According to Prof Black - and as clearly seems to be the case - Dr Simpson's miscalculation produced the result that there was a molar excess of ethyl α,α-dimethylphenylacetate over 4-chlorobutyl chloride in the reaction under Example 5(A).
70 According to the respondents, the result of Dr Simpson's miscalculation was that the final product obtained under Example 5(A) contained an excess of starting material. It was the view of the experts called on behalf of the respondents that this circumstance, alone, was sufficient to explain Dr Simpson's inability to obtain something that would be satisfactory starting material for Example 5(B). Although AMR contested that latter proposition - and submitted that the material obtained by Dr Simpson from Example 5(A) was little different from that obtained by Mr Gugger - it did not contest the proposition that Dr Simpson had made the miscalculation to which the respondents' experts referred. AMR did not go to the extent of accepting that the result of that miscalculation was that Dr Simpson ended up with more unreacted starting material than might otherwise have been present, but I accept the evidence of the respondents' experts that this was the case. Indeed, under crossexamination Dr Simpson himself accepted that his miscalculation would have accounted for an excess of starting material, at the completion of the synthesis under Example 5(A), of the order of 13%, which might have had an impact on the result.
71 In his affidavit of 22 January 2010, Dr Robertson referred also to "the quality of aluminium chloride used". He noted that Dr Simpson had weighed the aluminium chloride into an open beaker, and then transferred it by spatula to the reaction vessel. When Dr Simpson was under cross-examination by counsel for the Sigma respondents, he estimated that the aluminium chloride would have been exposed to the normal atmosphere in his laboratory for about 45 minutes (this time having been made longer than it might otherwise have been, by reason of the time taken by Dr Simpson to allow the temperature of the reaction vessel to adjust to -10 °C, after it had initially fallen to -30 °C). Dr Robertson noted that aluminium chloride was "highly hygroscopic", and would take up atmospheric moisture. In his opinion, this would affect the work of the aluminium chloride as a catalyst in the intended reaction. In his affidavit of 6 February 2009 (filed well before Dr Simpson had carried out his experiment), Prof Black referred to the importance of preventing water from entering the system in carrying out Example 5(A), and said that, if the reaction in the example did not otherwise work, he would consider carrying it out "in an anhydrous environment such as a nitrogen glovebox". However, Prof Black did not refer to this aspect in his criticism of Dr Simpson's first experiment. Because the respondents were, it seems, generally content to point to the calculation errors made by Dr Simpson in his first experiment, the hygroscopicity problem is more appropriately dealt with in the context of a second experiment carried out by Dr Simpson, to which I next turn.
72 Subsequently, and after affidavits setting out the respondents' criticisms of Dr Simpson's experimental protocol had been filed, AMR's solicitors asked Dr Simpson to prepare a second protocol, in which the inconsistency referred to in para 61 above was resolved by specifying the use of 48.4 g (0.252 mole) of ethyl α,α-dimethylphenylacetate. He did prepare such a protocol, and set about conducting an experiment in accordance with it. Under Example 5(A), when he reached the stage of stirring the 4-chlorobutyryl chloride and aluminium chloride for 15 minutes, he found that ambient temperature in his laboratory was below 25 °C. Accordingly, he used a temperature-controlled water bath to maintain the reaction mixture at 25 °C. He employed the same expedient at the point where the reaction mixture was stirred for 15½ hours, although, since this was done overnight, it turned out to be 16 hours and 20 minutes. At the end of Example 5(A), Dr Simpson had, as before, a brown oil rather than a solid.
73 Dr Simpson analysed the oil which he had obtained. His LCMS analysis was consistent with the presence of the product which should have resulted from carrying out Example 5(A). However, there were also present other ions of different masses which he was not easily able to explain. Under 1H NMR, Dr Simpson noted that there were three peaks at a point where, had the product contained a single compound only, he would have expected to see one peak. This suggested to him that there was more than one compound present in the material which had "two methyl groups bonded to the benzylic position of the phenyl acetate". He interpreted the 1H NMR results as indicating the presence not only of the desired product of Example 5(A) but also of the starting material and at least some amount of the meta regioisomer of the desired product. The three major compounds in the material were present in proportions of 2.0:2.5:1.0, which Dr Simpson interpreted as the meta regioisomer, the desired product of Example 5(A) and unreacted phenyl acetate starting material, respectively.
74 Having again modified his experimental protocol to accommodate the fact that he was commencing with an oil rather than a solid, Dr Simpson again embarked upon Example 5(B). As before, things seemed to have gone in accordance with what was contemplated in the example until the point which follows the addition of ethereal hydrogen chloride. At this point, the precipitate which Dr Simpson obtained "coalesced into lumps of a sticky solid". He filtered this solid, but, due to the sticky nature of the material, a complete transfer was not possible and an amount of the material remained on the filter paper. Dr Simpson analysed this material, and again concluded that unwanted regioisomeric forms of the desired product were present, together with the desired product itself.
75 In the recrystallisation stage of Example 5(B), Dr Simpson added hot methanol to approximately 4.21 g of the material which he had until it was completely dissolved, then added hot butanone. After the addition of approximately 100 ml of butanone, there was still no apparent cloudiness to the solution, and no indication that any solid was going to crystallise out. Dr Simpson then performed a hot filtration of the solution, and left it to cool to room temperature. That did not result in the formation of crystals. He then attempted to induce the formation of crystals by placing the solution in a refrigerator overnight, but that too failed to produce crystals. He cooled the solution to approximately -78 °C, but again no crystals formed. Using a rotary evaporator, Dr Simpson evaporated the solvents, and made a further attempt to recrystallise the material using less solvent. He dissolved the material in a minimum amount of hot methanol (approximately 20 ml) and then added 60 ml of butanone. However, again no cloudiness was apparent. Cooling of the solution to room temperature did not result in the formation of crystals. Finally, Dr Simpson placed the solution in a refrigerator overnight. The following morning a small amount of a fine white powder had formed. Dr Simpson filtered this powder and analysed the filtered material. Various analyses which Dr Simpson undertook of this powder suggested the presence, in significant proportions, of material other than that desired at the end of Example 5(B). Indeed, Dr Simpson thought it most likely that the white powder was principally the hydrochloride salt of the α,α-diphenyl-4-piperidinemethanol starting material.
76 As with his first experiment, Dr Simpson considered that, if he were to isolate the desired reaction product from the material which he obtained under Example 5(B), it would be necessary for him either to develop, by experimentation, a new solvent system or to consider other purification techniques. Save for the variations in the ratios of the products produced, Dr Simpson considered that the results of his second experiment were consistent with those of his first experiment. He did not carry out Example 2 or Example 3.
77 In his affidavit of 18 November 2010, Prof Black expressed his view that, in his second experiment under Example 5(A), Dr Simpson had failed to observe anhydrous conditions when handling 4-chlorobutyryl chloride and aluminium chloride. He said that 4-chlorobutyryl chloride was "a very moisture sensitive compound which will hydrolyse when exposed to water in the atmosphere", and that precautions to avoid the ingress of moisture were essential. Although Dr Simpson had taken some precautions, he weighed the 4-chlorobutyryl chloride into a glass beaker, and transferred it through a funnel into a flask, in the atmosphere present in the laboratory. The result, according to Prof Black, would have been that less of the compound was available to participate in the reaction. This meant that less of the 4-chlorobutyryl chloride would be available in the reaction, and that less of the ethyl α,α-dimethylphenylacetate would react. Prof Black said that, at the end of the reaction, unreacted ethyl α,α-dimethylphenylacetate would remain in the system.
78 Prof Black added that aluminium chloride also had a high affinity for water and was easily hydrolysed in the presence of moisture. He considered it to be a fundamental procedure when carrying out Friedel-Crafts acylation reactions using aluminium chloride to ensure that it was kept dry and not exposed to the atmosphere. He noted that Dr Simpson had weighed out the aluminium chloride in the laboratory atmosphere in a 250 mL beaker, and then added it to the reaction vessel in portions by spatula. In Prof Black's view, this would have permitted adventitious water to enter the reaction system.
79 Dr Robertson expressed a like opinion. He said that it was well-understood that a successful Friedel-Crafts acylation required dry conditions. While Carr 129 did not expressly state that the chemical synthesis of Example 5(A) should be conducted in a moisture-free environment, a person skilled in the art at the priority date would readily have understood that such an environment was required. Dr Robertson said that aluminium chloride was highly hygroscopic, and should be protected from moisture at all times because it readily converted into aluminium hydroxide when exposed to an open environment. Once converted to aluminium hydroxide, it ceased to function as a catalyst and would not be useful in driving the required reaction. He said that the techniques employed by Dr Simpson were not appropriate for conducting a reaction in anhydrous conditions.
80 Dr Simpson accepted that he had not handled the aluminium chloride or the chlorobutryl chloride under anhydrous conditions in either of his preparations. The period during which the aluminium chloride was exposed to the normal atmosphere in the laboratory (air conditioned though it was) was much less in the second preparation than in the first, since, on the second occasion, there was no need to wait while the contents of the reaction vessel, at the point of adding the aluminium chloride, reached the required temperature. On the first occasion, Dr Simpson had been able, by observation, to estimate that about 20% of the aluminium chloride had hydrolysed before it was used in the reaction. No such clear indication was available on the second occasion. Nonetheless, the observations made by Prof Black and Dr Robertson to which I have just referred related to the second preparation, and in point of principle, there was no satisfactory rebuttal of them offered either by AMR or, indeed, by Dr Simpson.
