Thursday, 14 July 2011

T 777/08 – Crystals Are A Girl’s Best Friends

This appeal was directed against the decision of the Opposition Division (OD) to revoke the patent.

Claim 3 of the main request (and claim 1 of the auxiliary request) read:
Crystalline Form IV atorvastatin (i.e. [R-(R,R*)]-2-(4-fluorophenyl)-ß,δ-dhihydroxy-5(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt)hydrate characterised by the following X-ray powder diffraction pattern expressed in terms of the 2θ, d-spacings, and relative intensities with a relative intensity of >15% measured using CuKα radiation:

The Board dismissed the appeal because it found this claim to lack inventive step.

[5.1] [… C]laim 3 of the main request and claim 1 of the auxiliary request are identical and relate to form IV of crystalline atorvastatin hydrate.

The board considers, in agreement with the [patent proprietor], that the amorphous form of atorvastatin, as obtained according to the processes of documents D1 and D2, represents the closest state of the art.

The [patent proprietor] defined the problem to be solved in view of this prior art as lying in the provision of atorvastatin in a form having improved filterability and drying characteristics.

The solution as defined in claim 3 of the main request and claim 1 of the auxiliary request relates to a specific polymorph of atorvastatin.

Having regard to the experimental results reported in document D25, which demonstrate shorter filtration and drying times for form IV compared to the amorphous form, the board is satisfied that this problem has been solved.

[5.2] It remains to be investigated whether the proposed solution would have been obvious to the skilled person in the light of the prior art and the relevant common general knowledge.

The skilled person in the field of pharmaceutical drug development would have been aware of the common general knowledge as reflected by documents D10, D27 and D28.

It is noted in this context that the [patent proprietor] has disputed that document D10 forms part of the state of the art within the meaning of A 54(2). This document was printed in the July 1995 issue of the journal “Pharmaceutical Research”, that is, in the same month as the present priority date of 17 July 1995. Although the exact day on which it was made available to the public could not be established, it is noted that document D10 is a review article, which is, by definition, an account of the common general knowledge and the state of the art prior to its own publication date. As will be explained in more detail below, this is corroborated by the disclosures of documents D27 and D28. Hence, the board considers document D10 to provide a legitimate basis for evidence of the common general knowledge of the skilled person at the priority date of the patent in suit (cf. T 1110/03 [2]).

From his common general knowledge, the skilled person would firstly be aware of the fact that instances of polymorphism are commonplace in molecules of interest for the pharmaceutical industry, as can, for instance, be inferred from the following passage of document D28 […]:
“Polymorphs have crystal lattices which differ in the ways in which the same molecule is bound in the unit cell. The differences may reflect different ways of packing molecules in the cell, or conformational changes, which can be large. Hydrogen-bonding will be involved for most molecules of interest to the pharmaceutical industry.”
The skilled person would also have known it to be advisable to screen for polymorphs early on in the drug development process, as explained in document D28 […] (cf. also document D10 […]):
“In giving each development candidate the best chance of progressing, it seems better to search for polymorphs rather than to leave their appearance to time and chance with the consequent disruption.”
Indeed, the skilled person would also have been aware of regulatory requirements to provide information on the occurrence of polymorphic, hydrated, or amorphous forms of a drug substance (cf. document D10 […]). Moreover, he would be familiar with routine methods for screening for polymorphs by crystallisation from a range of different solvents under different conditions (cf. document D28 […]; document D10 […]).

It follows from the above that, at the priority date of the patent in suit, it belonged to the routine tasks of the skilled person involved in the field of drug development to screen for solid-state forms of a drug substance. For the sake of completeness, the board therefore wishes to note that, in the absence of any technical prejudice, which has not been alleged by the [patent proprietor], the mere provision of a crystalline form of a known pharmaceutically active compound cannot be regarded as involving an inventive step (contrary to the statement in the patent in suit, paragraph [0011]).

However, in the present appeal proceedings, as outlined above under point [5.1], the [patent proprietor] relied in support of the presence of an inventive step on the improved filterability and drying characteristics of form IV atorvastatin hydrate compared to the amorphous form.

It must therefore be decided whether there was an incentive for the skilled person to arrive at the present solution in the expectation of achieving these improved characteristics.

As pointed out by the [patent proprietor], amorphous forms are generally known to be more soluble and have greater bioavailability than their crystalline counterparts. However, several disadvantages can also generally be expected for the amorphous form, namely, with respect to chemical and physical instability (see document D27 […], document D10 […], section entitled “Amorphous Forms”).

In addition, the following is stated in document D28 […]:
“Crystalline products are generally the easiest to isolate, purify, dry and, in a batch process, handle and formulate.”
Thus, in view of his general knowledge, as reflected in this excerpt from document D28, the skilled person, starting from the amorphous form of a pharmaceutically active compound as closest prior art, would have a clear expectation that a crystalline form thereof would provide a solution to the problem as defined under point [5.1] above. Although this might not be true of every crystalline form obtained (cf. document D28 […]), it was nevertheless obvious to try this avenue with a reasonable expectation of success without involving any inventive ingenuity.

The board cannot accept the [patent proprietor’s] contention that the skilled person would be dissuaded from attempting to obtain a crystalline form by the prospect of a potential loss of solubility and bioavailability when compared to the amorphous form. On the contrary, the skilled person would regard this as being a matter of trade-off between the expected advantages and disadvantages of these two classes of solid-state forms, as outlined above.

The [patent proprietor] further argued that the presence of an inventive step was supported by the fact that a specific polymorph was being claimed rather than crystalline forms in general. The board does not deny that there may be other options for solving the problem posed (see e.g. patent in suit, paragraph [0036]). However, an arbitrary selection from a group of equally suitable candidates cannot be viewed as involving an inventive step.

[5.3] Therefore, the subject-matter of claim 3 of the main request and claim 1 of the auxiliary request represents an obvious solution to the problem posed and does not involve an inventive step.

Since a decision can only be taken on a request as a whole, none of the further claims need be examined.

Consequently, the [patent proprietor’s] main and auxiliary requests are rejected for lack of inventive step of claims 3 and 1, respectively.

Should you wish to download the whole decision, just click here.

The file wrapper can be found here.

My friend Laurent has provided a nice summary here.

NB: Apparently this decision was found worthy of being published in the OJ EPO. Dont ask me why.


Anonymous said...

The area of polymorphs is of fundamental interest to the pharmaceutical industry, owing to financial imperatives of selecting the optimum solid-state form for manufacture, regulatory requirements, and the potential for creating patent thickets and extending the life cycle of existing products. Consequently, pharmaceutical companies have developed strategies of high-throughput screening in order to ensure that all relevant forms of an active pharmaceutical ingredient are identified, and dedicated companies have even been set up to provide services in this area (see e.g.

Against this background, it is hardly surprising that very large numbers of secondary patent applications have been generated in the area of polymorphs. This issue was brought into sharp political focus as a result of the EU pharmaceutical sector inquiry (see in particular paragraphs (341) to (344) under the following link:

It is therefore fair to say that there is a lively interest in the pharmaceutical industry with respect to issues relating to the patenting of polymorphs.

In view of the fact that decision T0777/08 addresses fundamental issues relating to the assessment of inventive step of polymorph patents, it will be of general interest to a wide circle of practitioners in the pharmaceutical industry and other IP professionals dealing with this technical area.

oliver said...

Fair enough.

I was just wondering why this decision was to be published, because I did not find it remarkable or surprising in any way. This may just reveal my ignorance.

No offense meant to the pharmaceutical world.