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You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Synthon BV v Smithkline Beecham Plc [2002] EWHC 2573 (Patent) (03 December 2002) URL: https://www.bailii.org/ew/cases/EWHC/Patents/2002/2573.html Cite as: [2002] EWHC 2573 (Patent) |
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CHANCERY DIVISION
PATENTS COURT
Strand, London, WC2A 2LL | ||
B e f o r e :
____________________
![]() ![]() | Claimant | |
- and - | ||
Smithkline Beecham plc | Defendant |
____________________
Andrew Waugh QC, Justin Turner and Geoffrey Pritchard
(instructed by Simmons & Simmons) for the Defendant
Hearing dates : 7-11 October 2002
____________________
Crown Copyright ©
Mr Justice Jacob:
Technical Background
Crystalline and amorphic forms
Amorphic forms, as their name implies, are shapeless, the molecules or atoms being largely randomly oriented. They generally have diffuse melting ranges.
Polymorphism.
Solvates and Hydrates
A compound may be able to form several sorts of solvate - different kinds of crystal containing solvent.
Crystallisation from solution
IR Analysis
Nuclear Magnetic Resonance - NMR
The SB Patent
The SB patent begins by pointing out that paroxetine is an "especially important" antidepressant and anti-Parkinson product and that it is used in therapy as its hydrochloride salt. The patent goes on to say:
"We have now surprisingly discovered a novel salt of paroxetine which may be used as an alternative to the currently marketed hydrochloride, or as an intermediate in the preparation of the hydrochloride.
According to the present invention there is provided paroxetine methanesulfonate as a novel compound.
In one aspect the novel salt of this invention is provided in non-crystalline form, which may be a solid or oil. The oil is preferably absorbed on a solid carrier, especially a carrier that is usable as a component of a pharmaceutical composition.
In another aspect the novel salt of this invention is provided in crystalline form. When the crystalline form exists as more than one polymorph, each polymorph forms another aspect of this invention."
"In a further aspect the present invention provides a process for the preparation of a paroxetine methanesulfonate by precipitation from a solution of a paroxetine methanesulfonate, spray drying or freeze drying a solution of a paroxetine methanesulfonate, evaporating a solution of a paroxetine methanesulfonate to a glass, or by vacuum drying of oils of a paroxetine methanesulfonate, or solidification of melts of a paroxetine methanesulfonate.
Preferably such process provides crystalline paroxetine methanesulfonate by crystallization or re-crystallization from a solution of a paroxetine methanesulfonate, and especially on a commercial scale in a reproducible manner.
Paroxetine methanesulfonate may be prepared by chemical modification of a precursor methanesulfonate salt. Suitable precursors are those which may be converted to the methanesulfonate salt by hydrogenation. For example, the N-benzyl derivative of paroxetine methanesulfonate in a suitable solvent (such as a C1-4alkanol) may be hydrogenated using a catalyst such as palladium on charcoal to generate a solution of paroxetine methanesulfonate.
Alternatively paroxetine methanesulfonate may be prepared by treating paroxetine free base or a labile derivative thereof with methanesulfonic acid or a labile derivative thereof. For example paroxetine methanesulfonate may be prepared by contacting stoichiometric amounts of the acid and paroxetine base, alternatively an excess of the acid may be used. Preferably the base is in solution and the methanesulfonic acid is used as a solid, liquid, or as a solution, for example in water, ethers, or lower alcohols such as methanol, ethanol, and propan-2-ol, or a mixture of solvents. There is no need for a pure form of paroxetine base to be used as a starting material in the preparation of the methanesulfonate salt."
"The paroxetine base or labile derivative thereof may be formed by evaporation of a solvent or solvent mixture in which the base or labile derivative is solubilized. Such a solvent or solvent mixture may for example be a solvent or solvent mixture medium in which paroxetine has been formed in situ e.g. in a preceding reaction step in the medium. The paroxetine base may be produced in an organic solvent or mixture such as those discussed herein, such as toluene or a medium containing toluene, which is then evaporated to leave a residue e.g. an oil, oily or solid or semi-solid residue. The unpurified paroxetine residue may be used in the preparation of paroxetine methanesulfonate. Alternatively the residue may be resolubilized in a suitable solvent such as a medium comprising an alcohol e.g. as discussed above, suitably propan-2-ol. The solvent may be heated and optionally agitated in order to effect complete dissolution of the residue.
