"24. I think that it is clear that those working at the forefront of NSAID research were in all probability aware of the existence of Cox II and of its importance. Indeed, it appeared from Dr Galbraith's evidence under cross-examination that all the information with which I am concerned was discussed at that conference by himself and the other speakers. The list of those attending survives, and although it represents a good cross-section of well-known chemical companies I cannot say that the attendees are representative of every company who might be interested in the subject matter of the patent. But a year elapsed from the Winter Prostaglandin conference to the priority date of the patent in suit, and another year until the application resulting in the patent in suit. By the application date for the patent in suit, I have no doubt that the Cox I/Cox II relationship, its importance and the fact that Cox II was a target for NSAID development was common general knowledge. On the whole of the evidence, and paying attention to that of Professor Flower, I think that it was also part of the knowledge of the skilled man, as a good basis for further action, at the claimed priority date."
"More specifically this invention relates to selected effective and safe compounds having anti-inflammatory and/or analgesic activity without erosion of the stomach."
"Prostaglandins play a major role in the inflammation process, and the inhibition of prostaglandin production, especially production of PGG 2 , PGH 2 and PGE 2 , has been a common target of anti-inflammatory drug discoveries. However, common non-steriodal anti-inflammatory drugs (NSAIDs) that are active in reducing prostaglandin-induced pain and swelling associated with the inflammation process, are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side-effects, including life-threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteriods which have even more drastic side-effects, especially when long-term therapy is involved. Previous NSAID's have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). Recently, the sequence of another heretofore unknown enzyme in the human arachidonic acid/prostaglandin pathway has been reported by T. Hia and K. Nielson, Proc. Natl. Acad, Sci, USA, 89, 7384 (1992) and named "cyclooxygenase II (COX II)" or "prostaglandin G/H synthase II"
"The compounds are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. The present invention also includes compounds which selectively inhibit cyclooxygenase II over cyclooxygenase I and do not significantly inhibit one or more other arachidonic pathway steps, such as thromboxane B 2 (TXB 2 ) production. Importantly, thromboxanes cause blood platelet aggregation and have vasoconstriction properties. Thus a lack of effect in the regulation of non-inflammation related thromboxane production is further evidence of the beneficial selectivity of the present compounds. Preferably the compounds of the present invention have a thromboxane B 2 inhibition lC 50 of greater than about 1.5 µM, as determined by a whole cell assay and preferably over 10 µM. The inhibition of the production of TXB2 by a whole cell assay is a better indicator of potential in vivo behavior as the assay also incorporates such factors as cell transport. More preferably the compounds also have a selectivity ratio of cyclooxygenase II inhibition over cyclooxygenase I inhibition of at least 50 and preferably of at least 100. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects, such as ulcers."
"32. The text may be picked up at page 31, where the biological evaluation of the compounds are described. Two in vivo and two in vitro tests are described. The in vivo tests are well established tests carried out on rats to evaluate NSAID's, and form part of the common general knowledge. It should be noted that such evaluations are performed only in respect of those compounds which have already demonstrated promise in vitro . In summary, the carrageenan foot pad oedema test is to determine whether the compound reduces the inflammation-induced swelling induced in a rat's paw caused by injection of a compound (carrageenan). The carrageenan-induced analgesia test consists of inflaming the paw, again by injection of carrageenan, and seeing whether the compound increases the time which it takes for the rat to remove its paw from a source of pain. A number of these evaluations were carried out for the purpose of this action. The results reported in the specification were in respect of 5 compounds only, and as will be apparent from Table I on page 32 of the specification not all 5 compounds were assayed on both tests. Example 1 is shown as analgesic but not as anti-inflammatory. Examples 2, 13 and 14, which are within the claim, are shown as having an anti-inflammatory effect, while the comparison example 4 shows comparable anti-inflammatory characteristics. It should be noted that Example 4 is said to be a comparison example. The compound is 3,4-bis (4-methoxyphenyl) thiophene. This compound does not fall within claim 1 because neither of the substituent aryl groups is itself substituted with methylsulphonyl or sulphamyl. 