Albany Molecular Research Inc v Alphapharm Pty Ltd

Division: GENERAL DIVISION

Category: Catchwords

Number of paragraphs: 223

Counsel for the Applicant: Mr A Archibald QC with Mr A Ryan SC and Ms K Beattie

Solicitor for the Applicant: Phillips Ormonde Fitzpatrick

Counsel for the Respondent Mr D Catterns QC with Mr N Murray in VID219 of 2007:

Solicitor for the Respondent in VID 219 of 2007: Mallesons Stephen Jaques

Counsel for the Respondents in VID 883 of 2007: Mr D Shavin QC with Ms H Rofe

Solicitor for the Respondents in VID 883 of 2007 Corrs Chambers Westgarth

IN THE FEDERAL COURT OF AUSTRALIA VICTORIA DISTRICT REGISTRY GENERAL DIVISION VID 219 of 2007

JUDGE: JESSUP J DATE OF ORDER: 18 FEBRUARY 2011 WHERE MADE: MELBOURNE

1. The parties file and serve memoranda setting out their submissions as to the orders which should be made to reflect the court's reasons published this day, together with any submissions as to costs, in accordance with the following timetable: (a) the respondent/cross-claimant within seven days; (b) the applicant/cross-respondent within a further seven days; (c) the respondent/cross-claimant in reply (if necessary), within a further seven days. Note: Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules. The text of entered orders can be located using Federal Law Search on the Court's website.

IN THE FEDERAL COURT OF AUSTRALIA VICTORIA DISTRICT REGISTRY GENERAL DIVISION VID 883 of 2007

AND: ARROW PHARMACEUTICALS PTY LTD (ACN 003 144 170)

SIGMA PHARMACEUTICALS (AUSTRALIA) PTY LTD (ACN 004 118 594)

JUDGE: JESSUP J DATE OF ORDER: 18 February 2011 WHERE MADE: MELBOURNE

1. The parties file and serve memoranda setting out their submissions as to the orders which should be made to reflect the court's reasons published this day, together with any submissions as to costs, in accordance with the following timetable: (a) the respondents/cross-claimants within seven days; (b) the applicant/cross-respondents within a further seven days; (c) the respondents/cross-claimants in reply (if necessary), within a further seven days. Note: Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules. The text of entered orders can be located using Federal Law Search on the Court's website.

IN THE FEDERAL COURT OF AUSTRALIA VICTORIA DISTRICT REGISTRY GENERAL DIVISION VID 219 of 2007

BETWEEN: ALBANY MOLECULAR RESEARCH, INC

AND: ALPHAPHARM PTY LTD

IN THE FEDERAL COURT OF AUSTRALIA VICTORIA DISTRICT REGISTRY GENERAL DIVISION VID 883 of 2007

BETWEEN: ALBANY MOLECULAR RESEARCH INC

AND: ARROW PHARMACEUTICALS PTY LTD (ACN 003 144 170)

SIGMA PHARMACEUTICALS (AUSTRALIA) PTY LTD (ACN 004 118 594)

JUDGE: JESSUP J DATE: 18 FEBRUARY 2011 PLACE: MELBOURNE

REASONS FOR JUDGMENT 1 There are two proceedings presently before the court. Each relates to Australian Patent No 699799 titled "Piperidine derivatives and process for their production", the priority date of which is 24 June 1993. The applicant in each proceeding is the patentee, Albany Molecular Research, Inc ("AMR"). In proceeding VID 219 of 2007, AMR alleges that the respondent, Alphapharm Pty Ltd ("Alphapharm") has infringed the patent by making, selling and otherwise dealing in the pharmaceutical product known as "Xergic", the active ingredient in which is fexofenadine hydrochloride, the hydrochloride salt of one of the compounds covered by the patent. In proceeding VID 883 of 2007, AMR alleges that the respondents, Arrow Pharmaceuticals Pty Ltd, Sigma Pharmaceuticals Ltd, Sigma Pharmaceuticals (Australia) Pty Ltd and Sigma Company Ltd (together, "the Sigma respondents") infringed the same claims of the patent by making, selling and otherwise dealing in various pharmaceutical products - many of which carry a label which includes the term "fexo" - of which the active ingredient is fexofenadine hydrochloride. 2 The respondents in both proceedings contend that the patent in suit is, and has at all material times been, invalid for want of novelty, lack of an inventive step, inadequate description of the invention, failure to define the invention, lack of clarity and succinctness in the claims, lack of fair basis in the claims and false suggestion. They also allege that the invention is not a manner of manufacture within the meaning of s 6 of the Statute of Monopolies, and that, if the patent is otherwise valid, the priority date is 15 September 1998. Likewise, in both proceedings, there are cross-claims for revocation, in which the grounds correspond broadly to the points taken by way of defence. In VID 219 of 2007, Alphapharm is the cross-claimant and AMR is the cross-respondent. In VID 883 of 2007, the Sigma respondents are the cross-claimants, AMR is the first cross-respondent and Aventis Pharmaceuticals, Inc is the second cross-respondent, joined as exclusive licensee of the patent in suit. 3 According to the "background" section of the complete specification to the patent in suit, the compound 1-(p-tert-butylphenyl)-4-[4'-(α-hydroxydiphenylmethyl)-1'-piperidinyl]-butanol, known as "terfenadine", is a nonsedating antihistamine. It is said that terfenadine has been linked to potentially fatal abnormal heart rhythms in some patients with liver disease, or who also take the antifungal drug ketoconazole or the antibiotic erythromycin. It is said that, in animal and human metabolic studies, terfenadine was shown to undergo high firstpass effect, resulting in readily measurable plasma concentrations of the major metabolite 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-α,α-dimethylphenylacetic acid, also known as terfenadine carboxylic acid metabolite. 4 To the extent presently relevant, the invention under the patent in suit is said to relate to substantially pure piperidine derivative compounds of the formula - wherein Rl is hydrogen or hydroxy; R2 is hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2; R3 is -COOH or -COOR4 ; R4 is an alkyl with 1 to 6 carbon atoms; A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, or alkoxy, or other substituents.

• or a salt thereof. It is said that "these compounds are useful in pharmaceutical compositions, particularly as antihistamines, antiallergy agents, and bronchodilators". When all the substituents marked as A, B and D are hydrogen, when R1 is a hydroxyl group, when R2 is hydrogen and when R3 is -COOH, the compound is 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-α,α-dimethylphenylacetic acid, the synthetic form of terfenadine carboxylic acid metabolite. This compound is known by the nonproprietary name "fexofenadine". 5 AMR sues on claims 1, 6, 7, 8, 9, 10 and 11 of the patent in suit. They are also the claims on which the respondents' validity case is based. To the extent presently relevant, Claim 1 is expressed in broad terms corresponding to those set out in para 4 above. Claim 6 is based on Claim 1, and R1 must be a hydroxyl group. Claim 7 is based on Claim 6, and R3 must be -COOH. Claim 8 is for "[a] pharmaceutical composition comprising … a pharmaceutical carrier and the substantially pure piperidine derivative compound according to any one of claims 1 to 7". Claim 9 is for "[a] unit dosage formulation comprising a pharmaceutical composition according to claim 8, wherein said substantially pure piperidine derivative compound is present in an effective antiallergic amount". Claim 10 is for "[a] method of treating allergic reactions in a patient comprising administering to the patient said pharmaceutical composition according to claim 8 in an effective amount". Claim 11 is for a compound, in accordance with Claim 1, with reference to certain preparatory examples contained in the patent.

The Carr Patents 6 Central to an understanding of the patent in suit, and to the respondents' novelty cases, is a series of previous USA patents of which the inventors were Carr and others. The two that are presently important are Nos 4,254,129 and 4,254,130. It is convenient to refer to them as "Carr 129" and "Carr 130" respectively. It is common ground that Carr 129 ostensibly disclosed piperidine derivative compounds of the classes covered by the patent in suit, including fexofenadine, but the inventor under the patent in suit asserted that, if the methods disclosed in Carr 129 were followed, substantially pure compounds would not be the result. Indeed, that circumstance lay at the core of the justification for - and the claimed inventiveness of - the present invention. These are aspects to which I shall have to give substantial attention in my consideration of the respondents' novelty cases, but my present concern is merely to identify the compounds disclosed in the Carr patents (and the Australian equivalent of Carr 129, to which I shall turn) and how they relate to the compounds claimed in the patent in suit. 7 Carr 129 was publicly available in Australia on or about 3 March 1981. It relates to: … novel substituted piperidine derivatives. More particularly, this invention relates to substituted phenyl 4-substituted piperidinoalkanol derivatives which are useful as antihistamines, anti allergy agents and bronchodilators and to methods of making and using the same. The compounds disclosed in Carr 129 are of the following formula: wherein R1 is hydrogen or hydroxy; R2 is hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2; n is an integer of from 1 to 5; R3 is -CH3, -CH2OH, -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; and each of A and B is hydrogen or hydroxy; with the provisos that at least one of A or B is hydrogen and one of A or B is other than hydrogen when R3 is -CH3; and pharmaceutically acceptable salts thereof. 8 Among the many examples of the compounds covered by the invention in Carr 129 is 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-α,α-dimethylbenzeneacetic acid, that is to say, fexofenadine. That compound exists when, in the formula diagrammatically depicted above, R1, R2, A and B are hydrogen, n is 3 and R3 is -COOH. Claim 1 in Carr 129 is for a compound of the formula set out above, wherein - … R1 represents hydrogen or hydroxy; R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2; n is an integer of from 1 to 5; R3 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; and each of A and B is hydrogen or hydroxy; with the proviso that at least one of A or B is hydrogen; and pharmaceutically acceptable salts and individual optical isomers thereof. As explained above, fexofenadine is also disclosed by this claim. 9 There is an Australian equivalent of Carr 129: Patent No 531146 ("Carr 146"), published on 16 October 1980. Although the terminology is not precisely the same in all instances, it is sufficient to say that this patent also ostensibly discloses compounds of the same classes as does Carr 129, including fexofenadine. The one special aspect of Carr 146 which may be presently material is that Claim 2 therein, which otherwise follows the terms of Claim 1 in Carr 129, claims a "substantially pure" compound of the formula set out above, and has the following additional wording: R3 may also be -CH3 or -CH2OH; There is an extra proviso that, when R3 is -CH3, "one of A or B is other than hydrogen"; "pharmaceutically acceptable bioprecurors [sic]" are also included. 10 In Carr 129, a series of examples (to which I shall return in some detail below) ostensibly sets out how to prepare 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1- hydroxybutyl]-α,α-dimethylbenzeneacetic acid, that is, fexofenadine. The first example describes a synthesis for the intermediate compound ethyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate. That is a compound in which the chlorobutyl ketone is substituted on the dimethylated benzene ring at the para position (ie at 6 o'clock relative to the existing substituent). However, according to the patent in suit: Applicant has discovered that the preparation of ethyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate by reaction of 4-chlorobutyryl chloride, aluminum chloride, and ethyl α,α-dimethylphenylacetate in carbon disulfide, as described in Example 1 of U.S. Patent Nos. 4,254,130 and 4,285,958 provides an inseparable mixture of monosubstituted aromatic regioisomers of the formula: wherein the chlorobutyryl substituent is attached at either of the three aromatic carbons which are meta or para to the dimethylacetate substituent. These regioisomers are not separable by standard techniques of thin layer chromatography, or column chromatography, and low field proton nuclear magnetic resonance spectroscopy is inconclusive in identifying the product of this reaction as a mixture. 11 It is stated that it was known in the art that a monoalkyl substituent on a benzene ring is ortho (ie at 2 and 10 o'clock relative to the existing substituent), para directing in electrophilic aromatic substitution reactions such as a Friedel-Crafts reaction. Thus, it would be expected that the Friedel-Crafts reaction of 4-chlorobutyryl chloride with ethyl α,α-dimethylphenylacetate would yield predominantly a para-substituted product, because of the electron donating, para-directing character of the dimethylalkyl substituent combined with the steric hindrance associated with substitution at the ortho positions. However, the inventor states that, in practice, "the inductive electronic withdrawing effect of the carboxylic ester of ethyl α,α-dimethylphenylacetate counteracts the expected alkyl electron donating effect, resulting in no significant directing effect for the aromatic substitution reaction." It is said that "a statistical mixture of meta to para regioisomers results, with the two meta positions predominating." (The meta positions are those which are situated at 4 and 8 o'clock relative to the existing substituent.) 12 In the patent in suit, the inventor claims that the mixture of regioisomers will endure if the product of this example in Carr 129, as achieved in practice, is further reacted in an attempt to derive any of the compounds claimed by that patent. Referring to the mixture -

• it is said: Although the … mixture of regioisomers can be analyzed by HPLC experiments, a practical separation to obtain gram quantities of substantially pure regioisomers has not been achieved. Each mixture (including the first), would be expected to contain 33% of the para isomer and 67% of the meta isomer. Since these components are inseparable, it has not been possible to obtain either of the regioisomers in each mixture in substantially pure form. Thus it is said that Carr 129 (and implicitly Carr 146) does not in fact give substantially pure parasubstituted compounds. 13 In the patent in suit, there is a claim for various methods to prepare these piperidine derivative compounds as such, ie to prepare compounds which are unembarrassed by the presence of meta regiosomers. However, it is not the method claim in the patent which is of principal concern in this proceeding. The inventor claims to have invented the compounds themselves, including, most relevantly for present purposes, fexofenadine. It is asserted in the specification that the relevant prior art, contrary to ostensible indications, did not disclose these compounds in substantial purity because any compound made in accordance with it would be "an inseparable mixture" of the para and meta regiosomers. By contrast, the inventor here makes a claim to "substantially pure" piperidine derivative compounds.

