Alcon Research, Ltd. v. Apotex Inc.

• Decision Date: 11 October 2012
• Docket Number: No. 2011–1455.,2011–1455.
• Parties: ALCON RESEARCH, LTD. (Formerly Known As Alcon Manufacturing, Ltd.), Alcon Laboratories, Inc., and Kyowa Hakko Kirin Co. Ltd., Plaintiffs–Appellees, v. APOTEX INC. and Apotex Corp., Defendants–Appellants.
• Court: U.S. Court of Appeals — Federal Circuit

687 F.3d 1362

103 U.S.P.Q.2d 1737

ALCON RESEARCH, LTD. (Formerly Known As Alcon Manufacturing, Ltd.), Alcon Laboratories, Inc., and Kyowa Hakko Kirin Co. Ltd., Plaintiffs–Appellees,

v.APOTEX INC. and Apotex Corp., Defendants–Appellants.

No. 2011–1455.

United States Court of Appeals, Federal Circuit.

Aug. 8, 2012.

Rehearing and Rehearing En Banc Denied Oct. 11, 2012.

Kannon Kumar Shanmugam, Williams & Connolly, LLP, of Washington, DC, argued for plaintiffs-appellees. With him on the brief were Adam L. Perlman, Kannon K. Shanmugam, Thomas H.L. Selby and Shelley J. Webb.

Robert B. Breisblatt, Katten Muchin Rosenman, LLP, of Chicago, IL, argued for defendants-appellants. With him on the brief were Craig M. Kuchii, Brian J. Sodikoff and Thomas J. Maas. Of counsel on the brief was Shashank Upadhye, Apotex, Inc., of Toronto, Ontario, Canada.

Before PROST, MOORE, and O'MALLEY, Circuit Judges.

MOORE, Circuit Judge.

Apotex Inc. and Apotex Corp. (collectively, Apotex) submitted an Abbreviated New Drug Application (ANDA) to the Food and Drug Administration seeking approval to market a generic version of the anti-allergy eye drop Patanol®. Alcon Research, Ltd. et al. (collectively, Alcon), who market Patanol®, sued Apotex for patent infringement under 35 U.S.C. § 271(e)(2)(A). Alcon asserted claims 1–8 of U.S. Patent No. 5,641,805 ('805 patent), which is listed in the Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) entry for Patanol®. For the reasons set forth below, we reverse the district court's holding that claims 1–3 and 5–7 would not have been obvious over the prior art but affirm the court's holding that claims 4 and 8 are not invalid.

Background

An allergic reaction is the body's mechanism for expelling antigens, such as pollen or pet dander. Exposure to an antigen causes the body to produce antibodies. These antibodies bind to the surface of mast cells, which are specialized cells that exist in many places in the body and are the primary cells involved in allergic reactions. This binding sensitizes the mast cells to that antigen. If the mast cells are subsequently exposed to the same antigen again, the antigen binds to the antibodies on the surface of the mast cell. This causes the mast cells to release chemicals called mediators, such as histamine and heparin. These mediators bind to receptors in surrounding tissues, triggering the reactions commonly identified as allergic symptoms, such as itching and redness. In the human eye, mast cells are located in the conjunctiva, which is the membrane that covers the inner surface of the eyelid and the white part of the eyeball.

Anti-allergy drugs can treat allergic symptoms by interfering at one of several points in this process. Antihistamines, for example, prevent the histamine that is released from mast cells from binding to receptors in surrounding tissues and also displace the histamine that is already bound to receptors. By contrast, drugs known as mast cell stabilizers prevent mast cells from releasing mediators, and thus counteract the effects of histamine and other mediators that cause allergic symptoms.

The '805 patent is directed to a method for treating allergic eye disease in humans comprising stabilizing conjunctival mast cells by topically administering an olopatadine¹ composition. ' 805 patent col.1 ll.7–15, col.2 l.64–col.3 l.3. The specification explains that the discovery that olopatadine can treat human eye allergies through this mechanism of action—stabilizing mast cells in the human eye—is the novel aspect of the ' 805 patent. See, e.g., id. col.2 ll.56–61 (“What is needed are topically administrable drug compounds which have demonstrated stabilizing activity on mast cells obtained from human conjunctiva, the target cells for treating allergic eye diseases.”); see also id. col.3 ll.18–23 (“[Olopatadine] has human conjunctival mast cell stabilizing activity, and may be applied as infrequently as once or twice a day in some cases.”).

