Abiraterone - USA

On Oct 26, 2018, Judge Kevin Mcnulty of District of New Jersey found method of use patent of Zytiga® invalid under obviousness.

This is Hatch-Waxman actions for infringement of US 8,822,438 brought by Janssen and BTG International Ltd. The ‘438 patent contains twenty claims covering - methods for the treatment of prostate cancer by administering various dosages of abiraterone acetate and prednisone in combination. Plaintiffs alleged infringement of claims 4, 8, 11, 19 and 20, all of which dependent on claim 1 of the 438 patent, based on the defendants’ filing of ANDAs. The Court conducted a bench trial beginning on July 23, 2018 and concluding on August 2, 2018. As a defense to infringement, defendants asserted that the ‘438 patent is invalid for lack of a written description and for obviousness.

Written Description:

Defendants alleged that the asserted claims in the ‘438 patent do not meet the written-description requirement of 35 U.S.C. § 112. Specifically, defendants argued that the specification is inadequate because it fails to disclose test results showing that prednisone itself provides an anti-cancer benefit. Also, it does not provide sufficient information to permit a POSA to understand that both agents, abiraterone and prednisone, “treat” prostate cancer. Court disagreed & said that the specification in the ‘438 patent sufficiently identifies prednisone as an anti-cancer agent for purposes of written-description requirement. The specification is directed to the administration of abiraterone acetate with “at least one additional therapeutic agent, such as an anti-cancer agent or a steroid.” Prednisone is explicitly identified as an antibiotic agent under broad category of anti-cancer agent. Second, the specification provides a list of steroids, including hydrocortisone, prednisone, and dexamethasone. The specification also provides the “amount of the steroid administered to a mammal having cancer is an amount that is sufficient to treat the cancer whether administered alone or in combination with a 170-hydroxylase/C17,2o-lyase inhibitor.” Thus, whether identified as either an “anti-cancer agent” or a “steroid,” prednisone is sufficiently identified in the specification as an agent that “treats” cancer. Therefore, claims have written description support.

Obviousness:

Defendants alleged that the combination therapy claimed in the ‘438 patent would already have been obvious to a person of ordinary skill in the art (“POSA”) under 35 U.S.C. § 103. Defendants asserted that, as of that date, a POSA familiar with the prior art would have been motivated to combine abiraterone acetate with prednisone for three reasons: (1) for its anti-cancer effects; (2) to mitigate abiraterone’s side effects; or (3) for prednisone’s palliative properties. The crux of defendants’ argument is that the prior art would have motivated a POSA to combine abiraterone with prednisone with a reasonable expectation of success.

Court in its analysis said that by the priority date of Aug. 25, 2006, it was understood that both ketoconazole and abiraterone were steroid inhibitors, and both inhibited the CYP17 enzyme. Barrie 1994 and O’Donnell 2004 both used ketoconazole as a starting point for their discussions regarding abiraterone and its potential to be a more selective inhibitor. Barrie 1994, comparing the inhibition levels of hormone production by abiraterone with ketoconazole, concludes that abiraterone was more effective than ketoconazole in decreasing testosterone levels. O’Donnell 2004 specifically notes that abiraterone’s ability to sustain testosterone suppression in castrate males, when given in 500 to 800 milligram doses, suggested that it could be used as a second-line treatment. From all of this, it can be concluded that abiraterone had been identified in the prior art as a second-line prostate cancer treatment. It can also be concluded that it was regarded as a superior swap for ketoconazole, in that it performed a parallel function in a more targeted manner. As for prednisone itself, Tannock 1996 suggested that corticosteroids provide some level of palliation to cancer patients. Sartor 1998 goes farther, and suggests that prednisone can cause reduced PSA levels, a marker of anticancer effect. That conclusion is supported by three other prior art references: Fossa 2001, Fakih 2002, and Harris 2002. Thus, there was more than sufficient motivation for a POSA to combine abiraterone with prednisone.

Moreover, Gerber 1990 suggests that a patient whose PSA levels are increasing can be treated with a combination of ketoconazole and a glucocorticoid, which can result in a decrease in PSA levels. Gerber 1990 also teaches that the combination of ketoconazole and 5mg a day of prednisone, twice daily, is safe and effective for treating hormone-refractory advance prostate cancer. O’Donnell 2004 corroborates that in the clinical use of ketoconazole, it was “common practice” to administer supplementary hvdrocortisone. It states cautiously that “further studies with abiraterone acetate will be required to ascertain if concomitant therapy with glucocorticoid is required on a continuous basis, at times of physiological stress, if patients become symptomatic or indeed at all.” Thus, A POSA would have interpreted ketoconazole’s clinical use as a basis to take the next investigative steps with abiraterone. It made sense to replace ketoconazole with abiraterone, as it became clear that abiraterone was a superior, more selective inhibitor. Co-administration of 10mg per day of prednisone would naturally carry over from the ketoconazole combination therapy to the abiraterone combination therapy. There would have been concerned about the potential reduction in cortisol as a side effect of abiraterone’s inhibition of CYP17. Specifically, a POSA would have seen the potential for resulting excess mineralocorticoid (aldosterone) and adrenal insufficiency. They do not, however, outweigh the clear teaching in prior arts & court did not agree, as plaintiffs suggest, that prior art “taught away” from the combination therapy. In short, to the POSA, the prior art would have suggested that abiraterone could be combined with prednisone with a reasonable probability of success.

With respect to secondary considerations court held that these factors do not overcome convincing evidence of obviousness.  As to the commercial success factor, there can be no dispute that ZYTIGA® has yielded billions of dollars in sales. “Evidence of commercial success . . . is only significant if there is a nexus between the claimed invention and the commercial success.” Moreover, “if the feature that creates the commercial success was known in the prior art, the success is not pertinent.” Onnco, 463 F.3d at 1311-12; see also fT. Eaton, 106 F.3d at 1571. Also, “where ‘market entry by others was precluded [due to blocking patents], the inference of non-obviousness of [the asserted claims, from evidence of commercial success, is weak.’” Galdenna Labs., L.P. v. Tolmar, Mc, 737 F.3d 731, 740 (Fed. Cir. 2013) (quoting Merck, 395 F.3d at 1377). Defendants argued that Abiraterone was previously known in the art & there is earlier blocking patent, US 5,604,213. From 1997 through 2016, that patent granted its holder the exclusive right to market abiraterone. Also the sales of ZYTIGA may not be wholly attributable to the patented combination therapy. These are powerful offsetting factors. With respect to long-felt need and unexpected results, Plaintiffs stated that the claimed invention was an advance on the prior art in that it had less toxicity, was better tolerated, and improved overall survival. Defendants pointed to existing contemporaneous alternatives: Jevtana was approved by the FDA in 2010, a year before ZYTIGA® was approved; Xtandi was approved in 2012. Therefore, court held that it does not suggest that all other efforts had failed, or that the abiraterone/prednisone combination therapy was unexpected “ in kind and not merely in degree.” Thus, balancing the entire prior art and the other indicia, court found that the evidence favors a conclusion of obviousness.

Judge also ruled on infringement issue & found patent infringed by Defendants if it would have been held valid.