33. A very large amount of evidence was provoked by the in vitro tests which the specification now describes. The tests as described depend upon having available the gene for either human or mouse Cox I and Cox II. A 2.0 kb fragment containing the coding region of either human or murine COX-I or human or murine COX-II was cloned into a BamHI site of the baculovirus transfer vector pVL1393 to generate the baculovirus transfer vector. Recombinant baculoviruses were isolated by transfecting 4µg of baculovirus transfer vector DNA into SF9 cells (2 x 10e8) along with 200 ng of linearized baculovirus plasmid DNA by the calcium phosphate method. Recombinant viruses were purified by three rounds of plaque purification and high titer (10E7 - 10E8 pfu/mI) stocks of virus were prepared. For large scale production SF9 insect cells were infected in 10 liter fermentors (Bioprocess group) (0.5 x 106/mI) with the recombinant baculovirus stock such that the multiplicity of infection was 0.1. After 72 hours the cells were centrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1% CHAPS. The homogenate was centrifuged at 10,000xG for 30 minutes, and the resultant supernatant was stored at -80ºC before being assayed for COX activity. 34. The identification of the gene coding for human or murine COX had been identified by the claimed priority date. Professor Flower's evidence was that Needleman's hypothesis of the existence of the two isozymes was accepted by 1992 and the cloning of the human gene had been achieved in 1992. This passage of the specification reinforces my view that Professor Flower's evidence as to what was generally known is correct, and that the genes were available. 35. The assay for Cox I and Cox II activity which is described in the specification is in fact that which was used by the claimants at the relevant time in assessing Cox I/Cox II activity. The basic idea of the assay is that the enzyme is pre-incubated with the compound under test. During the period of incubation, the enzyme will be inhibited if the compound is a COX inhibitor. The enzyme is then exposed to its substrate, arachidonic acid, and the amount of prostaglandin synthesised by the enzyme in a fixed period is measured. A good inhibitor will mean less prostaglandin. The compound is tested at a number of concentrations and the final figure which is used for comparison purposed between different compounds is the concentration of compound which is needed to produce 50% inhibition, the so-called ID 50 or IC 50 . Table II of the patent on page 33 shows the results of such tests. Fourteen compounds of the patent are shown as having been tested, mainly by reference to mouse Cox I and Cox II, although one of the results (Example 1) relates to human COX. The specification does not provide any interpretation of these results. The only guide to their interpretation is the passages to which I have already referred. There is no comparison with, for example, an established NSAID such as indomethacin which is used, incidentally, to stop the synthesis of prostaglandin during the assay. It seems to follow that this test is essentially a comparative test which is intended to reveal differences in Cox I and Cox II activity. 36. The final test to which the patent relates is the whole blood assay for thromboxane B 2 activity. This is an assay for Cox I inhibition. Professor Flower describes it as follows. This experiment tests for eicosanoid (i.e. prostaglandin derivative) synthesis as a consequence of blood platelet (red blood cell) aggregation. Briefly, blood is taken from a healthy volunteer. A sample is measured out together with the test compound and the blood is allowed to clot naturally in a 37°C water bath. During the clotting process, platelets are activated and arachidonic acid is released. Large amounts of prostanoids (that is, prostaglandin derivatives) will be produced by the platelets, as a result of Cox I acting on the arachidonic acid substrate. These prostanoids can be recovered (mainly in the form of thromboxane B 2 or TXB 2 ) in the serum. The presence in the blood of Cox inhibitors will reduce the TXB 2 formation. This is a very convenient way of assessing the activity of potential inhibitors in man and precise IC 50 values can be obtained. 37. Thus, the idea is that the thromboxane B 2 assay is that it provides a way of detecting Cox I inhibition alone. Professor Flower emphasises, and all the witnesses agreed, that it is not possible directly to compare the results of the thromboxane B 2 assay with that of the Cox I/Cox II comparative assay. The specification says nothing about the interpretation of the thromboxane B 2 assays that are set out. In general terms, however, it may be seen that the higher the IC 50 , the more of the compound is needed to achieve a 50% reduction in prostanoid synthesis, and thus the less effective is the compound as a Cox I inhibitor. Seen in the context of the passage in the specification to which I have referred in paragraph 26 above, this test enables the skilled man to identify those compounds included within the claim which do not significantly inhibit one or more "other arachidonic pathway steps, such as thromboxane B 2 production."