In addition to the above-mentioned solvents, most commonly used solvents are suitable for mobilising, e.g. dissolving or suspending, paroxetine base, for example aromatic hydrocarbon type solvents such as alkylbenzenes e.g. toluene, xylene; alcohols such as C1-8 alkanols which may be straight or branched chain e.g. methanol, ethanol, propan-2-ol; esters such as C1-5 alkanoate esters such as ethyl acetate; ketones e.g. di- C1-5 alkyl ketones such as acetone and butanone; amides such as C 1-5 alkyl substituted acetamides e.g. dimethyl acetamide; heterocyclic amines e.g. pyridine; halogenated hydrocarbons such as fluoro and/or chloro C1-10 alkanes e.g. dichloromethane; nitriles such as C1-10 alkyl nitriles e.g. acetonitrile, and ethers e.g. di- C1-5 alkyl ethers and cyclic ethers such as tetrahydrofuran and diethyl ether.
In particular the following solvents are suitable for mobilising paroxetine free base: toluene, alcohols such as methanol, ethanol, propan-2-ol, esters such as ethyl acetate, ketones such as acetone and butanone, halogenated hydrocarbons such as dichloromethane, nitriles for example acetonitrile, and ethers such as tetrahydrofuran and diethyl ether.
Suitably mixtures of solvents may also be used e.g. mixtures of the above mentioned solvents. The paroxetine base may be provided in solution in one solvent and then the solution diluted with another solvent, miscible with the first solvent. The second solvent may be added to a solution of the paroxetine base or alternatively the solution of paroxetine base in a first solvent may be added to the second solvent, in both cases optionally with stirring in the first solvent. The mixing of the paroxetine solution and a second solvent may occur at any convenient working temperature between e.g. - 20°C and the boiling point of the solvent, preferably between 15 to 80°C under an inert atmosphere such as nitrogen."
There is evidently nothing special about the solvent. It may be noted that ethanol is one of the solvents particularly mentioned after toluene.
"Methanesulfonic acid is commercially available. It may be used as a neat liquid, or as a solution, for example in water, ethers, or lower alcohols such as methanol, ethanol and propan-2-ol, or a mixture of solvents. More generally it may be added as a neat liquid or preferably in solution, for example in water, or a lower alcohol i.e. a C1-5 alkanol e.g. methanol, ethanol, or propan-2-ol; esters such as C1-5 alkanoate esters such as ethyl acetate; aromatic hydrocarbon solvents e.g. a C1-5 alkylbenzene such as toluene; di- C1-5 alkyl ketone such as acetone, butanone, isomethylbutyl ketone, or a mixture of such solvents. The methanesulfonic acid may also be added in the form of labile derivatives as discussed above, such as a soluble salt, for example ammonium methanesulfonate, or the methanesulfonic acid salt of an amine, for example a C1-5 alkylamine such as ethylamine or diethylamine."
"The concentration of paroxetine base or labile derivative thereof in the paroxetine feedstock is preferably in the range 5 to 80% weight/volume e.g. 5 to 50% weight/volume, more preferably in the range 10 to 50%, particularly 10 to 30%. The concentration of methanesulfonic acid or labile derivative thereof in the acid feedstock, when added in solution, is preferably in the range 0.1 to 7 molar e.g. 0.1 to 3 molar or 0.5 to 1.5 molar, but more preferably between 1 and 5 molar. A high or low concentration of the acid may be added to a low or high concentration, respectively, of the base, preferably a concentrated solution of the acid is added to a dilute solution of the base. Suitably, depending on the solvent(s) used, the concentration of paroxetine methanesulfonate formed may be in the range 2 to 50% weight/volume, typically 5 to 30%. The concentration ranges of the reactants as defined herein are found to facilitate formation in solution and subsequent precipitation of the paroxetine methanesulfonic acid salt in crystallized form."
"The reaction of methanesulfonic acid with paroxetine base is exothermic and results in a rise in temperature; typically by between 10 and 25°C, depending upon the concentration of the solution, unless controlled by cooling. Suitably the addition, in either order, is carried out above ambient conditions e.g. above 25°C such as between 30 and 80°C preferably above 30°C such as between 40 and 60°C and preferably under an inert atmosphere of nitrogen preferably with agitation e.g. stirring. Whilst temperatures above ambient suitably are used, so as to control the subsequent crystallisation process and to produce crystals having reproducible properties e.g. of uniform particle size distribution and habit, temperatures in excess of 90°C are preferably avoided since degradation occurs resulting in coloration and oil formation. Optionally seeds may be added to the paroxetine solution prior to the addition of the acid component."
