API and IP Newsletter
Contents
G 2/21: Enlarged Board of Appeal allows post-filed data to prove technical effect
The new frontiers of pharmaceutical innovation – according to investors
FDA approval in March 2023.
We follow FDA approvals for small molecules. Zavegepant approved recently. ZAVZPRET is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura.
ZAVZPRET (zavegepant) is a nasal spray. Zavegepant hydrochloride is described chemically as (R)-N- (3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl) piperazin-1-yl)-1-oxopropan-2-yl)- 4-(2-oxo-1,2-dihydroquinolin-3-yl) piperidine-1-carboxamide hydrochloride.
Zavegepant hydrochloride is a white to off-white powder, freely soluble in water, and has pKa values of 4.8 and 8.8. Each unit-dose ZAVZPRET device for nasal administration delivers 10 mg of zavegepant (equivalent to 10.6 mg of zavegepant hydrochloride) in a buffered aqueous solution containing dextrose, hydrochloric acid, sodium hydroxide, and succinic acid in water for injection. The solution has a pH of 5.3 to 6.7.
The compound is described in International Publication No. WO2011/123232. A brief process described is as below.
N-{(2R)-3-(7-Methyl-1H-indazol-5-yl)-1-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-1-oxo-2-propanyl}-4-(2-oxo-1,2-dihydro-3-quinolinyl)-1-piperidinecarboxamide
A flask was charged with (R)-3-(7-methyl-lH-indazol-5-yl)-2-(4- (2-oxo-l,2-dihydroquinolin-3-yl)piperidine-l-carboxamido)propanoic acid (2.9 g, 6.11 mmoles), triethylamine (3.00 mL, 21.5 mmoles), l-(l-methylpiperidin-4- yl)piperazine (1.23 g, 6.72 mmoles), and dimethylformamide (10 mL). The resulting solution was treated with 2-(lH-benzotriazole-l-yl)-l, l,3,3-tetramethyluronium tetrafluoroborate (2.26 g, 7.03 mmoles) in portions. The reaction was allowed to stir at room temperature overnight. The mixture was concentrated under vacuum to remove dimethylformamide. The crude product was dissolved in 7% methanol in dichloromethane and purified by flash chromatography using 7% methanol in dichloromethane containing 2% of aqueous ammonium hydroxide as eluent. The pure fractions were collected and solvent was removed under vacuum. The desired product was crystallized from hot acetone to give Compound I in 77% yield.
WO2022217008A1 patent family filed by Teva and it relates to Crystalline Form B of Zavegepant.
Many companies must be working on Zavegepant. Priority date of Teva application is in April 2021. Teva must have started API development two years prior to FDA approval.
General information
G 2/21: Enlarged Board of Appeal allows post-filed data to prove technical effect
So far, established European Patent Office case law requires that, in order for the examiners to account for data submitted after filing a patent, it must be plausible from the application as filed, in combination with common general knowledge, that the technical effect was already achieved at the date on which the patent was filed. Now the EPO’s Enlarged Board of Appeal (EBA) has confirmed this in its G 2/21 judgment.
News here.
The new frontiers of pharmaceutical innovation – according to investors
Pharma companies and world health stand to benefit from new technologies, but it’s a tough time to be an investor – and an even tougher one for firms seeking investment. From close to zero, central bank interest rates have risen to 3% in the Eurozone, 4% in the UK and nearly 5% in the USA. Further rate hikes could be on the way this year. For investors, dependable assets like government bonds have become a lot more tempting compared to volatile start-up shares. Venture capitalists are becoming increasingly discriminating. That means pharmaceutical entrepreneurs – inundated with investment opportunities mere months ago – are now competing for a shrinking pool of cash.
News here.
Intellectual Property
Deferasirox: Novartis Vs Teva and HGF
EP 3124018 was granted on the basis of 9 claims and issued to Novartis. The independent claim of the patent as granted read as follows:
"1. A film coated tablet for oral administration which contains deferasirox or a pharmaceutically acceptable salt thereof present in an amount of from 45% to 60% by weight based on the total weight of the tablet, and wherein the tablet contains 90 mg, 180 mg or 360 mg of deferasirox or a pharmaceutically acceptable salt thereof, wherein the tablet further comprises,
(i) at least one filler in a total amount of 10% to 40% by weight based on total weight of the tablet, wherein the filler is microcrystalline cellulose;
(ii) at least one disintegrant in a total amount of 1% to 10% by weight based on the total weight of the tablet, wherein the disintegrant is cross-linked polyvinylpyrrolidone (crospovidone);
(iii) at least one binder in a total amount of 1% to 5% by weight based on the total weight of the tablet, wherein the binder is polyvinylpyrrolidone (PVP);
(iv) optionally, at least one surfactant in a total amount of 0.0% to 2% by weight based on the total weight of the tablet, wherein the surfactant is poloxamer;
(v) at least one glidant in a total amount of 0.1% to 1% by weight based on the total weight of the tablet, wherein the glidant is colloidal silicon dioxide;
(vi) at least one lubricant in a total amount of less than 0.1 % to 2% by weight based on the total weight of the tablet, wherein the lubricant is magnesium stearate; and
(vii) a coating."