The respondents' primary case on novelty: Lundbeck and Apotex 14 The patent in suit will be susceptible to revocation if the invention to which it refers, so far as claimed in any claim, is not novel by comparison with the prior art base as it existed before the priority date (Patents Act 1990 (Cth) ss 138(3)(b) and 18(1)(b)(i)). The invention is to be taken to be novel in this sense unless it is not novel in the light of information of the kind referred to in s 7(1) of the Patents Act. The respondents say that Carr 129 and Carr 146 are part of the prior art base in the sense that they were documents that were publicly available at the priority date. That is undoubtedly so. The contentious question is whether the invention claimed in the patent in suit is not novel in the light of the information set out in Carr 129 and Carr 146. 15 The respondents say that the invention claimed in Claim 1 of the patent in suit is for a class of compounds that were in terms disclosed in the Carr patents, considered as documents. According to the respondents, in the case of a compound patent, once the specific compound is found to have been disclosed in terms in the prior art base, the conclusion follows that the invention is not novel and, therefore, not patentable. For this proposition they rely upon the recent judgments of the Full Court in H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151 and Apotex Pty Ltd v Sanofi-Aventis (2009) 82 IPR 416. In Lundbeck, Bennett J said (with the assent of Middleton J) (177 FCR at 192 [180]): "Where the prior publication discloses exactly what is claimed, there is anticipation". That was not the situation in Lundbeck itself, but it was in Apotex, in which case the court held that the disclosure of a particular enantiomer in the prior art anticipated a later patent which claimed that enantiomer, notwithstanding that a compound consisting only of that enantiomer had never, apparently, been made. 16 In the present case, it was accepted by AMR that the Carr patents disclosed the relevant compounds, including fexofenadine, in terms. It was also ultimately accepted by AMR that that disclosure was of compounds that were pure as such. In the case of fexofenadine, looking only at the Carr patents as documents, substantially pure fexofenadine was disclosed. However, it was submitted that the Carr patents were not anticipatory because they did not provide, for a skilled person working in the relevant area, information as to the means by which the compounds to which they referred could practically and effectively be brought into existence. In this respect AMR relied on Hill v Evans (1862) 1A IPR 1, 6, Acme Bedstead Co Ltd v Newlands Brothers Ltd (1937) 58 CLR 689, 707 and Olin Corporation v Super Cartridge Co Pty Ltd (1977) 180 CLR 236, 260-261. The respondents' primary case on novelty is that, even if this be so, it does not matter: if the prior art discloses exactly what is claimed in the patent in suit, the invention will not be novel. This first point is substantially one of law and, if correct, would require me to uphold the respondents' novelty cases without more. 17 AMR commences with the words of Lord Westbury in Hill v Evans (1A IPR at 6-7): The question then is, what must be the nature of the antecedent statement? I apprehend that the principle is correctly thus expressed: the antecedent statement must be such that a person of ordinary knowledge of the subject would at once perceive, understand, and be able practically to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful. If something remains to be ascertained which is necessary for the useful application of the discovery, that affords sufficient room for another valid patent. By the words of the statute of James, it is necessary for the validity of a patent that the invention should not have been known or used at the time. These words are held to mean "not publicly known or publicly used". What amounts to public knowledge or public user is still to be ascertained. One of the means of imparting knowledge to the public is the publication of a book, or the recording of a specification of a patent. If, therefore, in disproving that allegation which is involved in every patent, that the invention was not previously known, appeal be made to an antecedently-published book or specification, the question is, what is the nature and extent of the information thus acquired which is necessary to disprove the novelty of the subsequent patent? There is not, I think, any other general answer that can be given to this question than this: that the information as to the alleged invention given by the prior publication must, for the purposes of practical utility, be equal to that given by the subsequent patent. The invention must be shewn to have been before made known. Whatever, therefore, is essential to the invention must be read out of the prior publication. If specific details are necessary for the practical working and real utility of the alleged invention, they must be found substantially in the prior publication. …. Upon principle, therefore, I conclude that the prior knowledge of an invention to avoid a patent must be knowledge equal to that required to be given by a specification, namely, such knowledge as will enable the public to perceive the very discovery, and to carry the invention into practical use. AMR relies also on what Dixon J (in Acme Bedstead 58 CLR at 707) described as the "well-settled rule" - … that a prior paper publication, giving information that does not become part of common knowledge, does not invalidate a subsequent patent unless it supplies enough information to enable a person of proper skill in the art to produce the mechanical device or appliance or carry out the process claimed in the later specification. 18 According to AMR, the principle to which Lord Westbury referred was endorsed by Stephen and Mason JJ (with the concurrence of Barwick CJ) in Olin. That case concerned a patent for a plastic shotgun cartridge, in which an earlier patent, described as "the Core patent", had been cited as anticipatory. A plastic shotgun cartridge, and the general means by which it might be produced, had indeed been disclosed in the Core patent, but Stephen and Mason JJ held that the disclosure was not sufficiently developed to sustain the case of anticipation. Their Honours said (180 CLR at 260-261): The Core patent did not disclose a process or means of producing the wanted article. Nor did it reveal any advance in knowledge or development on which the appellant's patent depended for its success. All that the Core patent did was to describe an article without describing the effective means by which it could be produced. To our mind this is not enough to justify the conclusion that the appellant's claim fails for want of novelty. So much at least emerges from the remarks of Lord Westbury L.C. in Hills v Evans: "[in order to invalidate the subsequent patent] the antecedent statement must be such that a person of ordinary knowledge of the subject would at once perceive, understand, and be able practically to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful ... the information as to the alleged invention given by the prior publication must, for the purposes of practical utility, be equal to that given by the subsequent patent". In N. Guthridge Ltd. v Wilfley Ore Concentrator Syndicate Ltd., Griffith C.J. quoted Lord Westbury L.C. in Betts v Menzies, when his Lordship said that a prior patent "ought not to be held to be an anticipation of a subsequent discovery, unless you have ascertained that the antecedent specification discloses a practicable mode of producing the result which is the effect of the subsequent discovery". In the same case, Barton J, applied the observations of Lord Westbury L.C. in Hills v Evans and Betts v Menzies. 19 I should deal straight away with two submissions about Olin that were made on behalf of the Sigma respondents. They submitted first that the passage set out above was obiter, and that I am not, therefore, bound to follow it. Sitting as a single member of the Federal Court, I do not find this an attractive submission. It is true that, of a number of challenges to validity in Olin, their Honours in the High Court upheld the fair basis point, but they gave detailed consideration to the novelty aspect, explaining clearly the respects in which the Core patent would not have been anticipatory. If Olin stood alone and were directly applicable to the facts of the present case, clearly it would have to be followed. Secondly, the Sigma respondents submitted that the respects in which Olin had been followed or applied in this court related to aspects of validity other than novelty - obviousness and fair basis for instance. It was said that the principles set out by Mason and Stephen JJ on novelty had never been followed here. Whether or not this is so, the point is really no more than a development of the first one. For reasons to which I have referred, even in the absence of subsequent application in this court, I consider that the only course properly open to me would be to follow Olin, if it was not to be distinguished. 20 As it happens, the two recent Full Court judgments on which the respondents relied did deal with the principle for which Olin stands, and it is by reference to them, and to a proper understanding of them, that the legal dimension of the respondents' novelty case must be approached. 21 The novelty point which arose in Lundbeck was whether a patent which claimed the (+) enantiomer of a compound had been anticipated by certain prior art information which disclosed a racemic mixture of (+) and (-) enantiomers (177 FCR 151 at [193]), or by other prior art information which disclosed the (-) enantiomer as such, but stopped short of characterising the (+) enantiomer, the preparation of which would, it was conceded, require the taking of another inventive step (at [205]). Because the prior art considered in Lundbeck stopped short of disclosing the very thing claimed under the patent in suit, the result of that case is not directly applicable to the facts of the present case. 22 In Lundbeck, however, Bennett J (with the assent of Middleton J) undertook a detailed examination of the law of novelty in respects which are, on any view, presently relevant. Her Honour said (177 FCR 151 at [173]): The following general propositions emerge from the authorities: • An invention is a piece of information (Merrell Dow Pharmaceuticals Inc v HN Norton & Company Ltd (1995) 33 IPR 1 at 8). It follows that a disclosure is the communication of information. • Commonly the only question may be whether the prior publication describes the claimed invention with sufficient clarity (Bristol-Myers 97 FCR 524 at [67]). • The disclosure is assessed by reference to the skilled addressee, a person of ordinary skill in the art. • The question is whether the prior publication is sufficient to make the claimed invention apparent to the skilled addressee (Nicaro Holdings Pty Ltd v Martin Engineering Company (1990) 91 ALR 513 at 529). • A prior publication does not invalidate a patent unless it supplies sufficient information to enable a person of ordinary skill to produce the product subsequently claimed (Acme Bedstead Company Ltd v Newlands Brothers Ltd (1937) 58 CLR 689 at 707). A specification is not to be read as in a vacuum but by the reader having at least the common knowledge of the art (Acme Bedstead 58 CLR at 701; Nicaro 91 ALR at 530). • The requirement is that a person of ordinary knowledge of the relevant subject would be able practically to apply the prior published discovery without the necessity of making further experiments (Hill v Evans 1A IPR at 6-7). • The further experiments do not include those that formed part of standard procedure or common general knowledge. They are experiments with a view to discovering something not disclosed (Van der Lely 1A IPR at 90). • The further experiments do not mean ordinary methods of trial and error (Van der Lely 1A IPR at 90). • If the alleged anticipation is to a process that produces the claimed product, it is not an anticipation if the process would not necessarily achieve the result claimed for it (Olin Corporation v Super Cartridge Company Pty Ltd (1977) 180 CLR 236 at 260-261). • Something less than a full description of the invention allegedly anticipated may be sufficient to invalidate it for want of novelty (Nicaro 91 ALR at 529). • Something less than a full description of an effective means by which the combination claimed in a patent may be produced may be sufficient to a reader having common general knowledge in the art (Nicaro 91 ALR at 531). • A direction, recommendation or suggestion may be implicit in what is described (Bristol-Myers 97 FCR 524 at [67]). • A disclosure that describes an effective means by which a claimed invention may be produced falls short of anticipation if it requires the exercise of inventive ingenuity or the taking of any inventive step (Nicaro 91 ALR at 531). • Where the prior disclosure is to a broad chemical claim encompassing many compounds, there may not be anticipation in the absence of the skilled addressee understanding or perceiving a specific compound in the disclosure (Imperial Chemicals Industries Pty Ltd v Commissioner of Patents (2004) 213 ALR 399 at [64]-[65]). That is, there is no actual description of the particular compound to the skilled addressee; there is no relevant disclosure. There may be a distinction, albeit fine, between a "fleeting" or "paper" disclosure or the "intellectual content" of a disclosure on the one hand and a "disclosure for novelty purposes" or "enabling disclosure" on the other (Imperial Chemicals at [68]; University of Georgia Research Foundation v Biochem Pharma Inc (2000) 51 IPR 222, a decision of Dr Barker of the Patent Office described by Crennan J in Imperial Chemicals as a "sound account of the relevant distinctions between a 'paper disclosure' and an 'enabling disclosure' in the field of chemistry" (at 412)). It depends on what the skilled reader would understand. 23 Bennett J considered Hill v Evans and continued (at [178]-[183]): 178 Care must be taken to distinguish between the tests for novelty and want of inventive step, in particular when looking to see what the prior art "teaches". The concept of novelty in Australia involves a comparison between the invention as claimed in the claims of the patent and prior art information. Often, this must be determined by looking to prior publications which are to be read by the skilled addressee to determine what they disclose. Generally speaking, the consideration of what a prior publication "teaches", especially when one talks of "teaching away" from the claimed invention, tends to be relevant to questions of obviousness and inventive step. 179 As Lord Hoffmann said in Merrell Dow 33 IPR at 8, an invention is a piece of information and making matter available to the public therefore requires the communication of information. Whether or not such information has been communicated depends on the subject matter of the claim and the extent of the prior disclosure to the skilled addressee. 180 Where the prior publication discloses exactly what is claimed, there is anticipation. This can be objectively determined and, apart from an understanding of terms of art, the evidence of the skilled addressee is not likely to be of much further assistance. However, this does not always occur and many of the authorities contain discussions of the extent to which a disclosure less than the entirety of the claim constitutes an anticipation of a product or a process to deprive the claimed invention of novelty. 181 If the prior art discloses some but not all integers of a claimed patent to a product, such as a combination, there is anticipation if the skilled addressee would add the missing information as a matter of course and without the application of inventive ingenuity or undue experimentation (Nicaro 91 ALR at 530-531). 182 It may be that the prior disclosure is of a method that produces the claimed product. If that method leads inexorably to the product, there is anticipation (General Tire 1A IPR at 138). If it may or may not result in the claimed product, there is no anticipation. 183 It is these last two examples that, in Australia, could be said to be within a shorthand description of "enabling disclosure". That is, the disclosure is not complete but it is sufficient to enable the skilled addressee, in the ordinary course and without invention, to add what is missing in the prior publication to obtain the claimed invention. The term "enabling disclosure" may also be apposite to disclosure to the skilled addressee of an asserted prior use: whether what the skilled addressee observes on inspection is sufficient to enable him or her to comprehend the complete invention (eg Insta Image Pty Ltd v KD Kanopy Australasia Pty Ltd (2008) 78 IPR 20; Jupiters [Jupiters Ltd v Neurizon Pty Ltd (2005) 222 ALR 155]), that is, whether it is sufficient to amount to a disclosure of the invention. 24 Bennett J then considered the speech of Lord Hoffman in Smithkline Beecham plc's (Paroxetine Methanesulfonate) Patent [2006] RPC 10, and in particular the UK requirements of disclosure and "enablement" on a want of novelty case. Her Honour continued (at [189]-[190]): For the purposes of disclosure, the prior art must disclose an invention which, if performed, would necessarily infringe the patent. Once the very subject matter of the invention has been disclosed, the person skilled in the art is assumed to be willing to make trial and error experiments to get it to work. For the purposes of disclosure, the disclosure is either of an invention which, if performed, would infringe the patent, or it is not. When Lord Hoffmann went on to say that, for the purposes of enablement, the question is no longer what the skilled person would think the disclosure meant but whether he was able to work the invention which the Court has held it to disclose, his Lordship was talking of what, in Australia, is covered by sufficiency of disclosure or description. It follows that, where the prior publication is of the subsequently claimed invention, that is sufficient. Where the prior disclosure falls short of a complete disclosure, the question of the sufficiency of that disclosure arises. It is there that consideration must be given to the quality of a disclosure to the skilled addressee armed with common general knowledge. It is in that context that, in a limited fashion, questions of "enablement" can be said to arise. The use of that expression tends to cause confusion between anticipation and sufficiency. Rather, the Court, armed with the evidence of the skilled addressee as to terms of art and the nature and extent of the disclosure in the prior art document, must determine whether the prior disclosure is sufficient to enable the skilled addressee to perceive, understand and, where appropriate, apply the prior disclosure necessarily to obtain the invention. 25 In Apotex, the d-enantiomer of a compound was claimed. The Full Court held that the relevant prior art disclosed both that enantiomer and the l-enantiomer (82 IPR 416 at [77]). However, the prior art did not contain a "description of a process to obtain the enantiomers" (at [78]). This led the patentee to advance a submission identified by Bennett and Middleton JJ as follows (at [79]): Sanofi points out that no process of resolution of the racemate into the constituent enantiomers, or of preparation of the individual enantiomers of the derivatives, is described and that successful separation of the enantiomers was by no means assured, even if the prior art patents contained a direction to do so. Sanofi also says that, until the enantiomers are prepared, it is not known which is the d-enantiomer and which is the l-enantiomer, nor their levels of activity and toxicity. In short, Sanofi submits that further discovery is needed before the invention claimed in the patent is obtained. The patentee submitted (at [95]) that "to anticipate a claimed invention, a prior paper disclosure that does not itself clearly show the production of the claimed invention must inevitably result in the skilled addressee arriving at the claimed invention". Bennett and Middleton JJ noted that the patentee also made the following submission (82 IPR 416 at [96]): Sanofi submits that the requirement is for clear disclosure and that, in relation to the prior art patents, where: (a) the patentee had not made the d-enantiomer of PCR 4099; (b) the patentee did not show a method of producing it by resolving it; and (c) but it is possible that the skilled addressee, using known methods, might be able to make it. there is no clear disclosure of the d-enantiomer in the prior art patents. The position adopted by the party challenging the patent on novelty grounds, as recorded by their Honours, was as follows (at [103]): Apotex accepts that a disclosure will not be sufficiently clear if it is necessary to supplement the disclosure by means of experiments or other sources of information in order to perceive the disclosure. However, that is not the same as accepting that, where there has been disclosure of a product, the method of producing that product must also be disclosed. 26 Bennett and Middleton JJ referred to the judgment of the Full Court in Lundbeck, and specifically to the statement by Bennett J that, where the prior publication disclosed exactly what was claimed, there was anticipation. Their Honours continued (at [106]): In this case, there was a disclosure of the enantiomers in the prior art patents. Those enantiomers were not only described, they were also claimed. Thus there was a clear direction to the skilled reader to prepare the enantiomers and in addition, but not necessarily, it was made clear that such enantiomers were, or were likely to be, useful for the desired purpose. The primary judge was not in error in concluding that the prior art patents disclosed the enantiomers as part of the invention and as compounds predicted to have the beneficial qualities of the compounds exemplified. If his Honour were correct in his conclusion that the skilled reader would understand to separate the enantiomers and would know the methods to apply, and that the preparation of the d-enantiomer was routine and involved no inventive step, it is hard to see how his Honour erred in concluding that there had been disclosure of the d-enantiomer to the skilled addressee and that a claim to the d-enantiomer had been anticipated: Ranbaxy. Their Honours rejected the proposition that there could be no anticipation unless the compound disclosed in the prior art had actually been made and the making of it there described. Their Honours continued (at [108]): That is, Sanofi's submissions are to the effect that it would be necessary for a prior publication, in every case, to set out the method of preparation, no matter how routine, and presumably the detailed methodology of each step taken in the preparative process. That cannot be correct. 27 In the present case, the respondents say that the compounds of interest are disclosed, as such, in Carr 129 and Carr 146 and that, in accordance with Lundbeck and Apotex, that circumstance is sufficient to constitute anticipation. They point out that, in Apotex, the prior art disclosed no process for the preparation of the d-enantiomer and that there was no evidence that the denantiomer had ever been prepared. If the patentee could not, in that setting, resist a challenge to novelty, AMR could be in no better a position in the present case, whether or not the Carr patents contained a viable description of how substantially pure compounds could be made. 28 As I have indicated earlier, AMR's case on novelty is based on Hill v Evans, Acme Bedstead and Olin. It says that only if the prior art discloses both the compound in question and an effective means for preparing it will that art be anticipatory. The only exception to the requirement for the disclosure of effective means is where the skilled worker would, from the information about the compound given in the prior art, readily appreciate, as a matter of routine, how to go about preparing it. If that condition is satisfied, or if the effective means of preparation are disclosed as such, it does not matter that the compound may never have been prepared in fact. It is said that Apotex was a case in which, from the identification of the compound in the prior art, it was readily apparent to the skilled worker how it might have been prepared, and that that could have been done as a matter of routine. It was, according to AMR, neither here nor there that no-one had ever in fact prepared the compound. 29 AMR submits that the Full Court in Lundbeck could not have intended to set aside the principles long-established since Hill v Evans, and adopted in Australia in Acme Bedstead and Olin. Those principles required the disclosure not only of the compound claimed to have been invented under the patent in suit, but also an effective means of preparing that compound. AMR points out that Bennett J discussed Hill v Evans at some length, without any suggestion that it was not good law in Australia: and neither would such a suggestion have been easily sustained, in the light of the acceptance of the speech of Lord Westbury in Olin and elsewhere. As to Olin itself, it was pointed out that Bennett J referred to this important authority only in relation to a process patent (the 9th bullet point in para 173), and it is unlikely that her Honour intended to depart, sub silentio as it were, from the principles enunciated by Mason and Stephen JJ with respect to product patents. 30 The respondents - particularly in this regard the Sigma respondents - submitted that AMR had overstated the proposition for which Olin stood. Properly understood, to the extent that it relates to a patent for a product, Olin was to be seen as a case of a "missing integer". The critical claim in the patent in suit in that case defined a product with (180 CLR at 259): … [a] relatively thin walled tubular structure having a base at one end and formed of highly crystalline polyolefin polymer of substantially regularly ordered molecular structure, said structure being characterized by the fact that the wall of the structure has been formed in the solid state at an operative temperature below the crystalline melt temperature of the polymer to provide an increase in tensile strength of the polymer in said wall at a point remote from the base of at least twice the tensile strength of the polymer in said base. Having dealt with the respects in which Mason and Stephen JJ held that the Core patent did not disclose an effective means of producing the article in question, the Sigma respondents drew attention to the following passage in their Honours' reasons (180 CLR at 260): Moreover, the Core patent made no mention of highly crystalline polyolefin polymer. Even if such materials were comprehended by the language of the patent it does not arithmetically express the increase of strength which will be obtained, whereas claim 10 asserts a twofold increase in strength. Olin was, according to the Sigma respondents, more readily to be explained as a case of missing integers, rather than as a case in which the effective means of producing the product had not been disclosed. 31 There are indications in the judgment of Bennett J in Lundbeck that her Honour did not intend to endorse, or to apply to the facts before the Full Court, each of the "general propositions" set out in para 173 of her reasons. If read literally, some of those propositions would seem, with respect, to be difficult to reconcile with others of them, and, indeed, with the conclusions which her Honour expressed at para 180 thereof. I have in mind the proposition, drawn from Acme Bedstead, that - … [a] prior publication does not invalidate a patent unless it supplies sufficient information to enable a person of ordinary skill to produce the product subsequently claimed; and the proposition that - … [t]he requirement is that a person of ordinary knowledge of the relevant subject would be able practically to apply the prior published discovery without the necessity of making further experiments; and the proposition that - … [a] disclosure that describes an effective means by which a claimed invention may be produced falls short of anticipation if it requires the exercise of inventive ingenuity or the taking of any inventive step. I consider that Bennett J's purpose in para 173 of her reasons was to go no further than to lay out the general propositions that emerged from the authorities. Not all of them were to be assumed to be applicable to the questions which her Honour subsequently determined. 32 Notwithstanding that qualification, although it is true that Bennett J made only passing reference to Olin, her Honour considered Hill v Evans in some detail. She cited the passage on which AMR relies here (177 FCR 151 at 191 [174]), and noted that Lord Westbury had explained what that meant "in a context where a prior publication does or does not actually disclose the subsequent invention". Her Honour continued (at [174]): He said that the information as to the alleged invention given by the prior publication must, for the purposes of practical utility, be equal to that given by the subsequent patent. It is apparent that in Hill v Evans, the disclosures in the prior publications were not of the integers of the subsequently claimed invention. His Lordship did not say that the invention had to have been previously made but that it had to have been previously made known. Bennett J later said (at [177]): Lord Westbury endorsed the conclusions in Househill Company v Neilson 1 Webst Pat Ca 718. In that case, Lord Lyndhurst held that where a prior publication included a distinct and clear description of a machine, there was anticipation if the description corresponded with that in the patent, even though the machine as described in the prior publication had never been worked. In Hill v Evans, there was information missing in the prior publications and there was no anticipation. 33 It was against the background of this discussion that Bennett J expressed her "conclusion" on the matter of anticipation, which I have set out at paras 23 and 24 above. There can, in my view, be little doubt but that her Honour intended the statement that "where the prior publication discloses exactly what is claimed, there is anticipation" to be understood in the categorical terms in which it was expressed. As her Honour made clear, some form of qualification was to be introduced only where there was "a disclosure less than the entirety of the claim". 34 That understanding of Lundbeck was the very basis upon which the later case of Apotex was decided. It was submitted on behalf of AMR that Apotex could be explained by some less categorical proposition than that which I have identified as established by Lundbeck. Attention was drawn to the passage in the joint reasons in which their Honours observed that "the skilled reader would understand to separate the enantiomers and would know the methods to apply" (82 IPR 416 at [106]). AMR also stressed that its case here is in no sense inconsistent with what Bennett and Middleton JJ said at para 108, which I have set out at para 26 above. It was not AMR's case that, in every case, the method of preparation "no matter how routine" had to be set out in the prior art before there could be anticipation. If the method of preparation was to be readily discerned by the skilled reader, and could be applied as a matter of routine, the later invention would not be novel. AMR stressed that its case is concerned wholly with the situation in which the method of preparation did not satisfy this requirement and had not been disclosed as such in the prior art: then, according to AMR, mere disclosure of the compound by name would not amount to anticipation. 35 The extent to which Bennett and Middleton JJ, in Apotex, considered that the reasons of Bennett J in Lundbeck were particularly apposite to the case before them is to be seen in the following paragraph in their Honours' reasons (82 IPR at 433 [104]): Some of the same issues concerning novelty arose in Lundbeck, a case which also involved a claim to the (+)-enantiomer of a racemate. From the consideration in Lundbeck, the following is apposite to the consideration of anticipation by the prior art patents in this case: • Where the prior publication discloses exactly what is claimed, there is anticipation: Lundbeck at [180]. • There is anticipation if the skilled addressee would add missing information to what is disclosed in the prior art as a matter of course and without the application of inventive ingenuity or undue experimentation: at [181]. A disclosure is sufficient if it enables the skilled addressee, in the ordinary course and without invention, to add what is missing in the prior publication to obtain the claimed invention: at [183]. • If the prior art discloses the very subject matter of the invention, the person skilled in the art is assumed to be willing to make trial and error experiments to get it to work: at [189]. If the disclosure is of an invention which, if performed, would infringe the patent, there is anticipation. • The question is whether the disclosure is sufficient to enable the skilled addressee to perceive, understand and, where appropriate, apply the prior disclosure necessarily, but within the ordinary limits of trial and error, to obtain the invention: at [190]. Of these four points, the first is the simple proposition of law on which the respondents rely here. The second is concerned with the "missing integer" situation. The third complements the first in a situation in which the prior art discloses something which, without "trial and error experiments", does not "work". The fourth, perhaps, provides the most obvious support for the position of AMR in the present case, but when para 190 in Lundbeck is examined, it will be seen that Bennett J was there concerned with the situation in which the prior art did not give "complete disclosure" (ie of the compound in question). In my view, the only unstrained reading of her Honour's reasons in Lundbeck is that the disclosure of "exactly what is claimed" must be regarded as a "complete disclosure", whether or not it is accompanied by a statement of the effective means of preparation. 36 In the view I take of the law as expounded in Lundbeck and Apotex, the disclosure of a compound by exact naming in the prior art is sufficient, of itself, to constitute anticipation. As a single Judge of the court, I do not believe I am in any position to consider the consistency of these Full Court judgments with earlier authority, however high. That authority was within the jurisprudence to which Bennett J gave extensive consideration in Lundbeck. I am bound by her Honour's conclusions, to the extent that they relate directly to the facts of the present case. For reasons set out above, I take the view that they do so relate, and that the disclosure of the relevant compounds in Carr 129 and Carr 146 in terms anticipated the invention in Claim 1 of the patent in suit. It follows that it likewise anticipated Claims 6, 7, 8, 9 and 10. As indicated earlier in these reasons, Claim 11 is for a class of compounds made by reference to particular processes. It was no part of the respondents' cases that the mere disclosure of those compounds in the prior art anticipated the invention so far as referred to in Claim 11. My conclusion in this part of my reasons does not extend to that claim. 37 Before leaving this area of controversy, I should say something about the claim in the patent in suit to "substantially pure" compounds. Ultimately, it was not submitted on behalf of AMR that the Carr patents did not disclose the relevant compounds as such. AMR's point, rather, was that, if the skilled addressee set about to prepare any one of these compounds in accordance with the instructions in Carr 129, he or she would not obtain parasubstituted purity. But it was not submitted that, if the view I take of the law as expounded in Lundbeck and Apotex be the correct one, the patent in suit stood apart from Carr 129 only because of the claim to substantial purity. Thus the point raised particularly by the Sigma respondents that the invention in suit was on any view anticipated by Claim 2 in Carr 146, which claimed "substantially pure" compounds, does not arise. It would, however, have been a complete answer to any contention by AMR that the very compound claimed under the patent in suit had not, in terms, been disclosed in the prior art.

