API and IP Newsletter
Contents
GL CHEMTEC Partners with Edgewater Capital to Accelerate Growth
Teva temporarily padlocks a plant after FDA cites it for contamination
ANDA approvals in July 2022
We analyse ANDA approvals of Indian companies. In the month of July 2022, total about 78 ANDAs were approved, out of which about 35 approvals were for ANDAs filed by Indian companies. The four approvals out of ca. 35 approvals received by Indian companies, are tentative approvals (TA) and will not result in immediate business.
Some of our observations/comments are as below.
General Comments
Three ANDA approvals for Zydus, Laurus, Amneal (2 TAs), DRL (one TA)
Rubicon received approvals for 2 ANDAs
General information
GL CHEMTEC Partners with Edgewater Capital to Accelerate Growth
GL CHEMTEC (“GLC”), a specialist in advanced chemistry R&D and scale-up services to support Active Pharmaceutical Ingredient (“API”) development, and the development of advanced materials for drug delivery, medical devices, and other life science applications, today announced it is partnering with Edgewater Capital Partners (“Edgewater”), a lower middle-market private equity firm with deep sector expertise in Life Sciences and Pharma Services, accelerating the company’s growth as a leading North American chemistry-based contract research organization (CRO). GLC is uniquely positioned within the North American market to address the growing need for advanced chemistry services with a focus on speed, flexibility, and high customer-touch business model.
News here.
Teva temporarily padlocks a plant after FDA cites it for contamination
After FDA investigators unveiled a list of problems that were found at a Teva Pharmaceuticals plant in Irvine, CA, including mold stemming from water leaks, the company said it will halt production at that site until it is able to meet quality expectations.
A Teva spokesperson confirmed the temporary manufacturing stoppage Monday morning in an email to Endpoints News, saying that that production will resume after a review is conducted.
News here.
Intellectual Property
APIXABAN: UK High Court decision of revocation of patent.
Apixaban, trade name ELIQUIS, is a successful drug for treating thromboembolic disorders. In a judgment of 7 April 2022, the Judge held that a patent covering apixaban as such, and which also claimed apixaban for use in treating a thromboembolic disorder, was invalid. As a result, an associated SPC was also invalid. It was the first trial.
The patent in issue at the First Trial had a priority date of 21 September 2001.
This trial concerned four further patents relating to apixaban, all from the same family as one another and all having priority dates of 25 February 2010. They cover formulations of apixaban
Patentee was BMS. This was challenged by Sandoz and Teva.
The Patents are contested were
EP(UK) 3 246 021;
EP(UK) 3 017 811;
EP(UK) 3 251 660;
EP(UK) 3 257 500.
Sandoz reached a settlement with BMS so that only the first Patent (`021) remained in issue, and from that Patent, only claims 1-6 (it was these claims that Sandoz admitted were infringed if valid).
When this trial began, `021 and the second Patent (ending `811) had been revoked by the Opposition Division of the European Patent Office. Later, the third Patent (`660) was revoked by the Opposition Division.
When opening skeletons were submitted, the issues were:
Some issues over common general knowledge (CGK) relevant to obviousness.
Obviousness over a review article by Carreiro and Ansell, Apixaban, an oral direct Factor Xa inhibitor: awaiting the verdict, published in November 2008 in Expert Opinion on Investigational Drugs, (Carreiro).
Obviousness over a BMS press release of 10 June 2008 entitled Bristol-Myers Squibb and Pfizer Initiate New Study in the Apixaban Phase 3 Clinical Trial Program”, (the Press Release).
Obviousness over US 2006/0160841 A1
Several case laws were cited by both parties
This dispute is about claim 1 of `021, which, as proposed to be amended, is as follows:
(a) A tablet comprising up to 5mg crystalline apixaban particles having
(b) a D90 less than 89µm as measured by laser light scattering and
(c) a pharmaceutically acceptable diluent or carrier, wherein
(d) the formulation exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein
(e) the dissolution test is performed in an aqueous media buffered to a pH range 1 to 7.4 and controlled at 37° C, wherein
(f) the result is established as an average of 6 tablets, and wherein
(g) the dissolution test is performed in 900 mL of dissolution medium containing 0.05 M sodium phosphate at pH 6.8 with 0.05% SDS at 37 °C using USP Apparatus 2 (paddles) at a rotation speed of 75 rpm and the samples are analyzed for apixaban by HPLC at 280 nm.
Sandoz and Teva wanted to head off an argument that for example, while it might be obvious to go for a small particle size, they could not show that specifically a D90 of 89µm would be achieved.
Lack of technical contribution
Sandoz and Teva argued that a patent monopoly must be justified by a technical contribution and that a patent which does not solve any problem is not inventive. The reason this point mattered, at least potentially, was that Sandoz/Teva obviousness case assumed that the skilled addressee would find a problem with the dissolution rate of apixaban in a prototype formulation. But other than in the figures of the `021 Patent there was no demonstration of such a problem. Sandoz/Teva wanted to be able to say that either there was a problem of slow dissolution to be solved (in which case it would be identified routinely with smaller particle size being an obvious solution) or, if there was in fact no problem then there was no inventiveness.
In 2010, the Skilled Clinician would also have been aware of another (Direct oral anticoagulants) DOAC being developed, although not approved: apixaban. They would have been aware of apixaban from the scientific literature and conferences.
The judge observed, the Skilled Formulator typically joins a drug development project after the drug discovery team has identified a small number of lead candidate compounds, but before studies in humans have been carried out.