Two oppositions Teva and HGF were filed against the patent on the grounds that its subject-matter lacked inventive step, it was not sufficiently disclosed and it extended beyond the content of the application.
This matter was before the appeal board. This is very complex case there are many auxiliary requests. For this write-up only study inventive argument of the main request.
Following prior art documents were cited.
D1: WO 2007/045445 A1
D3: WO 2004/035026 A1
D7: WO 2009/067557 A1
D12: WO 2010/143006 A1
D13: Assessment report EMA/CHMP/107225/2016, published 28 January 2016
D18: Aulton, Aulton's Pharmaceutics: The Design and Manufacture of Medicines, Third Edition, 2007, 293, 296-297, 451 and 455
D22: Exjade: EPAR - Product Information Annex I published first published by European Medicines Agency on 20 August 2009
D27: EP 0 914 118 B1
D28: Eadala et al., Alimentary Pharmacology and Therapeutics, Vol. 29, 2009, 677-687
D29: Rowe, Raymond C et al., "Handbook of Pharmaceutical Excipients" PhP Pharmaceutical Press, 6**(th) Edition, 2009, 506-509 and 651-653
D33: "Remington: The Science and Practice of Pharmacy", 20**(th) Edition, 2000, chapter 45
D34: Declaration from Peter Rue dated 11 December 2020 (and CV)
D37: R. Sechaud et al., International Journal of Clinical Pharmacology and Therapeutics 2008, 46(2), 102-108
D39: Allen, Jr. Loyd V. et al., “Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems”, 9**(th) Edition, 2011, 128-132
Inventive step
THE Closest prior art
There was lot of interesting debate about prior art consideration, worth reading in the decision. Finally the board considered D7 as the closest prior art document. During oral proceedings, all parties considered example 26 as starting point within D7.
Distinguishing features
The following distinguishing features between the tablets according to claim 1 and the one of example 26 of D7 were undisputed:
(i) presence of a film coating,
(ii) specific absolute amount of deferasirox,
(iii) absence of SLS and lactose, and
(iv) presence of poloxamer.
However, the parties disagreed as to whether the feature "swallowable" constituted a distinguishing feature versus the dispersible tablet of example 26 of D7 or not.
The first issue is the interpretation of the feature "swallowable" in present claim 1. The Board considers "swallowable" as a tablet suitable to be orally ingested as it is i.e. without prior modification such as crushing, chewing or dispersing in water.
In this context, the Board disagrees with Novartis that this would amount to considering the intended use as a limiting feature of the claims.
The Board agrees with Teva and HGF that claim 1 is directed to a product per se merely suitable for being swallowed.
However this imparts a number of variable structural features to the product (size, palatability, thickness, hardness, ...) and is as such limiting.
As a consequence, a tablet which needs to be crushed (for example because too big) or dispersed before being orally ingested would not be according to the claims.
Conversely, this does not mean that a tablet according to claim 1 cannot be crushed, dispersed, solubilised and then administered in a different manner but it does not have to, since it is suitable to be swallowed as such.
Turning now to the tablet of example 26 of D7, the question to be answered is whether it would be suitable for swallowing without prior modification.
According to D7, the ingestion of a "dispersible" tablet requires prior dispersion. The Board considers therefore that the skilled person would not regard the "dispersible" tablet of example 26 as suitable for swallowing without prior dispersion.
In this context, Novartis argued that the size and the individual nature of excipients of the tablet of example 26 would allow the tablet to be swallowed.
In particular, this tablet would be smaller than the ExjadeTM tablet
This argument is however not convincing because not only the size of a tablet and the individual nature of the excipients are decisive for the suitability for swallowing. For example the overall palatability, the hardness or the shape of the tablet are expected to also have an impact.
The Teva and HGF did not provide any evidence that tablets of D7 may indeed be swallowed without prior dispersion.
Most of the arguments of the Teva and HGF relate to dispersible ExjadeTM tablets, in particular based on D12 and D37.
However, the dispersible ExjadeTM tablets are not identical with the tablets of D7. Even if they contain the same excipients, the relative amounts thereof differ from one composition to the other, so that no conclusion for the tablets of D7 can be drawn based on observations made with dispersible ExjadeTM tablets.
Moreover, the Board observes that the actual mode of administration of the ExjadeTM tablets in D12 is not specified.
Regarding D37, the Board observes that the undispersed tablets were cut into smaller pieces and swallowed with the same amount of water as used to prepare the dispersions. This does not correspond to the administration of a standard swallowable tablet.
The burden of proof in the present case rests with the Teva and HGF
Objective technical problem
Starting from D7, the objective technical problem resides in the provision of a deferasirox formulation having improved palatability and good bioavailability.