The respondents' alternative case on novelty: Effective means of preparation 38 In the alternative, the respondents submitted that, if it were necessary (to establish want of novelty) that the prior art base disclosed not only the compounds claimed in the patent in suit but also an effective means for their preparation, Carr 129 and Carr 146 did so. What would be perceived and understood, and what could be practically applied (see Hill v Evans) are, of course, questions to be approached from the perspective of the skilled addressee. Conformably with this requirement, the parties called organic chemists of some standing in their profession to opine on these questions. AMR called Prof Christopher Easton, Distinguished Professor at the Research School of Chemistry, Institute of Advanced Studies, Australian National University; Alphapharm called Prof David Black, Professor of Organic Chemistry at the University of New South Wales, and Prof Bruce Wild, Emeritus Professor in the Research School of Chemistry at the Australian National University; and the Sigma Respondents called Dr Alan Robertson, Chief Executive Officer and Managing Director of Pharmaxis Ltd. 39 Although both Carr 129 and the patent in suit disclose a series of compounds, the question of effective means of preparation was addressed by the parties with reference to one only of them, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1- hydroxybutyl]-α,α-dimethylbenzeneacetic acid, that is, fexofenadine. The parties' cases were based on the implicit assumption that the means of preparation of this compound disclosed in Carr 129 might stand, in effect, as a proxy for the like means so disclosed with respect to the other compounds. I shall proceed by reference to that assumption. 40 According to Carr 129, fexofenadine could be synthesised by the sequential combination of the methods described in Examples 5(A), 5(B), 2 and 3 therein, the product of each of which provided the starting material for the next. Part (A) of Example 5 is as follows: To 700 ml of carbon disulfide containing 36.5 g (0.254 mole) of 4-chlorobutyryl chloride is added 74.5 g (0.56 mole) of aluminum chloride with stirring at -10° C. Stirring is continued for about 15 minutes at about 25° C. then the mixture is recooled to 5° C. and 48.4 g (0.294 mole) of ethyl α,α-dimethylphenylacetate in 100 ml of carbon disulfide is added. The reaction mixture is stirred on an ice bath for 3½ hours then stirred to 15½ hours at 25° C. then poured into HCl-ice water and extracted with chloroform. The extract is washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated giving as a solid ethyl 4-(4-chloro-l-oxobutyl)-α,α-dimethylphenylacetate. Prof Wild described this as involving "a typical Friedel-Crafts acylation using aluminium chloride in carbon disulfide solvent". He identified the reaction scheme as follows: All of the experts who expressed a view on the subject gave effectively the same evidence as Prof Wild, namely, that, when they first looked at example 5(A), they anticipated a relatively uncomplicated Friedel-Crafts acylation. 41 Part (B) of Example 5 is as follows: A mixture of 4.5 g (0.0163 mole) of α,α-diphenyl-4-piperidinemethanol, 6.1 g (0.0205 mole) of ethyl 4-(4-chloro-l-oxobutyl)-α,α-dimethylphenylacetate, 5 g (0.05 mole) of potassium bicarbonate and 0.05 g of potassium iodide in 50 ml of toluene is stirred and refluxed for 72 hours then filtered. Ether then ethereal hydrogen chloride is added to the filtrate, and the resulting precipitate collected and recrystallized several times from methanol-butanone and butanone to give ethyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α- dimethylbenzeneacetate hydrochloride. M.P. 205.5°-208° C. Prof Wild said that this described "a reaction carried out in toluene over 72 hours under typical coupling conditions with use of potassium bicarbonate as base and potassium iodide as catalyst." He identified the reaction scheme as follows: 42 Example 2 of Carr 129 is as follows: Ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate hydrochloride A solution of 5.64 g (0.01 mole) of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride in 200 ml of absolute ethanol and 50 ml of methanol and 0.5 g of platinum oxide is hydrogenated at about 50 psi for about 1 hour until the infrared showed no evidence of a ketone carbonyl function. The solution is filtered and the filtrate concentrated leaving a residue which is recrystallized from butanone and methanol-butanone to give ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate HCl, M.P. 185°-187° C. Prof Wild described this as "a reduction of the carbonyl group of the keto-carbonyl group of [the product obtained under Example 5(B)] with hydrogen at 50 psi for 1 hour in ethanol-methanol over a platinum oxide catalyst". He added that Carr 129 indicated that sodium borohydride could also be used for this reduction step. He identified the reaction scheme as follows: 43 Example 3 of Carr 129 is as follows: 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyI]-1-hydroxybutyl]- α,α-dimethybenzeneacetic acid To a solution of 0.6 g of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-α,α-dimethylbenzeneacetate in 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 3½ hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanol-butanone to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1- hydroxybutyl]-α,α-dimethylbenzeneacetic acid, M.P. 195°-197° C. Prof Wild described this as "the hydrolysis of the ethyl ester to the desired acid under typical conditions". He identified the reaction scheme as follows: 44 Making reference to the steps described in these examples in Carr 129, Prof Black said that he would, as at 24 June 1993, have expected to be able to reproduce those steps and to prepare 4-[4-[(4-hydroxydiphenylmethyl)-1-piperidinyl]-l-hydroxybutyl]-α,α-dimethylbenzeneacetic acid as well as a pharmaceutically acceptable salt thereof. In his affidavit of 28 August 2009, which addressed Prof Black's affidavit in great detail, Prof Easton did not venture a comment on this aspect. Indeed, Prof Easton himself said that, if in 1993 he had wished to obtain fexofenadine of a purity which would be suitable for use as a component in a pharmaceutical substance, and had been provided with the synthesis described in Carr 129, he would have expected that, if he followed that synthesis, he would have obtained the desired product. It seems to have been common ground as between these two experts, then, that Carr 129 disclosed an apparently efficacious means of preparing fexofenadine. Nothing said by the other experts called by the parties contradicted that position. 45 However, beyond that basic level of consensus, Profs Black and Easton parted company. Fundamental to their disagreement on the subject of what might have been expected to occur when Example 5(A) was carried out was the effect of the ester attached to the alkyl group substituted on the benzene ring in the starting material (ethyl α,α-dimethylphenylacetate). As I understand it, the following propositions would be regarded as uncontroversial: an existing alkyl group substituted on the benzene ring is activating (ie electron donating), and leads predominantly to secondary substitution at the para and ortho positions; an existing ester group substituted on the benzene ring is de-activating (ie electron withdrawing), and leads predominantly to secondary substitution at the meta positions; depending on the size and structure of an existing alkyl substituent, steric hindrance may discourage secondary substitution at the ortho positions, with the result that substitution at the para position might be expected to predominate. 46 In the case of the starting material under Example 5(A) in Carr 129, there was a benzene ring with an alkyl substituent, but that group in turn had an ester attached to it. In his affidavit of 6 February 2009, Prof Black explained what he might have expected in these circumstances as follows: In my experience, this type of Friedel-Crafts acylation reactions commonly produce a mixture of regioisomeric products. I would predict that the para regioisomer would be the predominant product as the electron donating effect of the alkyl group induces the para arrangement. The electron withdrawing effect of the ester group also induces a meta arrangement. The effect of the ester is much weaker than the effect of the alkyl group however I would not be surprised to observe some meta isomer in the product. I would also predict that at least some ortho regioisomer could be formed, although steric hindrance of the bulky dimethylacetate functional group present in the ethyl α,α-dimethylphenylacetate reactant would limit the amount of ortho isomer formed. That is to say, although not directly substituted on the benzene ring, the existence of the ester group would result in the production of some meta-regioisomeric forms. I note that Prof Black expressed these views before he was given access to the patent in suit, and (at least so far as disclosed in the evidence) without having been informed of the outcome of attempts made on behalf of Alphapharm to synthesise the product said to be the product of Example 5(A). 47 Prof Easton did not agree. In his affidavit of 28 August 2009, he said: The Friedel-Crafts acylation described in example 5(A) of Carr '129 is said in that document to produce a para substituted regioisomer. Having regard to the fact that the mono-substituted starting material of example 5(A) of Carr '129 has a substituted alkyl substituent, which I would expect to be electron donating and therefore ortho/para directing, I would have expected that the Friedel-Crafts acylation of example 5(A) would have resulted in the production of the para regioisomer as described. While I would have expected that some amount of the ortho substituted regioisomer might form, I would have expected that there would be significant steric hindrance, such the para regioisomer would predominate. I would not have expected the formation of the meta regioisomer in any significant amount. In a mono-substituted benzene having an ester group directly attached to the aromatic ring, that ester group will have the effect of withdrawing electron density from the ring, thereby favouring substitution at the meta position. However, in the starting material used in Carr '129, the ester group is not directly attached to the aromatic ring, but rather is separated from the ring by an alkyl group. I would have expected that this separation would result in the ester group itself having no electron withdrawing effect on the ring. 48 Prof Black responded to this in his affidavit of 27 November 2009. He referred to "the first principles of electrophilic substitution … on a singly substituted benzene ring" as reported in standard teaching textbooks. He said: A simple (unsubstituted) alkyl group is activating and consequently ortho, para directing. Accordingly, if a simple (unsubstituted) alkyl group is present on a benzene ring it will be an ortho, para director. However, when the alkyl group is itself substituted, the activating nature of the alkyl group will be directly affected by the properties of the substituent. In the case of a strongly deactivating carboxylic ester substituent (like that in Example 5(A) of [Carr] 129), this will result in a predictable deactivating effect that will encourage meta substitution to occur. In my opinion, these First Principles were well known both before and after the Priority Date. They were familiar to me and, to my knowledge, to my colleagues from before this time. In his oral evidence in the concurrent session, Prof Black expanded on this by providing a simple explanation of the reason why the existence of a carboxylic ester substituent on the alkyl group would reduce the extent to which that group was activating. It related to the energy barrier of the transition state in the reaction by which the incoming group comes to be substituted on the ring. Prof Black said: Once you change the group on the benzene ring from just methyls and you have Cmethylmethyl and then an electronwithdrawing group, being the carboxylic ester, you have reduced the capacity of that group to be activating. What that means is that the energy barrier, the transition state for the formation of para, is raised and so it becomes closer to the same energy barrier for meta, and once you do that and you have the two trajectories relatively close together, then it is very difficult to get one of the isomers without getting the other one. 49 I should also set out a question and answer from the cross-examination of Prof Black: As to the potentiality for the meta isomer, your expectation was that there might be some, but not in a significant amount. Is that correct? - My expectation was that there would be some. Whether it would be small or - my expectation was that it would be less than the para. Essentially, the group, if I can just explain my reasoning, the group that is attached to the benzene ring, the atom directly attached, is the main atom of directing influence and that is normally electron donating favouring para and ortho. But once you associate with that an electron withdrawing group, it will weaken the electrondonating activation of the directly attached atom. Now, whether it is sufficient to override that directing influence or not is something that is a matter of guesswork, or was on my part at this stage. But it was clear that there would be an electronwithdrawing effect that would at least weaken the para drive of that group as a whole, and whether it completely wipes it out - Uggeri, I think, says it would wipe it out. That is something you would really have to do the experiment in order to find out, but it would decrease that advantage of getting the para direction and if you decrease that, you then increase the possibility of getting meta. In its written submissions, AMR referred to all but the first two sentences of this answer. I consider that Prof Black's statement that his expectation was that the meta regioisomer would be less than the para regioisomer is significant in the present context. 50 In those submissions, AMR also attributed to Prof Black (amongst others) an expectation that "[a]ny meta regioisomer would be present in 'small quantities' only". The quoted reference to "small quantities" appears to have come from Prof Black's affidavit of 6 February 2009, in which he said (apropos the product of Example 5(A)): No melting point is indicated for the solid product and the yield is also not reported at this first step so it is difficult to know precisely what the level of purity is. The impurities in the sample are likely to be small quantities of structural isomers. The only other impurity which may be present is unreacted starting material. This statement came immediately after the paragraph of Prof Black's affidavit which I have set out in para 47 above. Under cross-examination, Prof Black confirmed that the structural isomers referred to were the meta and the ortho regioisomers, and that, notwithstanding the presence of some of the meta regioisomer, his expectation would have been that the para regioisomer would predominate. 51 Prof Easton did not add anything to his earlier evidence in direct response to these explanations by Prof Black, but he made an observation in response to something said by Prof Black about the work of Prof Wild's technical assistant, Mr Paul Gugger, under Example 5(A) (to which I refer below) which, it seemed to me, encapsulated his (Prof Black's) position on the question whether some meta regioisomer might be expected from the reaction in Example 5(A). To set the context, what Prof Black said was: … there is very little evidence given in the patent, there are no spectra, there is no real data, but that is typical of most of these things and equally typical of the Australian patent. When writing up the description of a compound, it would be normal to say, "This compound was prepared in a certain way and delivered as the experimental procedure is written down for 5(A), 5(B) and so on." It is very rare and extremely unlikely that there would be any comment about how difficult it was to actually get this and, "We had to separate it from all sorts of other things," people just don't usually write this. They might mention it if it is in a learned journal publication, something like that could be mentioned in the discussion process, part of that paper, but it is almost never written in the experimental section. In describing how you would prepare a certain compound, you get the procedure for getting that compound without any discussion of a general nature. So it's not surprising, to me, that the patent says, where it describes the formation of 5(A), that it is the para isomer because it is the para isomer but with some other stuff there as well, but it goes on then to 5(B) because they are focusing on the synthesis of 5(B) and beyond. Prof Easton's comment was: … I would have to say that I would be very surprised to see a compound specifically named when it was only produced in 30 per cent purity or as a 1:1, approximately 1:1 mixture, of regioisomers. So I disagree with his comments that a compound specifically named as being the product of a protocol would not be produced essentially as a pure material. In this passage, "30 per cent purity" was a reference to the largest single component in the product which Mr Gugger obtained under Example 5(A): inferentially the para regioisomer (see para 98 below). 52 Prof Wild also expected that a mixture of the para and meta regiosomers could result from the reaction described in Example 5(A) of Carr 129. His theoretical justification for that expectation was: Due to the steric hindrance of the bulky dimethylacetate functional group present in the ethyl α,α-dimethylphenylacetate reactant, substitution at the ortho position of the aromatic ring would not be preferred. On the other hand, the para position of the ring is the least hindered and substitution in that position would lead to the major regioisomer of the product. Prof Wild supported his view with a reference to a publication by E.D. Morgan entitled "Synthesis of p-Alkylphenylacetic Acids" (Tetrahedron, 1967, 23, 1735-1738) in which it had been reported that, following similar Friedel-Crafts acylations of phenylacetic esters with several acyl halides, mixtures of alkyl esters of acylphenylacetic acids in ratios of ortho:meta:para (4-6):(38-49):(44-58) were obtained. The conclusion in that reference was that the meta and para positions were preferred, with ratios of 38-49 and 44-58, respectively. Prof Wild continued: Despite the para position being the least hindered and so preferred in the reaction, there is a similar proportion of meta regioisomer produced. This is due to there being two available meta positions, but only one para position. Despite there being two ortho positions, the proportion of ortho regioisomer formed is almost insignificant because of the severe steric hindrance of the dimethylacetate group that effectively blocks this position. 