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A Combination of Ingredients from Two Separate Solutions Previously Used Together as Part of an Overall Treatment Regimen Is Not Necessarily Obvious

May 19, 2011

Decision icon Decision

Last Month at the Federal Circuit - June 2011

Judges: Bryson (author), Dyk (concurring-in-part, dissenting-in-part), Prost

[Appealed from: D. Del., Chief Judge Sleet]

In In re Brimonidine Patent Litigation, Nos. 10-1102, -1103 (Fed. Cir. May 19, 2011), the Federal Circuit affirmed-in-part and reversed-in-part the district court’s validity determination with respect to five of Allergan, Inc.’s (“Allergan”) patents and reversed the district court’s determination that an ANDA filed by Exela Pharmsci, Inc. and Exela Pharmsci Pvt., Ltd. (collectively “Exela”) infringed one of Allergan’s patents.

In 1996, Allergan introduced Alphagan®, an aqueous eyedrop solution containing 0.2% brimonidine, an α-2 adrenergic agonist, to reduce elevated intraocular pressure of the eye associated with glaucoma.  Due to an allergic reaction many Alphagan® users experienced as a result of brimonidine, Allergan introduced Alphagan® P in 2001.  Alphagan® P was sold at two brimonidine concentrations:  0.15% and 0.1%.  For the 0.1% concentration, the formulation’s pH ranged from 7.6 to 7.8, while the 0.15% concentration’s pH ranged from 7.15 to 7.3.  Allergan found two therapeutic benefits from the higher pH of Alphagan® P as compared to Alphagan®:  (1) the higher pH is closer to that of the human eye and thus did not produce a stinging sensation when administered; and (2) because brimonidine is an ionizable drug, a lower concentration of brimonidine at the higher pH produced therapeutic benefits similar to that of Alphagan®, and thus reduced the risk of an allergic response.  In addition to brimonidine, Alphagan® P also contained carboxymethylcellulose (“CMC”) to enhance the solubility of brimonidine, and stabilized chlorine dioxide (“SCD”) as a preservative.  CMC and SCD were also components of Refresh Tears®, an Allergan artificial tears solution with a pH between 7.2 and 7.9.

Allergan submitted five patents to the FDA that were listed in the Orange Book as associated with Alphagan® P.  U.S. Patent No. 5,424,078 (“the ’078 patent”) was directed to a sterilized ophthalmic solution at physiological pH and osmolality.  The Court and parties referred to the other four patents as the “related patents.”

Apotex submitted two ANDAs for approval to make and sell generic versions of Alphagan® P with 0.1% and 0.15% brimonidine concentrations, while Exela’s ANDA was directed only to the 0.15% brimonidine concentration product.  Allergan sued Apotex and Exela in different districts and the matters were consolidated in the District of Delaware.  The district court concluded that the asserted claims of the ’078 patent and the related patents were not invalid as obvious.  Apotex stipulated to infringement, and the district court found that Exela’s proposed product would infringe the asserted claims.  Thus, the district court enjoined Apotex and Exela from making or selling the products described in their respective ANDAs.

Apotex appealed only the validity portion of the district court’s judgment, while Exela appealed only the court’s finding of infringement.

On appeal, the Federal Circuit agreed with Apotex that the asserted claims of the ’078 patent would have been obvious over a combination of two prior art references, but found that the claims of the related patents would not have been obvious.  With respect to the ’078 patent, the Court found that it would have been obvious to adjust the SCD solution disclosed in one prior art reference to approximate physiologic pH, include a buffer component to maintain that pH, and include a tonicity component to approximate physiologic osmolality as claimed.  The Court noted that a second reference relied upon by Apotex disclosed the modifications that Allergan argued imparted patentability to its claims—using SCD as a preservative in an ophthalmic solution and making the solution isotonic using well-known agents.

The Federal Circuit also rejected the district court’s finding that the second reference taught away from the claimed invention because its use of SCD as the sole preservative would have required a quantity so great, it would have irritated the eye.  The Federal Circuit noted that, “[e]ven if a reference discloses an inoperative device, it is prior art for all that it teaches.”  Slip op. at 8 (citation omitted).  Further, the prior art disclosed that SCD can be used effectively as a sole preservative for an ophthalmic solution.  Thus, the Federal Circuit found that it would have been obvious to create an ophthalmic solution that was adjusted to ocular pH and tonicity, and that relied on SCD as the sole preservative agent.

With respect to the four related patents, the Federal Circuit noted that neither party argued its validity case on a claim-by-claim basis either before the district court or on appeal.  Apotex argued on appeal that every asserted claim of the related patents reads on a combination of Alphagan® and Refresh Tears®, and thus combining the two solutions would have been obvious, or, at a minimum, obvious to try.  Although Apotex challenged three factual findings by the district court, the Federal Circuit rejected each of Apotex’s arguments.