81 It was, however, submitted on behalf of AMR that, as a matter of construction, Example 5(A) did not require the employment of anhydrous conditions. Reference was made to isolated phrases in the text of another example in Carr 129 where procedures were required to be carried out "under a nitrogen atmosphere". I must say that I do not find this a satisfactory response to the respondents' criticism of Dr Simpson. The issue is not one of construction at all. Quite clearly, Example 5(A) does not, in terms, require the employment of anhydrous conditions: the question is whether the skilled addressee, reading the terms of that example, and knowing what he or she ought to know about the characteristic of the reagents and the catalysts used, would take the customary steps to avoid such ingress of adventitious water as would compromise the reaction. His or her approach would, in my view, be more likely to be based upon scientific understanding rather than upon a grammatical construction inspired by the absence from the text of Example 5(A) of words found in possibly analogous situations elsewhere in the patent.
82 AMR next submitted that it was not "standard practice to handle acid chlorides (ie chlorobutyryl chloride) under nitrogen". However, the evidentiary basis for this submission was the evidence of Dr Simpson himself, in the following passage of his crossexamination by counsel for the Sigma respondents:
Had you used chlorobutyryl chloride before? Not that I recall.
So you didn't have any experience as to the extent to which it was hydroscopic in fact? I have in the past used a number of acid chlorides, so I assumed that it would behave similarly to those.
Why did you not then handle it under nitrogen? As far as I'm aware, it is not standard practice for people to handle acid chlorides under nitrogen all the time.
To the extent that adventitious water did enter it, what would be the consequence? The acid chloride would be hydrolysed to the corresponding carboxylic acid.
What impact would that have on the conduct of the reaction? The carboxylic acid is unlikely to take part in the FriedelCrafts reaction.
So it would again exacerbate the excess of starting material and the reduction in the catalyst to the extent that the aluminium chloride itself had hydrolysed? …. Yes, that may contribute to the remaining phenyl acetate starting material at the end of the process.
In the circumstances, I am not prepared to accept that this submission on behalf of AMR satisfactorily deals with the criticism of Prof Black and Dr Robertson.
83 AMR's next response related to the chlorobutryl chloride only. Attention was drawn to the fact that, under crossexamination, Prof Black had said that a scientist's failure to use a nitrogen glove bag when handling that material would be a matter of "gentle criticism" only. The gentleness of the criticism was based upon the fact, according to Prof Black, that the scientist would "lose a little bit" of the material in the reaction, with the result that the yield could be reduced. Essentially, this was the same evidence as that given by Dr Simpson, as set out above. Clearly the latter's omission to handle the chlorobutryl chloride anhydrously was a relatively minor circumstance affecting the outcome which he achieved, but circumstance it was. As Prof Black said, it was the aluminium chloride which was critical apropos the ingress of adventitious water.
84 Turning then to the aluminium chloride, the gravamen of AMR's case was that this catalyst was present in considerable excess, and that it would have taken very much more adventitious water than could ever have been attracted in the short time (in Dr Simpson's second preparation) that the material was exposed to the atmosphere for sufficient of it to be hydrolysed to compromise the reaction taking place under Example 5(A). However, the evidence on which AMR relied for this submission was that of Dr Simpson himself:
There are something of the order of two molar equivalents of aluminium chloride and I believe that one molar equivalent is required for a FriedelCrafts reaction. So that would mean half of the material will have to be hydrolysed for the reaction to not occur effectively.
But the position does not seem to be so simple, under the particular Friedel-Crafts acylation with which Dr Simpson was concerned. The reason for the specification of what appeared to be two molar equivalents of aluminium chloride in Example 5(A) became clear only when Dr Robertson was under crossexamination. He said that two molar equivalents of the catalyst were actually required in this reaction, because there was a chlorine atom at both ends of the chlorobutryl chloride. He said:
Yes, you need two molar equivalents. Although it is described as a catalyst and it is sort of regenerated in the reaction, you need one mole of aluminium chloride at the lefthand side of the chlorobutyryl chloride and one mole at the righthand side of the chlorobutyryl chloride. So your Stoichiometry is 2:1, at least that is how I understand the reaction going at this point.
Dr Robertson was crossexamined extensively as to his understanding of the stoichiometry involved in this reaction, but this evidence was not undermined. In the course of that crossexamination, Dr Robertson calculated that, with 0.254 mol of chlorobutryl chloride, 0.508 mol of aluminium chloride would have been required to give the two molar equivalents which he perceived to be necessary. The example specified 0.56 mol, which provided for what he described as "a small excess".
85 I accept Dr Robertson's evidence in these respects. It casts a light on an important aspect of Example 5(A) which has the potential to be relevant to the hygroscopicity problem. Understood in the light of this evidence, the example does not require the use of double the amount of catalyst than ought to be needed: it requires the use of only a small amount more. It follows that the problem of adventitious atmospheric water cannot be sidestepped by the robust approach proposed by AMR. A small amount of water would have had the real potential to reduce the effective amount of catalyst available below that which would have been necessary to achieve a successful reaction.
86 In the circumstances, I do not accept that it is established by the work of Dr Simpson that the synthesis of fexofenadine described in Carr 129 does not work. It is true that Dr Simpson's experiments did not work, but, in the respects discussed above, that was likely to have been at least partly the result of shortcomings in his experimental methods. It became clear during the trial of the proceeding that Dr Simpson's first attempt at Example 5(A) was in fact the first time that he had carried out a Friedel-Crafts acylation. Had his second attempt been beyond criticism experimentally, that might not have been a matter of concern. However, as discussed above, I am not satisfied that the ingress of adventitious water on the second occasion did not carry the real potential to compromise the viability of the catalyst being used. That being the case, there is a legitimate scientific explanation for Dr Simpson's failure to obtain fexofenadine under Carr 129, such that that failure cannot stand as conclusive proof that the methods specified therein do not work.
87 I turn next to the attempts which scientists engaged by Alphapharm made to synthesise fexofenadine using the methods set out in Carr 129. Prof Wild was asked by Alphapharm to prepare 4-[4-[(4-hydroxydiphenylmethyl)-1-piperidinyl]-l-hydroxybutyl]-α,α-dimethylbenzeneacetic acid, adhering as closely as possible to the experimental detail set out in Examples 5(A), 5(B), 2 and 3 of Carr 129, and following procedures appropriate to the facilities available in 1993. Commencing on 11 August 2008, Prof Wild directed Mr Gugger to carry out this work, giving him a copy of Carr 129. Mr Gugger has a BSc degree in Applied Chemistry from the University of Canberra (then the Canberra College of Advanced Education) and has worked in Prof Wild's group as a synthetic chemist since 1980. Prof Wild considers Mr Gugger to be an "extremely competent chemist", observing that "he is diligent in his record keeping and meticulous in his experimental work".
88 For much of the time that Mr Gugger was carrying out this work, Prof Wild himself was on sabbatical leave in Germany. However, before he left he had detailed discussions about the project and technical aspects of the experimental work with Mr Gugger. While he was away, Prof Wild kept in regular contact with Mr Gugger about the work that was being done. Prof Wild described Mr Gugger as "an outstanding photographer … [who] routinely took photos of the equipment and experiments he undertook, which he … sent to [Prof Wild] so that [Prof Wild] could review the steps taken".
89 Prof Wild received his instructions from the solicitor handling the matter on behalf of Alphapharm, John Cusick, by email on 1 July 2008. Attached to the email were two documents: Carr 129 and a single-page "handwritten synthesis", setting out diagrammatically a system for the preparation of terfenadine carboxylic acid (ie fexofenadine). That demonstrated that the result of Example 5(A) would be the para regioisomer, but providing, at the end Example 3, an alternative outcome which suggested that the meta regioisomer would co-exist with the para regioisomer in proportions of about "50:50". It was put to Prof Wild under cross-examination that he "knew from that moment, by reason of that consideration of that synthesis, that there was, if not a certainty, a likelihood of repetition of example 5(A) producing a mixture [of the para and meta regioisomers]". He rejected that suggestion, accepting only that, "[i]n someone's opinion, that was considered a possibility". He also said that he did not recall "taking any notice of the diagram".
90 Whether or not prompted by Mr Cusick's diagram, the fact is that the first (relevant) page of Mr Gugger's laboratory notebook contained diagrams of the reactions involved in the example which, according to Prof Wild, reflected the discussion which he had had with him. Showing only so much as indicated the expected reaction products, those diagrams were as follows:
Mr Gugger was not called, and I think it proper to infer from these diagrams that he set about carrying out Example 5(A) with the anticipation that a mixture of regioisomers might well be the result. I infer also that that anticipation had its basis in the detailed discussion which he had had with Prof Wild. As for the latter, I accept that it was his expectation that a mixture of regioisomers might be the result (see para 52 above), and I also accept his denial that he was influenced in coming to this view, by the attachment to Mr Cusick's email of 1 July 2008.
91 Mr Gugger carried out Example 5(A) on 11 and 12 August 2008. There was no suggestion by the respondents that he did not do so according to Carr 129. However, the material which he produced did lead to controversy. Instead of being a solid as indicated in the example, Mr Gugger's product was an orange oil. On 13 August 2008, he communicated with Prof Wild (by then overseas), informing him of this fact, and stating that he would start the next reaction (Example 5(B)) the following day, a Thursday, since it required 72 hours of reflux and could be worked up on the Monday. Mr Gugger's comment to Prof Wild was that an oil was "usual for crude products of Friedel-Crafts reactions".