53 To employ the words of Lord Westbury in Hill v Evans, all of Profs Easton, Black and Wild perceived and understood how to prepare fexofenadine from the examples given in Carr 129. However, Prof Easton's understanding was based upon his acceptance of the uncomplicated working of Example 5(A) in accordance with its terms. The understanding of Profs Black and Wild was based upon a perception that Example 5(A) would indeed give a mixture of regioisomers, which would then have to be resolved in the workings of the latter examples. What steps would be required in that regard, and whether the necessary departures from the text of Carr 129 would be within the principle in Hill v Evans, were matters of serious contention in the proceeding. The debate was played out in the context of attempts which scientists engaged by AMR and Alphapharm made to synthesise fexofenadine following these examples in Carr 129. I shall turn to such matters presently, but I first desire to say something about the legal setting in which the relevant issues arise. 54 The major focus of AMR's energies on the novelty point in the present proceeding was on the second dimension of Lord Westbury's injunction in Hill v Evans, namely, that, to be anticipatory, a prior art citation had to be such as would give the skilled addressee the ability to prepare the compound of interest, or, in the words of Stephen and Mason JJ in Olin, the "effective means" to do so. Here the onus of proof may be of some importance. AMR submitted that, since the respondents carried the legal onus of establishing want of novelty, the disclosure of effective means was a necessary part of their case, and they had to prove it. However, as pointed out above, a skilled addressee armed only with Carr 129 would have understood how fexofenadine could be prepared. That circumstance, in my view, effectively cast upon AMR the evidentiary onus of demonstrating that all was not as it seemed under Carr 129, and that Examples 5(A), 5(B), 2 and 3 did not "work". As it happens, and as will appear presently, I have not found it necessary to decide this aspect of the case by reference to the locus of the evidentiary onus. 55 As will become apparent, Lord Westbury's qualifier that it must be possible to apply the discovery "without the necessity of making further experiments and gaining further information" (1A IPR at 6) has become crucial in the present case. This qualifier, as I have called it, was the subject of elaboration by Lord Reid in Van der Lely NV v Bamfords Ltd [1963] RPC 61. According to his Lordship, the "further experiments" referred to in Hill v Evans did not include "the ordinary methods of trial and error which involve no inventive step and are generally necessary in applying any discovery to produce a practical result" ([1963] RPC at 71). In the submission of AMR, the only input that might be expected of the skilled addressee, in order to make the prior art work, are steps of an utterly routine or commonplace nature. It did not endorse the idea that there was a clear dichotomy between "ordinary methods of trial and error", on the one hand, and processes which involved an "inventive step", on the other hand. Departures from the prior art beyond the routine ought not be permitted, notwithstanding that they may not involve the taking of any further inventive step. 56 I was not referred to any decided case in which this distinction had been considered, or in which the actual content of Lord Reid's elaboration had given rise to controversy in a practical situation. However, approaching the matter at the level of principle, and informed by the observations of Bennett J in Lundbeck, I think that the following things can be said. First, the question is not whether the synthesis of the compound of interest would involve an inventive step in the light of the relevant prior art citation. Rather, the question is whether "the prior publication is sufficient to make the claimed invention apparent to the skilled addressee" (Lundbeck 177 FCR at [173]). Secondly, the question is not whether a series of instructions disclosed in the prior art would inevitably lead to the preparation of the compound of interest. That question arises in a case, such as Abbott GMBH and Co KG v Apotex Pty Ltd (2010) 87 IPR 561, in which the compound as such is not disclosed. That is not the present case. Thirdly, the issue is concerned with the sufficiency of the information in the prior art to make the compound of interest It is assumed that the scientist will bring all of his or her skill and experience to bear on the problem, and will not feel obliged to approach that information as though it were a recipe. In the present case, the information on which the respondents rely consists of a series of recipe-like examples, but there will be cases where less prescriptive modes of expression of the information will nonetheless enable the scientist to understand how the compound can be produced. Fourthly, the very idea of "trial and error" implies that the making of the compound in accordance with the prior art information may be neither straightforward nor uncomplicated. Where the information consists of a series of instructions, it implies that those instructions may be incomplete or unhelpful. The notional scientist is assumed to be equipped with the intellectual and practical wherewithal to perceive in the instructions how the compound may be produced, notwithstanding such shortcomings. And fifthly, the idea of "trial and error" also implies a certain degree of perseverance. Here, much will depend on the scientist's understanding of the general principles conveyed by the prior art information: if it seems to him or her, from that information, that preparation of the compound of interest should be possible, it might be expected that he or she would make every reasonable effort to achieve the intended result. 57 In the present case, two skilled organic chemists attempted to prepare fexofenadine by following Examples 5(A), 5(B), 2 and 3 in Carr 129. Dr Jamie Simpson, a lecturer in medicinal chemistry at the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University retained by AMR, carried out Examples 5(A) and 5(B) twice He was unable to isolate ethyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride, and proceeded no further. Mr Paul Gugger, technical assistant to Prof Wild, carried out Example 5(A) once, Example 5(B) seven times, and Examples 2 and 3 twice each, and eventually (subject only to the matter dealt with in para 150 below) obtained fexofenadine of high purity, albeit in a rather small quantity. AMR says that Dr Simpson's experience demonstrates that the examples set out in Carr 129 are ineffective as a means of preparing fexofenadine. It submits that Mr Gugger's work must be discounted, since he departed from the method set out in these examples in respects which involved more than ordinary trial and error. The respondents say that Dr Simpson's failure to obtain fexofenadine arose from experimental errors which infected his work, such errors arising because of his miscalculation of molar masses, and his unfamiliarity (due to inexperience in relevant areas) with the laboratory procedures necessary for the kind of reactions involved in these examples, particularly 5(A). They accept that Mr Gugger departed from the wording of the examples in Carr 129, but they say that such departures were no more than uninventive, routine variations which might be expected to be employed by any experimental worker of the necessary experience in the relevant area. 58 Dr Simpson has expertise in organic chemistry, particularly in organic synthesis and medicinal chemistry. He was asked by AMR's solicitors to provide his comments in relation to the synthesis described in Examples 5(A), 5(B), 2 and 3 of Carr 129. He was then asked to prepare an experimental protocol setting out in detail the steps that he would undertake if asked to perform that synthesis; and subsequently to conduct an experiment in accordance with the protocol he prepared. He was requested to refer only to Carr 129, and not to search for or to consult other documents or publications. 59 Dr Simpson read and understood Carr 129. He recognised that Examples 5(A), 5(B), 2 and 3 described a synthesis of fexofenadine. He recognised that Example 5(A) involved a Friedel-Crafts acylation. He recognised Example 5(B) as involving "a coupling reaction, known as an alkylation" between the product of Example 5(A) and α,α-diphenyl-4-piperidinemethanol to form ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride, which he anticipated would be "a relatively straightforward alkylation". He recognized Example 2 as involving a hydrogenation of the product of Example 5(B), to form ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl)-α,α-dimethylbenzeneacetate hydrochloride. He considered that "the chemistry involved was quite straightforward". He recognized Example 3 as involving a hydrolysis of the product of Example 2 to form fexofenadine. This appeared to him to be "standard chemistry". He did not expect that he would encounter any particular difficulty if asked to perform the reactions described in Examples 5(A), 5(B), 2 and 3. 60 Dr Simpson prepared the protocol requested by AMR's solicitors. Although placed into evidence, it was the subject of no submission of substance made by any party. In preparing his protocol, it was apparent to Dr Simpson that the examples in Carr 129 did not contain "a complete description of how the reactions [were] to be performed". Thus it was necessary for him to supply details of how the reactions would be performed, based on his experience in performing reactions of the relevant type. The extraction of the product with chloroform under Example 5(A) was one instance of this; recrystallisation from methanol-butanone and butanone under Example 5(B) was another. 61 There were two respects in which Dr Simpson found it necessary to apply his knowledge and experience by way of interpretation of what was set out in these examples. He noted that Example 5(A) specified the use of 48.4 g (0.294 mol) of ethyl α,α-dimethylphenylacetate. However, he calculated that 48.4 g of this reagent was not equivalent to 0.294 mol. He decided to opt for the molar quantity, and used what he calculated as 0.294 mol, namely, 56.5 g. He also noted that the product of example 2 was said to be ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- α,α-dimethylbenzeneacetate hydrochloride, a salt, while the starting material for Example 3 was ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate, the neutral form of the same compound. Due to the large excess of sodium hydroxide used in the reaction of Example 3, Dr Simpson considered that using the salt would not have a significant effect on the outcome of the reaction. 62 In performing the reaction described in Example 5(A), Dr Simpson initially, and mistakenly, used sufficient dry ice to cause the temperature of the material to fall to -30 °C and, by the time he realised his mistake, he had added "a portion" of the aluminium chloride catalyst to the reaction mixture. He then brought the mixture up to -10 °C, and added the remainder of the aluminium chloride. He then continued the reaction procedure as set out in the example. Carrying out the workup, he encountered no difficulty until the final evaporation step, at which point he obtained a brown oil, rather than a solid as specified. That oil could not be reduced to a solid by further evaporation. Using liquid chromatography-mass spectrometry ("LCMS"), Dr Simpson was able to conclude that the brown oil contained "a mixture of a number of compounds", but the conditions employed for this analysis were not suitable to achieve a good analytical separation of those compounds. The mass spectrometry data indicated the presence of an ion with a molecular weight corresponding to that of the desired product, but those data indicated also the presence of other ions of different masses which Dr Simpson was not easily able to explain. 63 Dr Simpson also undertook high performance liquid chromatography ("HPLC") analyses of the brown oil, and the result appeared to him to be consistent with the presence of the desired material, as well as with that of the starting material, ethyl α,α-dimethylphenylacetate. He also conducted a proton nuclear magnetic resonance ("1H NMR") analysis of the brown oil. From that analysis, Dr Simpson concluded that, in addition to the desired product and the starting material, there was at least one other compound having the same chlorobutyryl group as those two. Thinking that the additional compound might be the ortho-substituted regioisomer of the desired product, Dr Simpson used computer simulation software to predict the 1H NMR spectrum for that regioisomer. Having done so, he noted that it was not consistent with so much of the 1H NMR spectrum of the brown oil as indicated the presence of an additional compound. However, he carried out a like simulation for the meta-substituted regioisomer of the desired compound, and found that the 1H NMR spectrum for it "[had] peaks with a pattern and chemical shift similar to the additional peaks observed in the NMR of the reaction product". Thus, Dr Simpson considered it probable that, for some reason, the reaction had produced the meta regioisomer of the desired reaction product. To him, this was an "unexpected … outcome". 64 Having regard to the magnitude of the various peaks in the 1H NMR spectrum of the reaction product, Dr Simpson estimated that the product which he derived from carrying out Example 5(A) was made up of approximately 40% unreacted starting material, 30% desired reaction product (para regioisomer) and 30% meta regioisomer of the desired reaction product. He did not consider that it would be worthwhile proceeding with the experiment, but he was instructed by AMR's solicitors to do so. 65 Having modified his experimental protocol to accommodate the fact that he was commencing with an oil rather than a solid, Dr Simpson embarked upon Example 5(B). However, after he had added ethereal hydrogen chloride as described in the example, Dr Simpson found that the resulting material was "a highly viscous gum". He attempted to break up the gum by stirring, but without success. In these circumstances, it was not possible for him to filter the precipitate. Accordingly, it was necessary for him again to depart from his protocol in order to obtain a solid product. Having decanted off the remaining ether, he left the flask containing the gum to dry within a fume hood. After two days, the gum had "solidified to a hard mass". Dr Simpson scraped off some of this material to analyse. 66 The results of Dr Simpson's LCMS analysis were consistent with the presence of the reaction product desired at the end of Example 5(B). However, the 1H NMR analysis, while also consistent with the presence of that product, suggested that some of the original starting material was present, together with other unwanted regioisomers. This was unsurprising to Dr Simpson, since there was nothing about the reaction described in Example 5(B) which, in his expectation, would significantly alter the relative proportions of the regioisomers present in the material with which he commenced (ie that obtained from the workup under Example 5(A)). 67 Dr Simpson then took the remaining material which he had from carrying out Example 5(B) (to the extent that he had done so) and proceeded to the recrystallisation described therein. However, after adding about 50 mL of hot butanone, there was no apparent cloudiness to the solution, and no indication that any solid was going to crystallise. Dr Simpson 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 placed the solution in a refrigerator overnight, but this too failed to produce crystals. He cooled the solution to -78 °C, but again no crystals formed. Next, by boiling the solution, he reduced its volume to about 50%, allowed it to cool to room temperature, and again placed it in a refrigerator overnight. None of these steps yielded any crystals. 68 In this state of things, Dr Simpson considered that, if he were to perform a purification step on the material which he had, it would be necessary either to develop, by experimentation, a new solvent system suitable to that material, or to consider other purification techniques. Without experimentation, Dr Simpson did not consider it possible to determine what, if any, other solvent systems or purification techniques would be effective in purifying the material which he had. He was then instructed by AMR'S solicitors to terminate his work. 69 The experts called by the respondents were critical of Dr Simpson's protocol, and of his work, under Example 5(A). Their criticisms were sufficiently articulated in the evidence of Prof Black. He agreed with Dr Simpson that 48.4 g of ethyl α,α-dimethylphenylacetate represented 0.252 mol, not 0.294 mol as stated in Carr 129. However, he disagreed with the solution to this disparity adopted by Dr Simpson - to use 56.5 g of this material. Prof Black continued: I understand … that Dr Simpson considers 56.5 grams ethyl α,α-dimethylphenylacetate to be equivalent to 1.01 of the relative amount of 4-chlorobutyl chloride which is specified. However, in calculating the quantity of ethyl α,α--dimethylphenylacetate to use, Dr Simpson has erroneously calculated the number of moles which 36.5 grams of 4-chlorobutyl chloride represents. In this regard, I note that … Dr Simpson has calculated that the molecular mass of chlorobutyl chloride is 127, and that 36.5 g of 4-chlorobutyl chloride amounts to 0.287 moles. This is not correct. The molecular mass of 4-chlorobutyl chloride is 141 and 36.5 g represents 0.259 moles. Dr Simpson's miscalculations were summarised by Prof Black in the following table: Compound Molecular Mass Example 5(A) Experimental Protocol Calculated by Dr Simpson Actual Quantity Moles Quantity Moles Calculated by Dr Simpson Actual Moles Ethyl α,α-dimethylphenylacetate 192 192 48.4 g 0.252 56.5 0.294 0.294 4-chlorobutyl chloride 127 141 36.5 g 0.259 36.5 0.287 0.259