"Claim 1 of the unamended patent is as follows. I have added labels to the features for ease of reference. This subdivision of the features was given to me by the claimants without dissent from the defendants. I have also underlined those features of the claim which are relied on for the allegation of infringement. I A compound of Formula I wherein Y is selected from S, O and NR 1 ; wherein R 1 is selected from hydrido and C 1 -C 6 alkyl; wherein X is one or more substituents selected from (a) (i) hydrido (ii) halo (iii) cyano (iv) nitro (v) hydroxy (vi) acyl (vii) lower alkyl substituted at a substitutable position with a substituent selected from halo, hydroxyl, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryl optionally substituted with hydroxyl, a heterocyclic group, hydroxyimine and lower alkoxyimine, (viii) lower alkonyl optionally substituted at a substitutable position with cyano, (ix) amino optionally substituted at a substitutable position with a radical selected from acyl and lower alkylsulfonyl, (x) sulfo, (xi) sulfamoyl optionally substituted with a substituent selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxyl, lower alkylamino(lower)alkyl, a heterocyclic group and (esterified carboxy)lower alkyl, (xii) N-containing heterocyclicsulfonyl, (xiii) a heterocyclic group optionally substituted at a substitutable position with a substituent selected from the group consisting of hydroxyl, oxo, amino and lower alkylamino, provided that when Y is O or NR 1 then X cannot be hydroxyalkyl, (b) S(O) n R 5 , wherein R 5 is C 1 -C 6 alkyl optionally substituted at a substitutable position with fluoro, and n is 0, 1 or 2, (c) C(R 6 )(OR 8 )(R 7 ) wherein R 6 and R 7 independently are selected from CF 3 , CF 2 H, CFCl 2 , CF 2 Cl, CClFH, CCl 2 F, CF 3 CF 2 and C 1 -C 2 alkyl, and wherein R 8 is selected from hydrido, C 1 -C 4 alkyl, (C 1 -C 3 alkyl)C(O) and CO 2 R 9 wherein R 9 is C 1 -C 4 alkyl, (d) C(O)ZR 4 , wherein Z is O, N, or S, and R 4 is selected from hydrido, C 1 -C 5 alkyl and aryl, and when Z is N then R 4 is independently taken twice, and (e) C(R 9 ) (NHR 11 ) (R 10 ), wherein R 9 and R 10 are independently selected from CF 3 , CF 2 H, CFCl 2 , CF 2 Cl, CClFH, CCl 2 F, and R 11 is selected from hydrido and C 1 -C 3 alkyl, and wherein R 2 and R 3 are independently selected from aryl or heteroaryl, wherein the aryl or heteroaryl radical is optionally substituted at a substitutable position with a radical selected from halo, lower alkyl lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl , nitro, amide, amino, lower akylamino, sulfamyl and lower alkylsulfonylamino, provided that at least one of R 2 and R 3 is substituted with methylsulfonyl or sulfamyl; or a pharmaceutically acceptable salt thereof."
"The substituted thiophene compounds disclosed herein selectively inhibit cyclooxygenase II over cyclooxygenase I and relieve the effects of inflammation. These compounds, in addition, do not display substantial inhibition of cyclooxygenase I and produce a reduced amount of side effects."
"174. The compound sold by Merck as the active ingredient of Vioxx is 3-phenyl-4-(4-methylsulphonylphenyl)-2-(5H) furanone. It is referred to as MK-966 ( Figure B ). Figure B: MK-966 It is common ground that this compound is not among those explicitly listed in claim 1. In aqueous conditions, however, MK-966 undergoes a chemical process called tautomerisation, and it is from this fact that the allegation of infringement really springs. Before turning to the details of the allegation of infringement, I should first describe tautomerism."
"The same is true of tautomerism in aromatic molecules. Returning to the defendants' compound MK-966, this undergoes tautomerisation in aqueous solution. Its tautomeric companion is 3-phenyl-4-(4-methylsulphonylphenyl)-2-hydroxyfuran ( Figure C ). Figure C: tautomerism of MK-966"
"The hydroxyfuran is an acid, and will dissociate to some extent into an anion (a negatively charged ion) and a hydrogen ion (or proton). Figure D: formation of enolate The charges are shown by the plus and minus signs. The negatively charged ion is the enolate ion."
