Zentaris Aktiengesellschaft - [2002] APO 41

OFFICIAL NOTICE
DECISION OF A DEPUTY COMMISSIONER OF PATENTS
Patent: No. 671881 in the name of Zentaris Aktiengesellschaft

Title: Novel Process for the Preparation of Lyophilised Peptides

Action: Request under s.70 for an extension of the term of the patent, and objections thereto by the Commissioner's delegate.

Decision: Issued: 21 October 2002 .
Abstract

Patent relates to a lyophilisate of a polypeptide, characterised by a method of making the lyophilisate. Objection that a pharmaceutical substance per se was not in substance within the scope of the claims, on the basis that the claims were directed to a product by process. Following further information, application to extend the term accepted on the basis of the omnibus claim.
·The morphology of a polypeptide is often a critical factor in the biochemical activity of the polypeptide – such that a different morphology might result in a different 'pharmaceutical substance';
·The evidence indicated that the lyophilisation process involved in the invention resulted in a polypeptide with altered morphology. Having regard to the date of the patent, it was reasonable to expect the morphologically different polypeptide to be defined by its method of production, rather than by 3-D characterisation;
·The substance as described was consistent with the substance on the ARTG;
·The critical method step described in the specification was to dissolve the polypeptide in a 30% acetic acid solution. In the absence of this step, it could not be reasonably concluded that the morphological characteristic of the peptide would be the same. However, this step was not present in any of Claims 1 to 4, and thus it was not possible to conclude that the substance was in substance within the scope of any of these claims;
·However, it was found that the substance was in substance within the scope of the omnibus claim (claim 5).
·Observations concerning extension of term proceedings in situations where the claims relied upon are clearly prima facie invalid.

PATENTS ACT 1990
DECISION OF A DEPUTY COMMISSIONER OF PATENTS
Re:Patent No. 671881 in the name of Zentaris Aktiengesellschaft, Request under s.70 for an extension of the term of the patent, and objections thereto by the Commissioner' delegate.