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.

Inventive Step 152 For presently relevant purposes, subss (2) and (3) of s 7 of the Patents Act provide as follows: (2) For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with either of the kinds of information mentioned in subsection (3), each of which must be considered separately. (3) For the purposes of subsection (2), the kinds of information are: (a) prior art information made publicly available in a single document or through doing a single act; and (b) prior art information made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art in the patent area would treat them as a single source of that information; being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area. Armed with common general knowledge, and possibly also with one of the kinds of information referred to in s 7(3), the invention in question will have been obvious to the skilled person referred to in s 7(2) if he or she "faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not": Wellcome Foundation Limited v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262, 286; Aktiebolaget Hassle v Alphapharm Pty Ltd (2002) 212 CLR 411, 432 [50]. The content of the concept of "a matter of routine" approved by the High Court in the latter case was that provided by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157, 187-188: Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art … directly be led as a matter of course to try [that which was invented under the patent in suit] … in the expectation that it might well produce [the solution to the problem which gave rise to the invention in suit]? 153 In the present case, the problem which confronted the inventors was the production of substantially pure piperidine derivative compounds of the class referred to in the patent in suit. Because (save with respect to Claim 11, to which I shall refer separately) the patent claims compounds rather than a method, the invention will be obvious if there is any way in which those compounds in substantial purity might have been synthesised at the priority date by taking the approach of Graham J referred to above. The onus of showing that there was such a way lies, of course, upon the respondents. Principally, they relied upon Carr 129, and they did so in the alternative to their case on novelty. 154 Essentially, the respondents submitted that a skilled organic chemist would use his or her common general knowledge in the art to make Carr 129 work for the production of the relevant compounds as such. In this respect, they relied upon Mr Gugger's work. Although not articulated in precisely these terms, I understand that the respondents would wish to be taken as submitting that the notional research group would, at the priority date, directly have been led, as a matter of course, to try each of the variations from Examples 5(A), 5(B), 2 and 3 in Carr 129 that Mr Gugger did try, in the expectation that it might well produce substantially pure fexofenadine. I accept that submission in two respects: proceeding beyond Example 5(A) notwithstanding that an oily mixture of regioisomers was the material at hand, and utilising an alternative solvent under Example 3. However, I do not accept that such a research group would have directly been led, as a matter of course, to try the process which Mr Gugger ultimately employed under Example 5(B) in the expectation that it might well provide a link in the synthetic chain for the production of fexofenadine as specified in Carr 129. Rather, I accept the submission made on behalf of AMR that Mr Gugger's work under that example was much closer to what has been described as trying "each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful": In re O'Farrell (1988) 853 F 2d 894, 903, approved in Aktiebolaget 212 CLR at 442 [76]. Thus I reject so much of the respondents' obviousness case as is based on Carr 129. 155 The Sigma respondents proposed a further basis upon which the synthesis of the relevant compounds would have been obvious to a skilled organic chemist in 1993. They relied on the evidence of Dr Stephen Kawai, a research scientist in the Department of Chemistry at Boehringer Ingelheim Canada Ltd in Laval, Quebec, Canada. In 1989, he was completing his PhD in Professor George Just's laboratory in the Department of Chemistry at McGill University. In September or October of that year, Prof Just was asked by Phoenix International Life Sciences, Inc to synthesise the compound which is now known as fexofenadine. Prof Just asked Dr Kawai and his colleague, Dr Robert Hambalek, to try to synthesise fexofenadine. 156 According to Dr Kawai, Dr Hambalek first attempted the synthesis of fexofenadine via an intermediate prepared through the Friedel-Crafts acylation of a phenylacetic acid derivative, following a strategy similar to that described in a paper published by A.A. Carr and D.R. Meyer in 1982. However, in taking this approach, Dr Hambalek prepared not only a ketone precursor to fexofenadine, but also undesired regioisomers. Dr Hambalek attempted to separate the undesired impurity from the desired para regioisomer using standard purification techniques, but could not do so. Dr Kawai could not remember Dr Hambalek trying to modify the Friedel-Crafts acylation reaction to avoid the production of the undesired regioisomers; nor attempting more than "a couple" of standard purification techniques to try to purify the compound. 157 As the compound was required quickly and Dr Kawai had more time available than Dr Hambalek, it was the former whom Prof Just asked to take a new approach "and attempt a new synthesis of fexofenadine which included steps based on some other synthetic work he [Prof Just] had done recently on another series of related compounds". Prof Just suggested using a parasubstituted bromobenzene compound as starting material, with a palladium catalyst. He drew up a rough outline of the synthesis which he had in mind, and left it to Dr Kawai to work out what solvents, temperatures and other reaction conditions should be used, and to refine the synthetic pathway if necessary. Through the use of parasubstituted starting material, Dr Kawai avoided the emergence of undesired regioisomers. In his affidavit in this case, Dr Kawai said: "I recall thinking that Professor Just's suggested synthesis appeared to be a straightforward way of producing fexofenadine, and did not appear to me to be speculative". 158 One aspect of the synthesis which gave Dr Kawai some concern was that, at one point, it used a mercury salt as a catalyst. This was problematic in a product intended for human consumption, because of the toxicity of mercury. However, as there were numerous steps following the mercury-catalysed step, Dr Kawai took the view that the risk of the mercury "carrying through" was small. Subject to that reservation, Dr Kawai's synthesis was successful. He considered that the scheme involved was "reasonably straightforward" and required "no major tweaks" to the reaction sketched by Prof Just. 159 Because of confidentiality limits imposed upon Prof Just by his client, Dr Kawai was not immediately able to submit his work for publication. However, he did so in November 1993. His paper was published in early 1994 as S.H. Kawai, R. Hambalek, G. Just. "A Facile Synthesis of an Oxidation Product of Terfenidine", Journal of Organic Chemistry 1994, 59, 2620. 160 Upon analysis, it seems that the point being made here by the Sigma respondents may have two aspects. There is a sense in which they would say that, regardless of whether a Carr-type FriedelCrafts acylation was employed, the synthesis of fexofenadine was obvious in 1989 to Prof Just and his team. And there is a sense in which they would say that, assuming a failed attempt to synthesise fexofenadine by the employment of a FriedelCrafts acylation (such as was the experience of Dr Hambalek), the alternative means to which Prof Just, and on his instructions Dr Kawai, resorted were obvious. Either way, the Sigma respondents need to establish that the synthesis of fexofenadine would have been obvious to a person skilled in the art in the light of the common general knowledge in Australia. Quite clearly, the experience of Prof Just and his team in Canada goes no distance towards that end. Further, the court does not know, and cannot assume, that Prof Just regarded his alternative synthesis as obvious. Dr Kawai said that it "included steps based on some other synthetic work he had done recently on another series of related compounds". That is to say, Dr Kawai's evidence leaves open the very real possibility that Prof Just suggested his alternative synthesis not because it would have been obvious to a worker skilled in the art but because of some specific understanding which he had as an individual researcher. Dr Kawai himself did not say that he considered that that synthesis was obvious: he said only that, it having been suggested to him by Prof Just, it appeared to him to be "straightforward". That is not sufficient for the purposes of s 7(2) of the Patents Act. 161 In further support of their case on obviousness, the Sigma respondents requested Dr Robertson to suggest ways in which substantially pure fexofenadine might be synthesised, against the knowledge that the method proposed in Carr 129 led to an unwanted mixture of regioisomers. The Sigma respondents did not ultimately rely on Dr Robertson's evidence in relevant respects, but it is instructive to note that one of his proposals (that which he most strongly favoured) was to commence the whole process with a parasubstituted material. When he was later shown a copy of the Kawai paper, Dr Robertson expressed the view that there was a similarity between his own approach and that reported in the paper. Prof Easton strongly disagreed with that notion. In concurrent evidence, Prof Easton said: After this quite detailed, as I put it, retro synthetic analysis that Dr Robertson has gone through, he has come up with the proposal on the left hand side of this sheet, where there are three steps. None of them are actually the same as those proposed in Kawai. The first two are conceptually similar but they are not the same because Kawai uses a methyl ester, whereas Dr Robertson uses an ethyl ester. As I say, I accept that they are conceptually similar, but not necessarily without their problems because it is likely that a methylation required to go from step 2 to step 3 would be more likely to be successful in the presence of a methyl ester than in an ethyl ester. But there the similarity to my mind ends because in step 3 the routes take an entirely different turn. So I think the proposals that, separate to the discussion about terfenadine analogues and metabolites, the proposed synthesis and the analogy to Kawai, there is not a close analogy to Kawai and the proposals are a very broad indication of where an organic chemist would begin to do the synthetic to start the experimentation. Dr Robertson accepted what Prof Easton had said. In the circumstances, I would have to hold that the Just/Kawai synthesis was not obvious to Dr Robertson and, I infer, would not have been obvious to a synthetic chemist in his position in 1993. 162 For the above reasons, I am not satisfied that the invention in suit would have been obvious to a person skilled in the relevant art in the light of the common general knowledge in Australia before the priority date. It follows that the invention, so far as claimed in the product claims with which I am presently concerned, involves an inventive step. 163 I return to Claim 11 under the patent in suit. No attempt was made by the respondents to demonstrate that the synthetic methods incorporated into that claim would have been obvious to a person skilled in the relevant art in 1993. It follows that this claim too involves an inventive step.