"The salt may be isolated in solid form by conventional means from a solution thereof obtained as above"
"A crystalline salt may be prepared by various methods such as directly crystallizing the material from a solvent in which the product has limited solubility or by triturating for example with ethers such as diethyl ether or otherwise crystallizing a non-crystalline salt.
A number of solvents may be used for the crystallization process including those that are useful industrially; e.g. paroxetine methanesulfonate may be crystallized from a relatively crude feedstock such as is commonly produced during the final stage of the chemical synthesis of paroxetine. In particular solvent systems which are suitable for preparation of paroxetine methanesulfonates can also be used for recrystallization (including crystallization), for example toluene or lower alcohols followed by precipitation with ether or hexane. Alternatively, paroxetine methanesulfonate may be crystallized or recrystallized by cooling and optionally seeding a hot solution in a suitable solvent such as propan-2-ol. An improved yield of the salt is obtained by evaporation of some or all of the solvent or by crystallization at elevated temperature followed by controlled cooling, preferably in stages. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the production process and the particle size distribution and form of the product.
One method for preparing crystalline paroxetine methanesulfonate salt from solution comprises forming a supersaturated solution of the salt in a solvent and allowing the crystalline salt to precipitate from solution, for example by maintaining the solution in relatively quiescent conditions, e.g. under gentle stirring or leaving the solution to stand. Seeding of the solution is optional. By selection of a suitable solvent medium and concentration the present invention provides a process in which crystalline paroxetine methanesulfonate precipitates at temperatures above - 20°C e.g. above 0°C e.g. around ambient conditions of 10 to 25°C. Suitable solvent media for this method comprise C1-5 alkyl benzenes such as toluene, alcohols e.g. C1-5 alkanols such as 2-propanol, di- C1-5 alkyl ketones such as acetone, ethers such as C4-6 cyclic ethers such as tetrahydrofuran or mixtures thereof, and in particular mixtures of such alkyl benzenes with such alkanols or ketones e.g. toluene and 2-propanol or toluene-acetone mixtures.
Another method of preparing crystalline paroxetine methanesulfonate salt comprises forming a solution of the salt, for example as defined herein, and subsequently supersaturating the solution for example by evaporation of the solvent and/or the addition of an anti-solvent to precipitate the crystalline salt from solution. An "anti-solvent", as referred to herein, is a medium such as an organic liquid, which is miscible with a solvent for paroxetine methanesulfonate salt but in which the paroxetine methanesulfonate salt is less soluble than in the solvent. Preferably the solubility of paroxetine methanesulfonate salt in the anti-solvent is less than 1mg/ml, preferably less than 0.2 mg/ml, especially less than 0.1 mg/ml. Examples of anti-solvents include ethers, e.g. di- C1-5 alkyl ethers and alkanes, such as C5-10 alkanes which may be straight chain, branched chain or cyclic such as hexane. Solvent systems which are suitable for preparation of paroxetine methanesulfonate, e.g. those discussed above, e.g. with reference to the solvent systems used for the deprotection reactions discussed above, can also be used for recrystallization by precipitation with an anti-solvent."
"A preferred method of preparing crystalline paroxetine methanesulfonate salt comprises cooling and optionally seeding a solution in a suitable solvent in which the paroxetine methanesulfonate salt has a greater solubility at higher temperatures than at lower temperatures so that as the solution cools the solubility at lower temperatures will be exceeded and the paroxetine methanesulfonate salt crystallises out.
Suitably the solubility of the paroxetine methanesulfonate salt at or immediately below the boiling point of the solvent is 5x or more, preferably 10x or more than that at ambient temperatures (e.g. ca. 20ºC) or lower. Suitable solvent systems include alkylbenzenes, e.g. C1-3 alkylbenzenes such as toluene, alcohols such as C1-5 alkanols such as methanol, ethanol, 2-propanol, and butan-1-ol, ketones such as di- C1-5 alkyl ketones such as acetone, methyl ethyl ketone, methylisobutyl ketone, esters such as C1-5 alkyl C1-5 alkanoates such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and ethers such as methyl t-butyl ether and C4-6 cyclic ethers such as tetrahydrofuran. Single and mixed solvent systems may be used as the solvent or co-solvent of choice.
