyk (dissenting in part), Prost

Appellate review of obviousness assessments is highly fact-intensive.  Although there are several viable legal approaches that can be applied, from the Graham framework to the "obvious to try" analysis, the Federal Circuit's review of this issue largely boils down to an evaluation of the district court's express or implied factual determinations.  The CAFC's recent opinion in the Brimonidine patent litigation is no exception, and it highlights the degree to which Federal Circuit judges are willing to dig into the factual record to serve as the ultimate arbiters of obviousness.

Background
In the mid-1990's, Allergan introduced ALPHAGAN, an optically administered solution containing 0.2% brimonidine, a drug that reduces an eye problem associated with glaucoma.  An allergic reaction to  brimoninidine among some patients led to the introduction of ALPHAGAN P, a formulation with a lower concentration of brimonidine, higher pH, and solubility-enhancing component.  ALPHAGAN P also uses stabilized chlorine dioxide (SCD) as a preservative instead of benzalkonium chloride, which was known to be an eye irritant.  Although the formulators initially expressed concern that the SCD would oxidize brimonidine, they later found the two were compatible.

Following Apotex and Exela's submission of Abbreviated New Drug Applications seeking permission to market a generic version of ALPHAGAN P, Allergan sued them for infringement of five patents under 35 U.S.C. § 271(e)(2): Patent No. 5,024,078, covering a buffered, aqueous ophthalmic solution generally, and four patents (referred to as the "related patents") more specific to its brominidine-containing product.  The district court found all the patents nonobvious following a bench trial and Apotex stipulated to infringement.  The district subsequently found that Exela infringed one of the related patents and entered an injunction against both defendants.

Buffered Solution Patent: Obvious
The panel first addressed Apotex's challenge to the district court's nonobviousness ruling on the '078 patent.  After analyzing the content of the two prior art patents cited by Apotex, the panel unanimously concluded that the district court was wrong.  "Based on the evidence presented at trial, we are convinced that it would have been obvious to one of skilled in the art to adjust the SCD solution disclosed in Ratcliff to approximate physiologic pH, to include a buffer component to maintain that pH, and to include a tonicity component to approximate physiologic osmoloality."  Slip Op. at 8.  Although a re-evaluation of the evidence is inherent in the panel's analysis, the opinion frames the court's conclusion as one of law: "We therefore hold that the district court committed legal error in concluding that it would not have been obvious to one skilled in the art."  Slip Op. at 9.

"Related" Patents: Nonobvious
The majority reached a different result on the four "related patents," concluding that the district court correctly found the narrowest claims to be nonobvious.  Here, too, the panel engaged in a detailed analysis of the factual determinations made by the district court.  With respect to the "related patents," however, Judges Bryson and Prost agreed that the district court had reached the correct conclusions, giving particular deference to the district judge's weighting of the testimony.  The opposite conclusion was reached by Judge Dyk, who dug deeply into the factual record before concluding that the district court had clearly erred.

Reviewing Prior Art Patents vs Other Evidence of Obviousness
Although neither the majority nor dissent explicitly discussed the standard of review, the different ways in which the court handled the two groups of patents perhaps hints at the manner in which the Federal Circuit reviews obviousness determinations.  The prior art asserted against the '078 patent consisted of two earlier patents.  Although likely not intended by the panel, the opinion's discussion of the '078 patent reads like a de novo review.  The analysis of the "related patents" differs significantly.  Here, the majority explicitly defers to the district court's factual findings in places, while the dissent concludes that the district court made "clearly erroneous findings of fact," Dissent at 3, implicitly referencing the standard of review.  Although somewhat of a subjective assessment, it certainly seems plausible that the CAFC may be much more willing to engage in de novo review on the question of obviousness when the prior art consists of patents as opposed to other forms of evidence

Exela's Noninfringement Appeal
The panel also reversed the district court's determination that Exela's product would infringe one of Allergan's patents.  This section of the opinion is largely noteworthy for its discussion of the effects of statements made in ANDAs and the extent to which companies are bound by those statements.  The CAFC concluded that the statement in Exela's ANDA that its product would be manufactured with a pH of between 6.5 and 6.7 (the claims required a minimum pH of 7.0) overrode Allergan's argument that Exela might produce its product with a higher pH to account for a fall in the pH that occurs over time.  "Here, neither party disputes that if Exela complies with its ANDA, it will never manufacture or sell a product at a pH above 6.7.  We cannot assume that Exela will not act in full compliance with its representations to the FDA, and we accordingly reverse the district court's judgment [of infringement]."  Slip Op. at 22. 

9 thoughts on “In re Brimonidine Patent Litigation: Reviewing Nonobviousness Determinations

  1. 9

    A patent is referred to a set of rights granted to an individual or business by the state that gives them public disclosure of a new invention for a specific amount of time. This grant does not actually give the holder the exclusive right to practice the invention, but simply the right to preclude other outside parties from using or imitating it. Patent Litigation is a controversy or disagreement between two independent parties regarding a dispute of intellectual or physical property.