92 Mr Gugger sent the same communication to Mr Cusick. In reply, Mr Cusick noted that Example 5(A) was supposed to yield a solid, not an oil, and asked Mr Gugger to discuss the 1H NMR details of the oil with him before proceeding further. Mr Gugger replied that it was not unusual for the oil to take a few days to crystallize, and attached to his email the 1H NMR spectra and the mass spectrum details for the oil. He concluded that he had "a mixture of mainly ortho, meta[,] para isomers but apart from that not a lot of side products". He asked Mr Cusick whether he should place the oil sample in the refrigerator or "just wait". It seems that the former expedient was resorted to for a part of the sample, since Mr Gugger's laboratory notebook records that a portion of the oil was placed in a freezer at -15 °C for a week, but it did not crystallise.
93 It took Mr Gugger some time to analyse the oil which he obtained from Example 5(A). On the basis of gas chromatography and mass spectrometry ("GCMS"), on 15 August 2008 he informed Prof Wild and Mr Cusick that about 42% of the product did not constitute isomers of the molecule intended to be derived from the example, and that the product was, therefore, "rather impure". The other 58% (or "about 60%" as Mr Gugger put it) was considered to be made up of isomers of the desired molecule, in the percentages of 1:46:53, but it was not clear to Mr Gugger which was which. He hoped that the 1% component (actually 0.9%) was the orthoregioisomer. Prof Wild's response, also dated 15 August 2008, was as follows:
The GC MS idea was a good one and it seems to have given a credible result at 0.9:46:53 for the isomers of 5a. Any chance of correlating these values with the 1H NMR spectrum - integration of CMe2 peaks in 500 MHz spectrum? It will be interesting to see if you can get a fractional crystallization. Nevertheless, as I said in my comments to John, press on to the next step with 4.5g and hope for the best. If you can get some crystals at that stage with the right mp, NMR, etc., we might try for an X-ray structure. Keep up the good work and good luck.
94 On 21 August 2008, Mr Gugger sent an email to Mr Cusick, informing him that he had run a proton spectrum on the 5(A) oil, using a 500 Mhz NMR machine. Using that information and the results which he had from GCMS, Mr Gugger expressed the view that there was "a classic ortho/para splitting pattern", and that the percentages of the regioisomers were meta (1%), ortho (46%) and para (53%). However, on the following day, Mr Gugger told Prof Wild (by email) that he was "still wondering about the isomers" of Example 5(A), and proposed to "have a chat to Martin Banwell to work out a method to give an unambiguous assignment of the isomers".
95 It was not clear on the evidence when he did so, but at some point Prof Wild interpreted Mr Gugger's results as giving ortho (1%), meta (46%) and para (53%). In his affidavit sworn on 6 February 2009, Prof Wild provided the theoretical explanation which I have set out in para 52 above, and continued:
Accordingly, the ratios 1:46:53 are consistent with the presence of, respectively, the ortho, meta, and para regioisomers of the product. … The availability of two sites for meta substitution of the ring accounts for the high proportion of meta regioisomer observed.
As I understand it, Prof Wild's identification of the regioisomers in the 5(A) oil was done by inference from the information provided by the GCMS and the 1H NMR analyses which had been conducted.
96 Prof Easton did not accept that inference. He accepted that the three regioisomers were most probably present in the oil (along with various impurities), and he accepted that the data were consistent with Prof Wild's conclusion that the regioisomers existed in identifiable relative proportions each to the others, but he did not accept that the data warranted that conclusion. Dealing with the circumstance that three of the components of the oil had the same molecular weight, being the weight of the desired compound, Prof Easton said:
While it is correct that each of these regioisomers would have the same molecular weight, as do the three compounds analysed by MS, I do not consider that it is possible to definitively identify the three peaks of the GC trace as being these three regioisomers based on the MS analysis alone. One reason why it cannot be assumed that three compounds having the same molecular weight are the three regioisomers identified by Mr Gugger is that the chlorobutyryl chloride starting material used in this reaction is both an acylating and an alkylating agent. The acylation reaction will be preferred over the alkylation reaction and I would not have anticipated that alkylation would have occurred to any significant extent as part of this reaction. However, given that the reaction product appears, from the GC/MS analysis, to contain at least six compounds each present in a significant amount, I anticipate that alkylation may have occurred. The product of any such alkylation would have the same molecular weight as the desired acylation product.
Prof Wild took issue with this. In an affidavit in response, he said:
While the alkylation products … would have the same molecular mass as the acylation products, they would be hydrolysed to the corresponding acids in the hydrolytic workup (the reaction mixture is "poured into HCl-ice water") which have a different molecular mass …; therefore the alkylation products cannot be considered to be the reaction products seen in the GC MS of the product of Example 5(A).
Prof Easton did not rejoin. In the result, AMR did not ultimately contest Prof Wild's conclusion that the ortho-meta-para isomers were present in the oil in the relationship 1-46-53.
97 One point on which Profs Wild and Easton did agree was that the major component in the oil obtained by Mr Gugger from working up Example 5(A) was about 30% of the total composition of the oil. Prof Easton accepted that this was the para regioisomer.
98 Mr Gugger then proceeded to Example 5(B), using the oil which he had obtained under Example 5(A) as his starting material. AMR was critical of Mr Gugger - and of Prof Wild - for having proceeded to Example 5(B) notwithstanding that the product obtained under Example 5(A) did not correspond with that specified in the text. It was submitted on behalf of AMR that the balance of sound scientific opinion was that a chemist would not proceed beyond Example 5(A) unless he or she had derived the solid specified therein, or if he or she were confronted with the level of impurity that Mr Gugger then had. That was undoubtedly the view of Prof Easton. He said that using a starting material with that level of impurity was "highly likely to give rise to difficulties during subsequent steps in a synthesis" and that "proceeding with such material [was] not usual practice in organic chemistry".
99 AMR also relied on the evidence of Prof Black, in his affidavit of 6 February 2009, on this point:
If this reaction did not result in the expected outcome, I would assume that something had been done incorrectly, that there was a problem with the starting materials or water had entered the system. I would check the purity of the starting materials and repeat the experiment. I would also consider carrying out the reaction in an anhydrous environment such as a nitrogen glove box. However, the experiment described is entirely reasonable and rational and any initial difficulty would not lead me to doubt what was reported. I would repeat the experiment until satisfactory results were obtained, perhaps up to ten times, before considering an altemative approach. I would also routinely check the literature to see if a similar or identical reaction had been reported, and to see whether any similar problems had been reported.
However, it was not suggested by any party that further repeats of Example 5(A) by Mr Gugger would have produced anything closer to what was predicted by Carr 129. Indeed, the fact that this example led to a mixture of regioisomers was the inventor's starting point under the patent in suit. The issue here, rather, is whether Mr Gugger was justified in proceeding to Example 5(B) with the oily mixture of regioisomers. In Prof Black's view, he was. Here I refer to what I have said in para 46 above, which is based the same affidavit, and upon the following evidence in that affidavit:
As the product of the Friedel-Crafts acylation is a large molecule, I would generally expect it to be a solid, however I would not be surprised if the product was an oily liquid. An oil product may indicate that the product is impure, such that further purification may produce a solid or alternatively, the oil may be a pure liquid such that further purification will not result in the product solidifying. If the product was an oil, I would consider attempting to purify it using chromatographic separation. In any event, I note that the solvent initially used in the following step 5(B) is toluene which would readily dissolve an oily product.
100 AMR next submitted that "Dr Robertson certainly considered that the skilled addressee should not proceed to Example 5(B) with impure starting material where the desired reaction product was only present in approximately 30%". Perhaps the word "certainly" here is used in the sense of "on any view", since the evidence upon which AMR relied to make the submission related not to the work of Mr Gugger but to the work of Dr Simpson. What AMR seeks to do is to carry over the criticisms which Dr Robertson voiced of the latter to the context of the former, upon the basis that each had achieved about 30% of the desired compound after carrying out Example 5(A). However, the equivalence of the two exercises in presently relevant respects was not put to Dr Robertson, in which circumstances I am not prepared to read an implied criticism of Mr Gugger into his evidence.
101 Prof Wild justified his decision to instruct Mr Gugger to proceed to Example 5(B), notwithstanding the latter's achievement of an oil rather than a solid after 5(A), on two bases. First, he said that Friedel-Crafts reactions often generated oils that could take a considerable time to crystallise. Routine 1H NMR spectroscopic or HPLC analysis of the product could help to identify any impurities. He would recommend proceeding to the next step in the synthesis with impure material if purification proved difficult or crystallisation was slow. He said that it was sometimes easier to remove an impurity in a subsequent step of the synthesis. If the impurities could not be removed "downstream", it would still be possible to return to the earlier stage and to continue the attempted purification. Secondly, Prof Wild said that Example 5(A) was a large-scale synthesis requiring the use of 800 ml of carbon disulfide, 36.5 g of 4-chlorobutyryl chloride, 48.4 g of ethyl α,α-dimethylphenylacetate, and 74.5 g of aluminium chloride. He noted that carbon disulfide was carcinogenic and highly flammable. Mr Gugger's workup of Example 5(A) had given a product in high yield (89%), and Prof Wild did not want him exposed unnecessarily to large volumes of carbon disulfide.