BACKGROUND

Patent 671881 was applied for on 17 Feb 1994, claiming a priority date of 19 Feb 1993, and was subsequently granted. On 29 March 2001 the patentee (then Asta Medica Aktiengesellschaft) applied for an extension of the term of the patent. If the extension is granted, I understand the term will be extended from 17 Feb 2014 to 22 Feb 2016.
Three reports have issued from the Commissioner's delegate. The substance of those reports is that the specification does not include a claim to a pharmaceutical substance per se; that the claims relied upon are claims to a product by process. The attorney has argued that the claims do provide a proper basis, as the only way to properly characterise the pharmaceutical substance is by its method of preparation.
The matter was set for hearing on 24^th January 2002. The applicant was represented by Ms Shahnaz Irani, patent attorney of Spruson & Ferguson (Sydney). A number of days before the hearing I advised the attorney that I had a concern that prima facie claims 1 to 4 were not fairly based on the description, and that as a result the only claim where potentially a pharmaceutical substance both falls within the scope of the claim, and is in substance disclosed in the specification, is the omnibus claim (claim 5.)
At the hearing there was some discussion about the issues raised by the examiner and myself. The attorney requested time to consider the issue and possibly seek amendments, which I duly allowed. However, in the absence of any response I wrote to the attorney on 22 Aug 2002 advising that if amendments (or persuasive submissions) that dealt with the difficulties were not filed by 30 September 2002, I would proceed to determine the request for the extension of term. In the event the patentee filed some submissions and a statutory declaration, on 2 October 2002. They have since also filed (at my request) a more complete ARTG print-out for Cetrotide.
I have now considered the material, and on balance have come to the conclusion that it is appropriate to accept the application for an extension of term of this patent. However, having regard to the circumstances, I think it appropriate to set out my reasons.
The Specification
The specification is quite brief. It is entitled "Novel process for the Preparation of Lyophilised Peptides". The first paragraph is a statement of the invention, which is essentially the same as claim 1. The 2^nd paragraph is a statement of "a first embodiment", and is also essentially the same as claim 1. The third and fourth paragraphs refer to 2^nd and 3^rd embodiments of the invention - and relate to the use of the substance in the treatment of infertility in females, and protecting gonads.
The specification indicates that "Suitable peptides to which the invention can be applied include those which are the subject of European patent 229402" - which clearly indicates that the invention does not relate to the peptides per se. After identifying Cetrorelix as a particularly useful peptide, the specification continues:
"The synthesis and some pharmacological effects are described in European Patent Application 299 402. It should be possible to administer the active substance subcutaneously in a dose of 0.1 to 2 mg. Aqueous solutions of the decapeptide are unstable, autoclaving in the final container is not possible. With conventional sterilisation according to the prescribed conditions the decapeptide tends to decompose. To obtain an injectable solution it was therefore necessary to develop a lyophilisate."
The specification then describes how if lyophilisation is done with only the peptide present, only a 'loose fluff' results, and this is lost when sterilisation occurs; and that this is overcome by using bulking agents such as hexitols. It then continues:
"It was, however, found during development work on the lyophilisate that the active substance behaves in a widely different and unpredictable manner during processing. The first batches gave good results, but it soon transpired that difficulties occurred during the sterile filtration and faulty batches resulted.
"It is known from the literature …. that oligopeptides, particularly those with terminal acid amide function, tend to form gels. … It is then no longer possible to prepare a medicament with an exactly defined active substance content.
….
"To avoid this gel formation, the literature lists the following additives which may be tried out on an experimental basis:
….Acids that were used were …. and acetic acid. … These auxiliary substances were tested as filtration supporting agents to prevent gel formation.
"No satisfactory solution of the problem could, however, be found. Only acidification with acetic acid showed partial success. Here, too, it was, however, always necessary to accept high filtration losses. It was then surprisingly found that cetrorelix can be easily dissolved in 30% volume/volume acetic acid. The solution is then filled up to a final concentration of 3% cetrorelix with water for injection purposes and mannitol is added. Although it is stated in the literature that the terminal acid group hydolyses easily in acid medium, this was not found in the case of cetrorelix. Solutions prepared according to this method caused no difficulties during filtration. The correct amounts of active substance were always found."
The specification ends with 7 claims. The claims of relevance are claims 1 to 5, which are as follows:
1.A lyophilisate of a peptide with 3-15 amino acids and optionally one or several bulking agents, characterised in that 1 part by weight of peptide is dissolved in 100 – 10,000 parts by weight of acetic acid and then transferred to water, the solution so obtained being lyophilised.
2.A lyophilisate according to claim 1 characterised in that the peptide is of the formula:
X-R¹-R²-R³-Ser-Tyr-R⁶-Leu-Arg-Pro-R¹⁰-NH₂
wherein X is …..
3.A lyophilisate according to claim 1 or claim 2, characterised in that the peptide is cetrorelix.
4.A lyophilisite according to any one of claims 1 to 3, characterised in that the bulking agent used is mannitol.
5.A lyophilisate of a peptide with 3-15 amino acids and optionally one or several bulking agents, substantially as hereinbefore described with reference to the example.
The Pharmaceutical Substance
In support of the extension of term application, the attorney argued that this case was an instance where the substance could only be identified by the process steps for its manufacture. I should note here that the provisions for extending the term of a patent are in respect of a pharmaceutical substance per se. That usually means that a claim to a substance qualified by method steps would not form the basis for extending the term of a patent. The attorney's submission clearly relates to the observation in the Patent Office Manual of Practice and Procedure that:
"In limited circumstances, a substance could be new and inventive but can only be defined by reference to the process in which it was made (for example, compound X obtainable by process Y) because the chemical structure or composition is undetermined. In such circumstances, a claim which defines the substance by reference to such method steps would be a claim to the substance per se."
On a first reading of the specification the impression is readily obtained that the invention is not about obtaining a new form of cetrorelix. Rather, it is about putting the cetrorelix into a lyophilised form for use for its known properties. The specification does not suggest any desire to change the chemical or biochemical properties of the peptide – indeed, importance is placed on there being an exactly defined 'active substance' content. However, it is equally apparent that the usual lyophilisation processes led to a range of undesirable outcomes.
I am aware that the biochemical properties of polypeptides are largely determined by the way the protein chain folds – by its morphology. The specification does not make any direct reference to the morphology of the polypeptide. However, the declaration filed on 2 October by Dr. Matthias Rischer of the patentee states:
3. The lyophilisate of Cetrorelix acetate shows different physicochemical behaviour compared to the active principal ingredient (hereafter termed 'API') in the following ways:
(d)the API and the lyophilisate show different chemical stability, especially for low peptide content such as 0.25mg. The lyophilisate is much more unstable compared to the API itself due to the presence of deamidation product impurity. The reason for this impurity is that the lyophilisate has a different morphology compared to the API, this morphology leads to a solid phase reaction with water and formation of the deamidation product. The formation rate of the deamidation product is much higher compared to the same amount of API eg 0.25mg stored in the same primary packaging material.
