API and IP Newsletter
Contents
Mankind, IPCA, Torrent, Ajanta, Sun Lead Pharma Market Growth in November
FDA approval in October 2021
Regulatory
Asciminib approved in October 2021 by FDA
Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukaemia.
Chemistry
The chemical name of the drug substance is N-[4 (Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-3-yl) pyridine-3-carboxamidehydrogen chloride. Asciminib hydrochloride is a white to slightly yellow powder.
The molecular formula of asciminib hydrochloride is C20H18ClF2N5O3.HCl, and the relative molecular mass is 486.30 g/mol for the hydrochloride salt and 449.84 g/mol for the free base.
The chemical structure of asciminib hydrochloride is shown below:
Formulation
Scemblix film-coated tablets are supplied for oral use with two strengths that contain 20 mg and 40 mg of asciminib (equivalent to 21.62 mg and 43.24 mg, respectively, of asciminib hydrochloride).
The tablets contain colloidal silicon dioxide, croscarmellose sodium, ferric oxide, hydroxypropyl cellulose, lactose monohydrate, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.
The 20 mg tablets contain ferric oxide, yellow and ferric oxide, red. The 40 mg tablets contain ferrosoferric oxide and ferric oxide, red.
IP (Patent)
Asciminib originally described in WO 2013/171639 A1 (Novartis) as Example 9.
Crystalline forms of Asciminib are described in International Publication No. W02020/230099 (Novartis).
Teva patent family WO2021154980A1 relates to several crystalline forms. Priority date is in January 2020, this indicates, Teva must have started development in early 2019, almost 16-18 months in advance of FDA approval.
General information
Bayer wins again in latest Roundup cancer trial
Roundup did not cause a San Bernardino woman’s cancer, a jury found Thursday, adding another tally to the winner’s column for Bayer over claims that its signature herbicide is carcinogenic.
Donnetta Stephens, of Yucaipa, California, was diagnosed with non-Hodgkin’s lymphoma in 2017, which she attributed to 17 years of spraying Roundup twice a week in her yard. She sued Roundup maker Monsanto in 2020 for failing to warn her that glyphosate, the active ingredient in Roundup, could cause cancer.
Bayer AG, the German pharmaceutical conglomerate that owns Monsanto, announced last year that it would stop selling Roundup formulated with glyphosate in the U.S. consumer market by 2023.
But a jury decided that Roundup was not a substantial factor in Stephens' diagnosis.
News here.
Mankind, IPCA, Torrent, Ajanta, Sun Lead Pharma Market Growth In November
India's pharmaceutical market grew in November as sales recovered, aided by drugs used for chronic conditions from diabetes to heart diseases. The pharma industry value rose 6.6% year-on-year last month, Motilal Oswal said in a report. That compares with a 5% rise in October and 1% growth in November 2020.
News here.
Intellectual Property
Dapagliflozin decision by Delaware Court
AstraZeneca owns NDA No. 202293 for Farxiga (dapagliflozin) tablets for the treatment of diabetes and related diseases.
Zydus filed an ANDA on 20 March 2018 filing PIV on compound patent `117. AstraZeneca sued Zydus and the matter was before Delaware district court.
Zydus's argued non obviousness based on prior art references WO ' 128, Hongu, and Kees.
WO '128 discloses eighty structurally similar compounds as prospective SGLT2 inhibitors. Twenty-five of these compounds fall within the genus Formula IB, which the patentee designates as the “most preferred" set of embodiments. The Formula IB genus has preferred chemical moieties at certain positions, as shown below
The OB listed '117 patent is directed to compounds and methods for treatment of diabetes and related diseases through inhibition of sodium dependent glucose transporters (SGL T2) found in the intestine and kidney.
WO '128 Formula IB (Compounds) does not provide data of comparative biological activity (i.e., SGL T2 inhibition) for any of its listed compounds, nor does it indicate why Formula IB compounds are preferred candidates for development.
Hongu teaches away from replacing the methoxy at the 4-position on the distal ring with a heavier moiety because it shows decreased biological activity when the methoxy is replaced with larger distal alkoxy groups.
As the alkyl or alkoxy group became larger, the activity tended to be reduced.
Kees teaches away from replacing the methoxy at the 4-position on the distal ring with a larger alkoxy moiety because it shows decreased biological activity for compounds with larger alkoxy groups.
The preferred compound in Kees is an ethyl group at the R4 position rather than an alkoxy. SAR (Structure Activity Relation) analysis is an iterative approach to rational drug design used by POSAs to optimize a potentially therapeutic molecule by evaluating whether changes to its chemical structure affect the molecule's desired therapeutic property, which is typically a change in biological activity.
The molecular scaffold (i.e., the core structure) that is chosen for iterative permutation during SAR is called the "lead compound."
Because WO ' 128 does not evaluate the activity of its compounds, including those in Formula IB, it is not an SAR study.
WO '128 does not identify a lead compound because it did not test for favorable activity or pharmacological characteristics that would have identified a compound as such.
Based on the lack of biological activity data in WO '128 and the teaching away from the use of larger alkoxy groups at the 4-distal position by Hongu and Kees, a POSA would not have been motivated to swap the distal 4- methoxy in WO '128 's Example 12 with an ethoxy (which would otherwise yield the molecule claimed in the ' 117 patent).
Based on this the Court opined POSA would not have had a basis to expect dapagliflozin to exhibit better glucose-reducing effects than the closest prior art, such as Example 12. The Court stated Zydus failed to prove claims are obvious. 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.