102 One of the few advantages of Prof Wild's absence overseas while Mr Gugger was carrying out Example 5(A) is that it has provided a written record, of sorts, of communications between them that might otherwise have been both oral and informal. Copies of these communications were tendered by AMR. It did not appear to disconcert Mr Gugger in the least that he had an oil rather than a solid. Indeed, his first communication to Prof Wild was that an oil was usual for FriedelCrafts reactions. As noted above, Prof Wild was of a similar view. Indeed, under crossexamination, Prof Easton agreed that "it was quite frequent to see an oil in a FriedelCrafts acylation". In the light of this evidence, I would seem to be justified in concluding, as I do, that, were it not for the fact that Carr 129 specified that the product of Example 5(A) was a solid, the oily result achieved by Mr Gugger would have been quite uncontroversial amongst scientists skilled in the art.
103 Anticipating, not unreasonably, that the oil was probably indicative of the presence of impurities, Mr Gugger carried out GCMS and 1H NMR analyses to identify its constituents. Again, it could not be suggested that that was other than standard experimental practice in the circumstances which obtained. Although Mr Gugger himself was initially uncertain as to the identity of the regioisomers in the oil, Prof Wild, from the outset, regarded the percentages as credible. The existence of a mixture of regioisomers was consistent with his expectations from a reaction such as this; and it was consistent also with the physical properties of the material. Prof Wild and Mr Gugger knew that their object was to obtain a parasubstituted product. Their decision to use the oil as the starting material under Example 5(B) appears to have been a conventional scientific one, uninfluenced by any urgings from those instructing them. Indeed, Mr Cusick seems, if anything, to have been the one to sound a note of caution about proceeding further under those circumstances.
104 More importantly, perhaps, Prof Wild's decision to press on to Example 5(B) was based upon his perception of the kind of process that was involved in that example, and upon his expectation that it would have the potential to yield a parasubstituted product of greater purity. He said that he would -
… routinely proceed to the next step in a synthesis with an oil intermediate if it was known that the desired product of the next step in the reaction sequence could be purified. This is particularly the case if it was known - as is the case with the Example 5(B) Expected Product - that the next step should produce a high melting crystalline solid which would be much easier to isolate and purify.
Prof Wild added that the use of an impure oil as an intermediate was not an unusual approach in synthetic chemistry, particularly where the product of the next step was a high melting crystalline solid which would be easier to separate from impurities.
105 AMR also drew attention, critically, to the circumstance that, in trying to understand the outcome he was getting from Example 5(A), Mr Gugger referred to sources of information which postdated the 1993 priority date. In August 2008, having failed to obtain a solid, or pure parasubstituted material, from Example 5(A), Mr Gugger consulted a 2006 paper by Chen and others entitled "Synthesis and Biological Evaluation of a Novel Class of Rofecoxib Analogues as Dual Inhibitors of Cyclooxygenases and Lipoxygenases" ("Chen"). That paper described a Friedel-Crafts acetylation of ethyl phenylacetate which resulted in a mixture of meta and para regioisomers, and proposed a means of crystallising the para regioisomer by the use of hexanes-acetone. On 15 August 2008, Mr Gugger informed Prof Wild by email that he was "trying to crystallise a small amount of 5a from acetonehexane as suggested in the paper by … Chen". AMR submitted that this was an example of Mr Gugger straying beyond the confines of information that would have been available to a skilled addressee as at the priority date. Alphapharm's response was to point out that acetonehexane was not in fact used in any of Mr Gugger's attempts at Example 5(B), and that this (Chen-based) work should be regarded as no more than a "side experiment" which Mr Gugger undertook as a matter of interest. In the absence of Mr Gugger from the witness box, I am not prepared to make any inference as to his purpose in consulting Chen other than that sought by AMR, namely, that this was part of the trial and error process which he employed in his attempts to synthesise fexofenadine. In 1993, a scientist skilled in the art would not have had access to Chen. However, in the means which Mr Gugger in fact used to characterise or to resolve the 5(A) oil which he subsequently carried into Example 5(B), no resort was had to any information derived from Chen. I take the view, therefore, that ultimately nothing turns on Mr Gugger's recourse to Chen.
106 The question which presently arises for consideration is not whether a skilled addressee would necessarily achieve fexofenadine by following the examples in Carr 129. It is whether, Carr 129 having disclosed fexofenadine in terms, a skilled addressee would be able, using his or her general stock of knowledge and understanding, to achieve fexofenadine from the information contained in Carr 129. On the assumption - which, for present purposes only, I must make - that such a skilled addressee could otherwise have done so, I do not consider that his or her failure to derive a parasubstituted solid from Example 5(A) should be regarded as disqualifying, at least in a context in which he or she would, as I find, be unsurprised that a Friedel-Crafts acylation such as the one being employed here would yield an oil. In the present context, the examples in Carr 129 are not to be viewed as recipes, but rather as indications as to how the compound of interest might be synthesised by a skilled addressee. Against the understanding which such a person would bring to these examples, I do not consider that the prediction that the result of carrying out Example 5(A) would be a parasubstituted solid should be understood as an indispensable condition, the absence of which should disqualify the subsequent examples from playing any role in the derivation of the compound which Carr 129 disclosed.
107 I turn next to Mr Gugger's work under Example 5(B) of Carr 129. In this respect, as discussed above, in place of 6.1 g of pure ethyl 4-(4-chloro-l-oxobutyl)-α,α-dimethylphenylacetate, Mr Gugger used the impure substance that he had produced under Example 5(A).
108 In his affidavit sworn on 6 February 2009 (as amended in his viva-voce evidence), Prof Wild set out what he said were the "Results and Analysis" of Mr Gugger's carrying out of Example 5(B). Prof Wild said:
After treating the reaction mixture with diethyl ether and ethereal hydrogen chloride, 8.32 g [of] precipitate was collected, washed with diethyl ether, and dried in vacuo to give, after recrystallization, 3.27 g of almost colourless crystals of crude ethyl 4-[4-[ 4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride, MP 177°C-180°C.
Prof Wild referred to the 1H NMR spectrum for this material, and continued:
The expanded spectrum clearly shows the predominance of one regioisomer, and a small amount of another isomer. The yield of the crude product was 35% based on the amount of α,α-diphenyl-4-piperidinemethanol used. Two recrystallisations of the crude product from Example 5(B) from methanol-butanone and butanone afforded 0.92 g (10% yield) of analytically pure product as colourless crystals having MP 197°C-200°C … compared to the MP 205.5°-208°C reported in [Carr] 129 ….
Prof Wild expressed the view that the 1H NMR spectrum for this material was consistent with the presence of the para regioisomer, and that the material was of sufficient purity to proceed with the "next step (Example 2)". He said that the difference between the melting point of this material and that reported in Carr 129 "may be due to a minor impurity" in the material.
109 As now appears from Mr Gugger's laboratory notebook, the above uncomplicated explanation by Prof Wild of the workup of Example 5(B) conceals a great many difficulties which Mr Gugger encountered.
110 On 14 August 2008, Mr Gugger commenced work on Example 5(B). On 15 August, he emailed Mr Cusick with the news that the reaction was proceeding, and that he intended to do the workup on the following Monday (18 August) at about 2 pm. At 3.36 pm on 18 August 2008, Mr Gugger emailed Prof Wild that he (Gugger) had done the workup for Example 5(B), adding "we have a solid (deep breath)". That was, I infer, the precipitate that resulted from the treatment of the filtrate with ether and ethereal hydrogen chloride, rather than the result of any attempt at crystallization, since Mr Gugger went on to say that he would "characterise this by proton, carbon NMR before recrystallizing from methanol/methlyethyl ketone".
111 It is not always clear from the evidence how Mr Gugger's correspondence with Prof Wild related to the course of the workups which he was undertaking at the time. The workups themselves were initially recorded not in the laboratory notebook as such, but on a separate note pad, the relevant pages of which were then inserted into the notebook, and secured with adhesive tape. As Prof Easton observed, this was not always done in a way that was faithful to the chronological sequence of things.
112 Mr Gugger's laboratory notebook seems to indicate that he undertook three attempted workups of Example 5(B) in August 2008. That notebook was not tendered, or explained, by Alphapharm. It was tendered by AMR and explained by Prof Easton, who interpreted Mr Gugger's notes as indicating that he took the following steps in what, as things transpired, was the first of a number of workups:
(a) filtration of the reaction mixture to remove 3.9 g of salts in the form of crystals;
(b) addition of 50 ml of ether and ethereal hydrogen chloride (amount unspecified) to the filtrate;
(c). collection of 8.4 g of precipitate having a melting point of 130 to 168 °C;
(d) dissolution of the precipitate in 150 ml of methanol and 45 ml of butanone;
(e) reduction of the solution to 45 ml by boiling;
(f) collection of 1.0 g of crystals having a melting point of 132 to 140 °C;
(g) dissolution of the crystals in 75 ml of methanol and 30 ml of butanone; and
(h) reduction of the solution to 5 ml by boiling.
The final product obtained was an oil, which was discarded.
113 In what Mr Gugger described (in his notebook) as his "2nd batch", he recommenced Example 5(B) anew (presumably with a further 6.1 g of the 5(A) material). Prof Easton said that this second process "appears to set out a rather unconventional fractional crystallisation in that fractions appear to be first separated from each other and then later recombined with other fractions". It was not suggested by Alphapharm that Prof Easton was unjustified in this surmise; nor that he was inappropriately cautious in the terms he used to express it. I can well understand that Prof Easton was able only to identify what Mr Gugger "appeared" to be doing here. Mr Gugger himself did not give evidence, and Prof Wild did not identify exactly what Mr Gugger had done at the various stages in his second batch.
