API and IP Newsletter
Contents
Zydus gets USFDA nod, 180 days shared exclusivity for Brivaracetam
Merck KGaA says it'll consider 'larger-scale' acquisitions from 2023 onward
FDA approvals: Futibatinib
We follow FDA approvals, specifically small molecules. We study chemistry, a brief IP landscape.
Futibatinib is a kinase inhibitor with the chemical name 1-[(3S)-3-{4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]- 1H-pyrazolo[3,4-d]pyrimidin-1-yl}pyrrolidin-1-yl]prop-2-en-1-one. It has the following chemical structure:
Futibatinib is a white crystalline powder. The solubility of futibatinib is pH dependent with decreasing solubility with increasing pH, being practically insoluble at pH 3 or higher.
Futibatinib can be synthesized using the procedure described in WO 2013108809, in which futibatinib is described as example 2. The filing date of WO2013108809 is 17 January 2013. US equivalent patent expiration date is in February 2033. If one calculates Patent Term Extension (PTE) very roughly then there could be possibility of PTE till October 2036.
There is an another interesting patent family ie., WO2016159327A1, filing date 31 March 2016 and relates to crystalline forms. Three forms are reported Crystal I, Crystal II, Crystal III. Among them, Crystal II is reported to have high stability, excellent oral absorption, high crystallinity, high chemical purity, suitable for mass production, and has a uniform particle size distribution.
Based on this information, companies must evaluate their polymorph strategy very carefully. The formulators must select polymorphs for FDF development after analysis of IP landscape in different jurisdictions.
AMRI (Albany Molecular Research Inc.) is a contract research and manufacturing organization, it had ordered (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate in small quantities one year ago!
It could mean Indian companies have started process development of Futibatinib one year ago!
General information
Zydus gets USFDA nod, 180 days shared exclusivity for Brivaracetam
Brivaracetam is indicated for the treatment of partial-onset seizures in patients 4 years of age and older.
Zydus Lifesciences said that its US subsidiary Zydus Pharmaceuticals (USA) Inc. received final approval from the United States Food and Drug Administration (USFDA) to market Brivaracetam tablets USP 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg. (USRLD: Briviact).
Zydus was one of the first ANDA applicants to submit a substantially complete ANDA with a paragraph IV certification for Brivaracetam tablets. It is therefore eligible for 180 days of shared generic drug exclusivity for Brivaracetam tablets.
News here.
Merck KGaA says it'll consider 'larger-scale' acquisitions from 2023 onward
Merck KGaA has been investing heavily in its biopharma business as part of an effort to grow to 25 billion euros in global revenues by 2025. Starting next year, its expansion campaign could include M&A.
News here.
Intellectual Property
CAFC affirmed PATB (Board) decision in Sitagliptin
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 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 phosphate salt patent US 7,326,708 of sitagliptin valid in IPR proceedings. Decision here.
Mylan appealed against the PTAB’s (Board) decision.
As Merck (innovator) asserted, it developed a 1:1 sitagliptin DHP salt in December 2001 with experimental confirmation in early 2002.
Merck highlighted, Mylan did not argue that claim 4, directed to a crystalline monohydrate, was anticipated by `498, which it could have done had it believed that the `498 disclosed a crystalline monohydrate.
The Board’s finding that `498 does not specifically points towards 1:1 sitagliptin DHP was supported by substantial evidence in the Court.
CAFC therefore agreed with the Board that Merck reduced to practice more than what is shown in `498 for the claimed subject matter.
CAFC agreed with Merck that the Board’s decision that Mylan failed to show that claims 3 and 4 of the ’708 patent would have been obvious to a skilled artisan at the time the invention was made was supported by substantial evidence.
With respect to claim 3, the Board found that there was no motivation to combine `498 and other references to make sitagliptin DHP, that the two cited references did not provide motivation to make (S)-sitagliptin, and that there was no reasonable expectation of success in combining the references.
The Board adequately credited Dr. Chorghade’s testimony, which stated that the (S)-enantiomer was not disclosed in the `498.
The Board further highlighted that Mylan advanced no expected or theoretical benefit to making the (S)-enantiomer of 1:1 sitagliptin DHP, and that the general disclosure on diastereomers in the `498 encompasses millions of potential compounds and salts with no motivation to make the (S)-enantiomer with a reasonable expectation of success, particularly in an unpredictable activity like salt formation. CAFC agreed with Merck that the Board’s decision was supported by substantial evidence.
With respect to claim 4, the Board found that there was no motivation to combine prior art references and that a person of ordinary skill would have had no reasonable expectation of success in doing so.
Decision here
With this decision Sitagliptin brands viz Januvia, Janumet will be protected till May 2026 and Janumet XR will be protected till May 2027, which includes six months’ paediatric exclusivity. These dates will be potential Gx launch dates (LoEs) in US as per the settlement of Merck with multiple generic companies.
