API and IP Newsletter

 

Contents

• Analysis of patent applications of Biophore. 

• General information. 

• AstraZeneca to invest $360 million in Irish manufacturing facility. 

• Bulk drugs SMEs raise concern about Central Government giving only 11% share to MSMEs in second PLI scheme. 

• Intellectual Property. 

• T 2106/18 Boards of Appeal Decision: Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix.

 

Analysis of patent applications of Biophore 

Biophore, is engaged in the development and manufacturing of niche pharmaceutical products for the generic industry. As per their website information, they have filed over 60 DMFs so far. Biophore. 

In our firm we analyse development portfolio of many companies based on public domain information such as patent application filings and import-export database etc. Couple of weeks ago we analysed import/Export database to understand which could be probable under development candidates in R & D of Biophore.   

Those would be of course pipeline candidates. This week we analysed their past, we studied patent portfolio and publications of applications filed by Biophore since January 2019. Obviously, this development must have been done in 2016-2017 and 2018. Some of the observations are very interesting. Due to space constraint, only some of our findings are published below in Sidvim comments.

 

Publication Number	Title	Publication Date	SIDVIM comments
EP3820853A1	New high purity gadobutrol useful as a paramagnetic contrast agent for diagnosing MRI to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the CNS	2021-05-19	Contrast agent, Gadobutrol, approved in 2013. Biophore already filed DMF. This high purity gadobutrol must be part of their DMF.
WO2020165781A1	Preparation of sucroferric oxyhydroxide used for controlling serum phosphorus levels, involves mixing aqueous ferric chloride hexahydrate and bases, adding protic solvent, and isolating sucroferric oxyhydroxide containing ferrous ion.	2020-08-20	A process patent for sucroferric oxyhydroxide. It was approved for medical use in the United States in November 2013, and in the European Union in August 2014. Biophore is one of the DMF filer among 5 others
IN201941031924A	Preparing monohydrate form of erythromycin lactobionate useful as antibiotics, comprises adding lactobionic acid into reaction mixture of a solution of erythromycin in solvent, and isolating monohydrate form of erythromycin lactobionate	2021-02-12	Biophore filed DMF last year for erythromycin lactobionate along with Gland and Aurobindo. Biophore must be offering monohydrate.
IN201941031927A	Preparing nimodipine used to improve neurological outcome, involves coupling 3-nitrobenzaldehyde with methoxyethyl-oxobutanoate with base and reacting intermediate with isopropyl-amino-butenoate in presence of acid to form nimodipine	2021-02-12	Not many Gxs in market for nimodipine. Only 3 other DMFs. Biophore must be using this protected process in their DMF.
IN201941031930A	Manufacture of benserazide hydrochloride for treating Parkinson's disease, involves reducing (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)propane hydrazide hydrochloride formed by using e.g. DL-serine hydrazide hydrochloride	2021-02-12	Benserazide is not approved for use in the US. But it is marketed in UK and Canada. Biophore is eying other markets. Benserazide could be niche API. Many other US centric portfolio driven companies might not select this product for development.
IN201941005483A	Making selexipag, used to treat pulmonary arterial hypertension, comprises reacting benzil with 2-aminoacetamide hydrochloride in a base, chlorinating obtained 5,6-diphenylpyrazin-2-ol, and condensing obtained 5-chloro-2,3-diphenylpyrazine	2021-02-12	This could be process used by Biophore in their DMF. There are 6 other DMFs. Biophore seems to have some process advantages.
IN201941025908A	Preparing mexiletine HCl by reacting 1-(2,6-dimethylphenoxy)propan-2-one with hydroxylamine HCl in presence of protic solvent, reducing 1-(2',6'-dimethylphenoxy)-2-propane oxime, and treating mexiletine base with isopropyl alcoholic HCl	2021-01-01	Biophore is one among 5 other DMF filers for mexiletine. This is an old product. Innovator discontinued. Teva's product is RLD.

Conclusions:

1. There are about 55-60 priority applications (for about 30 molecules) have been filed in two and half years to three years by Biophore. This must be one of the highest patent filings by any generic API company.

2. Most of the applications are related to processes, purifications, polymorphs, solvates, adducts etc.

3. There must be 35-40 molecules under development (for these molecules 55-60 applications were filed) in the year 2016-2017 and 2018, which had potential technical effect.  

4. For many patent applications, one could see corresponding DMF filed. It indicates there could be some uniqueness in their DMF, maybe either cost effective process, or a typical solvate, hydrate or superior impurity profile.