114 The procedure followed by Mr Gugger in his third batch is set out on a page of his notebook which appears to be dated "20/8/08" (or possibly "26/8/08"). Again, Prof Easton described the procedure as "an unconventional fractional crystallisation in which fractions appear to be first separated from each other and then later recombined with other fractions". Prof Wild made no attempt to trace through what Mr Gugger had done here, and I must say that, to a lay eye, the notebook seems to bespeak a tortuous series of interlocking attempts to have the 5(A) oil yield something in crystalline form, the boiling point of which approximated that stated in Carr 129 (205.5-208 °C). No suggestion was made on behalf of Alphapharm that I should regard those attempts as successful: indeed, nothing ultimately came of whatever it was that Mr Gugger obtained from his third batch. From the date mentioned, however, I do infer that this third batch was probably the subject of an email at 12:16 pm on 22 August 2008, in which Mr Gugger informed Prof Wild that "5b has crystallised at last", adding that there were "two distinct type of crystals". At 4.16 pm on the same day, Mr Gugger informed Prof Wild of the melting point of the crystals which he had obtained: "softened at about 175 and melted at 190 C". Prof Wild replied to that email on the same day, in the following terms:
That was good news about 5b. Only 18 degrees to go! Continue to recrystallise as indicated in the patent. It reads to me that the final recrystallizations were from butanone and the earlier ones from methanol-butanone (several altogether indicated in the patent). Keep a record of yields, mps, and 1H NMR spectra as you proceed. I agree that the protons from the piperidine group are a nuisance in observing the aromatic protons of the parasubstituent we are interested in, but the AB systems look good. Are you getting one sharp CMe2 resonance? Also keep an eye on the OMe singlet and the CH2CH3 triplet. Please keep a record of the hours you are putting in on this work and the number of spectra you are recording.
115 It appears that Mr Gugger embarked upon his fourth batch of Example 5(B) on 4 September 2008. Prof Easton said of it (by reference to the flow-chart in the laboratory notebook):
This schematic also appears to describe a fractional crystallisation but of a more conventional type, with no recombining of previously separated fractions. This schematic representation suggests that Mr Gugger was unsuccessful in separating the various components of the reaction product from each other.
It is here that one sees clearly what Prof Easton would criticise as being outside the parameters of recrystallisation as generally understood, namely, the retention at times of the mother liquor and the discarding of the crystals derived therefrom. Mr Gugger appears first to have obtained 8.78 g of crystals, and discarded the mother liquor. At the next point, he discarded what appears to be 0.003 g of "salt" and continued with the mother liquor. At the next point, he discarded 0.61 g of some apparently crystalline material with a melting point of 130-132 °C and continued with the mother liquor. At the next point, he kept 2.90 g of a crystalline material with a melting point of 170-175 °C and discarded the mother liquor. At the next point, he achieved 1.57 g of a crystalline substance with a melting point of 186-198 °C. It is not clear whether he discarded this, but he did proceed to undertake a further procedure of some kind with respect to the mother liquor (he wrote "remove solvent" on the flow-chart at his point), the result of which was 0.43 g of a crystalline material with a melting point of 175-179 °C, and a consequent "yellow oil" mother liquor.
116 On 5 September 2008, Mr Gugger sent an email to Prof Wild, stating that, from a conversation which he had had with Mr Cusick, "I get the impression that this work is not going as they expected as I could only get mp of 193 not 205". He said that he had "put on another preparation" of Example 5(B) (presumably the fourth batch to which I have just referred). Mr Gugger continued:
John wants me to go no [sic] to the next step which is the hydrolysis, which looks straight forward (example 2) the last step, the reduction I am [a] bit unsure about which method to use.
There is no record of any response from Prof Wild in relation to that email, as the next communication on record is the one to which I refer in the next paragraph. I note that the "next step" at this point was Example 2, but it was the reduction: the hydrolysis was the subject of Example 3. AMR did not draw attention to this apparent mistake on Mr Gugger's part, and I say nothing further about it.
117 On 23 September 2008, Prof Wild sent an email to Mr Gugger on the subject "5(B) melting point". The text of the email was as follows:
It has occurred to me that recrystallising 5(B) from methanol-butanone is risky. 5(B) is an acid, a hydrochloride of an amine, and an ethyl ester. Hence, heating 5(B) in methanol could result in transesterification of the ethyl ester into the methyl ester. This should show up in the nmr and the MS. It would worth [sic] having a look for peaks for the methyl ester in the spectra of the recrystallised 5(B) samples that have lower mps. It would be safer to recrystallise 5(B) from ethanolbutanone or straight butanone. Perhaps taking 5(B) up in hot butanone and then distilling off most of the solvent would give pure product of reproducible mp.
It was not made clear in the evidence whether anything came of these suggestions by Prof Wild.
118 Mr Gugger's fifth batch of Example 5(B) was of central importance to his understanding, and ultimately to his successful completion, of the process described in the example. It is the subject of two sets of entries in his laboratory notebook. The flow-chart for this batch is inserted, apparently from sheets of the separate working pad to which I have referred, at p 145 of the laboratory notebook. Although that page is undated, it comes after other pages which are dated "4/9/08" (p 131), "22/9/08" (p 133) and "23/9/08" (p 139). Further, on 9 October 2008, Mr Gugger sent an email to Prof Wild, saying -
I am finishing the preparation of 5b as I have 5.6 g from 5 runs. In my hands I can only get about 1.2 g per run the maximum is about 4 g, not easy to separate and get the purity required but, I do have reliable method that is repeatable.
In the absence of Mr Gugger from the witness box (for which there was no satisfactory explanation), I would infer that he completed his fifth batch on or shortly before 9 October 2008.
119 At pp 123-125 of Mr Gugger's notebook, there is a write-up of the steps which he took, and the results which he achieved, under the fifth batch of Example 5(B). The first of those three pages is dated "13/8/08". The inference is irresistible, and I draw it, that Mr Gugger at least commenced this write-up on that date. However, the data there reported derive from the fifth batch as carried out, nearly two months later. Indeed, as I explain below, it was an important aspect of Alphapharm's case that this write-up and the flow-chart inserted at p 145 of the notebook were concerned with the same work. In the circumstances, I infer that Mr Gugger commenced his write-up of Example 5(B) on 13 August 2008, but did not then complete it. It was not until at least a week later that he attempted the third batch, with the outcome to which I have referred above. I think it probable that, when he commenced the write-up on 13 August 2008, he intended that it should record his work and results under the third batch. I infer that, because that work was both unsuccessful and inconclusive, Mr Gugger did not record it in his by then partially-completed write-up. It was not until his fifth attempt that he had devised a process, and had achieved a result, that made sense of Example 5(B).
120 Working from the flow-chart for the fifth batch set out in Mr Gugger's laboratory notebook, Prof Easton surmised that the following steps had been undertaken:
(a) filtration of the reaction mixture to remove 3.9 g of salts;
(b) addition of 100 ml of ether and approximately 32 ml of ethereal hydrogen chloride to the filtrate;
(c) collection of 8.32 g of precipitate;
(d) dissolution of the precipitate in unspecified solvent;
(e) reduction of the solution to 45 ml;
(f) separation of 0.88 g of crystals having a melting point of 125 to 130°C;
(g) reduction of the mother liquor to 20 ml, addition of 30 ml of butanone, further reduction of the solution to 10 ml, further addition of 30 ml of butanone, further reduction of the solution to 15 ml and further addition of 30 ml of butanone;
(h) collection of crystals and washing of those crystals with three 20 ml volumes of butanone giving 3.27 g of crystals having a melting point of 177 to 180°C;
(i) dissolution of the crystals in 7 ml of methanol, addition of 45 ml of butanone, reduction of the solution to 25 ml and further addition of 20 ml of butanone;
(j) collection of 1.62 g of crystals having a melting point of 183 to 189°C;
(k) dissolution of the crystals in 30 ml of methanol, reduction of the solution to 20 ml and addition of 30 ml of butanone;
(l) collection of 0.92 g of crystals having a melting point of 194 to 197°C.
Factually, Prof Wild did not take issue with this summary of what Mr Gugger had done.
121 Prof Easton drew attention to an alteration in the melting point of the substance eventually derived as reported on p 125 of Mr Gugger's notebook in his write-up of the fifth batch. Initially, the melting point was reported as 194-197 °C as in the flow-chart, but that was altered to 197-200 °C. An explanation for that latter aspect was provided by Prof Wild:
A melting point of 194 to 197 °C was recorded for Batch 5 alone, but when Batch 5 was combined with Batches 6 and 7 and the mixture was recrystallised, the melting point of the combined batch was 197 to 200 °C, as recorded on page 152 of the First Gugger Notebook.
To the extent that pp 124-125 of the notebook record the actual workup of the fifth batch, however, there can be no doubt but that the original melting point as observed at the time was later altered. As I shall note below, however, even Prof Wild's explanation does not accord with what is recorded on p 152 of the laboratory notebook.
122 Senior counsel for Alphapharm took Prof Easton through Mr Gugger's notes, in some detail, in order to identify what he had done with respect to his fifth batch, and the extent to which it lined up with the crystallisation process prescribed in Example 5(B). Because of the absence of Mr Gugger himself to explain the entries in his laboratory notebook, this was a cumbersome and unsatisfactory process. However, it was revealing and helpful for an understanding of what Mr Gugger had done and, in some respects, of why. The process also had the benefit of rendering Mr Gugger's flowcharts for the sixth and seventh batches more intelligible than would otherwise have been the case.
