Mayne Pharma PTY Ltd & Anor v Pharmacia Italia SPA

This is a patentee’s appeal in a case rightly subjected to the streamlined procedure. The litigation began on 17^th May 2004 when the respondents (“Mayne”) commenced proceedings for a declaration of non-infringement of Pharmacia’s UK patent No. 2,178,311. A counterclaim for infringement followed. The only issue was whether Mayne’s product falls within claim 1 of the Patent. The case was heard before Mr Roger Wyand QC, sitting as a Deputy Judge. He gave judgment, holding non-infringement, on 1^st November 2004 and granted permission to appeal. So the case has gone from start to determination on appeal in less than 9 months.

Mayne wish to sell an injectable solution of an anti-cancer drug called epirubicin (an anthracycline glycoside) hydrochloride. They say it does not fall within any of the claims of the patent. Pharmacia say it does. It is agreed that the whole question turns on claim 1. This reads:

“An injectable, ready-to-use, sterile, pyrogen-free, anthracycline glycoside solution which consists essentially of a physiologically acceptable salt of an anthracycline glycoside dissolved in a physiologically acceptable aqueous solvent therefor at an anthracycline glycoside concentration of from 0.1 to 50 mg/ml, which has not been reconstituted from a lyophilizate and the pH of which has been adjusted to from 2.5 to 5.0 solely with a physiologically acceptable acid, the said acid being selected from hydrochloric, sulfuric, phosphoric, acetic, succinic, tartaric, ascorbic, citric, glutamic, methanesulphonic or ethanesulphonic acid.”

“Lyophilization” (US spelling) means freeze-drying. What Mayne do is described, it is agreed accurately, by the Deputy Judge as follows:

“Mayne purchase epirubicin hydrochloride which has been subjected to a bulk lyophilization process. Mayne takes this lyophilizate, dissolve it in water, add […]. The resulting solution is […] and is then filled into vials […].”

So lyophilization of the epirubicin hydrochloride forms part of the history of Mayne’s product, but it is not the immediate precursor to its production – it is an “upstream” process. Is the final product nonetheless covered by the claim? This turns on its meaning, particularly the words solution … which has not been reconstituted from a lyophilizate. It is conceded that the Mayne process fulfils the remainder of the claim, pH adjustment with appropriate acid.

To decide upon that meaning one must construe the claim in context. I summarised the principles in paragraph 41 of my judgment in Technip SA’s Patent [2004] RPC 919. The House of Lords in Kirin-Amgen [2004] UKHL 46, through Lord Hoffmann’s speech, has approved those principles (save for one minor matter) and provided a much fuller justification for them than did I. As a practical working guide, it will generally be sufficient to use my summary as approved. I repeat it here, but stripped down to bare essentials:

“(a)

The first, overarching principle, is that contained in Art 69 itself.

(b)

Art 69 says that the extent of protection is determined by the terms of the claims. It goes on to say that the description and drawings shall be used to interpret the claims. In short the claims are to be construed in context.

(c)

It follows that the claims are to be construed purposively – the inventor’s purpose being ascertained from the description and drawings.

(d)

It further follows that the claims must not be construed as if they stood alone – the drawings and description only being used to resolve any ambiguity. Purpose is vital to the construction of claims.

(f)

Nonetheless purpose is not the be-all and end-all. One is still at the end of the day concerned with the meaning of the language used. Hence the other extreme of the Protocol – a mere guideline – is also ruled out by Art 69 itself. It is the terms of the claims which delineate the patentee’s territory.

(g)

It follows that if the patentee has included what is obviously a deliberate limitation in his claims, it must have a meaning. One cannot disregard obviously intentional elements.

(h)

It also follows that where a patentee has used a word or phrase which, acontextually, might have a particular meaning (narrow or wide) it does not necessarily have that meaning in context.

(i)

It further follows that there is no general “doctrine of equivalents”.

(j)

On the other hand purposive construction can lead to the conclusion that a technically trivial or minor difference between an element of a claim and the corresponding element of the alleged infringement nonetheless falls within the meaning of the element when read purposively. This is not because there is a doctrine of equivalents: it is because that is the fair way to read the claim in context.

(k)

Finally purposive construction leads one to eschew what Lord Diplock in Catnic called (at p.243):

“the kind of meticulous verbal analysis which lawyers are too often tempted by their training to indulge.””

In this case it is agreed that the “Protocol questions” do not assist. What matters is the meaning of the claim read in context. Since the claim is assumed to be read by the person skilled in the art, it is sensible to begin by summarising his relevant background knowledge - the common general knowledge. I accept here, as Mr Birss, for Mayne, contended, that the relevant notional skilled man would be a pharmaceutical manufacturer, not merely a hospital pharmacist. Such a man (or team) would have knowledge not only of how the end product was to be used but also how to make it.