 

General information

 

AstraZeneca to invest $360 million in Irish manufacturing facility 

AstraZeneca have announced that the company is planning to establish a next-generation active pharmaceutical ingredient (API) manufacturing facility for small molecules near Dublin in Ireland. According to the company, the new plant will allow for late-stage development and early commercial supply, adopting state of the art process technology and digital innovation that is designed to meet the needs of their new medicines pipeline with speed and agility.  

The $360 million planned investment at the Alexion Campus in College Park, Dublin, is expected to create about 100 highly skilled direct jobs and provide an important boost to the local economy and to the country’s life-sciences sector. (Read more) 

Bulk drugs SMEs raise concern about Central Government giving only 11% share to MSMEs in second PLI scheme 

Domestic pharmaceutical Small And Medium Enterprises (SMEs) which manufacture bulk drugs or Active Pharmaceutical Ingredients (APIs) have raised concern that Central Government has given more than 71% share to top few companies and only 11% share to the SMEs in the second production linked incentive (PLI) scheme aimed at giving boost to the domestic pharmaceutical industry. (Read more)

Intellectual Property

T 2106/18 Boards of Appeal Decision: Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix 

EP2564839 was granted based on a set of 11 claims.

Independent claim 1 as granted read as follows:

 

A pharmaceutical formulation in the form of an erosion matrix tablet comprising:

i) 35 - 55 % by weight of dimethyl fumarate (DMF).

ii) 3 - 6 % by weight of hydroxypropyl cellulose; and

iii) 40 - 60 % by weight of lactose.

 

An opposition was filed on the grounds that its subject-matter lacked inventive step, was not sufficiently disclosed, and extended beyond the content of the application as filed.

This is second instance decision in front of Board of Appeals as opposition division at first instance had rejected the opposition.

 

In oppositions at EPO two things are the most important, 1) the closest prior art and 2) the objective technical problem.

 

Many documents cited in opposition proceedings and WO 2007/042034 (D10) was considered as the closest prior art.  This D10 document was agreed as the closest prior art, in view of its examples 1 and 5, its example 5. There were three distinguishing features, namely

1.              the release from an erosion matrix tablet rather than a multiple unit tablet,

2.              the presence of 3-6 wt.% HPC, and

3.              the presence of 40-60 wt.% lactose.

 

After some deliberation, the objective technical problem agreed as the provision of a pharmaceutical formulation showing a zero-order release.

 

Claim 1 of EP2564839 did not require the HPC to cause sustained release, and there was no limitation in the claim that explicitly or implicitly required a low proportion of another sustained release polymer to be present.

The claim defined only 78 wt.% of the composition (35 wt.% DMF, 3 wt.% HPC, and 40 wt.% lactose) and so the other 22 wt.% of the composition could indeed comprise further sustained release polymers. Moreover, the function of the claimed excipients was not given in claim 1.

 

The question to be answered is whether the skilled person, starting from the disclosure of D10 (i.e. WO 2007/042034), would arrive at the subject-matter of claim 1 of EP2564839 in an obvious manner to solve the technical problem posed.

 

There is no teaching in D10 on how to obtain a tablet showing a zero-order release, and there is also no teaching to prepare tablets comprising HPC and lactose, even less in the claimed

 

concentration range, i.e. 3-6% by weight of hydroxypropyl cellulose and 40-60% by weight of lactose. It is not possible to see in the disclosure of examples 1 and 5 of D10 any suggestion or incentive to incorporate HPC in said formulations and to simultaneously increase the amounts of lactose, even less to get a different release profile of DMF.

 

Furthermore, the Board sees no reason to doubt that HPC is used as rate controlling polymer in the claimed formulation. The use of 3-6 wt.% of HPC in the context of an erosion matrix is not disclosed or suggested in any cited document and is not obvious for at least this reason. Moreover, there is no teaching in the prior art that would motivate the skilled person to employ the lower amount of 3-6 wt.% of HPC in the context of an erosion matrix tablet containing a high drug load of DMF, let alone any teaching that would give the skilled person a reasonable expectation of success that doing so would provide a zero-order release.

 

As to lactose, it is true that it is a common excipient for the preparation of tablets. The use of such a high lactose level in combination with a high drug loading and HPC in the claimed erosion matrix tablet for the obtention of a zero-order release is however not disclosed or suggested in any cited

 

document. Such use is also not obvious in view of the water solubility properties of lactose and the necessity to maintain the structural integrity of the tablet.

 

The board said, it is indeed clear that the choice of the excipients and their amounts for obtaining an erosion matrix and a zero-order release is not obvious. The design of a controlled release product providing a zero-order release is difficult to achieve.

Hence the Board opined, the solution according to the subject-matter of claim 1 is therefore not obvious and the main request meets the requirements of Article 56 EPC.  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.