Definition and Clarity: the Question of "Substantial Purity" 164 Under s 40(2)(b) of the Patents Act, a complete specification must end with a claim, or claims, "defining the invention". By subs (3), the claim, or claims, must be "clear and succinct". The claims in the patent in suit which are presently contentious all operate by reference to the expression set out in para 4 above, namely, "a substantially pure piperidine derivative compound" (or similar). The respondents submitted that, by reason of the inherent imprecision in the expression "substantially pure", the claims did not define the invention, and were not clear and succinct, as required by the provisions of s 40 to which I have referred. 165 A court may not either expand or contract the meaning of claims in a patent by reference to language derived from other parts of the complete specification. However, if there is some ambiguity in the language of the claims themselves, it is legitimate to have reference to the specification for the purpose of resolving that ambiguity. Although "substantially" is a word often found in instruments having legal effect, such as statutes, its content is almost always to be derived from the content, purpose and subject matter of the instrument as a whole. In the present case, there is a passage in the complete specification in which the inventor has given content to the expression "substantially pure": The term "substantially pure" is intended to cover pharmaceutically-acceptable, high purity piperidine derivative compounds. In this regard, the chapter of U.S. Pharmacopeia entitled " Impuritites [sic] in Official Articles>", recognises that pharmaceuticals have a general limit of 2.0% on ordinary impurities. This passage was inserted into the specification by an amendment filed on 15 September 1998 (ie during the course of the Examiner's consideration of the patent, prior to grant). For reasons which will appear, it has become necessary to consider the definition/clarity point with reference to the terms of the claims both before and after this amendment. 166 Commencing with the situation as it existed before the amendment, AMR submitted that the task of determining whether the words of the contentious claims failed to define the invention with clarity was at base one of construction. It was submitted that the court would, as in the case of any instrument, approach the language with a view to giving effect thereto, rather than to treating the controversial expression as "no more than an exercise in futility". It submitted that the expression "substantially pure" was both qualitative and relative. Although the expression did not admit of a precise identification of the extent of purity claimed by the inventor, that did not mean that it was unclear. There were many contexts in which instruments having legal effect, such as legislation, used the word "substantially". Likewise, for example, courts have long been familiar with giving content to the inherently variable concept of reasonableness. It was submitted: [I]t is unclear why there should be some particular requirement in respect of purity that demands a quantitative measure rather than a qualitative measure compared to other ingredients that may form the foundation of claims and indeed not confined to chemical compounds but throughout the whole range of the subject matter that may become the subject of patent claims. It was submitted that the expression was relative in character, in the sense that it involved some form of qualification upon absolute purity. According to the evidence, there was, at least in practical terms, "no such phenomenon as absolute purity in the field of chemical compounds". AMR pointed to passages in the evidence in which Prof Black, to take an example, had no difficulty with such notions as "low purity" and "high purity". In AMR's case, what the patent describes as "substantial purity" was what a person skilled in the art, in 1993, would have understood as "high purity". 167 The respondents submitted that the context for s 40(2)(b) and (3) was that a patent was not merely a document having operation inter partes, but was a public instrument which provided a statutory monopoly. This monopoly must be defined in terms which are "not reasonably capable of misunderstanding": Martin v Scribal Pty Ltd (1954) 92 CLR 17, 59. If "substantially pure" was a term with an accepted scientific connotation, that might be one thing, but the evidence in the case suggested otherwise. The term was not one of art in organic chemistry and, to the extent that it was used at all, it was used occasionally in conversation rather than in papers or other contexts having quantitative scientific relevance. According to the respondents, the term could never provide a clear line between a compound which was, and a compound which was not, covered by a particular claim. 168 In a session of concurrent evidence which involved Profs Easton and Black and Dr Robertson, these scientists were asked to provide their opinion of the meaning of "substantially pure" in Claim 1 of the patent in suit, both in isolation and in the context of the specification as a whole. Prof Black said that: The first aspect of the meaning of "substantially pure," as far as my understanding is, is that it is impure. A sample that is substantially pure is impure. If I have a research worker who comes to me and says, "I have made a new compound," and I say, "Is it pure?" and he or she says, "It is substantially pure," the meaning to me would be that it is not yet pure, but it is on the way and it is something that you cannot quantify … But the basic thing is that you cannot connote a percentage to the impurity level if you say something is substantially pure. As to the kind of impurities that were implied by the term "substantially pure", Prof Black opined that they were "presumably … pharmaceutical impurities, things that are benign, but that is not clear in the meaning of the document at all because there is no data, no information given to provide that". 169 Having noted that "substantially pure" did not convey any special meaning to an organic chemist, Dr Robertson continued: [P]urity is a source of great professional pride for an organic chemist. So when a chemist is joining two bonds together and making a new molecule that perhaps didn't exist before, or may have existed before, purity is one of the key objectives, getting it as pure as possible, but a chemist will never consider "substantially pure" to be an acceptable term and [it is] not a term that is used routinely, or indeed ever, in my experience, in any lab that I have been in. Dr Robertson then considered the question of purity in the particular context of a compound intended for pharmaceutical use. In that context, it would be the regulatory agent that would take a view on purity. Different drugs could be permitted different purities depending on the ease with which they could be purified. With some drugs, it was acceptable to have a purity of 90% or less - even 80% - if it were a lifesaving drug and the sponsor had gone to reasonable lengths to purify the entity. In such a case, if there were no alternative the regulator might well take a benign view on the level of purity which is required in the circumstances. In other cases, a very high level of purity might be required by the regulator, such as when very small levels of impurity could cause great harm. 170 Prof Easton said that "substantially pure" was a term that had a particular connotation to him, it was used in his laboratories and he had regularly heard used it by others, particularly in the context of asymmetric synthesis. He continued: My general understanding comes from the context of organic chemistry and "substantially pure" there means, to me, that it is not possible to either prepare a compound that is absolutely pure, although I recognise that "absolute" and "pure" are tautological, but it is pure in an absolute sense, nor is it possible to analyse a compound that is pure in an absolute sense, and that is simply a consequence of the large numbers of molecules that are involved; you can't purify a compound down to the level of an individual molecule or analyse it to the level of an individual molecule. The net result of that is that the term "pure" has to be qualified in a chemistry context and it is typically qualified with terms such as "substantially" that indicate the confidence limits to which purity can be claimed and understood according to the general levels of preparation and analysis of the compound, as well as the context in which the compounds are to be used. In turn, this means to me that "substantially pure" means that a material is likely to contain impurities and they are likely to generally be around the level of 1 to 2 per cent, or maybe up to 1 to 2 per cent, because the general techniques of organic chemistry, synthesis of compounds and purification and analysis of compounds generally means that the confidence of purity will be up to around 98 to 99 per cent, as they are typically and routinely applied. Prof Easton seemed to allow that toxic impurities were in a special category, recognising as he did a "lower limit on the level of toxic impurities that may … be necessary in a pharmaceutical application". In the particular context of the patent in suit, Prof Easton's view was that "substantially pure" meant that the compound contained no more than 1-2% "of any impurity and in particular the meta isomer impurity". He perceived in the specification an emphasis on the meta regioisomer, a solution to the problem of which he saw as "the main thrust of [the] specification". 171 It is apparent from this brief exposure to the views of the scientists who gave evidence in the case that there are two aspects of the term "substantially pure" which require attention for present purposes. The first is that which conveys a particular degree of purity, and is embodied in the word "substantially". The second relates to the kind of unintended presence that should be regarded as an impurity. As to the second, Prof Easton put toxic impurities in a special category, and I understand Dr Robertson's evidence in the same sense - that is, however successful the laboratory chemist may have been in excluding benign impurities, even a tiny amount of a toxic impurity should be regarded as disqualifying in a pharmaceutical context. I did not understand Prof Black to have taken a different view on that question. Still on the second aspect, I am disposed to agree with Prof Easton that the conspicuous concern of the patent in suit is with regioisomeric purity. He gave that evidence as a matter of his understanding, reading the specification as a skilled addressee. As a court called upon to construe the specification as a document, I would reach the same conclusion. I see nothing in it which shows a concern with the elimination of toxic impurities. It was not an aspect of the science which the inventor claimed to have introduced, or to have described, under the patent in suit. Rather, his claim was to have invented compounds of the relevant class as such: not, as he asserted arose under the prior art, a mixture of regioisomers. 172 Returning to the first aspect which I mentioned in the previous paragraph, I am unable to accept that, as a matter of construction, the word "substantially" calls up "the confidence limits to which purity can be claimed and understood according to the general levels of preparation and analysis of the compound" as proposed by Prof Easton. The specification provides no warrant for any such understanding of the term. If this were an understanding that had uncontroversial currency in the world of organic chemistry, it would have been familiar to Prof Black and Dr Robertson. Clearly it was not. Further, even that understanding required Prof Easton to take the next step of putting a figure on it. Here, there is, in my reading of it, nothing in the specification that would justify the adoption of a 1% limit, a 2% limit, or any other particular specific limit thereabouts. 173 The difficulty which confronted the inventor, and which led to the problem of want of clarity raised by the respondents, is that he needed a verbal formula that would set the invention apart from the prior art. Had there been no Carr patents, the inventor would simply have claimed the piperidine derivative compounds as such. An assertion of purity would have been neither necessary nor appropriate (since the invention teaches nothing about purification in the broader sense). However, the view may have been taken that an unqualified claim in such terms would have been anticipated by the Carr patents on the basis that they disclosed the very compounds claimed to have been invented, albeit that, according to the inventor, those compounds could in practice be obtained only as components within a regioisomeric mixture. The essence of the invention was that a practical entity could be synthesised which was not such a mixture. But the claims do not reflect that, or any, absolute position. They reflect only "substantial purity", that is to say, they speak of a compound which is substantially pure with respect to the para regioisomer. 174 With respect to AMR's submission summarised in para 166 above, I accept that, from a verbal or grammatical viewpoint, the expression "substantially pure" is not unclear. I accept also that "any purely verbal or grammatical question that can be resolved according to ordinary rules for the construction of written documents, does not, once it has been resolved, leave uncertain the ambit of the monopoly claimed": Welch Perrin and Co Pty Ltd v Worrel (1961) 106 CLR 588, 610. But the concern of s 40(3), in my view, is not confined to such matters. The purpose of a claim is to define the invention (s 40(2)(b)), and it is in that context that the requirement of clarity is to be considered. In my view, that requirement is that a claim must clearly define the invention, so far as it relates to the matter claimed. A claim which is a model of verbal or grammatical clarity may nonetheless fail the test of this requirement if it leaves the definition of the boundaries of the invention uncertain or variable. 175 In my view, the claims which are presently contentious did fail that test in the period before the specification was amended in 1998. I am not persuaded that the skilled addressee would unhesitatingly read the claims as Prof Easton did. Indeed, I think that he or she, like Prof Black and Dr Robertson, would wonder how much of a given compound had to be constituted by the piperidine derivative before the compound itself would be regarded as "substantially pure" with respect to the derivative. The claims would not provide for him or her a clear definition of what had been invented. 176 I turn next to the effect of the passage inserted by amendment in 1998, to which I have referred in para 165 above. Did that amendment bring the claims into conformity with s 40(2)(b) and (3)? It was submitted on behalf of AMR that the first sentence of that passage was definitional, and that the second was by way of example. As it happened, the definitional aspect coincided with the meaning which, in AMR's submission, ought to have been given to the unamended specification in any event. Thus AMR's point that the amendment made little or no difference to the meaning of the claims in presently relevant respects. Before dealing with these submissions, however, I should consider what the scientists called in the present case made of the amended specification. 177 For the purposes of the concurrent evidence session which involved them, Profs Black and Easton and Dr Robertson were asked what a person skilled in the art would have understood from the passage inserted in 1998. Prof Black's understanding was that any impurities that were present would be "pharmaceutically benign" in the sense of not including toxic impurities, but noted that there were "no data given to support or to clarify what is really meant by substantially pure there". Although he accepted that the reference to the US Pharmacopeia was designed to clarify what was meant by "substantially pure", it made the situation less clear because it introduced consideration of the various specific categories of impurities referred to in that document. 178 It is convenient here to refer to the US Pharmacopeia. The section headed "Impurities in Official Articles" opens with the following paragraph: Concepts about purity change with time and are inseparable from developments in analytical chemistry. If a material previously considered to be pure can be resolved into more than one component, that material can be redefined into new terms of purity and impurity. Inorganic, organic, biomechanical, isomeric, or polymeric components can all be considered impurities. Microbiological species or strains are sometimes described in similar terms of resolving into more than one component. The section proceeds to provide "definitions" of various things, namely, foreign substances, toxic impurities, concomitant components, signal impurities and ordinary impurities. As to concomitant components, it is said: Concomitant components are characteristic of many bulk pharmaceutical chemicals and are not considered to be impurities in the pharmacopeial sense. Limits on contents, or specified ranges, or defined mixtures are set forth for concomitant components in this Pharmacopeia. Examples of concomitant components are geometric and optical isomers (or racemates) and antibiotics that are mixtures. Any component that can be considered a toxic impurity because of significant undesirable biological effect is not considered to be a concomitant component. As to ordinary impurities, it is said: Ordinary impurities are those species in bulk pharmaceutical chemicals that are innocuous by virtue of having no significant, undesirable biological activity in the amounts present. These impurities may arise out of the synthesis, preparation, or degradation of compendial articles. Selections of test and assays allow for anticipated amounts of impurities that are unobjectionable for the customary use of the article. And: Unless otherwise specified in an individual monograph, estimation of the amount and number of ordinary impurities is made by relative methods rather than by strict comparison to individual Reference Standards. Nonspecific detection of ordinary impurities is also consistent with this classification. The value of 2.0% was selected as the general limit on ordinary impurities in monographs where documentation did not support adoption of other values. This value represents the maximum allowable impact from this source of variation, when taken with the variation allowed by the composite of other Pharmacopeial tests and assays for both the bulk pharmaceutical chemical and the preparations. Where a monograph sets limits on concomitant components, signal impurities, and/or toxic impurities, these species are not to be included in the estimation of ordinary impurities unless so stated in the individual monograph. This was the source of the reference in the 1998 amendment of the specification to the 2.0% limit on ordinary impurities. 179 Although Prof Black accepted that regioisomers were not geometric isomers, and were not, therefore, specifically mentioned as concomitant components in the Pharmacopeia, he said that, since the chemical process by which they came into being was similar to that which brought geometric isomers into being - individual formation as part of the same reaction process - they should be considered as concomitant components. Dr Robertson agreed, adding that "a concomitant impurity and an ordinary impurity may well overlap and you may find that a concomitant impurity becomes an ordinary impurity in the fullness of time and vice versa". Prof Easton did not agree. He drew a distinction between concomitant components and ordinary impurities which was based on the circumstance that the former consisted of mixtures of isomers which "interconverted" and, even if separated, reverted to their original (eg racemic) mixtures, while the latter referred to structural isomers which were generally not very similar in their properties, did not spontaneously interconvert and were not reliably always present in the same ratio. He added that, if one went through a different synthetic or purification procedure, the ratio of the isomers would change, which was a source of major concern in a pharmaceutical application. 180 Prof Easton considered that, in the context of the patent in suit, the meta regioisomer was to be regarded as an ordinary impurity within the meaning of the Pharmacopeia because it "may arise out of the synthesis". As to the passage introduced by amendment in 1998, Prof Easton said: [T]his excerpt obviously reinforces the opinions that I have already expressed, being that the compounds are intended for use as pharmaceuticals and that the expression "substantially pure" imposes a limit of around 1 to 2 per cent on ordinary impurities, that is, a general limit which is consistent with my thinking, general thinking, in this area and the way I operate in this area. Since this is part of a patent which is addressed to solving a problem with meta regioisomers, it also makes it clear to me - or I also interpret that paragraph as suggesting [-] that the meta isomers are ordinary impurities and therefore should be treated as having this upper limit of 1 to 2 per cent …. Prof Black disagreed with that analysis, adhering to his view that the meta regioisomer under the patent in suit was a concomitant component rather than an ordinary impurity. He accepted that it was an impurity, but "not an ordinary one" in the contemplation of the Pharmacopeia. 181 Quite clearly I am in no position to arbitrate the question upon which these two very senior organic chemists disagreed. However, it is significant that each considered that the meta regioisomer was to be regarded as an impurity. In the context of a patent whose manifest concern is the synthesis of a compound which is unembarrassed by the meta regioisomer, I consider that it would be both artificial and wrong not to include the meta regioisomer within the contemplation of the second sentence of the passage introduced into the specification by amendment in 1998. I accept Prof Easton's view that the passage as a whole requires that the meta regioisomer not exceed 2% of the compound claimed under the patent in suit. (Prof Easton referred to an "upper limit of 1-2%", but this effectively sets the upper limit at 2%.) The insertion of this passage does not change my view that the specification is wholly unconcerned with toxic impurities - if anything, it reinforces it. 182 I do not accept the submission made on behalf of AMR that the second sentence of the passage is merely by way of example. I would hold that a person skilled in the art would read the passage as a whole as giving content to the term "substantially pure", and as recognising that the amended patent claimed a compound in which regioisomeric impurity was limited to a maximum of 2% of the whole. As so understood, the relevant claims defined the invention with clarity. For the period subsequent to the making of the amendment, I would reject the respondents' challenges under s 40(2)(b) and (3) of the Patents Act. 183 On the question of clarity, the respondents urged me to give weight to a decision of the Technical Board of Appeal of the European Patents Office published on 12 May 2000 in relation to an application for a patent generally corresponding to the patent in suit. The Board found that the use of the term "substantially pure" deprived the claims of clarity. To that extent, I have decided the present point conformably with the submissions of the respondents, without the need to seek assistance from the decision of the Board. As to the situation of the patent in suit after amendment in 1998, I note that the document before the Board did not contain a passage corresponding to the one then inserted. With respect to the aspects which I have decided conformably with the submissions of AMR, the decision of the Board would, therefore, be of no assistance to me.

