Impurity Matters

Impurity matters

Abstract:

Vosaroxin, SNS-595 or AG-7352 or voreloxin, is a topoisomerase II inhibitor with anti-tumor activity.¹ The Patent application, 1992/CHENP/2012, was granted and covers a process for preparing substantially pure SNS-595 by controlling the amount of impurities, which affects purity and solubility.

Background:

The application, 1992/CHENP/2012, which is titled “Process for Preparation of a SNS-595 substance” covers a process for preparing nearly pure SNS-595. This application entered India as a National phase application, from an International application, PCT/US2010/047776, and takes priority from a US application, US 61/240,161.² Every patent application targets an unsolved problem in a particular domain, and this application covers synthesizing substantially pure SNS-595, see Scheme 1, with negligible fractions of other by-products, which was an unsolved problem in this domain. The initially filed claims covered for a process involving synthesis of substantially pure SNS-595 from Compound 3 (Claims 1 to 4), a separate process claims involving synthesis of compound 3 (claims 5 and 6), process covering the synthesis of SNS-595 from compound 1 (Claims 7 and 10), and composition covering SNS-595 (Claims 11 to 32), see scheme 1.

Analysis:

The Controller issued FER, which carried objections under non-patentable inventions, Section 3(d), Section 3(e), and inventive step (Section 2(1)(ja)).³ In the reply to FER, the Applicant deleted all the process related claims to overcome Section 3(d), which was already disclosed in WO 2007/146335 A2. Further, the Applicant argued that contrary to the prior art, the composition claims recognized the presence of impurities and its effect on solubility.⁴ The amended claims included composition and a method of obtaining the composition comprising SNS-595 as stated above. In regard to Section 3(e) objection, the Applicant pursued that the composition was a synergistic mixture, which affected purity and solubility of the composition, which was absent in the prior art composition. However, the Controller retained the inventive step objection in the hearing notice, stating “It would have been obvious to one of ordinary skill in the art at the time of the invention to have known that dehydrated SNS-595 with NaOH followed by neutralization and washing with water and ethanol to purify said product as taught by D1 and repeated the purification process in order to obtain a more pure product. It is well within the purview of the skilled artisan to know that multiple rounds of purification are typically necessary in order to obtain optimum purity. D1”. The propensity of a compound to form particles in aqueous solution depends on its solubility and the presence of other components in the solution. The applicant, in their supporting documents, argued that improved purification steps affected the number of particles formed in the aqueous solution and influenced solubility, which was outside the purview of ordinarily skilled in the art. And the data also showed less than 1000 particles with greater than 10 ߂ compared to the prior art, which would have a significant impact on purity and solubility of SNS-595. This application was eventually granted.