Strand, London, WC2A 2LL
B e f o r e :
| BASF AG||Claimant|
|- and -|
|SMITHKLINE BEECHAM PLC||Defendant|
Andrew Waugh QC, Justin Turner and Geoffrey Pritchard (instructed by Simmons & Simmons) for the Defendant
Hearing dates : 14, 15, 18–22 March 2002
Crown Copyright ©
Mr Justice Pumfrey :
The patent in suit
‘Subsequent repetition of the preparation described in Example 8 has failed to yield any type of paroxetine hydrochloride anhydrate, and there is no clear teaching elsewhere in the document of any alternative route or modification to the process which would generate the anhydrate.’
‘Paroxetine hydrochloride is also purported to be disclosed in the International Journal of Pharmaceutics 42, (1988) 135 to 143, published by Elsevier. The anhydrate is said to be produced by crystallising paroxetine hydrochloride from anhydrous propan-2-ol. Subsequent repetition of this process has resulted in a propan-2-ol solvate of paroxetine hydrochloride. That is to say that there is bound propan-2-ol in the product. This bound propan-2-ol cannot be removed by conventional drying techniques such as vacuum oven drying.’
‘Paroxetine hydrochloride anhydrate substantially free of bound propan-2-ol has not been described in the literature, nor has any method been disclosed which would yield such a product as an inevitable result. A method for preparing Paroxetine hydrochloride anhydrate substantially free of bound propan-2-ol has now been found.’
‘Accordingly, the present invention provides paroxetine hydrochloride anhydrate substantially free of bound organic solvent.
The present invention also provides paroxetine hydrochloride anhydrate substantially free of bound propan-2-ol with the proviso that it is other than Form Z.’
‘Substantially free of bound organic solvent is to be interpreted to be less than the amount of propan-2-ol which would remain solvated, i.e. bound, within the crystal lattice of the product under conventional vacuum oven drying conditions.’
‘It should be understood that the present invention comprising paroxetine hydrochloride anhydrate substantially free of bound propan-2-ol may contain unbound water, that is to say water which is other than water of crystallisation.’
‘Typically the amount of bound organic solvent on a weight for weight basis would be less than 2.0% preferably less than 1.8%, more preferably less than 1.5%, even more preferably less than 1.0%, yet more preferably less than 0.5% and most preferably less than 0.1%.’
I do not read this passage as limiting the scope of the monopoly set out by claim 1. The word ‘typically’ has the effect of giving an indication rather than setting a limit. The descriptions of the preferred crystalline forms is significant:
‘Preferred forms of paroxetine hydrochloride anhydrate substantially free of bound propan-2-ol or substantially free of bound organic solvent include:
i) paroxetine hydrochloride anhydrate in Form A; (as hereinafter defined)
ii) paroxetine hydrochloride anhydrate in Form B (as hereinafter defined)
iii) paroxetine hydrochloride anhydrate in Form C; (as hereinafter defined)
iv) paroxetine hydrochloride anhydrate in Form D; (as hereinafter defined)’
‘The forms of paroxetine hydrochloride anhydrate may be distinguished from each other and the material formed as a result of carrying out the procedures mentioned in [’403] and the International Journal of Pharmaceutics 42, (1988), 135 to 143 by crystalline shape, solvent analysis, or techniques such as IR, melting point, X-ray diffraction, NMR, DSC, microscopy and any other analytical techniques which differentiate one form from another.’ (page 3 lines 2–6)
‘The present invention also provides a process for the preparation of paroxetine hydrochloride anhydrate substantially free of propan-2-ol which comprises crystallising paroxetine hydrochloride in either
i) an organic solvent or mixture of organic solvents which form a solvate with the paroxetine hydrochloride and which are not removable by conventional drying techniques; or
ii) an organic solvent or mixture [of] organic solvents which do or do not form a solvate but which are removable by conventional vacuum oven drying;
thereafter in the case of i) displacing the solvated solvent or solvents using a displacing agent and in the case of ii) by removing the solvent.
The present invention also provides a process for the preparation of paroxetine hydrochloride anhydrate substantially free of bound organic solvent which comprises displacing the solvated solvent or solvents from a paroxetine hydrochloride solvate using a displacing agent.’
The claims in issue
‘1. Paroxetine hydrochloride anhydrate substantially free of bound organic solvate.
2. Paroxetine hydrochloride anhydrate substantially free of bound propan-2-ol with the proviso that it is other than Form Z.
