API and IP Newsletter
Contents
DMF filed by Indian companies in May 2022
We analyse DMFs filed by Indian companies. In May, about 48 DMFs were filed by 44 companies, and out of which more than 60% were filed by Indian companies.
Some of our observations/comments are as below.
General information
Internet of things hiring levels in the pharmaceutical industry rose in July 2022
The proportion of pharmaceutical companies hiring for internet of things related positions rose in July 2022 compared with the equivalent month last year, with 18.2% of the companies included in our analysis recruiting for at least one such position.
This latest figure was higher than the 14.6% of companies who were hiring for internet of things related jobs a year ago but a decrease compared to the figure of 19.7% in June 2022.
News here.
Import and domestic production of APIs
The Indian Pharmaceutical industry is the 3rd largest in the world by volume. India is one of the major producers of Active Pharma Ingredients (API) or bulk drugs in the world. India exported Bulk Drugs/Drug Intermediates worth Rs. 33,320 crore in financial year 2021-22.
However, the country also imports various Bulk Drugs/APIs for producing medicines from various countries and most of the imports of the Bulk Drugs/APIs being done in the country are because of economic considerations. India imported Rs. 35,249 crore worth APIs and Bulk drugs in 2021-22.
News here.
Intellectual Property
T 2213/18 (Method of preparing an enzyme containing granular formulation/DANISCO … of 3.5.2022
EP2285823 was issued to Danisco US Inc. and was opposed by Novozymes A/S.
The invention relates to methods for recovering one or more enzymes of interest from a microbial fermentation broth in the presence of microbial cells or cell debris, and solid and liquid formulations prepared from a composition containing recovered insoluble enzyme and microbial cells and/or cell debris.
The conventional recovery and formulation of enzymes includes multiple steps
Enzyme-containing granules are incorporated into products in several industries, including detergent, textile-processing, food (e.g., baking), animal feed, and fuel ethanol industries. Such granules may be prepared by several technologies, including fluidized bed spray coating, high sheer granulation, extrusion, spheronization, prilling, and spray drying.
Traditionally, such enzyme-containing granules contain enzymes that are in soluble form before incorporation into the granules, and if expressed in a microbial host, are at least partially purified to remove microbial cells and/or cell debris produced from lysis of the cells.
There is a need for granular enzyme formulations in which the enzyme is in insoluble form and in which cells and/or insoluble cell components are not removed.
EP2285823 allegedly had solved this problem and claimed
A method of making an enzyme-containing granular formulation comprising:
recovering insoluble enzyme from a microbial broth comprising microbial cells that express the enzyme and/or cell debris from microbial cells that express the enzyme, without removing the microbial cells and/or cell debris, thereby producing a composition comprising recovered insoluble enzyme and microbial cells and/or cell debris, wherein at least some of the enzyme is insoluble in the microbial broth;
producing an enzyme-containing granule that comprises said composition, wherein the enzyme is enzymatically active in the granule.
Prior to reaching to Board of Appeals at EPO, an opposition division considered the main request and auxiliary request 1 to lack novelty and decided to maintain the patent in amended form on the basis of auxiliary request 2.
The decision was unfavourable for both patentee Danisco US Inc and Novozymes. Both parties the patent proprietor Danisco (appellant I) and the opponent Novozymes (appellant II) lodged an appeal.
Definitions in each patent documents are very important.
The "insoluble enzyme" is defined in paragraphs [0075], [0085] and [0091] of the patent.
- [0075]: "An insoluble enzyme refers to an enzyme that is present in a solid phase. An insoluble enzyme separates (i.e. partitions) with a solid phase upon separation of solid and liquid phases, for example, solid and liquid phases of a microbial broth. It is understood that in a whole microbial broth some enzyme will typically also be found in the soluble phase in the medium in addition to the insoluble enzyme that is part of the solid phase. The insoluble enzyme may be bound to solids in the microbial broth, such as cell solids or other solid components or may be precipitated or crystallized within the microbial broth."
- [0085]: "In one embodiment, ... at least some of the enzyme is insoluble ... . In another embodiment, the expressed enzyme is soluble in the microbial broth, and at least some of the enzyme is rendered insoluble by addition of one or more precipitant(s)."
- [0091]: "In various embodiments, any of at least 90, 80, 70, ... 10% of the enzyme is insoluble ... ."
After knowing the definition of insoluble enzyme, it needs to be established what is encompassed by the step of recovering an "insoluble enzyme".
In the board's view there is no limitation in claim 1 to fermentation broths comprising only insoluble enzyme.
As long as at least some of the enzyme in a broth is insoluble, i.e. separating with cells or cell debris upon separation of solid and liquid phases, it is encompassed by this term.
A dispersion of enzymes is considered to fall under the definition of a microbial broth comprising an insoluble enzyme wherein at least some of the enzyme separates (i.e., partitions) with a solid phase upon separation of solid and liquid phases.
An enzyme produced intracellularly and not yet secreted will at least partially separate with a solid phase upon separation of solid and liquid phases - for example, solid and liquid phases of a cell culture broth - It follows that the recovered fermentation broth comprising both an enzyme and the microbial cells and/or cell debris will necessarily and inevitably comprise at least some insoluble enzymes.
Patentee stressed that the method of claim 1 had to comprise the step of recovering the insoluble enzyme from a microbial broth comprising microbial cells, ... without removing the microbial cells and/or cell debris, thereby producing a composition comprising recovered insoluble enzyme and microbial cells and/or cell debris, wherein at least some of the enzyme is insoluble in the microbial broth.
It submitted that the sole meaningful interpretation for the step of recovering the insoluble enzyme from a microbial broth in claim 1 was that the enzyme from the microbial broth was brought into contact with at least a solvent to allow the enzymes to partition with the soluble and/or insoluble phase.
Even if the solubility of the said enzyme in the solvent varies from completely insoluble to completely soluble, it was clear that small amounts of enzymes defined as completely soluble would nevertheless separate with the solid phase.
Hence, any interpretation which attributed to an enzyme from a microbial broth the status of insoluble enzyme separating with the solid phase because it was encapsulated in the cells rendered this feature redundant and meaningless, as enzymes encapsulated in cells were incapable of separating with the liquid phase.
The board agreed with patentee’s view that the method of claim 1 also comprises a step of recovering insoluble enzyme from a microbial broth comprising microbial cells. An insoluble enzyme encapsulated in the cells cannot be recovered from a microbial broth.
This interpretation is in line with the definition of microbial broth in paragraph [0074] of the patent: "Microbial broth" or "fermentation, broth" refers to a growth medium in which microbial (e.g., bacterial or fungal) cells are grown and which is suitable for expression of an enzyme as described herein.
Even if prior art contemplates the spray-drying of fermentation broth and enzyme containing liquid such as dispersion of one or more enzymes, it does not disclose or suggest that the method of preparing an enzyme particle could alternatively comprise the step of first expressing the enzyme at a higher yield than disclosed, i.e beyond their solubility limits, in the microbial broth, so as to produce and recover soluble and insoluble enzymes or poorly soluble enzymes in the microbial broth, and second without removing the microbial cells and/or cell debris.
So, the Board opined starting with the invention described in document D1 (WO 01/25411 A1), the skilled person faced with the technical problem of providing an alternative method, had no motivation without a pointer to devise an alternative method of preparing an enzyme containing particle with the features of claim 1. Hence, the Board concluded, the method of claim 1 involves an inventive step. Here