Priority date 184 The conclusion which I reached in the previous section - that the claims lacked clarity before the specification was amended in September 1998 but not thereafter - makes it necessary to consider the effect of s 114 of the Patents Act. By that provision, "Where a claim of a complete specification claims matter that was in substance disclosed as a result of amending the specification, the priority date of the claim must be determined under the regulations". The relevant regulation is reg 3.14(b) of the Patents Regulations 1991 (Cth), which provides that, in a case to which s 114 of the Patents Act applies, the priority date of a particular claim is "the date of filing of the statement of proposed amendments that resulted in the disclosure" referred to in the section. On the respondents' case, if the contentious claims were brought into conformity with the requirements of s 40(2)(b) and (3) only by the provision which was inserted by amendment in 1998, it follows that those claims claimed matter "that was in substance disclosed as a result of amending the specification" and, therefore, that the priority date became 15 September 1998. 185 Section 114 is concerned with what is claimed in a complete specification. One commences, therefore, with what was claimed before the filing of the amendment. The specification then claimed substantially pure piperidine derivative compounds, without further definition. Although claims in those terms lacked the clarity required by s 40, nonetheless they had a meaning. There was uncertainty as to how pure was "substantially" pure, but that uncertainty existed at the impure end of the spectrum, as it were. I would consider it very doubtful that a product would be considered substantially (regioisomerically) pure if it were only, say, 80% pure. 90% purity might be a marginal case; and 95% purity might represent a situation in which the compound in question would more convincingly be described as "substantially pure". It is sufficient for present purposes, however, for me to hold, as I do, that a compound of at least 98% purity would on any view have rightly been described as "substantially pure". 186 The effect of the amendment of September 1998 was that the claim to substantial (regioisomeric) purity was limited to compounds which were of at least 98% purity. On any view, such compounds fell within the wording of the claims as they stood before the amendment. Using the language of s 114, therefore, the matter that is now claimed in the complete specification was not "in substance disclosed as a result of amending the specification". Rather, that matter had been disclosed from the outset. It follows that, in relation to the presently contentious claims, there is no variation to the priority date pursuant to s 114.

Manner of Manufacture 187 Section 18(1)(a) of the Patents Act provides as follows: Subject to subsection (2), an invention is a patentable invention for the purposes of a standard patent if the invention, so far as claimed in any claim is a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. The word "invention" is defined as: … any manner of new manufacture the subject of letters patent and grant of privilege within section 6 of the Statute of Monopolies, and includes an alleged invention. 188 In Merck and Co Inc v Arrow Pharmaceuticals Ltd (2006) 154 FCR 31, 52 [63], the Full Court held that the following propositions were established on the authorities with respect to these provisions: 1. The opening words of s 18(1) ("a patentable invention is an invention that") impose a threshold requirement that the "patentable invention" be an "invention", that is to say an "alleged" "manner of new manufacture" within s 6 of the Statute of Monopolies (Philips at 663). 2. That requirement will not be met if, on the face of the specification, the subject matter: (a) lacks the necessary quality of inventiveness under the Statute of Monopolies (Philips at 664); (b) is not new ([National Research Development Corp v Commissioner of Patents (1959) 102 CLR 252] NRDC at 262; Philips at 664). 3. A new use of an old substance is not an invention if its known properties make it suitable for that use - in such a case the new purpose is "no more than analogous to the purposes for which the utility of the substance is already known" (NRDC at 262). 4. But there will be an invention if the new use consists in taking advantage of a hitherto unknown or unsuspected property of the substance (NRDC at 262). 189 The respondents' first submission in this area of discourse was based upon the statement in the specification, contained within the paragraph which I have set out at para 12 above, that "a practical separation to obtain gram quantities of substantially pure regioisomers has not been achieved". It was said that this amounted to an admission that less than gram quantities of substantially pure regioisomers had been achieved. Since the claims in contention were not limited by reference to gram quantities of the compounds claimed, it was said that the specification showed, on its face, that the subject matter if the invention was not new. AMR's response to this submission was as follows: The respondents contend that the Patent admits, at page 6, line 2 to 3, that separation of less than gram quantities of substantially pure regioisomer has been achieved. That is not a proper characterisation of the statement, "a practical separation to obtain gram quantities of substantially pure regioisomers has not been achieved." There is no admission that a separation to obtain lesser quantities has been achieved. Further, the statement is qualified by the last sentence of the same paragraph, "it has not been possible to obtain either of the regioisomers in each mixture in substantially pure form." Of course, separation of less than gram quantities by the inventor in the course of developing the invention would not be an admission that the invention is not "new". As will be apparent, this passage contains three points in response to the respondents' submissions. I shall return to the first presently, after I have dealt with the second and third. 190 The statement in the last sentence in the relevant paragraph - "it has not been possible to obtain either of the regioisomers in each mixture in substantially pure form" - refers to the previous sentence which, in my view, is both theoretical and tendentious, stating what the mixture "would be expected to contain". In the final sentence in the passage, the inventor is, in my view, stating no more than that he was unable to separate out the para and meta regioisomers in the proportions of 33% and 67%. I do not consider that this statement would be effective to neutralise the implication upon which the respondents rely (that less than gram quantities of the para regioisomer had been obtained) if otherwise such an implication fairly arose. 191 As to the submission that AMR's manner of manufacture case could not be defeated by pointing only to the experimental work done in the inventor's own laboratory in the course of devising the invention itself, if the work referred to were part of the inventive process, I would be inclined to agree. However, the passage upon which the respondents rely appears in the "background" section of the specification, and constitutes a statement by the inventor of the shortcomings in the prior art. Properly understood, this passage described not the process of inventing something new, but the outcome which one would achieve (or rather, in the inventor's words, would be unable to achieve) by following the prior art. If we were to find an effective admission that less than gram quantities of the compound claimed to have been invented were obtainable in 1993 by routine HPLC, it would be no answer that the inventor came to that position as part of his background work in connection with the invention in suit. 192 That brings me back to the first of the three points made by AMR. Is the statement that a practical separation to obtain gram quantities of substantially pure regioisomers had not been achieved the equivalent of an admission on the face of the specification that less than gram quantities of the substantially pure para regioisomer had been separated out? How the jurisprudence referred to in Merck has application to a circumstance in which the relevant admission is said to be implicit from some words, not expressly admitting anything, on the face of a specification is not a question upon which I was addressed by any party. I was not referred to any authority on the point. At the level of principle, I consider that a court should be cautious before treating a negative express statement in a specification as the equivalent of an implied admission in terms which would be conveyed by the corresponding positive statement. In the context of the present case, I am not prepared to hold that the specification, on its face, admits that the subject matter of the invention was not, at the priority date, new. I reach that conclusion for the following reasons. 193 First, the question of what is admitted on the face of the specification must be addressed by reference to the terms of the specification as a whole. No narrow, fragmentary or nicely grammatical approach is called for. I accept AMR's submission that it is as clear as may be, from the terms of the specification in the present case, that the inventor is asserting that the relevant piperidine derivative compounds could not, consistent with the prior art, be synthesised at the level of substantial purity. I should be slow to treat that assertion as wholly negated by what is said to be an implication arising from an apparently uncontentious proposition that the inventor was unable to achieve gram quantities of substantially pure regioisomers. For all the reader of the specification knows, the inventor may never have attempted to achieve separation at less than gram quantities; or he may have attempted to do so and failed, but regarded that circumstance as inconsequential in a setting in which his objective was to achieve "a practical separation to achieve gram quantities". 194 Secondly, what the respondents essentially seek to undertake here, in my view, is not the reading of an implication from the terms of the specification as such, but the drawing of a logical conclusion from the statement expressly made that the separation of gram quantities has not been achieved. There is an important distinction between the two. The first would involve a perception of something implicitly stated by the inventor, and would satisfy the requirement that the admission appear on the face of the specification. The second would involve , as it were, a joining of the dots between things stated in the specification to reason, as a matter of logic rather than terminology, that the inventor most probably had been able to synthesise the subject matter of the invention from the disclosures in the prior art. While this second approach may have some currency in the normal world of curial factfinding, it is, in my view, inappropriate as a means of identifying what appears on the face of the specification. 195 Thirdly, it was an important aspect of the respondents' submission that, as at the priority date, HPLC could be used, and was routinely used, as a means to separate components from a mixture of regioisomers. Factually, that appears to be uncontroversial. According to the respondents, therefore, when the specification states that the mixture of regioisomers resulting from the examples in Carr 129 "can be analysed by HPLC experiments", this should likewise be taken as an admission that the regioisomers could be separated by HPLC. But, in applying this branch of the law, I believe I am restricted to the terms of the specification itself. I am not permitted to bring to those terms some appreciation, obtained elsewhere, of what the techniques employed by the inventor would have permitted him to do. It does not appear on the face of the specification that the inventor in fact resorted to what has been called "preparative HPLC", and I should not supply that deficiency in order to assist the respondents to make good their point. 196 Thus, I am not satisfied that the invention was not a manner of manufacture by reason of the "gram quantities" point. 197 It was also submitted on behalf of Alphapharm that the patent went no further than to claim a known compound with desirable attributes, that is to say, substantial purity. It was said that this was no more than a claim for "a mere desideratum", in which respect reliance was placed upon NV Philips Gloelampenfabrieken v Mirabella International (1993) 44 FCR 239, 264-265. As it happens, the judgment of Lockhart J in that case says nothing about "mere desideratum" and, for my own part, I have difficulty finding any support in it for the point now advanced by Alphapharm. That was a case in which, relevantly to the present point, it was held that the combination of known, unremarkable, characteristics in an existing product (thereby giving the product an advantage over like products which lacked those characteristics) was not a "manner of new manufacture" or a "manner of manufacture". 198 In Eli Lilly and Co v Pfizer Overseas Pharmaceuticals (2005) 218 ALR 408, Heerey J referred to the Full Court judgment in NV Philips as authority for the proposition that a "mere desideratum", which his Honour paraphrased as "something which is disclosed as no more than a wished for result", was not an invention in the sense of involving a manner of new manufacture within the meaning of s 6 of the Statute of Monopolies (218 ALR at 444-445 [212]). Like his Honour in that case, however, I consider that the specification in the present case, on its face, goes further than to disclose "a wished for result". It asserts that the prior art does not permit the synthesis of the compounds of interest in substantially pure form and, therefore, that those substantially pure compounds did not previously exist. It "tells the reader the manner in which the desired object is to be achieved" (Eli Lilly 218 ALR at 445 [213]). In my view, there is no substance in this ground of objection advanced by Alphapharm. 199 It follows from what I have said above that I reject the respondents' manner of manufacture cases.

Sufficiency 200 The respondents submitted - perfunctorily if I may so observe without disrespect - that the patent in suit did not describe the invention fully, giving the best method known to the inventor of performing the invention, as required by s 40(2)(a) of the Patents Act. However, the patent sets out in detail the means by which compounds of the relevant class as such might be prepared, and none of scientists called by the respondents proposed that these methods would be insufficient for the purpose. Rather, the respondents' case would require me to pass judgment upon the sufficiency of the specification, as perceived by a worker skilled in the art, without the assistance of the opinion of any such worker. 201 The respondents submitted that the specification was silent as to the identification, and the means of elimination, of impurities other than regioisomeric ones. As explained elsewhere, however, I take the view that the essence of the invention was a compound of substantial regioisomeric purity. I do not consider that the inventor was concerned with purity in other senses, from which it follows that he had no need, under s 40(2)(a), to describe the means by which it might be achieved. 202 Alphapharm also advanced a submission which was, in effect, in the alternative to its case on novelty. In its written outline, Alphapharm's point was expressed as follows: First, as submitted above, the Patent relies extensively on the skill of the skilled addressee in adjusting ordinary laboratory techniques in order to perform the alleged invention. If these skills are not available to the skilled addressee in construing or following the prior art, they cannot be relied upon by AMR and the Patent will be insufficient. The limited basis upon which I have found, in my reasons above, that Carr 129 did not provide an effective means of preparing fexofenadine as such does not amount to a holding that "the skill of the skilled addressee in adjusting ordinary laboratory techniques" was not available to him or her in construing or following the prior art. Indeed, I would understand Alphapharm to have made common cause with the inventor in proposing that the crystallisation and other procedures referred to were within the synthetic stockintrade of the organic chemist at the priority date. That the inventor assumed an appreciation of such techniques, rather than describing them, does not warrant the conclusion that the specification in suit did not describe the best method known to the inventor of performing the invention. 203 I reject the respondents' case under s 40(2)(a) of the Patents Act.

