API and IP Newsletter
Contents
FDA approval in December 2022
Wishing a happy New Year to all our readers.
Free image from internet
We monitor FDA approvals of small molecules.
This month FDA approved Lenacapavir to treat adults with HIV whose HIV infections cannot be successfully treated with other available treatments due to resistance, intolerance, or safety considerations. It is significant addition in Gilead's HIV portfolio. Morningstar analyst Karen Andersen said in October that lenacapavir sales are expected around $1.5 billion at the peak.
Initial patent disclosure WO 2018/035359 A1, this could be composition of matter patent family, published on 22 February 2018.
Different formulations and salts are reported in families WO 2019/035904 A1; WO 2019/035973 A1
Optimised synthesis is reported in WO 2019/161280 A1 family, paragraph 00633 reports the process of lenacapavir.
Cipla has imported 250 grams Lenacapavir intermediate. Few other companies are importing derivatives of 3,6-dibromopicolinaldehyde and there could be possibility that 3-4 Indian companies are working on this complex API synthesis.
General information
JRS Pharma plan to continue expanding our footprints in India, including producing quality excipients and introducing new products
Dr Vijay Ahire, Head, Pharma Business Unit at JRS Pharma, India, speaks on his company's growth trajectory, major milestones, plans for this decade, business plans for India market and more, in an exclusive interaction with Express Pharma
News here.
China’s daily output of ibuprofen, acetaminophen quadrupled in quick response to market needs
China's daily output of ibuprofen and acetaminophen is now four times higher than at the beginning of December, Wang Jiangping, vice minister of the Ministry of Industry and Information Technology (MIIT), said on Thursday. This is happening as the government and drug producers are ramping up measures to secure the supplies of cold and fever reducing drugs in responding to surging market demand.
In view of the short-term concentrated demand for ibuprofen, acetaminophen and other drugs in the early stage, the government has mobilized manufacturers to increase production and expand capacity, while fully guaranteeing the supply of these two key drugs, Wang said at the press conference on the guarantee of key medical supplies for epidemic prevention and control held by the MIIT.
News here.
Intellectual Property
T 1742/19 (Pharmaceutical composition containing an anti-nucleating agent/ MERCK … of 10.11.2022
EP 1819323 was granted on the basis of a set of 9 claims. It relates to pharmaceutical composition of Raltegravir Potassium.
Assignee : Merck Sharp and Dohme LLC.
Claims 1, 2 and 6 as granted read as follows:
"1. A pharmaceutical composition for oral administration as a solid dose, which comprises: (a) from 0.5 to 20 wt.% of an anti-nucleating agent which comprises hydroxyalkylcellulose, and (b) an effective amount of from 5 to 75 wt.% of a potassium salt of Compound A (Raltegravir Potassium), wherein Compound A is:
2. The pharmaceutical composition according to claim 1, wherein the potassium salt of Compound A is Form 1 potassium salt of Compound A.
6. The pharmaceutical composition according to claim 5, wherein the potassium salt of Compound A is Form 1 potassium salt of Compound A."
The patent had been opposed by Ter Meer Steinmeister & Partner Patentanwälte mbB
Georg Kalhammer/Stephan Teipel under Article 100 (a), (b), (c) EPC on the grounds that its subject-matter lacked inventive step, was not sufficiently disclosed and extended beyond the content of the application as filed.
The appeal lies from the decision of the opposition finding that the patent in amended form meets the requirements of the EPC.
We will cover inventive step discussions in this write-up. The prior art documents cited during the opposition proceedings included the following:
D1: WO 03/035077;
D2: EP 1 904 067 B1;
D3: M. E. Aulton, Pharmaceutics, The Science of Dosage Form Design, 2nd Edition, 2002, Chapter 20, 289-305;
D4: Leuner Ch. et al, Eur. J. Pharm. Biopharm., 2000, 50, 47-60;
D5 : WO 03/086319;
D6 : Usui F et al, Int. J. Pharm., 1997, 154, 59-66;
D7: WO 2004/064846;
D8 WO 00/18384;
D9: Gao P et al., Drug Development And Industrial Pharmacy, 2004, 30, 221-29;
D10: WO 02/056878;
D11: WO 2006/060730;
D12: Overview of claim 1 of the main and auxiliary requests 1 to 5;
D13: Raghavan S.L. et al, Int. J. Pharmaceutics, 2001,212, 213-221
The arguments of MSD were revolving around following
WO 03/035077 (D1) was the closest prior art and disclosed a large number of compounds, without any highlight to compound A.