The specification states that at the time of invention, it was already known in the art that olopatadine was an effective antihistamine and that some chemicals in olopatadine's genus may have mast cell stabilizing activity. Id. col.1 l.16–col.2 l.61. Indeed, both the olopatadine compound itself and a method of treating allergies using the class of chemicals that encompasses olopatadine were both already patented. SeeU.S. Patent No. 5,116,863; U.S. Patent No. 4,923,892. The '805 patent specification states, however, that it was not known whether olopatadine would stabilize mast cells in human eyes. Id. col.1 ll.43–58. The specification explains that this was because mast cells in different species, and in different tissues within the same species, exhibit different biological responses—a concept called mast cell heterogeneity. Id. col.1 ll.43–58. As a result, a compound's activity in a rodent's conjunctival mast cells or in mast cells located elsewhere in the human body cannot predict its ability to stabilize mast cells in the human eye. Id. col.1 l.43–col.2 l.19. The '805 patent's inventors conducted in vitro testing showing that olopatadine stabilizes conjunctival mast cells in humans. '805 patent col.3 ll.18–23, col.3 l.43–col.5 l.55.

The '805 patent claims are limited to a method of treating human eye allergies that comprises stabilizing conjunctival mast cells. Claim 1 reads:

A method for treating allergic eye diseases in humans comprising stabilizing conjunctival mast cells by topically administering to the eye a composition comprising a therapeutically effective amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz(b,e) oxepin-2-acetic acid or a pharmaceutically acceptable salt thereof.

'805 patent col.1 (emphases added). The parties do not dispute the district court's construction of “stabilizing conjunctival mast cells” as “preventing or reducing release of mediators including histamine from mast cells in the conjunctiva to an extent clinically relevant in the treatment of allergic eye disease.” J.A. 176. Although independent claim 1 does not specify the “therapeutically effective amount” of olopatadine required to stabilize conjunctival mast cells, dependent claims limit the method of claim 1 to specific concentration ranges. Claims 2 and 6, for example, are limited to using a composition that contains from about 0.0001% w/v to about 5% w/v of olopatadine. Claims 4 and 8 are limited to a concentration of 0.1% w/v of olopatadine.

Alcon's Patanol® product, an anti-allergy eye drop with a 0.1% w/v concentration of olopatadine, is a commercial embodiment of the '805 patent. Apotex filed an ANDA seeking permission to sell a generic version of Patanol® and included a Paragraph IV certification that the '805 patent was invalid, unenforceable, and/or would not be infringed by Apotex's generic product. Alcon sued Apotex for patent infringement, asserting claims 1–8. In a bench trial, the district court held that the '805 patent was enforceable and not invalid, and that Apotex's generic product infringed the asserted claims. Alcon Research, Ltd. v. Apotex Inc., 790 F.Supp.2d 868, 944–45 (S.D.Ind.2011).

On the issue of validity, the district court held that Apotex failed to establish that the claims would have been obvious by clear and convincing evidence. The court recognized that olopatadine was known to be an effective antihistamine, but found that at the time of invention a skilled artisan “understood that there were significant barriers to adapting a known systemic antihistamine for topical use in the eye.” Id. at 877. The court also found that the prior art as a whole, and specifically an article by Kamei et al., taught away from using olopatadine as a mast cell stabilizer. Kamei tested an ophthalmic formulation of olopatadine in guinea pig eyes at concentrations that overlap with those recited in most of the '805 patent claims. Kamei discloses that, although olopatadine is a good antihistamine, it is not an effective mast cell stabilizer. J.A. 10162–63. The court further found that Kamei's disclosure of using olopatadine eye drops in guinea pigs would not give a skilled artisan an expectation of success because it does not show whether olopatadine is safe to use in the human eye. The district court rejected Apotex's argument that the prior art need not teach mast cell stabilization because this mechanism of action is an inherent property of olopatadine. In reaching this conclusion, the court relied largely on testimony by Alcon's expert, Dr. Kaliner, that not every concentration of olopatadine will stabilize human conjunctival mast cells to a “clinically relevant” extent, as required by the court's claim construction.

The district court also held that objective evidence supported its holding of nonobviousness. For example, the court found that Patanol® showed unexpected results because a person of ordinary skill would not have expected it to be an effective mast cell stabilizer in the human eye. Alcon v. Apotex, 790 F.Supp.2d at 905. The court concluded that Patanol® satisfied a long-felt but unmet need for a human conjunctival mast cell stabilizer. The court further found that Patanol® has been “an outstanding commercial success,” achieving nearly a 70% market share within two years of its launch. Id. at 904.

Apotex now appeals from the district court's final judgment that the '805 patent would not have been obvious over the prior art and from the grant of a permanent injunction barring Apotex from selling its generic product. We have jurisdiction under 28 U.S.C. § 1295(a)(1).

Discussion

A patent is invalid for obviousness “if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains.” 35 U.S.C. § 103(a). “Obviousness is a question of law, which we review...