  2. 8

    Thanks Ned. I have yet to read the Decision. Will do that now, and get back to you.

  3. 7

    Max, I am not so sure. Note, the evidence with respect to ‘078 patent was just two patents. The Feds reversed because the patents speak for themselves. However, with respect to other patents, the evidence was based on evidence of what one of ordinary skill in the art would have expected when two products were combined. How could they reverse unless they found these findings of fact clearly erroneous?

    Just a snippet below. Observe, however, that the dissent does a good job of showing why the District Court was wrong even so.

    “Apotex points out that every asserted claim reads on a combination of two Allergan products: Alphagan® (bri-monidine) and Refresh Tears®. Refresh Tears® is a non-medicated eyedrop adjusted to a pH of 7.2 to 7.9. It includes SCD as a preservative and CMC as a viscosity agent. Apotex argued to the district court that combining the two solutions would have been obvious, but the district court disagreed. The court found that one skilled in the art would have expected brimonidine to present solubility problems at the elevated pH of Refresh Tears®. The court did not agree with Apotex that one skilled in the art would have expected CMC to increase the solubility of brimonidine. And it found that one of ordinary skill in the art would have expected SCD to oxidize brimonidine. Apotex challenges those fac-tual findings.”

  4. 5

    Stuart,

    This was a bench trial. The issue was invalidity of a patent. The required level of proof is clear and convincing evidence. The particular issue is obviousness that is decided de novo, based on the facts as found by the trier, that must be established by clear and convincing evidence. The review of findings of fact from a court as opposed to a jury is under the clearly erroneous standard.

    I assume, therefor, to reverse the district court here the Federal Circuit had to

    1) come to a different legal conclusion regarding obviousness on the facts as found by the district court; or

    2) come to a differenct legal conclusion based on its own assessment of the facts after finding the court’s findings clearly erroneous.

    The only “facts” of record were two patent references. Because the patents speak for themeselves and inherently meet the clear and convincing evidence standard, the Feds were entitled to reverse and hold the claims invalid if they simply disagreed with the District court.

    Isn’t this right?

  5. 4

    In the mid-1990’s, Allergan introduced ALPHAGAN, an optically administered solution containing 0.2% brimonidine, a drug that reduces an eye problem associated with glaucoma. An allergic reaction to brimoninidine among some patients led to the introduction of ALPHAGAN P, a formulation with a lower concentration of brimonidine

    LOLOLOLOL.

    higher pH, and solubility-enhancing component.

    LOLOLOLOL. This is biotech equivalent of a new method for organizing a toolbar on a computer screen.

    ALPHAGAN P also uses stabilized chlorine dioxide (SCD) as a preservative instead of benzalkonium chloride, which was known to be an eye irritant. Although the formulators initially expressed concern that the SCD would oxidize brimonidine, they later found the two were compatible.

    Aw, too bad. They should have expressed MORE concern, in the gravest possible terms. And they should have paid 100 scientists the maximum amount possible to do the study. And they should have made sure to screw up the study ten times to show how “difficult” it was. That way they could have presented evidence about how awesomely expensive and hard it was for them to reach the ultimate formulation (never mind that these methods of testing formulations are standard and old in the art). Then they could have cited Judge Newman’s opinion in her decision wherein a known stereoisomer purified from a racemate according to an old method was found non-obvious. Of course, they’d need Newman to be selected for their appeal panel.

    Oh well, maybe next time.

  6. 3

    It would be interesting to have a comparison of the number of Fed. Cir. panel decisions seriously reviewing District Court 103 decisions before and after KSR [which you will recall, was on summary judgement]. My impression is that such 103 issue reconsideration on appeal has become far more common since KSR, but that infringement disputes, not 103 disputes, still make up the vast majority of Fed. Cir. patent decisions?

  7. 2

    England say that obviousness is a “mixed question” of fact and law. The judge at first instance is called upon to “don the mantle” of the person skilled in the art. The x-exam of the opposed technical experts fielded by the opposing sides provides the thread with which the court stitches together the “mantle” that the court is wearing when it utters its decision on obviousness.

    I’m not an attorney at law or a maker of haute couture garments, but it seems to me that the court of appeal is free, as a matter of law, to stitch the evidence together differently, to make a somewhat different mantle,thereby giving it the freedom to reverse the district court, on obviousness, as a matter of law.

  8. 1

    The CAFC, as usual, assumes the role of PHOSITA and determines ” obviousness” ” based on the evidence submitted at trial”.

    These appellate court judges are geniuses: they are better. PHOSITAS than any expert who testified and their opinion is a ” matter of law”. Was the trial court’s decision ” clearly erroneous”” ) the standard of review all other appellate courts follow)?

    Nah! What was the ” error of law” made by the trial court? Hey, who cares?

    These judges are the ” Deciders”!

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