3. Paroxetine hydrochloride anhydrate substantially free of bound propan-2-ol in Form A, which is characterised in that
(a) it has a melting point of about 123-125°C when obtained in similar purity to the material described in Example 1
(b) and has significant IR bands at about 513, 538, 571, 592, 613, 665, 722, 761,806, 818, 839, 888, 906, 924, 947, 966, 982, 1006, 1034, 1068, 1091, 1134,1194, 1221, 1248, 1286, 1340, 1387, 1493, 1513, 1562, 1604, 3402 and 3631cm–1
(c) and the DSC exotherm, measured at 10°C per minute shows a maximum at about 126°C using an open pan and a maximum at about 121°C using a closed pan;
(d) it also has a substantially similar X-ray diffractogram to that shown in Figure 4, including characteristic peaks at 6.6, 8.0, 11.2 and 13.1 degrees 2q
(e) and a substantially similar solid state NMR spectrum to that shown in Figure 7 including with characteristic peaks at 154.3, 149.3, 141.6 and 138.5 ppm.
7. Paroxetine hydrochloride anhydrate as defined in claim 3, which is in the form of needles.
10. A process for the preparation of paroxetine hydrochloride anhydrate substantially free of propan-2-ol which comprises crystallising paroxetine hydrochloride in either;
(i) an organic solvent or mixture of organic solvents which form a solvate with the paroxetine hydrochloride and which are not removable by conventional vacuum oven drying techniques; or
(ii) an organic solvent or mixture or organic solvents which do or do not form a solvate with the paroxetine hydrochloride but which are removable by conventional vacuum oven drying;
thereafter in the case of (i) displacing the solvated solvent or solvents using a displacing agent and in the case of (ii) by removing the solvent.
11. A process for the preparation of paroxetine hydrochloride anhydrate substantially free of bound organic solvent which comprises displacing the solvated solvent or solvents from a paroxetine hydrochloride solvate using a displacing agent.’
Construction—principles, and the skilled man
8. The crystalline state is one in which there is a very high degree of internal order. The atoms or molecules of which the crystal is composed are arranged in a precise regular way that is repeated over and over in three dimensions forming a crystal lattice.
Crystal habit and morphology
9. Crystal habit and morphology are interchangeable terms that refer to the physical shape or form of the individual crystalline specimens, for example, the crystal habit of a specimen could be described as “needles”, “prisms” or “plates”. The term “form” in this context should not be confused with “form” as in polymorph. Crystal habit is not necessarily an indicator of different polymorphic forms, as one polymorph may exist in a range of different crystal habits. Also, different polymorphs may exist in the same crystal habit.
Polymorphism occurs when a given compound of a specific molecular formula and chemical structure exists in two or more physical phases resulting from differing arrangements of the molecules in the solid state, i.e. exhibiting different crystalline lattices. These phases are often referred to as “forms”, “polymorphs” or “modifications” and can be characterised on the basis of unique analytical data. The interpretation of the terms “form” and “modification” must be made in the correct context, however, as these terms can also be used in reference to the crystal habit.
The consequences of polymorphism is that the different solid-forms can have different physicochemical properties such as solubility, bulk density and hardness. The pharmacokinetic profile e.g. the bioavailability of an active pharmaceutical ingredient is closely related to properties such as solubility and intrinsic dissolution rate, and is therefore dependent on the choice of polymorphic form. It is usual in the development stage of the drug discovery process to implement a polymorph screen on the active pharmaceutical ingredient both to optimise the properties based on the solid-form and to ensure that the selected solid-form is stable.
14 A solvate is a single crystalline phase of a given compound of specific chemical structure in which a solvent molecule or molecules have been incorporated into the crystal lattice. In a solvate each solvent molecule will occupy a specific lattice point within the crystalline lattice, and a solvate is thus a discrete crystalline form that can be characterised as such on the basis of unique analytical data. The solvent molecule is often referred to as “bound” although this term can also be used in a different context.’
A bound solvent molecule in a solvate is one that occupies a discrete lattice position in the crystal structure.
Free solvent is that which is retained in the sample after crystallisation but prior to drying. This solvent does not occupy a discrete lattice position within the crystal structure and therefore does not make the sample a solvate. This solvent is present as agglomerated, occluded or clathrated solvent within the microcrystalline powder and exists as an impurity only, the amount of which may be determined from NMR spectroscopy performed on a solution of the sample. Such NMR spectroscopy would not, however, be capable of distinguishing such free solvent from solvent that is present as a solvate. The agglomerated, occluded or clathrated solvent can be removed by drying, although occasionally it may be hard to remove it completely using conventional vacuum oven drying techniques. In this case the remaining solvent is often confusingly described as being “bound”, i.e. in the context of its being adhesive and hard to remove from the sample.’
‘Conventional vacuum oven drying conditions’
The meaning of ‘substantially free of bound organic solvent’
‘A process for the preparation of paroxetine hydrochloride anhydrate [having] less than the amount of propan-2-ol which would remain solvated, i.e. bound, within the crystal lattice of the product under conventional vacuum oven drying conditions.’