In particular he would know that:

With that, I can turn to the specification. Its title is “Injectable ready-to-use solutions containing an antitumor anthracycline glycoside.” The opening general words say this:

“The present invention relates to a stable intravenously injectable ready-to-use solution of an antitumor anthracycline glycoside, e.g. doxorubicin, to a process for preparing such a solution, and provide the same in a sealed container, and to a method for treating tumors by the use of the said ready-to-use solution.”

Next it acknowledges that the anthracycline glycoside compounds are well known and used as anti-tumor agents. It then sets out the nature of the existing products on the market:

“At present, anthracycline glycoside antitumor drugs, in particular, e.g., doxorubicon, are solely available in the form of lyophilized preparations, which need to be reconstituted before administration.”

After summarising two references which discuss the dangers to medical personnel from this type of agent in general, the patent says this:

“To administer a lyophilized preparation, double handling of the drug is required, the lyophilized cake having to be first reconstituted and then administered and, moreover, in some cases, the complete dissolution of the powder may require prolonged shaking because of solubilization problems.”

It then states the problem to be solved by the invention:

“As the risks connected with the manufacturing and the reconstitution of a lyophilized preparate would be highly reduced if a ready-to-use solution of the drug were available, we have developed a stable, therapeutically acceptable intravenously injectable solution of an anthracycline glycoside drug, e.g. doxorubicin, whose preparation and administration does not require either lyophilization or reconstitution.”

Next it sets out what the invention is in the so-called consistory clause. It is repeated in claim 1 so I need not set it out again. There then follows a second consistory clause, which corresponds to independent claim 31:

“A process for producing a solution according to any one of the preceding claims; which process comprises dissolving the physiologically acceptable salt of the anthracycline glycoside, which salt is not in the form of a lyophilizate, in the physiologically acceptable aqueous solvent therefor; adding solely the physiologically acceptable acid to adjust the pH within the said range as desired; optionally, adding an additional component selected from a co-solublizing agent, a tonicity adjustment agent and a preservative to the solution; and then passing the resulting solution through a sterilising filter.”

There then follows detail about how the solution is made. None of the detail matters for present purposes save this: that the description of the detailed variants of the process at no point mentions the use of lyophilized product. All the 12 examples start with the words “Doxorubicin.HCl was dissolved …” without explicitly saying whether it was lyophilized or not.

The last passage I need mention is a general statement on p. 9 about an advantage of the invention:

“With the solutions of the invention it is possible to obtain compositions having a very high concentration of the anthracycline glycoside active substance even at 50 mg/ml. This constitutes a great advantage over the presently available lyophilized preparates wherein high concentrations of anthracycline glycoside can only be obtained with difficulty because of solubilization problems encountered in reconstitution, mainly with saline. The presence of the excipient, e.g. lactose, in the lyophilized cake, and its generally high proportion in respect of the active substance, even up to 5 parts of excipient per part of active substance, has a negative effect on solubilization so that difficulties may arise in obtaining dissolution of the lyophilized cake, especially for concentrations of anthracycline glycoside higher than 2 mg/ml.”

Mr Richard Miller QC for the patentees contended that the patent was essentially about formulation of the ready-to-use solution. It was this formulation step which had not to involve lyophilization and its reconstitution on the ward. The starting materials for the formulation were not part of the invention. He submitted in detail that:

Mr Birss submits that his case is crucially dependent upon whether the Deputy Judge was right in his paragraph 36:

“36.

On a fair reading of the claims and in the context of the specification and such evidence of common general knowledge as is before me I find that the skilled addressee would form the view that the patentee regarded lyophilization as not just an unnecessary but as an undesirable process step in the production of the injectable solution and intended to exclude a solution made by the use of such a step, even if it were to be followed by other steps, such as the adjustment of pH and sterilising by filtration.”

Putting it another way, he submitted that the whole teaching of the patent is about the complete avoidance of lyophilization. You do not need lyophilization at any stage. And it is that which is to be avoided if you are to avoid danger to workers during any part of the manufacture. As he put it “you can throw away the lyophilizing machine.”

He drew a homely analogy – with instant coffee. If you want a cup of real coffee (i.e. coffee which has not been reconstituted from a lyophilizate) containing milk and sugar you will not be satisfied with a cup of instant coffee where the milk and sugar has been added after the reconstitution.

Mr Birss further relied upon the process aspect of the invention – claim 31. First he pointed out that if the examples were truly indifferent as to whether the starting material was lyophilized or not, then none of them would be examples of the process of the invention. So it was implicit that the starting material was not lyophilized. Second he submitted that claim 31 tracks claim 1 and in particular both claims use the word “lyophilizate”. If Mr Miller were right then the word would have a different meaning in each claim which was improbable.

I have already quoted the most crucial paragraph of his judgment. But I should mention some other points too. First there is the way he dealt with claim 31. He said this:

“28.

Pharmacia counters by saying that claim 31 is effectively dependent on claim 1 and is therefore narrower than claim 1 and should be construed in such a way. This is not strictly correct. Claim 31 is a process claim whereas claim 1 is a product claim. Whilst it is correct that the process of claim 31 may not be the only process that will produce a product within claim 1 this does not mean that it must necessarily be construed as a subset of the processes that can produce such a product. There may be other processes: there may not. It is neutral.”