Obviousness discussion
The improved palatability having been considered credible based on common general knowledge, it cannot confer inventiveness to the present tablets. The provision of a film coating to this aim is therefore obvious.
The specific absolute amounts of deferasirox of present claim 1 appear to constitute obvious modifications of known specific doses within usually used ranges. This feature cannot therefore provide inventiveness to the claimed tablet. This was not disputed.
As argued by Teva and HGF, the skilled person would have been aware of the potential drawbacks in terms of gastrointestinal irritation and tolerance linked to the presence of SLS and lactose in the composition of D7 (see e.g. D28 and D29).
D7 generally discloses microcrystalline cellulose (MCC) as one of the alternative excipients to lactose as well as poloxamer as a suitable surfactant.
The individual replacement of SLS and lactose in the formulation of example 26 of D7 by for example poloxamer and MCC might have appeared obvious to the skilled person willing to avoid the above mentioned drawbacks.
Furthermore, the idea of providing a swallowable tablet to improve the ease of administration may appear obvious per se.
However, in the present case, the key point is whether good bioavailability would have been expected for a swallowable tablet of deferasirox with the claimed excipients.
The Board observes that dispersible tablets are generally expected to have a better bioavailability than swallowable tablets, as confirmed by D18.
The skilled person would therefore have had no reasonable expectation of success of achieving good bioavailability when formulating deferasirox as a swallowable film coated tablet, let alone with the present excipients.
The Teva and HGF argued that the bioavailability ranking of dosage forms provided in D18 was however not an absolute rule and that, in the specific case of deferasirox, experimental data were actually available (see D37, treatment A versus treatments B to D) indicating that the dispersion would have no influence on the bioavailability.
According to these data, whether the ExjadeTM tablet was dispersed or not before administration, the bioavailability remained unaffected.
As a consequence, the skilled person would have learned from D37 that in the case of deferasirox, dispersion would have no influence on bioavailability. Furthermore a dispersible tablet would merely be one embodiment of D7, which also described oral dosage forms as alternatives to dispersible tablets.
The aim of D7 being good bioavailability, it would be expected for any formulation disclosed in D7.
During oral proceedings, Novartis underlined in this context that example 26 of D7 has an improved dissolution compared to Exjade TM which is at least qualitatively indicative of a good bioavailability.
Teva and HGF thus concluded that the skilled person would have expected that, by modifying the dispersible tablet of example 26 of D7 into a swallowable tablet, good bioavailability would be maintained.
This argument is however not convincing.
The purpose of D37 was to study the impact on bioavailability of an administration of commercial dispersible ExjadeTM tablets which would not be according to registration study, i.e. dispersion in a different medium or uncomplete dispersion.
Treatment A of D37 indeed corresponds to the administration of an ExjadeTM tablet cut into pieces and swallowed without prior dispersion.
However, contrary to the argumentation developed by Teva and HGF, the Board considers that no indication regarding the bioavailability of film coated swallowable tablets can be inferred from this study.
Film coated swallowable tablets contain per definition different excipients in different amounts than dispersible tablets.
In particular a dispersible tablet is made such as to dissolve fast in an appropriate liquid. This is not the case of a film coated swallowable tablet. Even if, as argued by Teva during oral proceedings, both type of tablets contain a disintegrant, the relative amount thereof is usually higher in a dispersible tablet (20% crospovidone in ExjadeTM, see D3 example 2, which was indicated by the parties as representing the composition of ExjadeTM) as in a film coated swallowable tablet (1-10%, see paragraph [0012] of the patent).
Moreover, in D37 treatment A the tablet was administered with the same volume of water as the one used to disperse the tablets prior to administration in treatments B and C.
These conditions do not represent standard administration of a swallowable tablet. In the case of D37 treatment A it is indeed to be expected that the large amount of water ingested with the tablet will participate to the dispersion of the tablet in the stomach.
Furthermore, as indicated by Novartis during oral proceedings, the tablet "in the form of an oral dosage form" generally disclosed in D7 cannot be equated with a film coated swallowable tablet.
While oral dosage form tablets encompass film coated swallowable tablets, they also encompass further types of tablets, such as chewable tablets or sublingual tablets. D7 does therefore not provide any hint that good bioavailability would be obtained when formulating deferasirox specifically in a film coated swallowable tablet.
As a result, the Board considers that neither the disclosure of D7 nor the results of D37 would have provided a reasonable expectation of success of good bioavailability when formulating deferasirox in film coated swallowable tablets.
As explained by Novartis, the skilled person would furthermore be aware of the fact that SLS may contribute to the dissolution of the tablet of example 26 of D7. While its replacement by poloxamer so as to avoid GI irritation might have appeared obvious, there is no indication in the prior art documents that good bioavailability would indeed necessarily be obtained with such a replacement.
Hence board came to conclusion that claims are inventive.
Decision here