While this approach to the construction of claim 10 is attractive, it is confronted by claim 11, which is to
‘A process for the preparation of paroxetine hydrochloride anhydrate substantially free of bound organic solvent which comprises displacing the solvated solvent or solvents from a paroxetine hydrochloride solvate using a displacing agent.’
The law of anticipation
‘7.5 In the case of a prior document, the lack of novelty may be apparent from what is explicitly stated in the document itself. Alternatively, it may be implicit in the sense that, in carrying out the teaching of the prior document, the skilled person would inevitably arrive at a result falling within the terms of the claim. An objection of lack of novelty of this kind should be raised by the examiner only where there can be no reasonable doubt as to the practical effect of the prior teaching…’ (Guidelines for Examination Part C chapter IV)
‘However for commercial use it is also important that the solid product should have good handling qualities.
We have found that amorphous paroxetine hydrochloride is a hygroscopic [water absorbing] solid of poor handling qualities.
It has now been discovered that paroxetine hydrochloride can be produced in crystalline form in a manner reproducible on a commercial scale.
Accordingly the present invention provides crystalline paroxetine hydrochloride as a novel material, in particular in pharmaceutically acceptable form.
It has been discovered that crystalline paroxetine hydrochloride can exist in at least two different pseudo-polymorphic forms,
1) a hemihydrate
2) an anhydrate
It has also been discovered that paroxetine hydrochloride can form crystalline solvates with certain solvents such as certain lower alcohols and acetone, in particular isopropyl alcohol.
Accordingly the present invention provides as novel forms of crystalline paroxetine hydrochloride:
1) paroxetine hydrochloride hemihydrate
2) paroxetine hydrochloride anhydrate
3) paroxetine hydrochloride isopropanol solvate.’
‘The solvent is fairly weakly bound and may be removed by heating under vacuum. The solvate contains approximately 1 mole of isopropanol per mole.’
‘The crystalline anhydrate form of paroxetine hydrochloride may be prepared via the initial formation of a crystalline solvate e.g. propan-2-ol or acetone solvate, of the hydrochloride and followed by removal of the solvating solvent. The IPA [propan-2-ol] solvate may be conveniently obtained by crystallisation from propan-2-ol, ideally under anhydrous conditions, by adding gaseous or concentrated hydrochloric acid to a solution of the free base or acetate in propan-2-ol., or by crystallising or recrystallising preformed paroxetine hydrochloride from propan-2-ol solution. The solvent of solvation may be removed by drying, typically under vacuum at high temperature e.g. 60ºC, to give the hygroscopic anhydrate.
(page 6 lines 19-25) In practice the earlier described procedure for producing the anhydrate may result in the formation of some hemihydrate. The proportion of anhydrate to hemihydrate can be increased by drying at elevated temperatures .
(page 6 line 35) To obtain the anhydrate by crystallisation/recrystallisation the solvent of choice is anhydrous isopropanol.’
‘The acetate salt was dissolved in isopropanol (2.4 litres) and treated with a mixture of concentrated hydrochloric acid (75ml) and more isopropanol. After standing at 0ºC for about 16 hours, the crystals of the hydrochloride salt containing isopropanol were filtered off and dried. The salt was stirred in distilled water (0.5 litres) for about 20 minutes, filtered off and dried, giving paroxetine hydrochloride anhydrate (m.p. 118ºC).’
‘The solvate of solution was fairly weakly bound and could be removed by drying at high temperatures.’
‘Although I would suspect that there may be a problem with the example 1 procedure, this is not stated clearly in the 407 application. There is a suggestion along these lines on page 6 lines 19-25 [see paragraph 49 above] …This passage would ring a warning bell in my mind, that there were two forms of paroxetine hydrochloride, and that we need to do more work to investigate the stability of each form to make sure that it could be manufactured reliably. There is an indication that this may be a problem in particular with the anhydrate.’
These considerations are not relevant to anticipation. Indeed, none of Dr Lee’s doubts and worries based on what he considered to be difficulties in carrying the experimental technique over to volume production are in any way relevant to the question of anticipation. However, Dr Lee’s further evidence, which is that the function of the water wash in Example 1 of ’407 is not disclosed, is correct as a matter of language. The skilled man would have to appreciate that he had started with the propan-2-ol solvate, washed the crystals, and come out with the anhydrate. There is no doubt that this is very surprising. The skilled man would certainly have appreciated that this is what the example appeared to be teaching: Dr Fishwick described it as curious, and in cross-examination he said his reaction to the passage was ‘Oh, what on earth is going on there?’ My firm impression was that the skilled man reading this passage would have the same reaction as Dr Fishwick. I do not think that he would appreciate that what was happening (if the experiment was an accurate account of an experiment which had taken place) was that the solvent of solvation was being removed. My view is that this surprise at finding a water washing step at all in the context of a preparation which is supposed to produce an anhydrate would provide a context in which the skilled man would be left in real doubt whether he was in fact washing the propan-2-ol solvate regardless of the passage on page 5, or merely washing the anhydrate already prepared.