The starting temperature of the solution containing the paroxetine methanesulfonate salt to be crystallized may vary depending upon the solubility of the reactants in the solvent system. Suitable temperatures are between minus 20°C and (+) 80°C, although temperatures between (+)10°C and (+)70°C are preferred and temperatures above (+)30°C e.g. between (+)40° and (+)60°C are most preferred. The solution is cooled to a temperature within the metastable zone in initiate crystallisation. Once crystallisation is underway, the temperature of the mixture may be reduced steadily or in stages in order to maintain a moderate degree of supersaturation and a controlled crystallisation at a high yield. The cooling rate is preferably within the range 0.1 to 5°C/minute and even more preferably is between 0.1 to 2°C per minute. The final temperature at the end of the crystallisation process is preferably around or below ambient e.g. 5 to 25°C even more preferably 10 to 20°C. Advantageously the methods provided herein do not require low temperatures i.e. less than 0°C in order to enable the crystallisation process. An improved yield and quality of the paroxetine methanesulfonate salt may be obtained by combining two or more of the aforementioned crystallisation methods. For example by evaporating some or all the solvent and/or by crystallisation at elevated temperature followed by controlled cooling, preferably in stages."
"In further aspects the present invention provides for the use of techniques such as insonation in the preparation of crystalline paroxetine methanesulfonate salt. Insonation and/or vigorous stirring may be used to initiate nucleation for example in addition to the use of anti-solvent(s), cooling, evaporation and/or seeding. Vigorous stirring is particularly useful when the crystallization vessel used has been used previously in the manufacture of the methanesulfonate salt."
"The abovementioned processes for preparing the paroxetine methanesulfonate salt may be carried out in various types of reaction vessels. The crystallisation of paroxetine methanesulfonate salt suitable for use as a pharmaceutical may be carried out in a vessel such as a stirred tank reactor, which may be constructed from glass-lined or stainless steel, fitted with baffles and one or more jackets to control the temperature profile during crystallisation. Alternatively, the crystallisation may be carried out in a specially designed batch crystalliser, in which fine control of the crystallisation conditions can be maintained. Suitable batch crystallisers include draft tube baffled (DTB) crystallisers, double propeller (DP) crystallisers and fluidised bed crystallisers (Oslo cooling crystallisers). Various continuous crystallisers, such as draft tube cooling, direct contact cooling, scraped surface and turbulence crystallisers may also be employed.
Suitably crystallisation is carried out in a vessel provided with one or more high intensity ultrasonic horns, for example with titanium alloy resonant horns which enable acoustic energy to be coupled to the crystallizing medium at a frequency of 20 kHz and an amplitude of 12 microns or more, and with a device that modifies the power output according to the acoustic parameters of the load. Insonation may be intermittent, limited to part of the apparatus, or discontinued once sufficient nuclei have been generated."
"In a further aspect the present invention provides the paroxetine methanesulfonate salt in a crystalline form having an infra-red spectrum identical or substantially identical to that listed under Example 2 or Example 3 below. Suitably the crystalline paroxetine methanesulfonate has inter alia one or more of the following characteristic IR peaks: 1603, 1513, 1194, 1045, 946, 830, 776, 601, 554, and 539 ± 4 cm-1."
(a) Claim 1 and those dependent on it (2-20). These are all tied to crystalline paroxetine mesylate having a particular IR spectrum - which means a particular crystalline form.
(b) Claim 21 and those dependent on it (22-30). These are all pharmaceutical composition claims, not tied to a crystalline form at all;
(c) Claim 31 and those dependent on it (31-36). These are process claims, not tied to any particular crystal form;
(d) Claim 37 A "Swiss-type" claim for use of paroxetine mesylate in the preparation of a medicament. This is not tied to any form of the compound
(e) Claims 38 - 45 - a set of independent pharmaceutical composition claims containing various amounts of paroxetine mesylate. None of these are tied to any form, crystalline or not.
"Paroxetine methanesulfonate in crystalline form having inter alia the following characteristic IR peaks: 1603, 1513, 1194, 1045, 946, 830, 776, 601, 554, and 539 ± 4 cm-1.; and/or the following characteristic XRD peaks: 8.3, 10.5, 15.6, 16.3, 17.7, 18.2, 19.8, 20.4, 21.5, 22.0, 22.4, 23.8, 24.4, 25.0, 25.3, 25.8, 26.6, 30.0, 30.2, and 31.6 ±0.2 degrees 2 theta."