There were many choices to perform in D1 to arrive at the claimed subject-matter.
This became even harder if it was considered that the addition of a hydroxyalkylcellulose could improve the bioavailability of the claimed compound A (Raltegravir Potassium).
The arguments of the appellant-opponents Ter Meer Steinmeister & Partner Patentanwälte mbB and Georg Kalhammer/Stephan Teipel may be summarised as follows:
D1 explicitly described the preparation of Compound A and specifically hinted to the skilled person that Compound A was one lead compound of D1 for any drug formulation.
Claims are related to Form 1 of the potassium salt of Compound A, and was characterized in the contested patent. However, seeds of Form 1 were used to prepare Form 1, but neither the patent, nor the available prior art did teach how to prepare said seeds.
The solid formulations of the examples of the opposed patent comprised crystalline Form 1 of Compound A potassium salt. This salt was not sufficiently disclosed. Thus, these data were not suitable to show any technical effect.
The tests of examples 4 and 5 were in any case not suitable to show any credible effect over the prior art.
The difference between the composition according to claim 1 and the compositions of D1 was the use of Compound A in the form of its potassium salt, its specific amount and the presence of a specific amount of an anti-nucleating agent comprising hydroxyalkylcellulose.
Starting from D1, the technical problem, therefore, could only be seen in the provision of an oral pharmaceutical composition comprising Compound A or pharmaceutically acceptable salts having a certain suitable bioavailability.
In view of D1, the skilled person was motivated to provide Compound A potassium salt in such an oral dosage form so that enough solubility was obtained in acidic environment.
In order to provide an oral dosage form resulting in sufficient bioavailability, the skilled person would have chosen excipients known to improve solubility and thereby bioavailability (see D4, D6, D9 or D13).
In D13, the addition of HPMC as anti-nucleating agent was in particular disclosed.
D1 disclosed compound A in example 19, compositions were disclosed on pages 55 and the salts on page 62.
D1 did not disclose the presence of an anti-nucleating agent, the amount of anti-nucleating agent and the amount of compound A.
The amount of active agent was not linked with any technical effect. With regard to the anti-nucleating agent, there was no evidence of any effect, since the experiments of examples 4 and 5 were given in the form of pure statements, and since it was not plausible that an effect was achieved over the whole scope of claim 1.
The problem had to be defined as the provision of an alternative composition. The solution was obvious in view of the common general knowledge and D4, D9, D6, D3 and D13
The decision of the Board
The question with regard to obviousness is in the present case whether the skilled person, starting from D1 as the closest prior art, would have been incited to choose all the features disclosed therein and combine them with the teaching of the other cited documents to arrive at the claimed subject-matter, in order to provide a pharmaceutical formulation comprising compound A and having certain suitable bioavailability.
In the Board's view, there is no incentive neither in D1 nor in any other prior art document to combine the potassium salt of Compound A with an anti-nucleating agent comprising hydroxyalkylcellulose, not to mention to use this combination of substances in a solid dosage form for oral administration; all documents D4, D6, D9, D10 and D13 focus on the use of hydroxyalkylcellulose for the improvement of bioavailability of poorly water-soluble drugs.
However, the fact that Compound A and its potassium salt is a drug that converts to a less soluble form of the drug under certain acidic conditions was not known at the effective filing date of the contested patent.
Therefore, unaware of this particular behaviour of Compound A, the skilled person, based on the common general knowledge would not have combined this drug with an anti-nucleating agent in order to solve the problem posed, i.e the provision of a pharmaceutical formulation comprising compound A having certain suitable bioavailability.
Patent was upheld.