I take this as being an assertion that the lyophilisation process of the patent results in a changed morphology in the cetrorelix. While the specification is entirely silent on the morphology, I accept that this explanation is prima facie consistent with the changed properties of the lyophilisate compared to earlier attempts to lyophilise cetrorelix. On the basis of the material before me I have no reason to doubt this assertion, and accordingly will proceed on the basis that it is correct.
[Curiously, the statement asserts that the lyophilisate is 'much more unstable compared to the API itself'. This is in apparent contradiction to the specification as quoted in para 7, where in the aim was to obtain increased stability. But having regard to tabular data in the declaration, I cannot exclude the possibility that 'stable' was intended. Notwithstanding this, I do not believe this issue is of any particular importance to my considerations.]
The significance of the different morphology is great. It is well known that the biochemical properties of a polypeptide can be critically dependent upon the morphology. When a polypeptide chain is folded, cross-linking bonding occurs between different parts of the chain. When the morphology is different, the cross-linking bonds will be at different locations. For the purposes of the definition of a "pharmaceutical substance" it is my view that, despite having a common chain of peptides, a polypeptide chain that is folded differently (and therefore has different cross-linking bonds) is a different pharmaceutical substance.
I should note here that, at least in patent literature, the detailing of the 3-dimensional folding patterns of polypeptides is a relatively recent occurrence. The absence of any 3-D structural specification in the description of the present patent is not surprising. I think that it is reasonable to infer (having regard to the date of filing the specification) that the only reasonable way to specify the particular morphological form of the polypeptide was by reference to its manner of production. And I think that it is appropriate to make this inference even though there is no explicit reference in the specification to the fact that the lyophilisate was of a different morphological form.
Accordingly, I have come to the conclusion that, while the specification is primarily directed to a method of lyophilising a polypeptide, it properly discloses a particular morphological form of polypeptide per se. I have also concluded that it would be reasonable to expect that the only way to properly characterise the particular morphological form at the time of filing the application would be by reference to the method steps required to prepare it.
An important issue arises in those situations where a substance per se is characterised by the method of producing it. Inevitably those method steps must be an essential component of any identification of the substance. It would, for example, be difficult to establish that compound X that can only be defined as being derived using method steps A and B is the same as compound Y that can only be defined as being derived using method steps C, D and E.
From my reading of the specification, the method steps critical to the formation of the particular morphological form of cetrorelix are:
1.Dissolve Cetrorelix in 30% acetic acid
2.Add water
3.Lyophilise
In particular, I would note that the addition of bulking agents - such as mannitol - would not appear to impact upon the folding. Also, the specification does not indicate a concentration of acetic acid different from '30% volume/volume' as being suitable. It clearly indicates that a lower concentration of acetic acid does not work. But there is no indication that a higher concentration (e.g. 100% acetic acid) will produce the same morphological form of the polypeptide. That is, the only method disclosed requires the use of a 30% solution of acetic acid.
I should note here that the reference to 30% on page 3 of the specification is '30% volume/volume'. I understand the density of pure acetic acid to be about 1.05. The example refers to mixing 210g water with 91.17g of acetic acid as being a 30% acetic acid. This corresponds to a density of 1.013. Ultimately I am of the view that this difference is of little significance, and within the range that might reasonably be expected to be covered by the reference to 30%.
Substance on the ARTG
Goods containing, or consisting of, the pharmaceutical substance must be included on the Australian Register of Therapeutic Goods (ARTG). In this case:
·    The printout from the ARTG for Cetrotide indicates that there is one active ingredient, being cetrorelix 250mg (as acetate) powder. It also refers to the presence of mannitol (as an excipient);
·    Cetrorelix or Cetrotide are not yet monographed in the British pharmacopoeia – the default standard for identifying the composition of goods on the ARTG [see Merck & Co Inc v Arrow Pharmaceuticals Limited[2002] APO 13 at paragraph 38]; and
·    During prosecution of the extension application, the patentee provided "Manufacturing Instructions" for cetrorelix lyophilisate. Those instructions, on my calculations, involve the step of dissolving cetrorelix acetate in 30% acetic acid.
Accordingly I have no reason to believe that the substance included on the ARTG is any different to the substance described in the specification.
The Claims
In order to grant an extension of the term of a patent, the pharmaceutical substance per se must fall within the scope of a claim of the patent. Claims 6 and 7 are method claims per se, and prima facie do not provide a basis for an extension.
It might normally be expected that where a patent has a single chain of dependent claims to a substance, a claim in that chain would provide the basis for an extension of the term of the patent. However, that would not appear to be the case here.
As discussed previously, the critical method steps required to produce the morphological form of the polypeptide is the dissolution in 30% acetic acid. The difficulty is that claim 1 contains no reference to the concentration of acetic acid. Nor do any of dependent claims 2 to 4. Instead, these claims define a process of dissolving 1 part by weight of the peptide in 100 – 10,000 parts by weight of acetic acid, with no reference to concentration. Interestingly, this 'parts' requirement is nowhere specified in the description. Indeed, on my calculations the sole example in the specification involves dissolving 1 part of cetrorelix in about 55 parts of acetic acid – which prima facie is well outside the scope of these claims.
Accordingly, to the extent that dissolving the peptide in a 30% solution of acetic acid is necessary to generate the particular morphological form of cetrorelix, I am unable to conclude that the morphological form of cetrolelix is in substance within the scope of any of claims 1 to 4.
Claim 5 is an omnibus, which is in the following terms:
5. A lyophilisate of a peptide with 3-15 amino acids and optionally one or several bulking agents, substantially as hereinbefore described with reference to the example.
The construction of an omnibus claim in essence involves two steps. Firstly, identification of the subject matter of the claim (the essential features); secondly, identifying the specific forms of the essential features of the claim from the description and specific examples.
The subject matter of the claim is a lyophilisate of a peptide with 3 to 15 amino acids. I take the reference to 'optionally one or several bulking agents' to be a short-hand way of writing the claim to include options of (i) no bulking agent, and (ii) one or several bulking agent – with the detail of the bulking agent (if present) being as per the example. For present purposes, I need only be concerned with the option of 'no bulking agent'.
Given the apparent lack of fair basing for claims 1 to 4 in the specification, I think it is inappropriate to look at those claims to ascertain whether there are any other essential features inherent in the subject matter of the omnibus claim. In particular, I do not believe that there is any basis to take the requirement in claim 1 of "1 part by weight of peptide is dissolved in 100 – 10,000 parts by weight of acetic acid" as being an inherent essential feature of the omnibus claim.
The detail of the essential features of the lyophilisate is to be found in the description and example. To this end, the example refers to cetrorelix - so that the reference to 'peptide with 3 to 15 amino acids' clearly encompasses cetorelix per se. The example involves making a 30% solution of acetic acid [210g water with 91.17g acetic acid], and dissolving 1.62 - 1.695g of acetic acid in the 30% solution. As previously discussed, this is the essential step (as described) required to obtain the particular morphological form of cetrorelix and is thereby incorporated in the claim. The example also adds mannitol as a bulking agent - but for present purposes I disregard this, as it is not an element of the particular form of the omnibus claim that I am considering. That is, the claim defines inter alia the lyophilisate of cetrorelix prepared by being dissolved in 30% acetic acid.

