API and IP Newsletter
Contents
Givinostat
This week let us discuss Givinostat.
It is not approved yet by USFDA. It is not a drug yet! Givinostat (originally ITF2357) was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.
Italfarmaco announced recently that the USFDA has extended the review process of the New Drug Application (NDA). The company is seeking approval for the treatment of Duchenne Muscular Dystrophy (DMD).
The new date for a decision under the Prescription Drug User Fee Act (PDUFA) is now set for 21 March 2024.
There is high likelihood that Givinostat will be approved by FDA in March 2024.
It has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis, polycythaemia vera and Duchenne Muscular Dystrophy.
Givinostat lUPAC name {6- [(diethylamino)methyl]naphthalen-2-yl}methyl [4 (hydroxycarbamoyl)phenyljcarbamate is a hydroxamic acid, used in the form of hydrochloride thereof, in particular hydrochloride monohydrate, that acts as an inhibitor of Histone Deacetylase (HDAC) and exerts its action on the homonymous class I and II enzymes.
WO 1997043251 relates to the preparation of Givinostat, while WO2004065355A1 deals with the preparation and characterization of one polymorph monohydrate thereof.
WO2011092556A1 describes the preparation and characterization of an anhydrous polymorph of Givinostat.
WO2020178776A1 describes purification of Givinostat and relates to Givinostat which is having an amount of any single unknown impurity equal to or lower than 0.10%. This patent family is filed by Chemi SpA, who had filed DMF in April 2023! Interesting to note Chemi SPA is an Italian pharmaceutical company, owned by Italfarmaco Group.
The methods for preparing Givinostat described in the cited documents first provide for the synthesis of the acyl chloride (II) from intermediate (I) (STEP 1 ), which is then added as THF-wet solid to a solution of hydroxylamine in water and THF to generate the final product (STEP 2), according to the following Scheme 1 :
Very common raw materials will be required for the synthesis of Givinostat, such as 2,6-Naphthalic acid and 4-Aminobenzoic acid. There should be many suppliers of this RMs.
General information
20 Most Expensive Drugs in the World
The size of the global drug market reached $1136.2 billion in 2022. Forecasts suggest that the market is expected to reach $1848.5 billion in 2027, exhibiting a compound annual growth rate (CAGR) of 11.4%.
News here.
The ANDA boost
The leadership position of the research-based Indian pharmaceutical companies continues in getting the Abbreviated New Drug Applications (ANDA) approvals from the US FDA. In spite of several headwinds, the Indian pharmaceutical companies have grabbed higher ANDA approvals from US FDA during the first nine months ended September 2023.
News here
Intellectual Property
Vortioxetine hydrobromide tablets
This litigation was pertaining to two OB listed patents, and a third patent at issue in this case was US 9,101,626 (the ’626) patent, concerning a process for manufacturing vortioxetine. Vortioxetine is used as a treatment for major depressive disorder.
OB listed patents which were part of the litigation are as below.
The `626 patent is process patent and non-OB listed patent. However, Lupin filed an ANDA seeking approval to market vortioxetine prepared by a process that Lundbeck/Takeda contend will infringe claim 12 of the `626 patent.
Lundbeck sued Lupin for infringement and to bar Lupin from using the process before the expiration of the ’626 patent.
In this write-up we will discuss about this process patent `626.
Claim 12 of the ’626 patent depends from independent claim 1 and dependent claim 11. Claim 1 recites
1. A process for the preparation of
or a pharmaceutically salt thereof, the process comprising reacting compound II
wherein R′ represent hydrogen or a mono-valent metal ion,
with a compound of formula III
wherein X1 and X2 independently represent halogen, and a compound
wherein R represent hydrogen or a protecting group, in the presence of a solvent, a base and a palladium catalyst consisting of a palladium source and a phosphine ligand at a temperature between 60° C. and 130° C.
11. The process according to claim 1, wherein said phosphine ligand is selected from the group consisting of
2,2′-bis-diphenylphosphanyl-[1,1′]binaphtalenyl(rac-BINAP),
1,1′-bis(diphenylphosphino)ferrocene (DPPF),
bis-(2-diphenylphosphinophenyl)ether (DPEphos),
tri-t-butyl phosphine (Fu's salt),
biphenyl-2-yl-di-t-butyl-phosphine,
biphenyl-2-yl-dicyclohexyl-phosphine,
(2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine,
[2′-(di-t-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and
dicyclohexyl-(2′,4′,6′-tri-propyl-biphenyl-2-yl)-phosphane.
12. The process according to claim 11, wherein said phosphine ligand is rac-BINAP.
The parties disputed the construction of the term “reacting.” After a bench trial, the district court agreed with Lundbeck’s construction and found that Lupin infringes under that construction. Lupin timely cross appealed. And matter was before CAFC.
Lupin on its cross appeal argued that the district court erred in construing “reacting” in the ’626 patent to mean “the changing of a reactant(s) to product(s)” and in finding infringement under that construction. CAFC saw no error in this interpretation.
The ’626 patent’s specification does not define the word “reacting.” The 2004 Fifth Edition of the Oxford Dictionary of Chemistry defines “chemical reaction” as “a change in which one or more chemical elements or compounds (the reactants) form new compounds (the products).”
Lundbeck’s expert agreed with this definition, as did Lupin and Co’s expert. The district court noted that the claims of the ’626 Patent do not expressly recite ‘added,’ ‘reaction vessel,’ ‘beginning of the process,’ or ‘starting material,’ and they do not otherwise limit Claim 12 to a process in which the specified chemicals are added to the reaction vessel at the beginning of the process as starting material.
Lupin primarily argued on appeal that the district court erred by discounting evidence from the prosecution history. In the referenced office action, the examiner used the phrase “starting compound” to refer to the materials that are reacted together. The examiner here appears to have used “starting compound” to distinguish between claimed reactants and the claimed products.
But the examiner said nothing about the scope of “reacting,” and the examiner’s use of the word “starting compound” in isolation does not suggest that he defined reacting as referring only to starting materials. In any event, there are no statements by the patentee during prosecution that limited the scope of “reacting,” and the examiner’s unilateral remarks alone do not affect the scope of the claim.
Lupin also argued that the claims must be read to restrict the construction of “reacting” because claim 2, which depends from claim 1, involves a two-reaction sequence that first reacts compounds II and III and then reacts the product of that reaction with compound IV in a subsequent reaction.
Lupin failed to explain how claim 2 is inconsistent with the district court’s construction, which requires only the changing of reactants to products. Moreover, Lupin’s construction is in tension with dependent claim 3, which recites “the process according to claim 1, wherein compound II, compound III and compound IV are mixed together at the start of the process.” Lupin’s construction requires that the compounds be added “at the beginning of the process as starting material,” rendering claim 3 superfluous.
The district court did not err in its construction of “reacting” or in its determination of infringement.
District court earlier held that Lupin and cos’ ANDA did not infringe two patents US 9,278,096 (use of vortioxetine in patients who have previously taken certain other antidepressant medications and had to cease or reduce use due to sexually related adverse events) and US 9,125,910 (use of vortioxetine to treat cognitive impairment).
CAFC affirmed that the district court did not err in finding no infringement of the ’096 or ’910 patents.
CAFC also found that Lupin’s cross appeal challenging the district court’s determination that Lupin infringed the ’626 patent is without merit. Court said that though it is true that the specification only refers to using compound II as a starting material, nothing in the claims, specification, or file history requires Lupin’s narrower reading. Federal Circuit thus held that the district court did not err in its construction of “reacting” or in its determination of infringement.
Decision here
