Methylene Blue - USA

IPR decision: Jul 02, 2019

AIA Review	Filing Date	Institution Date	Petitioner	US Patent	Respondent	Final Written Decision
IPR2018-00182	12/18/2017	07/05/2018	Provepharm Inc.	9,382,220	WisTa Lab. Ltd.	Claims are patentable
IPR2018-00323	12/19/2017	07/06/2018	Provepharm Inc.	9,675,621	WisTa Lab. Ltd.	Claims are patentable

US 9,382,220 (WisTa Laboratories Ltd.; Exp: 07/10/2027*TD): Non-OB

1. A diaminophenothiazinium composition comprising a diaminophenothiazinium compound of the following formula: ##STR00097## wherein: each of R.sup.1 and R.sup.9 is independently --H, C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.3NA and R.sup.3NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.7NA and R.sup.7NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; and X is one or more anionic counter ions to achieve electrical neutrality; wherein the composition is characterised by the following by weight in the composition: at least 98% of the diaminophenothiazinium compound; less than 1% Azure B as impurity; less than 0.15% Azure A as impurity; less than 0.15% Azure C as impurity; and less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.

2. A diaminophenothiazinium composition comprising a diaminophenothiazinium compound of the following formula: ##STR00098## wherein the composition is characterised by the following by weight in the composition: at least 98% of the diaminophenothiazinium compound; less than 1% Azure B as impurity; less than 0.15% Azure A as impurity; less than 0.15% Azure C as impurity; and less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.

US 9,675,621 (WisTa Laboratories Ltd.; Exp: 07/10/2027): Non-OB

1. A method of treatment of a tauopathy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a high-purity diaminophenothiazinium compound of the following formula: ##STR00097## wherein: each of R.sup.1 and R.sup.9 is independently --H, C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.3NA and R.sup.3NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.7NA and R.sup.7NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; and X is one or more anionic counter ions to achieve electrical neutrality; wherein high-purity is defined by: at least 98% pure; less than 1% Azure B as impurity; less than 0.15% Azure A as impurity; less than 0.15% Azure C as impurity; and less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.

13. A method of treatment of a methemoglobinemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a high-purity diaminophenothiazinium compound of the following formula: ##STR00099## wherein: each of R.sup.1 and R.sup.9 is independently --H, C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.3NA and R.sup.3NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.7NA and R.sup.7NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; and X is one or more anionic counter ions to achieve electrical neutrality; and wherein high-purity is characterized by: a purity of greater than 98%; less than 1% Azure B as impurity; less than 0.15% Azure A as impurity; less than 0.15% Azure C as impurity; and less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.

CONCLUSION:

PTAB concluded that Petitioner has not shown, by a preponderance of the evidence, that the challenged claims are unpatentable.

First of all the cited prior arts disclosed “total content” of methylene blue measured as “Assay”, which includes impurity also. When someone does the titration to measure the content of drug then that method does not separately identifies pure compound & impurities. Prior arts did not disclose or suggest that more than 95% methylene blue means more than 95% “pure” methylene blue. Moreover, Petitioner has not provided any evidence to support their arguments.

Second argument with respect to reasonable expectation of success in using HPLC method to purify methylene blue was also failed. Because it was contradicted by Petitioner’s own submissions in EP & AU patent offices.  During prosecution of Petitioner’s patent application which claims less than 3% impurity in methylene blue, Petitioner said that this cannot be achieved by conventional techniques such as HPLC. These statements made in foreign patent offices undermine Petitioner’s argument here. As per “Mylan v Aurobindo” decision (Isosulphan Blue; CAFC 2017), purity claims can be given patentable weights if the route or method to obtain said pure compound is inventive.