First, Apotex argued that the district court erred by finding that one of skill in the art would have expected brimonidine to present solubility problems at the elevated pH of Refresh Tears® in light of a table in an NDA filed by Allergan.  The Federal Circuit noted that Apotex did not focus on the table at trial, did not provide any supporting testimony calling the district court’s attention to the table, and did not explain how one of skill in the art would have assessed the information from the table.  Thus, the Court declined to do so for the first time on appeal.

Second, Apotex argued that one of skill in the art would have expected CMC to increase the solubility of brimonidine contrary to the district court’s finding because Alphagan® and Refresh Tears® were routinely prescribed together.  The Federal Circuit rejected Apotex’s argument because that fact alone did not mean that the combination of the two products in one solution would have been obvious:  “Two ingredients might be therapeutically effective when used separately as part of an overall treatment regimen, yet be incompatible or ineffective when combined in a single solution.”  Id. at 13.

Further, the Federal Circuit found that two journal articles relied upon by Apotex did not disclose or suggest the use of CMC in connection with any α-2 adrenergic agonist, let alone brimonidine.  Although Apotex acknowledged that deficiency, it argued that the articles would have suggested that CMC enhanced the solubility of many soluble active ingredients.  The Court rejected Apotex’s argument since it was not supported by expert testimony or other evidence, and thus did not undermine the district court’s contrary finding.  Finally, the Federal Circuit noted that the articles also required a heating step which was incompatible with brimonidine, thus supporting the district court’s conclusion that the articles did not teach the combination of brimonidine and CMC.

Third, Apotex argued that the district court erred in finding that one of skill in the art would not have been motivated to combine Alphagan® and Refresh Tears® because of concerns that SCD would oxidize brimonidine.  The Federal Circuit rejected Apotex’s challenge because Allergan’s expert testified that one of skill in the art would have been extremely hesitant—if not, directed away from—formulating brimonidine with a chlorite solution, such as SCD.  In addition, the Court noted that Allergan’s documents touting an SCD solution as less reactive than hydrogen peroxide did not establish that one of skill in the art would not have expected SCD to oxidize brimonidine.

In addition, the Federal Circuit rejected Apotex’s obvious-to-try argument because the district court found that the solutions that Allergan identified and claimed would not have been an “anticipated success.”  In light of the district court’s well-supported factual findings, the Federal Circuit agreed that the claimed inventions were not invalid as obvious to try.

Finally, with respect to Apotex’s appeal, the Federal Circuit found that the district court was well within its discretion in refusing to consider Apotex’s post-trial obviousness arguments based on references that were admitted into evidence, but not supported with expert testimony or otherwise relied on at trial.  Although the Court noted that there is no invariable requirement of expert testimony, “it is well within a trial judge’s discretion to require expert testimony supporting technical references that are relied on to establish obviousness.”  Id. at 17-18.

With respect to Exela’s appeal, the Federal Circuit agreed that the district court erred in its finding of infringement of U.S. Patent No. 6,641,834, one of the related patents, and the only patent Allergan asserted against Exela.  The Court noted that the only issue was whether the product described in Exela’s ANDA infringes the claim element that requires a pH of 7.0 or greater.  The Court found that because Exela and Allergan agreed that the highest pH at which Exela requested FDA permission to manufacture and sell its proposed product is 6.7, Exela’s proposed product did not infringe under 35 U.S.C. § 271(e)(2)(A).  Unlike Abbott Laboratories v. TorPharm, Inc., 300 F.3d 1367 (Fed. Cir. 2002), where the Federal Circuit held that the district court could consider other relevant information outside of TorPharm’s ANDA because the ANDA did not speak to the precise element claimed, Exela’s ANDA does provide its proposed product’s pH.  Thus, because “neither party disputes that if Exela complies with its ANDA, it will never manufacture or sell a product at a pH above 6.7,” the Court would not “assume that Exela will not act in full compliance with its representations to the FDA . . . .”  Slip op. at 21.

Accordingly, the Federal Circuit reversed the district court’s determination that the asserted claims of the ’078 patent were not invalid, affirmed the district court’s finding that Apotex failed to show that the claims of the related patents were invalid as a matter of law, sustained the district court’s injunction against Apotex, and reversed the district court’s judgment that Exela’s ANDA filing was an act of infringement.

Judge Dyk dissented from the majority’s conclusion that the four related patents were nonobvious in light of the combination of Alphagan® and Refresh Tears®.  According to Judge Dyk, obvious to try does not require absolute predictability of success, but rather a reasonable expectation of success.  In this case, a person of skill in the art knew that (1) Alphagan® caused two negative side effects, including eye irritation; (2) the higher pH of Refresh Tears® would likely reduce eye irritation; (3) SCD in Refresh Tears® would likely be less toxic than another preservative in the Alphagan® product; (4) CMC present in Refresh Tears® would likely further reduce eye irritation; and (5) physicians routinely prescribed Refresh Tears® and Alphagan® together.  Under these circumstances, Judge Dyk would have found the combination of the two commercially successful products “obvious to try.”  Dyk Dissent at 2 (citation omitted).