123 Prof Easton accepted that the "unspecified solvent" referred to at step (d) in para 120 above, was in fact methanol, and mentioned as such in the write-up. It was this solution that was reduced to 45 mL. Mr Gugger allowed this reduced solution to stand overnight, after which (according to his write-up), "a very fine precipitate formed, this could only be filtered with difficulty". Prof Easton accepted that it was likely that the material thus filtered out was what Mr Gugger described in his flow chart as 0.1 g of a salt, which was discarded. The crossexamination of Prof Easton then proceeded thus:
At this stage, what is happening, isn't it, is he is dissolving it in methanol and waiting before he adds the butanone to see if any rubbish impurities come out? - I'm not sure how he decides what these compounds are.
But anyway, he adds the methanol and pauses, must have seen some cloudiness, and then tried to get rid of it by filtration at first or to get it out by filtration at first? - He's done more than that, he's reduced the volume of the methanol that he's used, so he is attempting to get a crystallisation from methanol.
And only a tiny amount is able to be filtered out? - Yes.
124 At this point, Mr Gugger's write-up discloses that a "new strategy was employed". Still working with the methanol solution which had been reduced to 45 mL, Mr Gugger used a centrifuge to remove solid material therefrom, and this time obtained 0.88 g. This was the stage identified as step (f) by Prof Easton. As noted, the solid had a melting point of 125-130 °C (125-132 °C in the write-up). This material was discarded. Prof Easton accepted that what Mr Gugger had here done was: "paused, attempted to filter, centrifuged, then … look[ed] at the melting point of what he'[d] centrifuged out".
125 Next, there is a sub-heading in Mr Gugger's write-up: "1st Recrystallisation". Beneath that, Mr Gugger describes taking the steps identified as (g) and (h) by Prof Easton. Having obtained the 3.27 g of crystals, Mr Gugger discarded the mother liquor. Next, under the sub-heading "2nd Recrystallisation", Mr Gugger's write-up describes that he took the steps which Prof Easton identified as (i) and (j), obtaining 1.62 g of crystals. On this occasion, Mr Gugger did not discard the mother liquor but (in a procedure mentioned neither in his write-up nor in Prof Easton's summary set out in para 120 above) treated it with methanol and butanone, reduced the volume of the resulting solution, allowed it to stand for two hours, and obtained an unidentified quantity of crystals with a melting point of 170-175 °C. Nothing further was done with that material. Referring to what the write-up does disclose, under the sub-heading "3rd Recrystallisation", Mr Gugger took the 1.62 g of crystals which he obtained from the previous stage and carried out the steps identified by Prof Easton as (k) and (l).
126 Prof Easton was then crossexamined as follows:
So would you agree with this proposition: this is a three step recrystallisation, with two additional aspects, one is the filtration or centrifuging of the crystals after the first addition of methanol? Do you agree with that so far? - As I said before, I think there is fractionation and choices made along the way. The route that you particularly follow does constitute, I think, I'm not sure, three recrystallisation processes. But along the way, two crystal forms have been discarded, an oil has been discarded, an oil has been continued to work with, and the mother liquor has been continued to work with. So there is a fractionation process.
The two deviations from a standard recrystallisation, do you agree, are, if I may call one, a filtration/centrifuge step, and the working on the mother liquor out to the right? - On the three occasions, as well as the discarding the 0.1 gram of material and the 0.88 grams of material.
What counsel referred to as "working on the mother liquor out to the right" was that part of Mr Gugger's work which involved treating the mother liquor with methanol and butanone, and ultimately obtaining crystals with a melting point of 170-175 °C, as described above. In their final submissions, counsel for Alphapharm described this as an extra step at the side, carried out because Mr Gugger had an enquiring mind as to the constitution of the mother liquor, and proposed that, ultimately, it had little to do with the question whether Mr Gugger was able, following Carr 129, to obtain fexofenadine. AMR's position (and also that of Prof Easton), as I understand it, is that it is only after the event that Alphapharm is able to make this submission: had Mr Gugger obtained a melting point from this material that was consistent with the presence of the desired para regioisomer in it, his procedure would have been much more than a matter of scientific curiosity.
127 Prof Wild returned to Australia on 17 October 2008, and was present when Mr Gugger worked up the sixth and seventh batches of Example 5(B). From this time, no further email correspondence between himself and Mr Gugger with respect to the latter's work on Carr 129 is in evidence.
128 The page of Mr Gugger's laboratory notebook which sets out the flowchart for the sixth batch of Example 5(B) is also undated. Working from that flowchart, Prof Easton surmised that the following steps had been undertaken:
(a) filtration of the reaction mixture to remove 4.1 g of salts;
(b) addition of 100 ml of ether and approximately 35 ml of ethereal hydrogen chloride to the filtrate;
(c) collection of 8.4 g of precipitate;
(d) dissolution of the precipitate in unspecified solvent;
(e) reduction of the solution to 54 ml and standing overnight;
(f) separation of 0.49 g of crystals;
(g) addition of 2 ml of methanol and 45 ml of butanone to the mother liquor, reduction of the solution to 20 ml, further addition of 30 ml of butanone, and standing overnight;
(h) filtration of crystals and washing of those crystals with three 20 ml volumes of butanone giving 3.43 g of crystals having a melting point of 180 to 185°C;
(i) dissolution of the crystals in 7 ml of methanol, addition of 40 ml of butanone, reduction of the solution to 30 ml and further addition of 20 ml of butanone;
(j) collection of 2.18 g of crystals having a melting point of 185 to 190°C;
(k) dissolution of the crystals in 30 ml of methanol, reduction of the solution to 7 ml, addition of 35 ml of butanone, further reduction of the solution to 15 ml, standing to allow crystallisation and further addition of 5 ml of butanone;
(l) collection of 2.83 g of crystals having a melting point of 189 to 192°C.
129 There is no write-up of the sixth batch in Mr Gugger's laboratory notebook, but Alphapharm submitted, in effect, that it could be inferred that Mr Gugger followed steps broadly in accordance with his write-up of the fifth batch. I accept that submission. Under crossexamination, Prof Easton accepted that there were steps in Mr Gugger's flowchart for the sixth batch which corresponded with steps in his flowchart for the fifth batch. Further, the illumination which was given to both during that crossexamination sustains the inference, which I draw, that Mr Gugger's write-up for the fifth batch is likewise applicable, mutatis mutandis, to the sixth. I am confirmed in that conclusion by the statement made to Prof Wild by Mr Gugger in his email of 9 October 2008 that he then had a reliable method that was repeatable.
130 The page of Mr Gugger's laboratory notebook which sets out the flowchart for the seventh batch of Example 5(B) is also undated. Working from that flowchart, Prof Easton surmised that the following steps had been undertaken:
(a) filtration of the reaction mixture to remove 5.0 g of salts;
(b) addition of 120 ml of ether and approximately 35 ml of ethereal hydrogen chloride to the filtrate;
(c) collection of 5.70 g of precipitate;
(d) dissolution of the precipitate in 200 ml of unspecified solvent;
(e) reduction of the solution to 55 ml and standing for 2 hours;
(f) separation of 0.29 g of crystals;
(g) addition of 2 ml of methanol and 45 ml of butanone to the mother liquor, reduction of the solution to 15 ml further addition of 30 ml of butanone, and standing for 2 hours and refrigeration for 1 hour;
(h) filtration to give 2.37 g of crystals having a melting point of 178 to 185°C;
(i) dissolution of the crystals in 20 ml of methanol, addition of 30 ml of butanone, reduction of the solution to 20 ml, further addition of 20 ml of butanone and standing for 2 hours;
(j) collection of 1.16 g of crystals having a melting point of 186 to 190°C.
What I said about, and the inferences I drew with respect to, the sixth batch in the previous paragraph are equally applicable to the seventh batch.
131 Page 152 of Mr Gugger's laboratory notebook is headed "Summary of yields". In a table, it sets out the gram-yield and the melting point of the product achieved in each of the fifth, sixth and seventh batches of Example 5(B). The products of the sixth and seventh batches (not of the fifth) were combined to give a total of 3.98 g of material. This material was then further worked up by dissolution and crystallisation to achieve a final yield of 2.9 g. It was this material which had a melting point of 197-200 °C. It was to no extent derived from the fifth batch. According to Prof Easton, it represented a combined yield from the sixth and seventh batches of approximately 20%.
132 That brings me back to the explanation of Mr Gugger's workup of Example 5(B) provided in Prof Wild's affidavit of 6 February 2009, to which I have referred in para 108 above. A careful analysis of that affidavit, and of Mr Gugger's notes, undertaken by Prof Easton reveals that the 3.27 g of colourless crystals with a melting point of 177-180 °C was in fact the product of step (h) in the fifth batch (see para 120 above) and that the 0.92 g of analytically pure product was the product of step (l) therein. However, as noted above, the melting point of 197-200 °C set out in Prof Wild's affidavit related not to that product but to the combined products of the sixth and seventh batches. As Prof Easton noted, Prof Wild seems to have been working from Mr Gugger's write-up of the fifth batch, but using the melting point derived from those other combined batches (the sixth and seventh batches themselves not being the subject of any write-up).
133 Prof Wild caused the material derived from the sixth and seventh batches - the melting point of which was 197-200 °C - to be analysed. It was 96.39% the para regioisomer specified as the product of Example 5(B) in Carr 129.