The Synthon
Application
"The present invention relates to a group of tri-substituted, 4-phenylpiperidines, to a process for preparing such compounds, to a medicament comprising such compounds, and to the use of such compounds for the manufacture of a medicament.
But the following paragraphs launch straight into paroxetine, its uses and problems with the prior art forms of paroxetine:
"The compound paroxetine … is known and has been used in medicaments for treating,amongst other ailments, depression.
Paroxetine has been used as a therapeutic agent in the form of a salt with pharmaceutically acceptable acids. The first clinical trails were conducted with the acetate salt.
A known useful salt of paroxetine is the hydrochloride. This salt is considered to be the active substance in several marketed pharmaceutical products, e.g. Paxil or Seroxat. A number of forms of paroxetine hydrochloride have been described:
¾ the anhydrous form in several crystalline modifications (…);
¾ the hydrated form – a hemihydrate (…..) and in the solvated forms.
…..
Most of these known salts of paroxetine have unsuitable physico-chemical characteristics for ensuring safe and efficient handling during production thereof and formulation into final forms, since they are unstable (acetate, maleate) and possess undesirable hygroscopicity.
Furthermore their formation by crystallization from both aqueous or non-aqueous solvents is generally low-yielded and troublesome as they usually contain an undefined and unpredicted amount of bound solvent which is difficult to remove.
The crystalline paroxetine hydrochloride hemihydrate approaches these problems, but as stated in WO 95/16448, its limited photostability causes undesired colouration during classical wet tabletting procedure.
Moreover, crystalline paroxetine hydrochloride hemihydrate exhibits only limited solubility in water.
It has been generally suggested that where the aqueous solubility is low, for example less than 3 mg/ml, the dissolution rate at in vivo administration could be rate-limiting in the absorption process. The aqueous solubility of the paroxetine hemihydrate at room temperature exceeds this threshold by a relatively small margin."
- a typical (for a patent) class. The substitutents R, R1, R2, and X are each a specified range of chemical groups, the details of which do not matter. Synthon
then go on to specify the advantages of their invention:
"The inventors have found that these compounds exhibit good stability and very high solubility. This yields the advantage that high concentrations of the compound are obtainable in small volumes."
"The compounds can have a solubility at about 20oC of at least about 10 mg/ml water, preferably having a solubility in water of at least 100, for example 500 and most preferably of at least 1000 mg/ml water."
That is a very high solubility - about as much compound as water.
"The compounds of the invention can be prepared from the free base of the 4 phenylpiperidine, having the formula II, this preferably being paroxetine, by treatment with a sulfonic acid as defined above in a suitable solvent to form a solution of the desired acid addition salt, whereafter this is precipitated out of the solution."
"The forming of a solution may preferably proceed at temperatures from about 0oC to the boiling point of the solvent."
"A seeding crystal of paroxetine methane sulfonate was made as follows:
2.7 g (8.2 mmol) of paroxetine was dissolved in 15 ml of hot ethanol.
1.0 g (10.4 mmol) of methanesulfonic acid in 15 ml of ethanol was added and the mixture was cooled to room temperature. When the mixture had reached room temperature the mixture was put in the freezer at -20oC overnight. No crystalline compound was obtained.
The mixture was evaporated to dryness leaving an oil.
After 1 month at room temperature a waxy solid was obtained.
Part of this solid was taken apart and the rest was dissolved in 10 ml of EtOAc. The waxy crystals were added and the mixture was put in the freezer of -20oC overnight. A white crystalline product was precipitated.
After filtration and drying in a vacuumoven 2.5g (5.9 mmol) of paroxetine methane sulfonate was obtained. Yield 72%"
531, 546, 777, 838, 931, 962, 1038, 1100, 1169, 1208, 1469, 1500, 1515, 1615, 2577, 2869, 2900, 3023
"The compounds of the invention are crystalline, with defined melting points, DSC curves and IR spectra. It cannot be excluded that, under different conditions of their formation and under specific conditions, they could exist also in other crystalline or polymorph modifications which may differ from those as described herein. The compounds of the invention are also generally very stable and non-hygroscopic."
A comparison between the Synthon
and SB patents on their face
(1) Synthon
is concerned with a wide class of compounds whereas SB with just one;
(2) However Synthon
is particularly concerned with paroxetine mesylate
(3) In their general teaching neither patent indicates any particular difficulty with either making the compounds or crystallisation from an unseeded reaction mixture. Indeed both suggest the contrary by referring to a wide range of reaction and crystalline conditions.
