API and IP Newsletter
FDA approvals in April 2021.
General information.
FDA issues ICH Q12 guidance and others on clinical trials, safety testing and biowaivers.
Pharma industry faces shortage of raw material
Intellectual Property.
PTAB held Sitagliptin Patent valid in IPR proceedings in the US.
FDA approvals in April 2021
Every month we follow FDA approvals of small molecules and post our observations/comments. Our comments in this section are more related to API synthesis and we do not provide information about mechanism of action of the drug. In this Newsletter we are covering Viloxazine.
Viloxazine:
1. The drug was first marketed in 1976.
2. FDA granted it an orphan designation for cataplexy and narcolepsy in 1984. As per Wikipedia it was withdrawn from markets worldwide in 2002. The drug is repurposed by Supernus Pharmaceuticals as a treatment for ADHD and approved by FDA in April 2021.
3. Example 1 in US 3857839 discloses the process, in very low yield. Melting point is reported. One must optimize this process.
4. Though this an old API, there’re no active DMFs. Neuland could file DMF quickly. However, it is interesting to note Neuland is supplying API to the innovator Supernus Pharmaceuticals @ USD 2800/Kg!
General information
FDA issues ICH Q12 guidance and others on clinical trials, safety testing and biowaivers
Effective implementation of this guidance will provide an opportunity for the FDA to focus attention and resources on higher risk postapproval changes, incentivizing manufactures with additional flexibilities to continually improve their manufacturing processes, which can reduce the likelihood of quality-related supply disruptions and related drug shortages
News here.
Pharma industry faces shortage of raw material
Suspension of air transport between China and India has caused a shortage of salts, raw material for preparing medicines, which, in turn, enhanced their prices in the domestic market. China took this measure following a surge in the Covid-19 cases in India. The biggest hike was noticed in methylprednisolone which rose from Rs 85,000 to Rs 2.30 lakh within a week. The medicine is in high demand to clear the chest of Covid-19 positive patients. (here)
Intellectual Property
PTAB held Sitagliptin Patent valid in IPR proceedings in the US.
Inter Partes Review (IPR)
This is a process of challenging validity at USPTO (United State Patent and Trademark office).
An IPR is used to challenge the patentability only on a ground that could be raised under Novelty and Inventive step (non-obviousness). Also it should be noted that these grounds could be raised only on the basis of prior art consisting of patents or printed publications.
The procedure is conducted by the Patent Trial and Appeal Board (PTAB) at USPTO.
Sitagliptin case before PTAB
Mylan DRL, Sun Pharma filed IPR for claims 1–4, 17, 19, and 21–23 of US 7,326,708 patent.
Claim 1 is as follows, specific salt.
A dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine of structural formula I:
or a hydrate thereof
Claim 3 relates to S-configuration.
The salt of claim 1 of structural formula III having the (S)-configuration at the chiral center marked with an *
Claim 4 relates to monohydrate of sitagliptin.
The salt of claim 2 is characterized in being a crystalline monohydrate.
This patent is under Hatch-Waxman (HW) litigation. This write-up is not about the HW litigation but as mentioned, about the petition filed at USPTO by Mylan and Co in front of PTAB.
The petitioners, Mylan, DRL and Sun argued, WO2003/004498 (`498) teaches the phosphoric acid salt of sitagliptin.
PTAB, though agreed to the disclosure in prior art (`498), said, Mylan, DRL and Sun failed to prove the benefit of making an (S)-enantiomer or crystalline monohydrate of 1:1 sitagliptin dihydrogenphosphate salt.
PTAB further stated, Prior art WO ’498 is mere general disclosure, which encompasses millions of potential compounds and salts, does not show a motivation to skilled person to make 1:1 (S) or crystalline monohydrate of sitagliptin dihydrogenphosphate salt with a reasonable expectation of success.
Petitioner (Mylan and Co) attempted to fill this hole by citing vaguely to pages of testimony from Merck’s expert, Dr. Myerson. But Dr. Myerson’s testimony that a skilled person may generally prefer “crystalline substances . . . over amorphous forms” does not explain why the specific hydrate of claim 4 would have been pursued or preferred.
As a result, PTAB held the phosphate salt patent US 7,326,708 of sitagliptin valid in IPR proceedings. Decision here.
Disclaimer
Sidvim LifeSciences Private Ltd has taken due care and caution in developing this document. Since the data used for analysis in this document is based on the information available in the public domain, its adequacy or accuracy or completeness cannot be guaranteed. This document is for information only and Sidvim is not responsible for losses that may or may not arise due to any decisions made based on the same. No part of the document shall constitute or be represented as a legal opinion of any kind or nature. No warranties or guarantees, expressed or implied, are included in or intended by the document, except that it has been prepared in accordance with the current generally accepted practices and standards consistent with the level of care and skill exercised under similar circumstances by professional consultants or firms that perform the same or similar services.