134 The major criticism made by AMR of Mr Gugger with respect to Example 5(B) was that he employed the technique of fractional crystallisation rather than of repeated recrystallisation as specified. Of the distinction between the two, Prof Easton said:
Recrystallisation is typically performed on a solid having relatively minor amounts of impurities and involves dissolving the solid in a solvent system and then causing that solid to come out of solution leaving behind the undesired impurities. In a recrystallisation essentially all of the material which will come out of the solution is allowed to do so. Fractional crystallisation is typically performed on a reaction product containing a number of different components or fractions with the intention of separating each of those fractions from each other. Fractional crystallisation involves dissolving the solid in a large excess of solvent and then altering the volume and ratio of solvents in the solution to find a point at which one of the fractions will come out of the solution. The variation of volume and ratio of solvents is achieved by adding amounts of one or more of the solvents used and reducing the volume of the combined solution.
I did not understand Prof Wild to take issue with this statement, but, at least to the extent relevant to Mr Gugger's work, he considered that the distinction proposed by Prof Easton was one which did not involve a difference. He stated that fractional crystallisation and recrystallisation were "in effect the same process". Indeed, in his email to Mr Gugger of 15 August 2008 (see para 93 above), Prof Wild said, with reference to the oily product of Example 5(A), "it will be interesting to see if you can get a fractional crystallization". Although Prof Wild denied it under crossexamination, it is clear that he here had in mind the process contemplated under Example 5(B).
135 It was Alphapharm's submission that, by the time he had completed the fifth batch of Example 5(B), Mr Gugger had established a procedure which, when properly understood, involved conventional recrystallisation, with three stages. Those stages came after what Alphapharm described (in its submissions) as an initial step of "standing and centrifuging to get rid of irrelevant material". I am, however, disposed to think that this is a submission made with the considerable advantage of hindsight. The inference is clearly open that it was only by the time Mr Gugger was part-way through his fifth batch that he appreciated that, in the precipitate derived at step (c) as identified by Prof Easton, he had something in the material with which he was working that would complicate the process of recrystallisation and which, therefore, had to be removed. There is no reference to this in Carr 129. In the absence of Mr Gugger, I would draw that inference. Indeed, I would infer that, without the removal of this unwanted substance, Example 5(B) would not provide an effective means of synthesising ethyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α- dimethylbenzeneacetate hydrochloride from the oil which Mr Gugger obtained under Example 5(A).
136 It was only at some point during his fifth attempt to make Example 5(B) work that Mr Gugger devised what was, in effect, a protocol which he was able to follow in the sixth and seventh batches. Looking only at the terms of Carr 129, that such a protocol was necessary would not, in my view, have been apparent to a scientist skilled in this kind of synthetic organic chemistry. As Prof Wild pointed out, Mr Gugger was such a scientist of very considerable experience. From what Prof Wild said about Mr Gugger, if he was unable to make Example 5(B) work over four attempts, it is hard to imagine that any scientist skilled in the relevant area would have been able to do so.
137 Returning to the submission of Alphapharm to which I have referred at the start of para 135 above, for the reasons I have attempted to explain, I am not persuaded that a scientist skilled in the art, as at the priority date, would have known that there was some "irrelevant" material that had to be removed before, and under a different operation from, the process of recrystallisation referred to in Example 5(B). Absent that knowledge, the example would not have worked for him or her. There is no suggestion in the terms of the example itself that irrelevant material had to be removed. Under the example, recrystallisation follows immediately upon the collection of the precipitate under the previous step. It is no answer to say that, working with an oil which he or she may be assumed to have inferred included impurities, the scientist would have expected to have been obliged to remove some unwanted material before embarking on recrystallisation. Mr Gugger appears to have made several attempts to make Example 5(B) work before he realised that this additional step was necessary. It may be one thing to forgive the inventors under Carr 129 for having predicted the achievement of a parasubstituted solid at the end of Example 5(A) rather than an oil, but it would be, in my view, another thing altogether to attribute to them an undisclosed intention that the putative synthetic chemist would realise that the steps thereafter prescribed in Example 5(B) were insufficient to resolve such impurities as may have been involved in the 5(A) oil.
138 Although, as I have said, the principle derived from Van der Lely allows for a degree of perseverance in the trial and error process which it contemplates, in my view Mr Gugger's work demonstrates that more than perseverance, and more than "the ordinary methods of trial and error", were required to achieve ethyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride at the end of Example 5(B) of Carr 129. Mr Gugger was required to do more than apply his laboratory experience to make the recrystallisation referred to therein work: he was required, first, to discern the presence of unwanted material that had to be removed, and secondly, to devise a means of removing that material. To say that this point was reached as a result of trial and error would be, in my view, to make a considerable understatement. Without Mr Gugger to assist on the subject, I would infer that reaching this point involved a significant challenge for him, during which he was, for much of the time, working with, and in, the unknown. In the result, he devised a means of making Example 5(B) work with reference to an impure oil obtained under Example 5(A). It was not a means disclosed in Carr 129.
139 According to Mr Gugger's laboratory notebook, it was on 22 September 2008 that he commenced work on Example 2. That timing is consistent with an email which he sent to Prof Wild on 5 September 2008, to which I have referred in para 116 above. If Mr Gugger did commence work on Example 2 on 22 September 2008, he could not have been using, as starting material, anything he derived from batches of his workups under Example 5(B) subsequent to the fourth. As is clear from para 115 above, the evidence as to the results achieved from the fourth batch under Example 5(B) leaves open a number of possibilities with respect to the material which he carried into Example 2 on 22 September. It was common ground that this attempt at Example 2 was unsuccessful. It was the evidence of Prof Wild that this was because of the inferior quality of the platinum oxide catalyst used, but, given the origin of the starting material used, it may be doubted whether anything would have come of this attempt.
140 Mr Gugger's second attempt at working up Example 2 commenced on 25 October 2008. By then, he had worked up the sixth and seventh batches of Example 5(B), and it was 1.9 g of the combined material from these batches that he used as the starting material. Prof Wild described this workup as follows:
A subsequent reduction of the [1.9 g of material obtained from Example 5(B)] with freshly prepared platinum oxide was then run overnight and a significant reduction in the intensity of the keto-carbonyl absorption at 1682 cm-1 was observed after 18 hours. … After 38 hours at 50 psi the reduction was complete, as indicated by the disappearance of the keto-carbonyl absorption group in the IR spectrum. Variations in reaction times for hydrogenations are not unusual for reactions involving heterogeneous catalysts. … Centrifugation of the reaction mixture to remove catalyst, followed by concentration of the mother liquor to a small volume, afforded[,] over 2 days, colourless crystals of the reduction product, which were filtered off and suspended in butanone. The resulting crystals were filtered off and dried in vacuo to give 1.8 g of crude product (95% yield). Recrystallisation of this material from methanol-butanone gave 1.2 g of the product of Example 2 as colourless needles, MP 180°C-182°C (67% yield) …. This melting point compares favourably with the value reported for this compound in Example 2 of [Carr] 129 (MP 185°C-187°C) ….
Save for offering some rather benign commentary as to the length of time taken to achieve reduction, and as to the use of a centrifuge, AMR did not venture any criticism of Mr Gugger's workup of this example. It seems to have been accepted by AMR that Mr Gugger did derive 1.2 g of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate HCl.
141 Mr Gugger's work under Example 3 of Carr 129 was, however, more contentious. He commenced his first attempt at Example 3 on 23 September 2008. Although it seems that he could then only have been working with whatever material he derived from his unsuccessful attempt at Example 2, no explanation of this aspect was offered in the evidence. After recrystallisation from methanol-butanone, what did happen under this attempt at Example 3 was, however, the subject of a series of emails passing between Mr Gugger and Prof Wild on 25 and 26 September, or thereabouts.
142 Mr Gugger first told Prof Wild, in a very short email, that he had "made Example 3 as the free base" with a melting point of 142 °C. He said that Mr Cusick wanted him to "make the hydrochloride" as it had a melting point of 193-195 °C. Prof Wild replied, advising Mr Gugger to "Look carefully at the NMR spectrum of 3, as, being a zwitterion, it could crystallise with solvents …." He continued:
I suggest making the hydrochloride by dissolving the free acid in dilute HCl and evaporating the solution in vacuo, or boiling off on the steam bath, if you are game. If the acid dissolves in ether, bubble HCl gas through the solution - the hydrochloride should precipitate. Recrystallise from methanol-butanone or butanone, as for 5B. The patent mentions the hydrochloride of fexofenadine, but does not describe it. I will be very keen to hear the mp you get.
I infer that Mr Gugger, following Prof Wild's advice, made the hydrochloride form of the Example 3 product, since he reported that he had "a rough melting point for Example 3 HCl 187-190 C". However, the 1H NMR indicated the presence of butanone, from the solvent used. In his email to Prof Wild, he continued:
I like your method of forming the HCl using ether and HCl gas il [sic] will give it a try. I was looking at a [sic] the C. Mazier Bioorg. Med. Chem. Lett. 14 (2004) 5423-5426 paper they purify Fexofenadine using Flash Chromatography using CH2Cl2/ CH3OH eluant containing acetic acid 1% to give a product with a 193-195 Mp. I would thought [sic] the zwitterion would have formed the acetate unless it was already the HCl.
143 In his next email to Mr Gugger, Prof Wild said:
There is confusion about the mps of fexofenadine and its hydrochloride. The patent in question, the one you are following, gives 195-197 C for the free acid recrystallised from methanol-butanone; the article by Mazier gives 193-195 C for a sample of the free acid obtained by column chromatography as you describe; and John gives 199-203 C for the hydrochloride from his client (no experimental details). I am surprised that the free acid and the hydrochloride have similar mps and your lower value for the free acid appears reasonable. It will be important for you to get enough of the pure acid and the hydrochloride for characterisation.