"60(1) (a) where the invention is a product, he makes, disposes of, offers to dispose of, uses or imports the product or keeps it whether for disposal or otherwise; … (2) Subject to the following provisions of this section, a person (other than the proprietor of the patent) also infringes a patent for an invention if, while the patent is in force and without the consent of the proprietor, he supplies or offers to supply in the United Kingdom a person other than a licensee or other person entitled to work the invention with any of the means, relating to an essential element of the invention, for putting the invention into effect when he knows, or it is obvious to a reasonable person in the circumstances, that those means are suitable for putting, and are intended to put, the invention into effect in the United Kingdom."
"197. I must be satisfied that the construction which I place on the claim satisfies the requirements of the Protocol by providing fair protection for the patentee and a reasonable degree of certainty for third parties. Were the claim to be construed so as not to cover a compound which is necessarily present with a compound expressly claimed, and which would be prepared with that compound, I think that there is no offence against this principle. I believe that it is helpful to consider the phrase used by Fox LJ which is quoted by Hoffmann J in Improver , "within the ambit of the language"
"196. … It is not altogether easy to apply the principles of construction articulated in these cases [ Improver and STEP v Emson ] to a claim in which every term is unambiguous and devoid of any question of degree (except as to the number of carbons embraced by the phrase "lower alkyl" and similar matters) but which would nonetheless be read as necessarily involving the presence of other species which are not mentioned but which would play a role in the chemical properties of the compound claimed. The third Improver question also presents a difficulty. It is in the nature of class claims that not every member of every class will be exemplified and described. If there is no description of a hydroxy-substituted compound, there will be nothing in the specification likely to help to decide whether the patentee intended as a matter of words to exclude the tautomer, but, since the presence of the tautomer is a matter of common general knowledge the fact that there is no reference to suggests a deliberate exclusion."
"(c) the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art."
"60. It is a generally recognised principle of patent law that the patentee is not entitled to protection wider than the contribution which he has made to the art. It goes without saying that the patentee's claim should not cover that which is old or obvious. If it were otherwise, the patentee would be able to prevent others from doing what was old or obvious at the priority date, and this is intuitively wrong. Of course, this principle must be qualified. Merrell Dow v Norton[1996] RPC 76 establishes that it applies only to matters rendered old or obvious by information disclosed before the priority date. Other forms of protection (rather than invalidity) are provided by the statute for those who have used the invention before the priority date but in a manner which conveys nothing. 61. When one turns to the extent of the patentee's contribution to the art, the problem becomes more difficult. The essential underlying concept is that of the enabling disclosure. The patentee may not obtain a monopoly for matter which he has not told the public about and enabled them to do for themselves on the basis of what he has disclosed in the specification. This concept is manifested in two substantive requirements for the specification and claims. Subsection 14(3) of the Act requires that the specification of the application shall disclose the invention in a manner clear enough and complete enough for it to be performed by a person skilled in the art. Subsection 14(5) of the Act, mirroring Article 84 EPC, requires that the claim be supported by the description. It has never been the law that the claim must be co-extensive with the embodiments specifically disclosed by the patentee in his specification. Protection limited in this way would in all probability be illusory. When the patentee makes an invention, he may not appreciate its ramifications, and, when he files an application, he has in effect a year in which to develop and refine his invention before describing it in a further application which will result in the patent. The process of development and refinement may result in further applications along the way, but the application which will result in the patent must be made within a year. If, and only if, the claim is supported by the matter disclosed in the earliest application will it be entitled to priority from that application; and the intervening applications may form the bases of other claims to priority. The claims of the patent itself must be supported by the description given in the application for the patent, and the patentee may not add further to the disclosure of the application during the process of prosecution. As Lord Hoffmann explained in Biogen v Medeva[1997] RPC 1 at page 46, when the Act provides in section 72 for revocation of the patent on the ground that the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a man skilled in the art, it gives effect not merely to the substantive requirement of subsection 14(3) but to that of subsection 14(5)(c) as well."