‘Section 2(2) [of the Patents Act 1977] does not purport to confine the state of the art about products to knowledge of their chemical composition. It is the invention which must be new and which must therefore not be part of the state of the art. It is therefore part of the state of the art if the information which has been disclosed enables the public to know the product under a description sufficient to work the invention.
…If the recipe which inevitably produces the substance is part of the state of the art so is the substance as made by that recipe. CPC/Flavour Concentrates Decision T 303/86  EPOR 95 was a case about actual recipes for cooking. The application was to patent a process for making flavour concentrates from vegetable or animal substances by extracting with fat solvents under pressure in the presence of water. The claim specified certain parameters for the ratio between the vapour pressure of the water in the meat or vegetables and the vapour pressure of the free water. Opposition was based upon two cook-book recipes for pressure-frying chickens and making stews which in non-technical terms disclosed processes having the same effect. The Technical board of Appeal said (at page 98):
“It is sufficient to destroy the novelty of the claimed process that this process and the known process are identical with respect to starting material and reaction conditions since processes identical in these features must inevitably yield identical products.”
Furthermore, it did not matter that the cook did not realise that he was not only frying a chicken, but also making a “flavour concentrate” in the surplus oil. It was enough, as the Board said, that “some flavour of the fried chicken is extracted into the oil during the frying process even if this is not the desired result of that process.”’
Anticipation by ’407: acetone
Obviousness in the light of 407
‘An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art…’
‘There are, we think, four steps which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as being “known or used” and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention.’
‘In applying the statutory criterion and making these findings the court will almost invariably require the assistance of expert evidence. The primary evidence will be that of properly qualified expert witnesses who will say whether or not in their opinions the relevant step would have been obvious to a skilled man having regard to the state of the art. All other evidence is secondary to that primary evidence. In the past, evidential criteria may have been useful to help to elucidate the approach of the common law to the question of inventiveness. Now that there is a statutory definition, evidential criteria do not form part of the formulation of the question to be decided.
In the nature of things, the expert witnesses and the court are considering the question of obviousness in the light of hindsight. It is this which may make the court’s task difficult. What with hindsight, seems plain and obvious, often was not so seen at the time. It is for this reason that contemporary events can be of evidential assistance when testing the experts’ primary evidence. For instance, many people may have been industriously searching for a solution to the problem for some years without hitting upon the allegedly obvious invention. When this type of evidence is adduced, the court can quickly find itself caught up in an investigation of what was or was not obvious to certain identified individuals at certain dates during the history of the development of the product or process involved. This gives rise to complications because the state of knowledge of these individuals, though skilled, may not correspond to the statutory definition of the state of the art. A particular inventor may have been unaware of some aspect of the state of the art as defined in section 2(2), and may therefore have genuinely taken what was actually an inventive step, but nevertheless be unable to claim a patentable invention since the step was, in the terms of the statute, obvious. Further, this type of evidence invites the court to speculate whether particular individuals were of an inventive disposition, because the earlier making of the same invention by another others does not necessarily mean that at a later date the invention was obvious Yet again, evidence of the commercial success of the invention can lead into an investigation of the reasons for this success; there may be commercial reasons for its success unrelated to whether the invention was or was not obvious in the past.
Secondary evidence of this type has its place and the importance, or weight, to be attached to it will vary from case to case. However, such evidence must be kept firmly in its place. It must not be permitted, by reason of its volume and complexity, to obscure the fact that it is no more than an aid in assessing the primary evidence.’
The history of the invention
Obviousness: other solvents
‘MR. WYAND: You look at example 7, what I suggest to you is that if you were carrying out a solvent screen, this is just the sort of thing that you would do. There is nothing in this that is unusual, out of the ordinary, unconventional. A. I would reiterate my earlier point that if I were doing a solvent screen, I would start from preformed hydrochloride rather than the practical difficulties of using the free base and the hydrogen chloride gas. A simple solvent screen - that would be my starting material.
Q. So are you saying that you regard this as unconventional because they have decided to take the free base? A. It is not unconventional. You asked me how I would approach it.
Q. I am sorry. I thought that I said that this is exactly what you would expect the skilled person .... I am sorry if you understood that to be you personally. A. We are talking around ----
Q. You might not choose to use this method, but there is nothing unconventional. A. There is nothing unconventional. It would be a less preferable approach.
Q. But it would be something that you would expect the skilled man to try. A. If his earlier approach had been unsuccessful.’
‘14. Paroxetine hydrochloride anhydrate crystallised from propan-2-ol having less than 2% bound propan-2-ol characterised in that [as claim 3]
15. Paroxetine hydrochloride anhydrate crystallised from acetone having less than 1.2% bound acetone charaterised in that [as claim 3]’