API and IP Newsletter
Contents
DMFs filed in November 2022
We monitor DMFs filed by Indian companies. FDA publishes list of DMF filers every quarter, the new list of DMF filers in last quarter of year 2022 was published recently.
This week we analysed DMFs filed in the month of November 2022. About 50 DMFs filed in the month of October.
Some of our observations are as below.
General information
Manufacturing processes for active pharmaceutical ingredients (APIs)
API process validation occurs in the late phases of clinical development, where the focus is on the performance of the manufacturing process and the quality of each intermediate and final API. Three frequently employed process evaluation events that prepare the API manufacturing process for commercial launch include the campaigns to prepare registration, engineering and validation batches.
An initial formal scale-up evaluation of the planned manufacturing process may be considered the registration batches program. This portion of process evaluation creates material for the necessary formal stability testing needed for the registration filing, which will eventually be considered the intended commercial process. This evaluation is ideally conducted close to commercial scale using the requisite commercial equipment at a site where commercial manufacturing will take place.
The FDA makes allowances for necessary adjustments to the process during the GMP manufacturing production of registration batches while expecting them to be wholly representative of the final commercial process. After the registration batch experience, the team will usually conduct a post-action review to determine how the process ran and identify specific aspects that may need to be further defined.
News here.
UAE strengthens foundation for pharmaceutical industry
The recent agreement between DoH and Hayat Biotech aimed to enhance the country’s R&D, clinical research, and manufacturing capabilities.
News here.
Intellectual Property
T 1426/19 : Process for the preparation of morphinan-6-one compounds.
The patent relates to oxymorphone sold under the brand names Numorphan and Opana among others. It is a highly potent opioid analgesic indicated for treatment of severe pain.
MacFarlan Smith is one of the world's leading manufacturers of opiate alkaloids. Together with sister companies within the Johnson Matthey group, they can provide full spectrum drug development, from drug discovery through to bulk production. Here.
In this patent application the patentee MacFarlan Smith tried to address a recent concern in the pharmaceuticals industry which is to prepare Active Pharmaceutical Ingredients (APIs) which are free or substantially free of potentially genotoxic impurities (PGIs). Compounds which contain an α, β-unsaturated ketone (ABUK) moiety have been identified as potential genotoxins which need to be controlled.
MacFarlan filed the process patent application EP 3027621 at EPO. It was rejected by examining division. MacFarlan appealed the examining division’s decision of refusing the grant of patent application.
Documents D3 and D5 were referred to, inter alia, during examination proceedings:
D3: WO 2008/072018 A1
D5: WO 2008/118654 A1 (brief claimed process in D5 is as below)
We will confine the discussion to inventive step for the following claim.
"1. A process for preparing an aqueous acid solution of a compound of formula (3), the process comprising the steps of:
(a) providing an aqueous acidic solution comprising a starting material which is a compound of formula (1) and, as an impurity, a compound of formula (2); and
(b) treating the aqueous acidic solution of step (a) such that the compound of formula (2) dehydrates to form a compound of formula (1) and the compound of formula (1) is reduced to form an aqueous acidic solution of the compound of formula (3),
wherein:
the treating of step (b) is carried out at one or more temperatures in the range of >= 75°C to <= 100°C in the presence of a hydrogenation catalyst and hydrogen gas; and
the aqueous acidic solution of step (a) is heated to one or more temperatures in the range of >= 75°C to <= 100°C before it is exposed to the hydrogen gas; and
wherein for the compounds of formulae (1), (2) and (3):
i) R1 is -OH, R2 is -OH and R3 -H; or
iv) R1 is -OCH3, R2 is -H and R3 -H; or
v) R1 is-OH, R2 is-H and R3-H; or
vi) R1 is -OCH3, R2 is -OH and R3 -H."
Key prior art:
Document D5 was regarded as the closest prior art.
According to the patentee, the objective technical problem in view of D5 had to be seen as the provision of a process for preparing the claimed compounds of formula (3) having improved impurity profiles and exhibiting a greater resistance to alpha,beta-unsaturated ketone (ABUK) regrowth.
Nothing in D5 or the other available prior-art documents prompted the skilled person to arrive at the claimed process.
It had to be concluded that the claimed subject-matter involved an inventive step.