Accordingly, I am satisfied that within the scope of the omnibus claim is the morphological form of cetrorelix that is obtained by lyophilising cetrorelix prepared using a 30% solution of acetic acid. That is, the omnibus claim claims a pharmaceutical substance per se – being a substance that is in substance disclosed in the specification, and is included in a good listed on the ARTG.
CONCLUSION

31. I have indicated that I believe there may be some problems with claims 1 to 4 of this patent. It is not for me to make any determination in these proceedings of whether or not there is in fact a problem with these claims. If the problems were associated with novelty or inventive step, it would be open for the Commissioner to separately initiate re-examination of the patent under s.97(2) of the Act. However the problem, if any, that I have identified relates to fair basis – which is not a ground of re-examination.
32. In circumstances where all the claims relied upon to support the extension are clearly prima facie invalid, the question might reasonably arise of whether an extension of term of the patent should be granted. However I have no reason to question the validity of the omnibus claim which supports the present extension, so that I do not need to resolve this question. I should also add that given a claim that supports the extension of term, I do not believe that the presence of other claims that might be defective is a barrier to the extension of term of the patent being granted.

Accordingly, having regard to:
·the declared assertion that the method gives rise to a different morphological form of cetrorelix; and
·my observation that at the date of the patent the only reasonable way to define the morphological form would have been by way of the method steps;
I am satisfied that it is appropriate to accept the application for the extension of term of this patent on the basis of the omnibus claim.
D Herald
Deputy Commissioner of Patents
Patent attorneys for the applicant : Spruson & Ferguson, Sydney