The Skilled Formulator would typically test an APIs equilibrium solubility at human physiological temperature Intrinsic dissolution rate testing ("IDR")
Particle Properties: During pre-formulation the Skilled Formulator will investigate the characteristics of the particles of the API such as particle size, shape, and the compressibility of the API. Methods for particle size reduction
There are a number of different methods available to the Skilled Formulator to reduce the particle size by compression forces, impact, cutting and/or attrition.
The dispute therefore concerns whether or not it was CGK that the dissolution rate (as distinct from disintegration) of a BCS Class III drug could hinder its rate of absorption.
The Judge thought it is useful to start with whether the dissolution rate could in fact hinder absorption. The answer is quite clearly that it could. It is a basic proposition because if dissolution is too slow then not all the drug is available to permeate the gut wall when, or soon after, it leaves the stomach.
As the Judge understood it, Counsel for BMS accepted that a drugs being Class III could not guarantee sufficiently rapid dissolution.
It was agreed to be CGK that particle size reduction was a way to improve slow dissolution rates.
Based on various discussions, the Judge came to conclusion the aqueous solubility (40 µg/ml at all physiological pH) of apixaban suggests that the tablets with less than 10 mg apixaban (dose/solubility ratio = 250 mL) should not demonstrate dissolution rate limited absorption since dissolution rate limitations are only expected when the dose/solubility ratio is greater than 250 mL. Based on this dose and solubility consideration, the particle size of the compound should not be critical for achieving consistent plasma profiles, according to the prediction based on the Biopharmaceutics Classification System.
However, it was determined that formulations that were made using a wet granulation process as well as those using large particles of apixaban drug substance resulted in less than optimal exposures, which can present quality control challenges.
That is, one would expect that the dissolution rate for a drug that has high solubility (as defined by the BCS) would not be limited by the particle size. It has surprisingly been found, however, that the particle size that impacts apixaban absorption rate is about a D90 of 89 µm. Thus apixaban can be formulated in a composition having a reasonable particle size using a dry granulation process, to achieve and maintain relatively fine particles to facilitate consistent in vivo dissolution.
Table 6 and Table 6a in patent document provide the dissolution data from tablets made with different manufacturing processes (comparative wet and dry granulation according to the invention) and drug substance different particle sizes. As shown in Table 6, apixaban tablets that had 77% dissolved in 30 minutes or 86% dissolved in 30 minutes both had AUC values that met bioequivalence criteria (Confidence Interval between 80% to 125%) when compared to the tablets that had 89% dissolved in 30 minutes.
As discussed earlier, this dispute is about claim 1 of `021, which, as proposed to be amended, is as follows:
(a) A tablet comprising up to 5mg crystalline apixaban particles having
(b) a D90 less than 89µm as measured by laser light scattering and
(c) a pharmaceutically acceptable diluent or carrier, wherein
(d) the formulation exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein
(e) the dissolution test is performed in an aqueous media buffered to a pH range 1 to 7.4 and controlled at 37° C, wherein
(f) the result is established as an average of 6 tablets, and wherein
(g) the dissolution test is performed in 900 mL of dissolution medium containing 0.05 M sodium phosphate at pH 6.8 with 0.05% SDS at 37 °C using USP Apparatus 2 (paddles) at a rotation speed of 75 rpm and the samples are analyzed for apixaban by HPLC at 280 nm.
It was not said by patentee BMS that features (f) and (g) contributed to inventive step in any way (as opposed to clarifying the scope of the claim), and the same applies to feature (e), which was present as granted. Feature (c) is trivial and irrelevant to inventive step.
Feature (a) requires up to 5mg crystalline apixaban, and Carreiro, discloses tablets of either 2.5mg or 5mg.
So what really matter to the decision was whether it was obvious to make an apixaban tablet of 2.5mg or 5mg with the particle size profile of feature (b) and the dissolution rate of feature (d).
Teaching of Carreiro
The authors of prior art “Carreiro” were two workers at Lenox Hill Hospital in the USA.
The upshot is that Carreiro describes tests of apixaban in a variety of clinical trials. It gives the dose sizes and dosing intervals used in the trials and basic pharmacokinetic and pharmacodynamic parameters. It explains why direct Factor Xa inhibitors would be attractive. The only completed trials that it describes are phase 2 trials and its optimistic tone is qualified as a result, with statements that the outcome of the phase 3 trials cannot be taken for granted.
The judge agreed with BMS that Carreiro contains no specific teaching about actually formulating apixaban, although the information in Carreiro would provide necessary and useful inputs to the formulation task.
The parties agreed that the formulator would make prototype formulations and test them. Sandoz and Teva’s position is that by this stage and probably a good deal earlier it would have been obvious to settle on a target dissolution rate of 85% in 15 or 30 minutes. BMS’s position is that the formulator would have had a lot of confidence that the dissolution rate would be all right, simply from apixaban at the doses under consideration being a Class III drug (or alternatively that a much less ambitious target would be chosen). For reasons given in connection with the CGK ,the Judge agreed with Sandoz-Teva on this issue.
Sandoz-Teva submitted that if there remained a problem, one CGK way to address it would be by reducing particle size. BMS did not really dispute this, but said that excipient optimisation would be a more preferred route. The Judge found that it would be uninventive to address dissolution rate issues by choosing a more appropriate particle size, and he found in dealing with CGK that the size specified by the claims of `021 is well within the CGK range. Exactly what size would be chosen would depend on the specific circumstances of any given case including the details of the prototypes.
On his (the Judge) findings, the formulator would know that there might be a problem, would look for it by routine means, and would be able to solve it with CGK (Common General Knowledge).
So the Judge concluded that all the Patents are invalid for obviousness over Carreiro.
Decision here