"Section 72(1)(c) of the 1977 is not only intended to ensure that the public can work the invention after expiration of the monopoly. It is also intended to give the court in revocation proceedings a jurisdiction which mirrors that of the Patent Office under section 14(3) or the E.P.O. under article 83 of the EPC, namely, to hold a patent invalid on the substantive ground that, as the E.P.O. said in Exxon/Fuel Oils (T 409/91) [1994] O.J. E.P.O. 653, paragraph 3.3, the extent of the monopoly claimed exceeds the technical contribution to the art made by the invention as described in the specification. In the 1949 Act, this function was performed by another ground for revocation, namely that the claim was not "fairly based on the matter disclosed in the specification" (section 32(1)(i)). The requirement of sufficiency was therefore regarded as serving a narrower purpose. But the disappearance of "lack of fair basis" as an express ground for revocation does not in my view mean that general principle which it expressed has been abandoned. The jurisprudence of the E.P.O.
"67. This seems to me to be a clear statement that the applicable principle is that the claim must equiparate (to use Graham J's phrase in Olin Mathieson v Biorex[1970] RPC 157 ) with the invention, and, if it does not do so, the claim will not be enabled across its full width, because it will cover matter which owes nothing to the invention disclosed. It follows that if the claim covers compounds which do not satisfy the representations made about them in the specification, it is likely to be invalid, because, again, the claim will be covering compounds which owe nothing to the teaching of the specification. This is not to say that when the claim reflects a new feature uniting the class as a class, and relating the desirable quality of the compounds to this feature, it is bad if a few members of the class do not possess the desirable quality or possess it in an attenuated form. But the qualities of the class must be related to the features of the claim. If compounds having the features of the claim may or may not possess the qualities which the patent says unify the class, it cannot be said that the claim reflects a true class at all. It is just a generalised description of a large number of chemical compounds. Such a claim is not analogous to a claim to a new principle, since the patentee has given no information, such as a structure/activity relationship, which enables the reader of the specification to draw any conclusions as to the properties of any particular compound without further experiment. All he has done is to describe the scope of the claim with spurious precision."
"Since Genentech I/Polypeptide expression the E.P.O. has several times reasserted the well established principles for what amounts to sufficiency of disclosure. In particular, in Exxon/Fuel Oils (T 409/91) [1994] O.J. E.P.O.
"'The concept of an enabling disclosure is central to the law of patents. For present purposes, it touches the matters in issue at three different points. First, as we have seen, it forms part of the requirement of "support" in section 5(2)(a). Secondly, it is one of the requirements of a valid application in section 14. And thirdly, it is essential to one of the grounds for the revocation of a patent in section 72. I shall start with section 14. Subsection (3) says: "
"the Act can hardly have contemplated a complete application for a patent lacking some of the material necessary to sustain the claims made"
"Section 72(1)(c) of the 1977 is not only intended to ensure that the public can work the invention after expiration of the monopoly. It is also intended to give the court in revocation proceedings a jurisdiction which mirrors that of the Patent Office under section 14(3) or the E.P.O. under article 83 of the EPC, namely, to hold a patent invalid on the substantive ground that, as the E.P.O. said in Exxon/Fuel Oils (T 409/91) [1994] O.J. E.P.O. 653, paragraph 3.3, the extent of the monopoly claimed exceeds the technical contribution to the art made by the invention as described in the specification. In the 1949 Act, this function was performed by another ground for revocation, namely that the claim was not "fairly based on the matter disclosed in the specification" (section 32(1)(i)). The requirement of sufficiency was therefore regarded as serving a narrower purpose. But the disappearance of "lack of fair basis" as an express ground for revocation does not in my view mean that general principle which it expressed has been abandoned. The jurisprudence of the E.P.O.
"5. The specification of the Patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art. In particular (a) the specification of the patent fails to identify which (if any) compounds among those classes of 3,4 diaryl thiophenes, furans and pyrroles claimed: (i) are Cox II selective or enable the skilled addressee of the patent to predict which compounds are Cox II selective; (ii) exhibit anti-inflammatory activity or enabled the skilled addressee of the patent to predict which compounds exhibit anti-inflammatory activity; (iii) exhibit reduced gastric side effects when administered to patients or enable the skilled addressee of the patent to predict which compounds will exhibit reduced gastric side effects. (b) the specification of the patent fails to teach the skilled addressee how to synthesise the substituted pyrrole and furan derivatives of the invention and in particular the hydroxyfurans of the invention. In the premises the claims of the Patent extend beyond the technical contribution to the art (if any) of the specification of the Patent."
