Case Name: Insite Vision Inc. v. Sandoz Inc., Civ. No. 11-cv-3080, 2013 U.S. Dist. LEXIS 160280 (D.N.J. Oct. 4, 2013) (Cooper, J.) (Patents-in-suit claiming compositions, methods of preparation, and methods of treatment concerning azalide antibiotics were not obvious.)
Drug Product and Patent(s)-in-Suit: AzaSite® (1% azithromycin); U.S. Patent Nos. 6,861,411 (“the ’411 patent”), 6,239,113 (“the ’113 patent”), 6,569,443 (“the ’443 patent”), and 7,056,893 (“the ’893 patent”)
Nature of the Case and Issue(s) Presented: Plaintiffs’ patents claim compositions, methods of preparation, and methods of treatment related to azalide antibiotics. Plaintiffs manufacture, market, sell, and use AzaSite, which is used in the treatment of bacterial conjunctivitis. Defendants filed ANDAs containing paragraph IV certifications against the patents-in suit. Plaintiffs filed suit alleging patent infringement and defendants responded with affirmative defenses and counterclaims, including allegations that the asserted patents were invalid due to obviousness. An eight day bench trial was held from June 11, 2013 to Aug. 13, 2013, and the court decided the case on October 4, 2013 in plaintiffs’s favor.
Why Plaintiffs Prevailed: The court first considered whether the ‘411 patent was invalid as obvious. The parties framed the issue in very different ways. Defendants argued that the question facing a person having ordinary skill in the art at the time of invention was whether one could treat conjunctivitis with a topical opthalmic formulation of azithromycin. The answer according to defendants was that such a person of ordinary skill would have considered it obvious to use a topical formulation azithromycin to treat conjunctivitis. Plaintiffs, on the other hand, argued that defendants had improperly used the ‘411 patent as a guide to frame the question of obviousness through impermissible hindsight.
The court first addressed defendants’ arguments concerning the motivation to combine and evidence of a reasonable expectation of success. Defendants argued that the prior art taught that azithromycin, when dosed orally, was an important drug for the treatment of trachoma. An oral dose of azithromycin was as effective at treating trachoma as the traditional regimen of topical tetracycline. Therefore, a researcher at the time of the invention would expect a topical application of the drug to have a greater spectrum of activity when administered topically than when administered orally, in light of the fact that topical applications could be administered in higher concentrations. Second, there were studies indicating that azithromycin had a demonstrated affinity for ocular tissue and a prolonged half-life. Third, topical antibiotic treatments for ocular infections were known to have advantages over systemic treatments. Lastly, erythromycin was effective when dosed topically, and azithromycin was basically a newer and better version of erythromycin.
Plaintiffs countered that the prior art had generally discouraged the use of macrolides (the class of drugs that include azithromycin). Second, a person of skill in the art would not have inferred that azithromycin was a good choice for topical administration merely because it worked well when dosed orally. The ability of the drug to penetrate the eye when applied topically could not have been predicted based on the drug’s properties after systemic administration. Plaintiffs argued that the chemical characteristics of azithromycin, including its high molecular weight and insolubility made it an unlikely candidate to cross natural ocular barriers. Additionally, oral administration of azithromycin depended upon blood-level phagocytosis for the delivery of the drug. Generally, phagocytosis does not occur with topical application of a drug. Plaintiffs also pointed to the fact that there were a number of other, more promising compounds or combinations of such compounds that could have been used. Lastly, plaintiffs argued that defendants improperly limited their inquiry to treatment options for conjunctivitis, when the claims of the ‘411 patent related to ocular infections in general, which could occur in any part of the eye.
The Court found plaintiffs’ arguments more persuasive. Nothing in the record suggested that the delivery of azithromycin to ocular and other tissues through phagocytosis demonstrated that azithromycin could permeate conjunctival and corneal tissues when applied topically. Moreover, defendants’ experts failed to consider many other options of compounds known to opthalmic art, and the various ways to formulate them. The availability of nearly innumerable other options was far from the finite number of identified, predictable solutions necessary to demonstrate obviousness. The court also relied on evidence that azithromycin’s characteristics taught away from its use as a topical opthalmic treatment. Such evidence included the fact that azithromycin was known to be a large molecule, and poor corneal penetration had been observed with drugs of similar molecular size. It was also important that opthalmic drugs be soluble in tear fluid to be effective, and azithromycin was known to be practically insoluble in water.
Next, the court considered the ‘113, ‘443, and ‘893 patents (which were referred to as the “ISV Patents”). First, the court addressed defendants’ argument that a person of ordinary skill in the art would have been motivated to combine azithromycin and polycarbophil because skilled artisans would have been aware of in-situ gelling systems. Such systems would increase viscosity and a drug’s residence time in the eye, thereby enhancing absorption. Additionally, defendants argued that a prior art patent taught the use of 0.1% to 6.5% crosslinking agents to change the concentrations to get the desired viscosity. It also taught the incorporation of certain medicaments and antibiotics.
The court again found in favor of plaintiffs. The prior art taught away from the use of azithromycin for topical ophthalmic treatments. It was well known that azithromycin was unstable in water and generally insoluble, so a skilled artisan would not have selected it for inclusion in an aqueous delivery vehicle. Defendants also failed to demonstrate that a skilled artisan would have been motivated to create a topical opthalmic formulation using polycarbophil. Defendants’ expert admitted that he did not think to combine azithromycin and polycarbophil when he was developing and patenting in-situ gelling systems. The court further found that the pH ranges in the ‘893 patent would not have been obvious to a skilled artisan. The pH of a formulation most suitable for comfort is approximately 7.4. Yet azithromycin is most soluble at a pH of 5.0 or below. The ‘893 patent claimed a pH of 6.3, and there was nothing in the prior art that would have indicated stability at such a pH.
The court also noted that the plaintiffs had provided evidence of secondary indicia of nonobviousness, including unexpected properties. For example, the concentrations of azithromycin were unexpectedly high when topically applied using polycarbophil. In fact there was a 60-fold increase in azithromycin concentrations 24 hours after a topical dose than after an oral dose. Additionally, AzaSite® was shown to have increased activity against bacteria that were previously believed to be resistant to azithromycin. Finally, the court found that the invention solved a long-felt, but unsolved need. Specifically, there was a need for a once daily, topical azithromycin treatment. Prior formulations required extended dosing multiple times per day for many days. Once-daily dosing resolved many issues such as bacterial resistance and patient compliance.