Fair basis 204 The respondents submitted that the claims presently in contention were not fairly based on the matter described in the specification, as required by s 40(3) of the Patents Act. Their point was that the claims (with the exception of Claim 11) are for compounds, whereas the specification is confined to processes for synthesising those compounds. Where the specification describes processes only, claims for the compounds as such (however made) were not, it was said, fairly based. 205 This submission requires me to undertake a brief survey of the structure and content of the complete specification. Such a survey reveals the following: Pages 1A-6 are concerned with the "background of the invention" and deal with the limitations of the prior art (substantially the Carr patents) in respects to which I have referred at some length above. Pages 6-9 contain a "summary of the invention", identifying the family of compounds covered thereby, and setting out, in very broad outline, how the compounds may be prepared. Pages 9-19 provide a "detailed description of the invention", identifying the specific compounds that are covered by the various combinations referred to diagrammatically in the formula to which I have referred to in para 4 above. Certain compounds which are "particularly preferred" are identified. Various pharmaceutically acceptable salts, which are also included within the invention, are identified. The means by which the compounds covered by the invention might be administered therapeutically are referred to. Then the specification identifies a means by which the compounds may be prepared, moving on to the processes next mentioned. Pages 20-31 identify a series of synthetic processes for producing compounds covered by the specification. Pages 31-38 set out 13 examples of the preparation of various compounds covered by the invention. Pages 39-43 set out the claims. 206 So far as I can see, this appears to be a fairly conventional compound patent, in which the compound is identified and, conformably with s 40(2)(a) of the Patents Act, the known methods of preparing the compound are set out. With respect to the respondents, I have difficulty appreciating how it might be said that claims for the compounds are not fairly based in a specification such as this. The compounds for which claims are made are unambiguously referred to in the specification. The respondents' point seems to be that the devising of a means to prepare compounds of substantial purity is the only advance which the specification made over the prior art. That is, of course, a separate point, but even then it must be remembered that the actual compounds to which the claims relate are substantially pure piperidine derivatives, it being asserted that the prior art contained no instance of such compounds. Assuming for present purposes, as I must, that the inventor was justified in making that assertion, I do not accept that the claims are not fairly based on the ground proposed by the respondents. If the claims are for a new invention, the compounds to which they relate are, in my opinion, correspondingly dealt with in the specification.

False suggestion 207 The respondents' final point is that the patent was obtained by false suggestion, and should be revoked under s 138(3)(d) of the Patents Act. This requires the court to consider first whether a false suggestion was made, and secondly whether that suggestion "materially contributed to the commissioner's decision to grant the patent or was a material, inducing factor, which led to the grant": Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC (2008) 77 IPR 449, 468 [82]. 208 Alphapharm's false suggestion case was based on two letters sent by the then applicant for a patent to the Examiner on 20 June and 14 September 1997. Those letters came to be sent in the following circumstances. On 20 February 1997, the Examiner cited Carr 129 as anticipatory with respect to Claims 1-11 and 13 of the patent as applied for. In its letter of 20 June 1997, the applicant responded to this objection at length, in terms which, to a considerable extent, later found expression in the patent as granted. Relevantly to the present point, the letter covered the ground which I have traversed at paras 10-12 above, and continued: The presence of meta isomer is not disclosed in US Patent No. 4,254,129. However, attempts to repeat the synthesis disclosed in these patents has demonstrated the existence of a sizeable quantity of the meta isomer. … US Patent No. 4,254,129 does not mention the meta impurity problem, which the HPLC data … shows to be a major contaminant. The synthesis described in Example 5(A) of US Patent No. 4,254,129 calls for recrystallization; there is no indication of why this is needed or how it is carried out. However, as set forth in the attached August 25, 1993, letter from Louis J Wille … Corporate Patent Counsel, Marion Merrell Dow, Inc., then assignee of these patents, analysis of the actual sample corresponding to this example was found to contain 96.3% of the para isomer and 3.7% of the meta isomer. A second scientist at Marion Merrell Dow, Inc. followed this procedure and found that the product contained 95.9% para isomer and 4.1% meta isomer. Applicant's study of this chemistry has demonstrated that the Friedel-Crafts acylation of the ethyl ester of α,α-dimethylphenylacetic acid with 4-chlorobutyric acid reproducibly and consistently provides about a 67:33 mixture of the para to meta isomers. The purity levels achieved by Marion Merrell Dow, as described in the August 25, 1993, letter from Mr Wille, were apparently obtained by using a chromatography or crystallisation method. However, even such mixtures with higher levels of the para isomer do not constitute a "substantially pure" product, as required by the claims of the [p]resent application. Notwithstanding the ostensible indication in this extract, Mr Wille's letter of 25 August 1993 made it clear that the samples of 96.3% and 95.9% para-purity referred to were in fact derived at the completion of Example 5(B), not Example 5(A), of Carr 129. Relevant extracts from Mr Wille's letter were on the Commissioner's file, and I doubt that the Examiner would have been under any misunderstanding on the point. 209 The letter of 20 June 1997 next referred to the importance of purity in pharmaceutical settings, and to relevant passages in the US Pharmacopeia. It concluded on this aspect: From the above passage of USP, it is apparent that a pharmaceutical compound is considered "substantially pure", in accordance with the present invention, where the level of impurities is less than 2%. As noted above, the level of meta impurities present when the subject piperidine derivative compound of the present invention is prepared in accordance with the process of US Patent No. 4,254,129 is significantly higher than 2%, even when that product is subjected to chromatography or crystallization steps which are at most poorly described in this reference. Accordingly, the compounds prepared by the prior art process are not "substantially pure", as claimed by applicant, and therefore, it is respectfully submitted that the rejection based on this citation should be withdrawn. 210 Alphapharm's first point about the letter of 20 June 1997 is that it contained a representation that "the product described in Carr US 129 was an 'inseparable mixture' of the meta and para regioisomers". In terms, that was not strictly so. The letter stated that the product of Example 5(A) was "an inseparable mixture of monosubstituted aromatic regioisomers". Speaking of the end product (ie that derived after Example 3), the letter stated: "Since these components cannot be completely separated, it has not been possible to obtain either of the regioisomers in each mixture in substantially pure form". What was meant by "cannot be completely separated" is to be derived from the remaining passages to which I have referred. The applicant, while asserting that Example 5(A) of Carr 129 yielded an inseparable mixture of regioisomers, recognised that, with appropriate laboratory techniques, something of the order of 96% para-substituted purity was obtainable. However, according to the then applicant, that was not good enough. For a pharmaceutical compound, purity of at least 98% was required. It is as clear as may be that the applicant was asserting that such purity could not be obtained under Carr 129, even if 96% purity, or thereabouts, was achieved at the end of Example 5(B). 211 Although the "cannot be completely separated" statement in the letter of 20 June 1997 referred to the product of Example 3, that letter wholly ignored the contribution which Examples 2 and 3 may have made to purifying the product of Example 5(B). As Alphapharm submitted, Mr Gugger's work in the present case demonstrated that a 96.39% pure compound at the 5(B) stage could, by ordinary methods applied under Examples 2 and 3, be converted into fexofenadine of 100% purity. The letter of 20 June 1997 contained the clearest of suggestions that this was not possible. That suggestion was, in my view, false, thereby satisfying the first requirement of s 138(3)(d), a deliberate intent to deceive not being a necessary ingredient of the provision: Pfizer Overseas Pharmaceuticals v Eli Lilly and Co (2005) 225 ALR 416, 495 [394]. 212 In a letter dated 15 July 1997, the Examiner maintained the objection based on anticipation by Carr 129, but elaborated on it by reference to what seems to have been a different point from any that were dealt with in the applicant's letter of 20 June 1997. There was no suggestion that the proposition that the 96% purity level achieved at the end of Example 5(B) under Carr 129 could not be improved on was not accepted. I infer that it was accepted. After some subsequent correspondence of no presently material importance, the patent proceeded to grant. 213 Given the stress which the letter of 20 June 1997 placed on the importance of at least 98% purity in the pharmaceutical context, I am in no doubt but that the suggestion in that letter which I have held to be false materially contributed to the Commissioner's decision to grant the patent in suit. The present case is an instance of one in which "it may … be inferred that a representation in fact contributed to the decision to grant a patent, … [when] the representation was objectively likely to contribute to such a decision and the patent was in fact granted": Ranbaxy 77 IPR at 468 [83]. It follows that the ground referred to in s 138(3)(d) of the Patents Act has been made out. 214 Alphapharm had another point about the letter of 20 June 1997. It related to the statement therein that "low field proton nuclear magnetic resonance spectroscopy is inconclusive in identifying the product of [the reaction in Example 5(A) of Carr 129] as a mixture". It will be noted that this statement found its way into the corresponding part of the specification in the patent as granted. Alphapharm relied upon a declaration made on 30 January 1995 by the inventor under the patent in suit, and filed in the United States Patent and Trademark Office, which contained the following paragraph: My experimental work started on or about May 9, 1992. However, I was unsuccessful in utilizing the synthesis disclosed in the Carr patents, because, according to nuclear magnetic resonance testing, there was a significant quantity of impurity in the product I prepared …. As a result, I concluded that if I continued with the approach of the Carr patents, I would only produce a mixture of para and meta aromatic regioisomers. This was said to be directly contradictory of the statement in the letter of 20 June 1997, and to demonstrate that the latter was false. 215 I should deal first with a possible source of confusion on this point, to which the parties did not refer. The relevant passage in the letter of 20 June 1997 related to the product of Example 5(A) in Carr 129. The passage in the inventor's declaration of 30 January 1995 was not specifically tied to any particular aspect of the Carr process. However, there was no suggestion by AMR that the inventor and the writer of the letter were not effectively speaking of the same stage in the synthesis - that resulting from the FriedelCrafts acylation. Indeed, as I shall show below, counsel for AMR responded to Alphapharm's point on the unstated assumption that they were. I shall proceed in accordance with that assumption. 216 In response to this point, AMR first submitted that the inventor, having come to the end of Example 5(A) (or equivalent) with a regioisomeric impurity, "made the educated assumption that, if he continued, he would only produce a mixture of para and meta isomers". Undoubtedly that is correct so far as it goes, but it does not tell the full story conveyed by the inventor's declaration. That story included also the representation that he had used nuclear magnetic resonance testing to arrive at the conclusion that he had regioisomeric impurity. The present question is not whether such testing was sufficient to provide a quantitative regioisomeric characterisation of the material: it is whether such testing was conclusive in identifying the product as a mixture. The inventor's declaration seems clearly to suggest that it was. 217 AMR next submitted that "Mr Gugger had the same problem … [t]hat is, the 1H NMR was insufficient to identify the three compounds present" in the material obtained under Example 5(A). However, Alphapharm submitted that "[i]t was not suggested to any of Alphapharm's witnesses that the NMR data for the product of Example 5(A) of Carr did not reveal a mixture of regioisomers". By the use of double negatives and slightly different concepts ("identify the … components" - v - "reveal a mixture"), these parties are here attempting to have essentially the same evidence perform service to opposite ends. What is the truth of the matter? 218 In his affidavit setting out the results achieved by Mr Gugger under Example 5(A), Prof Wild used the GC-MS data as the basis for his conclusion that the ortho:meta:para regioisomers were present in the proportions 1:46:53. He said that the 1H NMR spectrum was consistent with that. In his affidavit in response, Prof Easton said that, although the NMR analysis demonstrated the presence of more than one compound in the 5(A) material, and that the desired reaction product was probably present, it was not possible to say that the impurities were the other regioisomers of that product. In an affidavit in reply, Prof Wild did not accept Prof Easton's reservations, but repeated his evidence that "[t]he patterns and chemical shifts of the NMR peaks for these impurities are, in my opinion, consistent with there being the expected ortho and meta regioisomeric by-products of the Friedel-Crafts acylation reaction". 219 One of the topics covered in a concurrent evidence session (which did not involve Prof Wild) related to the analytical techniques used to test the purity of a substance as at the priority date. By reference to the 1H NMR analysis of the material obtained by Dr Simpson under his second run of Example 5(A), Prof Black explained what could be inferred from the various peaks there shown. He concluded that "the only clear thing that you can see is that there is some para isomer plus some other things". Dr Robertson agreed, adding: "NMR indeed is seldom used as a pure analytical technique to look for very low levels of impurities, … because of the complications inherent in proton NMR spectroscopy". In the course of a later concurrent session (which did involve Prof Wild), Prof Easton closely examined the 1H NMR analysis of Mr Gugger's 5(A) product and reiterated, quite emphatically as I heard him, his view that that analysis did not permit one to reach any conclusion about the presence or absence of particular regioisomers. Prof Wild's response was: I agree with Prof Easton's comments. If you look at the spectrum that we have been shown, it's an overlapping spectrum and we have relied completely on the gas chromatography measurements and did not attempt to integrate or deconvolute these peaks in this NMR spectrum. We had the answer already, and the peaks for those three isomers are in here because it is the same material that is being used to determine the two different results. Prof Black also seemed to accept what Prof Easton had said, adding in relation to the 1H NMR spectrum "I think all you can say is that there is an indication". 220 On the basis - which I take to be uncontroversial - that the "mixture" referred to was a mixture of regioisomers, the evidence to which I have referred would justify the statement that 1H NMR was inconclusive in identifying the product of Example 5(A) as a mixture. "Conclusive" is, of course, a strong term which implies an absolute. Anything short of that standard is to be regarded as "inconclusive". That is, in my view, as accurate a description as one might get of the opinions of the scientists called in this case about the utility of 1H NMR in the analysis of the 5(A) material. I am satisfied, therefore, that the statement in the letter of 20 June 1997 was correct. I consider that it was the inventor's declaration of 30 January 1995, rather than the letter of 20 June 1997, which may have conveyed a false impression in this respect. 221 While I have dealt above with Alphapharm's submissions on false suggestion in terms, counsel for the Sigma respondents sought to have their own submissions similarly understood. I do not need to deal separately with the latter.

Infringement 222 It was common ground as between AMR and each of the respondents that the latter produced and sold into the Australian market products that were amply within the 2% substantial purity tolerance of the patent in suit as I have construed it. The respondents accepted that, if their clarity point were not upheld, then, subject always to their other challenges to the validity of the patent, they had infringed claims 1, 6, 7, 8, 9 and 10 of the patent in suit. However, because of the findings I have made on the respondents' validity cases, AMR's infringement case under these claims cannot be upheld. The method claim - claim 11 - is in a different category. However, since there was no evidence of the methods used by the respondents to produce fexofenadine, this aspect of AMR's infringement case must also be rejected.

Disposition of the proceeding 223 It follows from my reasons above that, so far as it relates to claims 1, 6, 7, 8, 9 and 10, the patent in suit should be revoked under s 138(3)(b) of the Patents Act for lack of novelty. It also follows that AMR's infringement proceeding should be dismissed. There is a question whether the patent as a whole should be revoked for false suggestion under s 138(3)(d). I received no submissions specifically on this aspect, but I assume that the parties will address it in the written submissions which I shall require them to file as to the terms of the orders required to reflect these reasons, and as to costs. I certify that the preceding two hundred and twenty-three (223) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Jessup.