(4) In particular so far as general teaching goes both disclosures in effect say that the specific solvent used does not matter. Synthon
says use a "suitable solvent", SB give a long list of "commonly used" solvents for paroxetine base.
(5) In the specific examples where paroxetine mesylate is made by the reaction between free base and sulfonic acid and crystallised out without seeding, Synthon
use ethanol as the solvent whereas SB use toluene as well as other solvents.
(6) Ethanol is a solvent specifically mentioned by SB as suitable for "mobilising" (i.e. dissolving) paroxetine free base.
(7) The only hint of any difficulty in crystallisation is in the Synthon
example - the fact that the reaction mixture took a month after evaporation to dryness to "obtain a waxy solid" would suggest to the skilled man that he may have problems in crystallisation.
(8) The reported IR spectra are different. The differences are, as is common ground, such that the skilled reader would take the two parties to have made different crystalline forms. He would not however know why there were different forms or what made one form rather than the other.
(9) Neither patent suggests that the particular crystalline form is what matters.
Is the Synthon
example repeatable?
"This is the procedure under the "Experimental" heading in theSynthon
Patent …."
A. If someone had told us or if he [Dr Adlington] had been smart enough to realise that ethanol and methanesulfonic acid give ether and water, we could have run the NMR spectrum on the following day after the (inaudible) experiment.
Q. If you had been smart enough to realise?
A. Yes. We were not smart enough to realise that.
Does the Synthon
specification enable the making of paroxetine mesylate crystals?
Q. If you were looking at this document and considering making paroxetine mesylate, you would certainly start with the examples. That is right, is it not?
A. Yes, yes, I certainly would.
Q. But you certainly would not feel bound by them, would you? You would expect to make paroxetine mesylate using a variety of other reactions and conditions?
A. Yes, I think I would.
Q. And crystallize it successfully?
A. That is perhaps another matter. I think I might be inclined to say, "Once I have actually got some sort of crystals, then I might investigate a better way of making crystalline material." In order to get your seeds, then it might be sensible to do what is in the document rather than go shooting off and doing your own thing.
Q. I think we agree you would start with the examples. You start with the examples. Let me assume that you perform "Experimental" and it does not work. What do you do next?
A. I think I would do the sort of thing that I have mentioned in my expert report. I would look at the chemistry that I was trying to carry out and say, "Well, maybe I need to make some changes." I think I have suggested the sort of changes I would make. I might well readjust the stoichiometry, the molar equivalents.
Q. And you would get a hint that that might be a good idea from looking at example 1, would you not?
A. You might and you might not. I am not necessarily convinced by that. In my experience of making salts of bases, it is sometimes actually advantageous to make the first sample with an excess of acid. This is frequently done with things like hydrochloride salts. I am not necessarily convinced that you would necessarily always go down in molarity.
Q. You might go up?
A. You might go up, yes. You might change the concentration; you might change the solvent.
Q. But these would all be straightforward changes, and you would expect, fairly quickly, to succeed, based on what is in this document?
A. I would certainly have an expectation of success, yes.
Q. Let me put this to you. Based on what is in the SB patent, you would come to exactly the same conclusion, would you not?
A. Yes. I think you are asking me a slightly different question. I think when we started on this, you said clear your mind of all the information you have and let us talk about this document.
Q. I am now asking you a different question.
A. Right.
MR. JUSTICE JACOB: I think he is now asking you to put the Synthon
patent out of your mind and the SB patent and supposing you had not been the inventor and it was given to you.
A. Yes. I agree that in that position I would have the same expectation, yes.
What sort of crystals are enabled?
I say that for a number of reasons:
(a) Synthon
have, notwithstanding searches, not found any IR spectrum print out or result which has anything other than the "SB" spectra.
(b) Synthon
have got a number of other IR spectra made from other, subsequent, batches of crystalline paroxetine mesylate. These all have the same IR spectra. Mr Benneker was indeed looking for evidence of polymorphism - but found none. This was well before anyone had any inkling of this dispute.
(c) Given the common ground as to the effect of seeding it is probable that all the later samples have the same crystalline form as the original. It was with experimental that Mr Benneker's laboratory lost its virginity – to the SB form.
(d) Mr Benneker was "quite sure" that "pot.mes" was the original chart of the IR for Experiment 1. He made two IRs and they were together, where they should be in his records.