Mr Gugger replied as follows:
There is confusion about the melting points, in the Hambalek paper J. Org. Chem 1994,59, 2620-2622 their [sic] give the Mp of Fenofenadine [sic] as 142-143 C and the purity as >99% recrytallzed [sic] from methanol. This is very close to what I obtained. The other thing is they brought the pH to 7 upon hydrolysis. The Mazier paper drop the pH to 3 when hydrolysing and form the HCl. Mp 193-195. very close to what I obained [sic] but the patent Mp is a bit of a mystery did they form the HCl even through [sic] the pH was brought to 7 , this is the question?
Prof Wild responded as follows:
I agree about the confusion with the mps. I go along with the Hambalek figure for the acid, recrystallised from methanol. Send this paper to John. The Mazier figure is surprising - would the hydrochloride run on the column? (When you have some pure, we could try running some on a plate under their conditions.) I am also suspicious of the patent figure, if they say it is the free acid. As you say, perhaps they did not get the pH to 7.
To isolate the acid after the hydolysis [sic], Example 3, I would suggest evaporating the reaction mixture to dryness, and then extracting the residue with ether or benzene, perhaps methylene chloride, to leave behind the sodium chloride. Hopefully, the acid will be in the organic solvent. HCl gas bubbled through the ether or benzene solution will precipitate the hydrochloride, which should recrystallise well from methanol - butanone or ether.
144 There was no evidence of what became of this first attempt by Mr Gugger to carry out Example 3. It was common ground that it was unsuccessful, and AMR was, it seems, content to leave it at that. AMR did, however, draw attention to the references, in these email exchanges, to works by Hambalek and Mazier. These were published in 1994 and 2004 respectively. They would not have been available to a synthetic chemist in 1993. AMR pointed also to the information given to Mr Gugger by Mr Cusick that the melting point of fexofenadine hydrochloride was 199-203 °C: there were no further particulars as to this presumably post-1993 piece of information. Under crossexamination, Prof Wild's denials as to the utility (to Mr Gugger) of the information obtained from Hambalek, Mazier and Mr Cusick were unconvincing. Ultimately, in what I consider to be the closest he got to the truth of the matter, Prof Wild accepted counsel's suggestion that "[a]ll of this material … was being assembled to assist Mr Gugger in progressing his work in relation to the repetition of Carr".
145 It was not until 10 November 2008 that Mr Gugger commenced his second attempt at Example 3. No difficulty arose until the step of recrystallisation from methanolbutanone. According to Prof Wild, "the recrystallised material contained butanone … even after drying in vacuo". It seems that Mr Gugger then recommenced the recrystallisation, using another solvent system. Prof Wild said:
The crude product, MP 208°C, was purified by recrystallisation from aqueous methanol, from which separated large, colourless plates, which were filtered off and dried in vacuo at 50°C. Yield: 0.39 g. MP 224°C-225°C. … The HPLC chart for the product having MP 224°C-225°C indicated two components, one having a retention time of 16.671 minutes (99.77%) and the other having a retention time of 18.387 minutes (0.23%).
Prof Wild recognised the component present to the extent of 99.77% as the para regioisomer intended to be derived from Example 3. He was not challenged on this understanding. He said that Mr Gugger undertook a further recrystallisation of the product which he had obtained, the result of which was a compound consisting wholly (100%) of the para regioisomer. That Mr Gugger did achieve that result was not contested by AMR.
146 However, Prof Easton did not accept Prof Wild's evidence as a satisfactory, or as a complete, description of what Mr Gugger had done. Working from Mr Gugger's notebook, Prof Easton explained what had in fact been done as follows:
However at page 35 of the Second Gugger Notebook it is stated that difficulty was encountered in recrystallising the product in methanol-butanone. There is no description of the nature of this difficulty. It is then stated that the product was recrystallised from ethyl acetate to give 0.39 grams of a product having a melting point of 142°C. This product was then recrystallised from methanol/water to give a product having a melting point of 208°C and recrystallised again to give a product having a melting point of 224 to 225°C.
Prof Wild agreed with this commentary, adding (viva voce) -
[B]ecause of time restraints and perhaps frustration in recrystallising the final product of the series of reactions in example 3, [Mr Gugger] tried a recrystallisation from ethyl acetate, which produced a nice crystalline compound that could be isolated ….
AMR pointed out that Mr Gugger departed from Carr 129 in his use of ethyl acetate followed by methanol/water. Under cross-examination, Prof Wild accepted that, in this respect, Mr Gugger had "abandoned what Carr prescribed". However, he said that ethyl acetate was "a common solvent on the shelf and is known to have intermediate properties between an alcohol and ketone". Again, Prof Easton did not agree. He said:
Solvents are chosen for different reasons. Ethyl acetate and other ketones, such as butanone, are referred to as dipolar or protic solvents. Methanol, for example, is a protic solvent, so it depends on whether you want a protic solvent, a nucleophilic solvent or whether a nucleophilic solvent is a problem. So you make a choice. They are independent choices.
147 Prof Black regarded Mr Gugger's use of a different solvent under Example 3 as of no consequence. He said:
The other comment I'd make in general about deviations from the description in Carr is that when you're repeating chemistry, everyone who does this is, in a sense, individual, we all have our own individual experience, we have our own favourite solvents for recrystallisation. Many compounds that are reported to be recrystallised from ethanol, for example, I would personally use isopropanol because my experience with isopropanol is that it gives you a better outcome in many cases. Ethyl acetate is also a very good replacement for ethanol and it is a matter of preference, there is no magic about changing solvents. If I have a report in the literature that says the compound was recrystallised from ethanol and I repeat that experiment and I do my recrystallisation from isopropanol, I don't go and write a paper telling the world that you can recrystallise this from isopropanol and it is better because that is considered to be completely trivial, it is a matter of choice for the experimentalist as they are doing their work. So to my mind it is not even worth considering as a deviation, it is a very, very literal but very, very minor deviation from standard practice.
Prof Easton's response was a simple one:
I think you either follow Carr or you don't is the simple answer and if you change solvents, for example, you're not following Carr.
148 However, the question is not simply whether Mr Gugger followed Carr 129. Had that been the question, it is doubtful whether there would have been any debate at all: Alphapharm accepts that, in this and other respects, Mr Gugger departed from Carr 129. The question, rather, is whether those departures were more than would be involved in ordinary trial and error of the kind that would be required to give practical application to any invention. I do not understand the last answer from Prof Easton, set out above, to have asserted so. I accept Prof Easton's evidence that solvents are chosen for different reasons. But I impute to the skilled organic chemist a ready appreciation of those reasons, and a sufficient familiarity with the utility of solvents to know what would be likely to give a satisfactory result in a particular situation. I accept Prof Black's evidence that, for an experienced worker like Mr Gugger, the choice of solvents was a matter of triviality; or at least was such a commonplace concern as to be well within the bounds of ordinary experimental trial and error in the Van der Lely sense.
149 Returning to AMR's criticism of Mr Gugger for having consulted sources of information (Hambalek and Mazier) that became available after the priority date under the patent in suit, I do not accept that that criticism may be dismissed merely on the ground that the evidence of Mr Gugger's reference to these sources is limited to his failed attempt at Example 3 in late September 2008. Such understanding as he derived of relevant matters from those sources would still have been in his mind when he undertook his second attempt in November. I also accept AMR's submission that, not having called Mr Gugger, Alphapharm is in no position to invite me to draw benign inferences as to the extent to which he was ultimately assisted by those sources. However, the fact is that AMR did not articulate the inference of fact that I should be the more ready to draw in relevant respects because of the absence of Mr Gugger. AMR's case under Example 3 related to Mr Gugger's choice of solvents, and it was not suggested that he derived any assistance in that regard from the post-1993 sources which he consulted. Thus I accept Alphapharm's case that, although Mr Gugger did consult such sources, ultimately nothing turns on it.
150 In his oral submissions, senior counsel for AMR described Mr Gugger's use of nonCarr solvents as the "fundamental point" arising with respect to Example 3. He made no reference to an additional point of criticism which was the subject of two paragraphs in AMR's lengthy written submissions, namely, that the final product obtained by Mr Gugger was not fexofenadine at all, but fexofenadine dihydrate, a circumstance which had been frankly acknowledged by Prof Wild in his affidavit of 6 February 2009 and to which, in his oral evidence, Prof Wild attributed the departure from Carr with respect to the melting point of the product obtained. It may be that those written submissions were prepared before Prof Easton was crossexamined by counsel for the respondents, for I must say that they seemed to pay no regard to the evidence then given. The fact that the compound derived by Mr Gugger had two molecules of water attached to it appears to have been regarded as inconsequential in the overall scheme of things by the scientists who gave evidence in the case, a perspective which is, in my view appropriately, reflected in the decision by senior counsel for AMR to make no reference to the point.
151 In the result, I find that Carr 129 did not disclose an effective means of preparing fexofenadine. I reach that conclusion because the means otherwise disclosed broke down at the point of Example 5(B). That is to say, there was, in my view, no such means disclosed as would, within the limits of ordinary trial and error in the Van der Lely sense, lead to the synthesis of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α- dimethylbenzeneacetate hydrochloride when the starting material was, as it would be, an oily mixture of regioisomers rather than the product ostensibly synthesised under Example 5(A). It follows that, if I am wrong about the law as established in Lundbeck and Apotex, I would hold that the invention, so far as claimed in the claims which are presently relevant, was not anticipated by Carr 129. And the same conclusion must apply in the case of Carr 146.