Document D5 (pages 2 to 4, page 7, page 9, second paragraph, page 10, and the examples on pages 12 to 19) discloses a process for producing an aqueous acidic solution of oxymorphone (formula III in D5) from an aqueous acidic solution of 14-hydroxymorphinone (formula II in D5), by exposing the latter to hydrogen gas in the presence of a hydrogenation catalyst at high temperature.
Examples 3 to 7 disclose such a process, in which a two-step hydrogenation is carried out first at ambient temperature and then at 80°C. In examples 8 to 12, the hydrogenation is carried out directly at a temperature of 85 to 90°C. D5 also discloses the formation of a solid salt of the obtained oxymorphone.
Distinguishing features
The patentee argued that the subject-matter of claim 1 differed from the process of D5 in the preparation of the four individualized nor-morphinan-6-ones listed under alternatives i), iv), v) and vi) in claim 1.
Moreover, unlike the process in D5, the solution of step (a) was heated to a temperature of from 75°C to 100°C before exposure to hydrogen gas.
However, the board noted that claim 1 does not require the preparation of all four individualized compounds listed under alternatives i), iv), v) and vi), but only one of them. In view of the conversion of 14-hydroxymorphinone into oxymorphone disclosed in D5 the claim 1 only differs from the process of D5 in that substituent R3 is -H.
In 14-hydroxymorphinone and oxymorphone as disclosed in D5, this substituent is methyl. As regards the temperature, the board concurs with the patentee that, according to the examples of D5, the mixture is heated to the disclosed temperature (80°C in examples 2 to 7, 85°C to 90°C in examples 8 to 12) while being exposed to hydrogen gas, and not before as required by claim 1.
Hence, the distinguishing features of alternative i) of claim 1 over D5 are:
(a) the substituent R3 in the compound involved in the claimed process, this substituent being hydrogen according to claim 1 but methyl in D5, and
(b) the fact that the mixture is heated before being exposed to hydrogen gas, whereas in D5 it is heated while being exposed to hydrogen.
Objective technical problem
The patentee referred to the examples of the application (pages 19 to 21) and argued that the distinguishing features had the technical effects of improving the impurity profile of the product (reduced 6-beta isomer of compound (4)), this product exhibiting a greater resistance to alpha,beta-unsaturated ketone (ABUK) regrowth. In view of this, it submitted that the objective technical problem was the provision of a process for preparing the claimed compounds of formula (3) having improved impurity profiles and exhibiting a greater resistance to ABUK regrowth.
The board disagrees.
According to the problem-solution approach, technical effects, if any, must be associated with the features distinguishing the claimed subject-matter from the closest prior art. The results reported in the application on pages 19 to 21, invoked by the patentee, show a reduction especially of nor-14-hydroxymorphone after hydrogenation at 80°C as compared with hydrogenation carried out at ambient temperature.
However, D5 also discloses a hydrogenation at temperatures of 80°C and 85°C to 90°C.
Therefore, the results reported in the application are not suitable for establishing the presence of a technical effect of the claimed process over the disclosure in D5. Also, the remaining part of the application does not disclose any technical effect deriving from heating the solution of step (a) to the required temperature before exposure to hydrogen gas.
Nor has a technical effect deriving from the selected substituent R3 been put forward.
In the absence of any technical effect, the objective technical problem must be seen as the provision of an alternative process for preparing an aqueous solution of compounds of formula (3).
The patentee also submitted that it did not attempt to reproduce the examples of D5, as this was considered unsafe in view of the use of excess peroxyacetic acid in the presence of Pd/C hydrogenation catalyst. It referred to the hazardousness of using peroxyacetic acid.
The board noted that, in the examples of D5, peroxyacetic acid is only used in the conversion of oripavine into 14-hydroxymorphinone and not in the reaction of the latter to give oxymorphone, i.e., in the process at issue.
Moreover, according to several examples in D5, excess peroxyacetic acid is neutralized before the hydrogenation reaction in the presence of the hydrogenation catalyst.
According to examples, a separate vessel is used for the hydrogenation. Therefore, this assertion by the patentee of not reproducing prior art disclosed in D5 is not convincing.
Hence the board opined the subject-matter of claim 1 did not involve an inventive step in view of document D5.
Decision here.