(e) No one has ever made any other polymorph.
(a) that it is a pity Mr Benneker was not more meticulous in his records. He himself agreed that was regrettable that was so.
(b) a scientist might well say there is not enough evidence here to "prove" that there is only one polymorph. But a judge's job is not that of a scientist. He has to come to a firm result. He works in 0's and 1's, choosing between them on a balance of probability no more.
The Law and its application here
"To determine whether a patentee's claim has been anticipated by an earlier publication it is necessary to compare the earlier publication with the patentee's claim. The earlier publication must, for this purpose, be interpreted as at the date of its publication, having regard to the surrounding circumstances which then existed, and without regard to subsequent events. … If the earlier publication, so construed, discloses the same device as the device which the patentee by his claim, so construed, asserts that he has invented, the patentee's claim has been anticipated, but not otherwise.
The earlier publication and the patentee's claim must each be construed as they would be at the respective dates by a reader skilled in the art to which they relate having regard to the state of knowledge in such art at the relevant date.
If the prior inventor's publication contains a clear description of, or clear instructions to do or make, something that would have infringed the patentee's claim if carried out after the grant of the patentee's patent, the patentee's claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated.
If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to what the patentee claims to have invented: Flour Oxidising v Carr ((1908) 25 RPC 428 at 457, line 34, approved in BTH v Metropolitan Vickers (1928) 45 RPC 1 at 24, line 1). A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee."
[43] A claim can be anticipated in two ways. First, if the prior art describes something falling within its scope then, assuming that it is enabling, the claim is anticipated. In such a case it is not necessary to carry out experiments, or give evidence of what would have happened if the prior art was put into practice, because it already describes what it achieves. Expert evidence may be needed to explain the terminology used because the prior art may be written in technical language which is different to that used in the patent. The patentee may decide that the only way to avoid anticipation, other than by amendment of his claims, is to demonstrate that, notwithstanding its disclosure, the prior art is not enabling. He can do this by proving that what is described could not be achieved on the basis of the disclosure. Such proof would be secured by expert testimony, perhaps supported in some cases by experiments.
[44] The second way of proving anticipation is by showing that the inevitable result of carrying out what is described in the prior art would be a product or process falling within the scope of the claim. The classic statement on this issue is contained in the judgment Sachs LJ in General Tire [quoted]
[45] The second paragraph in this quotation points out the difficulty faced by someone trying to prove anticipation by this route. A disclosure which is 'capable' of being carried out in a manner which does not fall within the claim, does not anticipate - although it may be a basis for an obviousness attack".
"Clearly the differences are fairly trivial. But obviousness is irrelevant. The problem is whether the differences are on the lack of novelty side of the borderline between the two conceptions. Mr. Thorley says they are not, relying on the well-known statement of principle in General Tire:
'To anticipate the patentee's claim the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented."
Mr. Kitchin, for Valmet, says they are, relying upon the equally well-known statement of Lord Westbury in Hills v. Evans (1862) 4 De G.F. & J. 288 at 301:
'The information given by the prior publication must, for the purposes of practical utility, be equal to that given by the subsequent patent."
Mr. Kitchin says the Japanese application discloses four sections. So, for practical purposes it discloses to the skilled man that he could have more if he wanted. Likewise it is clear that one can have the first inverted section after the first or second section (or indeed further sections). He is told all he needs to know by the Japanese document.
Both the General Tire and the Hills v. Evans formulations have recently been held applicable to anticipation (lack of novelty) under the 1977 Act, see Asahi per Lord Jauncey at 543. But that was in rather a different context: whether the information given had to be "enabling". Here I am really concerned with scope of claim. I think the test is whether the Japanese specific embodiment would fall within claims 12 and 13. If it would, the claims are not novel, if it would not, they are. Lord Westbury's statement, made in a context where the distinction between anticipation and obviousness did not matter, is not concerned with the case where an artificial line has to be drawn, as section 2(3) requires."
"Neither does [the citation] which is to be taken into consideration with regard to Article 54 EPC , take away the novelty of the valve according to Claim 1. The appellant conceded that the whole content of this document including any features implicit to a person skilled in the art failed to disclose a valve which comprises completely the features mentioned in Claim 1. He is, however, of the opinion that the 'whole contents' of an older document within the meaning of Article 54(3) EPC comprise features which are equivalents to the features according to the document. In support of his view he refers to the EPC and Part C, chapter IV, 7.4, of the Guidelines.