I think that is right. In general in a patent with product and process claims one may perhaps expect the process to produce the product, but there is no necessary corollary that the product must be made only by the process. All depends on the language used in context.

In the preceding paragraph the Judge said this:

“27.

Mayne submit that their product is made by the process of claim 31 except that the salt of the anthracycline glycoside which they dissolve is in the form of a lyophilizate. Thus, they do not infringe claim 31, as is acknowledged by Pharmacia. They point out that the examples being silent as to how the API is produced, it must be assumed that the API is not a lyophilizate otherwise there is no example of the process claimed. Thus, they say, the skilled addressee would understand the phrase in claim 1 “which has not been reconstituted from a lyophilizate” as excluding a solution which has been made by the process of claim 31 but with the starting material, the API, being a lyophilizate.”

Mr Birss submitted that the Judge’s comment about the claim 31 argument being “neutral” did not apply to this paragraph. I think he is right. On the other hand the Judge here does no more than record Mr Birss’ argument about the examples. He never found it necessary to take the argument specifically into account, though he may have done in his crucial paragraph 36.

Next I should mention the Judge’s paragraphs 33 and 34:

“I have two problems with Pharmacia’s approach to construction of the disputed phrase. The first is that even if the patent does not teach achieving stability by adjusting the pH the claim also refers to an anthracycline glycoside concentration of from 0.1 to 50 mg/ml. The passage set out above from page 9 line 11 of the patent explains that this is an advantage over “the presently available lyophilized preparates”. I have heard no evidence as to how the skilled addressee would regard this passage but on its face it seems to be teaching away from the use of lyophilizates.

The second problem is more fundamental. If one concludes that the skilled addressee does not regard the disputed phrase as necessarily excluding any lyophilization/reconstitution step, where does he/she draw the line? The suggestion by Pharmacia is that the skilled addressee would understand the phrase to mean that lyophilization was not used on the final product but could have been used on a precursor. This, says Pharmacia, would only exclude precisely what was done before in the hospital pharmacy.”

I do not agree with either of these points. As Mr Miller pointed out the passage on p.9 is by way of contrast with the existing product – “the teaching away from lyophilizates” relates only to lyophilizates in the final product.

Nor do I see any real problem about where the line is drawn. Mr Miller put it this way: “only if the step of reconstitution produces a ready-to-use solution is there no infringement.” Mr Birss suggested there was a problem here: suppose you reconstituted and then diluted the solution or added saline for isotonicity – as you sometimes did with the prior art. Would that mean no infringement? I see no problem. The product is either ready-to-use or it is not. If it is, then if the immediately prior step was reconstitution, there is no infringement – otherwise there is.

Finally the Judge thought there was support from a linguistic analysis of the claim. I do not go into the detail of this – Mr Birss did not seek to support it as such. His support for the Judge, as I have already said, rested essentially on paragraph 36.

I have come to the conclusion that Mr Miller is right, essentially for the reasons he advanced. I need elaborate only a little. I think the skilled man would see the real point of the teaching in the description as being the provision of a stable, ready-to-use solution. Such a desirable substance was not previously available. The patent teaches him how to make it. He can make it without having to lyophilize the material in the vials. He knows he will have to start his formulation with active ingredient raw material. But he would not regard the nature of that as part of the formulation process. The patent teaches him how to do away with a previously essential lyophilization.

When he comes to read claim 1, knowing that its purpose in law is to set out the monopoly, he sees that it is the “ready-to-use solution” which must not “have been reconstituted from a lyophilizate.” With the understanding of the purpose and teaching of the description he would read it as meaning that the solution itself has not been made by reconstitution – it is avoidance of that which fulfils the purpose of doing away with the previously essential step. If he considered the nature of the starting raw material, lyophilized or not, he would see it made no real difference – just that starting with lyophilizate would introduce an unnecessary complication.

I think this construction is that which is consistent with the inventor’s purpose as disclosed in his specification – the manufacture of a ready-to-use solution which does not involve the previously essential lyophilization stage.

As to Mr Birss’s coffee example, like many analogies it is beguilingly misleading – there is no true analogy because coffee in its raw material form can never be lyophilized. Nor do I think it matters whether the examples are read as starting with unlyophilized material – whether they do or not is not what matters because they are essentially about producing the stable solution.

Accordingly I would allow the appeal. I would not want to part from this case without paying tribute to the high quality of the argument on both sides. Sadly, however, I must also record the fact that I was most disappointed to see the quite extraordinary number of files of paper produced, quite unnecessarily, for this appeal. We were only referred to two pages not included in the one main file. They were obviously not wanted on voyage or to put it more formally not “relevant to proceedings in the Court of Appeal” within the meaning of para. 15.1(1) of the Practice Direction to Part 52 of the CPR. No doubt this will be taken into account on assessment of costs.

I agree.

I also agree.