The patent relates to the delivery of mRNA for the augmentation of proteins and enzymes in human genetic diseases.
Brief outline of the case
The MR in opposition corresponded to the claims as granted with the deletion of claim 20.
The OP decided that claim 1 of the MR infringed Art 123(2) and that claim 1 of AR1 suffered a lack of sufficiency. The patent was maintained according to AR2.
The proprietor and both opponents appealed this decision.
The board confirmed that claim 1of the MR infringed Art 123(2). Claim 1 of AR1 suffered not of a lack of sufficiency, but also infringed Art 123(2). The same applied to AR 2-15. The patent was thus revoked.
The MR and the original disclosure
Claim 1 of the MR defines the feature of preferential distribution of the composition into liver cells and expression of the encoded protein in the liver cells of the subject together with the feature of the size of the transfer vehicle of less than 100 nm.
Concerning the size of the liposomal transfer vehicles the application as originally filed explicitly teaches:
- “Selection of the appropriate size of the transfer vehicle must take into consideration the site of the target cell or tissue (…)”.
In this context, the original disclosure indicates that it may be desirable to limit transfection to certain cells or tissues and describes the liver as an example of an important target organ.
The original disclosure mentions that accordingly to target for example hepatocytes a liposomal transfer vehicle may be sized such that its dimensions are smaller than the fenestrations of the entdothelial layer lining the hepatic sinusoids in the liver. The application as filed further describes that alternatively the liposomal transfer vehicle may be sized such that its dimensions are larger than these fenestrations to limit distribution to hepatocytes.
In the immediately following passage the application as filed states:
- “Generally, the size of the transfer vehicle is within the range of about 25-250 nm, preferably less than about 250nm, 175nm, 150nm, 125nm, 100nm, 75nm, 50nm, 25nm or 10nm.”
The proprietor’s point of view
The application as originally filed specifically explained the importance of the liver as a target organ and expressed a general preference for delivery of the synthetic mRNA and its expression in vivo in the liver and in particular the hepatocytes, in the discussion following the presentation of the in vivo experiments.
The application as originally filed disclosed for the transfer vehicle a size of less than 100 nm as part of a list of converging preferred options. The size of less than 100 nm was further indicated as preferred in the introduction of example 1, which presented the example as generally illustrating a process for preparing formulations of liposomes with a size of <100 nm.
In line with the common general knowledge expressed in document D18 as well as the information in document D17 relied upon in the decision under appeal the teaching in the application as filed that the liposomal transfer vehicle may for the purpose of targeting hepatocytes be sized such that its dimensions are smaller than the fenestrations in the liver was consistent with the definition of a size of less than 100 nm. This teaching therefore provided a further pointer to the defined combination of features.
The limitation to the delivery and expression in the subject’s liver, in particular the subject’s hepatocytes, together with the definition of the size of the liposomes of less than 100 nm thus corresponded to the single selection of the size of the liposomes from a list of convergent options to which the application as originally filed provided specific pointers. In line with the considerations in T 1621/16 no information extending beyond the content of the application as originally filed was thereby generated.
The board’s decision
For the board, the skilled person cannot directly and unambiguously derive from this section of the original disclosure that the defined transfer vehicles with a size of less than 100 nm allow for the targeting of liver cells, because this section of the original disclosure fails to disclose the link between this specific size limit of 100 nm for the transfer vehicle and liver cells as target for the defined composition.
The application as originally filed indicates that Example 1 illustrates a process for the preparation of small sized, i.e.< 100 nm) liposomal formulations. However, this reference to the preparation of liposomal formulations with a size of less than 100 nm is not related to the targeting of liver cells.
The application as originally filed further mentions as part of the discussion of the experimental results that mRNA encapsulated in lipid-based material can be used for the delivery and expression of genes in vivo in liver, in particular hepatocytes. In this discussion regarding the delivery and expression of genes in liver cells no mention is made of a required size of the liposomal transfer vehicle of less than 100 nm.
These passages in the examples relied upon by the proprietor do therefore not provide any pointer to the combination of a size of less than 100 nm of the transfer vehicle and their targeting to the liver.
Even if the skilled person would conclude from the information provided in relation to the examples that liposomes with a size of less than 100 nm as well as the targeting of liver cells represented originally disclosed preferred embodiments, the skilled person could not without such pointer directly and unambiguously derive the combination of these embodiments from the original disclosure.
D17 indicates that the dimensions of the endothelial fenestrae are in humans without liver pathology 107 ± 1.5 nm and that these dimensions significantly vary between species.
D18 states that for encapsulating nucleic acid the method involving stepwise ethanol dilution generates small (diameter <100 nm), well-defined, stable systems with high encapsulation efficiencies that exhibit the extended circulation lifetimes required to achieve preferential accumulation at target sites such as solid tumours or liver.
The Board did therefore not recognize that taking account of the information from D17 or D18, the teaching in the patent regarding the targeting of liver cells by liposomal transfer vehicles with dimensions smaller than the fenestrations in the liver implies, as a matter of necessary consequence, that liposomes with a size of less than 100 nm will target liver cells as defined in claim 1 of the main request.
In this context the board observed that the common general knowledge may be relied upon for assessment of what the skilled person may derive directly and unambiguously from the original disclosure, but cannot compensate for what might be obvious, but has not been disclosed in the application as originally filed itself. The board referred to T 3035/19, Reasons 1.7.3.
For the board T 1621/16, Reasons 1.7.3, a claim may be amended on the basis of multiple selections from lists of converging alternatives and may comply with Art 123(2) if the subject-matter resulting from the multiple selections is not associated with an undisclosed technical contribution, and the combination is supported by a pointer in the application as filed. Hence, the considerations in T 1621/16 have no pertinence for the assessment in the present case
Comments
The decision is interesting in that it specifies that CGK can be used to assess what is directly and unambiguously disclosed, but cannot compensate for information lacking in the original disclosure.
It might appear obvious to use a transfer vehicle with a size <100 nm when targeting the liver, but this combination was not disclosed as such.
The original disclosure mentions on the one hand, liver cells as target, and on the other hand, transfer vehicles with a size of <100 nm, but both have not been originally disclosed in combination.
The combination was thus infringing Art 123(2).
On the procedure
In view of the board’s decision, the present patent should never have been granted as claim 1 infringed Art 123(2).
The present decision of the board is also one of the numerous decisions of an OD set aside by a board.
https://www.epo.org/en/boards-of-appeal/decisions/t211302eu1
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