The Board cannot agree with this point of view on the following grounds: In order to mitigate the harsh effects of the 'whole contents approach', its application is confined to novelty (cf. Article 56 EPC, second sentence). Further, in order to reduce the risk of 'self collision' it has always been considered justified for a strict approach to novelty to be adopted. For this reason, Part C, chapter IV, 7.2, of the Guidelines expressly states that when considering novelty, it is not correct to interpret the teaching of a document as embracing well-known equivalents which are not disclosed in the document; this is a matter of obviousness. This approach has been consistently followed in the practice of the European Patent Office and the appellant completely failed to satisfy the Board that it is wrong on any ground."
"Section 2(2) 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."
"3. A closer examination should begin by focusing on the wording of the relevant provisions. Under Art.54(2) EPC (and the relevant provisions of the national patent laws) any matter is novelty-destroying which has been made available to the public "by means of a written or oral description, by use, or in any other way". This clearly goes beyond a written or diagrammatical description; the content of the information, not the form in which it is imparted, is decisive. This allows a number of conclusions to be drawn, some of which also find expression in EPO jurisprudence.
(a) The information may to a certain degree be hidden, provided the skilled practitioner would ultimately be able to discover it without undue effort. The language used is irrelevant. It may even be a computer language. The chemical composition of a product that has been made available to the public also forms part of the state of the art if the skilled practitioner is able to analyse it. Conversely, disclosure of a process also discloses its inevitable result.
(b) Furthermore, matter will have to be viewed as also having been disclosed which the skilled practitioner is required to add from his technical knowledge as a matter of course or as being virtually essential to carrying out a given teaching.
Let us consider a simple example: A cook who finds that a soup being prepared from a recipe is lacking in flavour may well add salt, regardless of whether the recipe makes any mention either of adding any salt at all, or of adding a smaller amount than actually used. The addition of salt does not result in a new recipe. Quite the reverse: to a person skilled in the art it is so obvious as not to warrant particular mention."
"4. The practice of taking a broad view of the disclosed content of a particular item of prior art is supported by the fact that the content of an earlier, unpublished patent application is also viewed as comprised in the state of the art (Art. 54(3) EPC).
This meets the requirements of the Strasbourg Convention of 1963 (Arts. 4(3) and 6) and is intended to prevent matter from being patented that is already, or could become, the subject-matter of another patent. In that respect it does not genuinely contribute to the advance of the state of the art, and hence there is no objective justification for rewarding it with the grant of a patent. Added to which, double patenting clouds the legal position and is therefore undesirable.
It would be to ignore this legislative imperative if inventions exhibiting only the slightest of differences were to be described as "new". (Further) patents would then have to be granted for subject-matter which, although not literally anticipated, would predictably fall entirely or primarily within the scope of protection of an earlier patent, scope which should, however, remain the exclusive preserve of the owner of the prior right. Were this not so, we would have no way of effectively restricting double patenting.
It would therefore seem consistent to regard an earlier patent application as simultaneously anticipating, so as to be novelty-destroying, the entire range of subject-matter which it could conceivably cover, and in particular all possible equivalents. In fact, this view is encountered not infrequently in the relevant literature."
"6. One could argue about a number of points, and it will not always be possible to decide cases on logical grounds alone. We should not however lose sight of two things:
- Examination as to novelty should not be restricted to a purely formal comparison with known prior art, but must include the actual information content which goes beyond the words used.
- Earlier applicants must be given reasonable scope to defend their inventions."
"I do not accept [the petitioner's] argument that there is a double test of enablement. In the passage from his speech in Asahi quoted above, Lord Jauncey was not purporting to set such a test. He was only saying that describing a result as being achieveable was not enough to prove it to be achievable in fact. It is the latter which amounts to enablement. Nor was such a test being proposed in Schering or Beloit. As Lord Hoffmann said at page 47 in Asahi, the requirement of an enabling disclosure in a patent application is a matter of substance not form. Therefore, to this extent, I accept [the patentee's] argument. The reader will not necessarily be misled by incorrect nomenclature or other errors of description in the priority document. I think [the patentee] is right when it says that it is sufficient if the document sets out the useful properties of the technical advance and identifies a practical route which achieves it. That does not mean that the general description in the priority document is to be ignored and only the examples looked at. The priority document must be read as a whole. Its general description is no less a part of the technical content than the examples it contains."