"2. Without prejudice to the generality of the plea, hereunder the Defendants repeat the groups of compounds listed in paragraph 1(a), 1(b), 1(d)-(f) above as examples of those compounds which are claimed in the patent but which are not COX II selective and do not exhibit reduced gastric side effects. Further compounds which R 3 is a phenyl group substituted in the 2 position by an alkyl group and substituted in the 6 position by any group occupying a space larger than flourine; or compounds in which R 3 is a non phenylaryl group substituted in the 2 position by any group occupying a space larger than flourine, are claimed in the Patent but are not COX II selective and do not exhibit reduced gastric side effects."
"71. I can turn to the details of the experiments. The ELISA plates are made of translucent plastics material and contain 96 "wells" in which reagents are successively added to the compound under test. This is a standard technique which utilises an antibody which can bind specifically to PGE2. It results in a colour change which can be measured using a spectrophotometer and is inversely proportional to the amount of PGE2 present. The ELISA used is based on a proprietary kit produced by Cayman Chemicals. There are a number of prescribed concentrations of compound, expressed as micro moles or µM, which enables the results of the assay on different compounds to be compared. If a compound is insufficiently soluble to pass into solution, the results are said to be valueless because not all the compound is in solution and the nominal concentration is not achieved. 72. The concentrations selected by the defendants were 0.0064µM, 0.032µM, 0.16µM, 0.8µM, 4µM, 20µM, 100µM and 1000µM. Each successive concentration is five times the preceding one (except, obviously, between 100 and 1000µM). There was precipitation in all of the defendants' experiments at 1000µM. There is some dispute as to the extent to which there was precipitation in the others."
"96. Class D is intended to show that substitution at the 4 position in R 2 is essential, a move to either the 2 or 3 positions resulting in an inactive molecule. This the experiments did show: there were no counterexamples. The claimants say that the result is to be explained by insolubility, and those otherwise analogous compounds in class A which did work are to be explained by the fact that sufficient got into solution to work. In fact, a check of the results show that these compounds showed no activity at any concentration whether there was precipitation or not. This experiment establishes that a compound in which the methylsulphonyl or sulphamyl group is not at the 4 position will be inactive."
"98. Class F was a somewhat miscellaneous class, intended to show that various bulky groups on the aryl ring not substituted at the 4 position with methylsulphonyl or sulphamyl would prevent inhibitory activity. The claimants complain, with some justification, that Class F represented a moving target. There were three classes of compounds. The Notice of Experiments states that the fact to be proved is …compounds in which the aryl or heteroaryl group R 3 is substituted with a bulky group, or are disubstituted, are inactive as measured by either h-Cox I or h-Cox II inhibition in vitro (see for example compounds 27 - 34 and 37). In his report, Professor Baker relied not only upon this experiment but upon three other compounds. Thus his class F in its entirety consists of compounds B50 to B63 inclusive. In support of the fact, however, Professor Baker also relied on a number of compounds in Class A (which, it will be remembered, the defendants considered to be active and Cox II selective). His evidence was this: Section F of the Table contains a list of compounds that differ from selective COX-2 molecules only in that they have a large group on the other aryl group (R 3 ). Comparison of Sections A and F indicates that, whilst there is some space around the second aryl group, such that fluoro (B1), methyl (B6), methoxy (B3), thiomethyl (B13) and amino (B14) can be tolerated, anything significantly larger cannot be accommodated in the enzyme. The examples which he gives of the effect of such substitutions is complicated, and he summarises them in his report thus: (a) A second 4-methylsulphonylphenyl or sulphamylphenyl group is not tolerated by either COX-1 or COX-2 (see compounds B50 & B51). Further, a 4-methylsulphinylphenyl group is not tolerated (B58); (b) Even relatively small groups are not tolerated in the 2-position (see B52, B55 and B56). This effect may be aggravated if there is a substituent in the X position opposite the 4-methylsulphonylphenyl because this may cause the twisting of the aromatic ring (see B62). (c) Whilst there appears to be more space around the 4-position, moderately large alkyl or alkylamine groups in these positions result in inactive compounds against either form of the enzyme (see B53 and B54). (d) The 2, 6 or 3,5 di-substituted compounds for example in which R3 is 2, 6-dichlorophenyl and 3,5-difluorophenyl are inactive (see B60 and B61). Professor Flower introduced a number of additional compounds into the discussion, with the result that RJF 25 contains 30 compounds in class F. It should be recalled that the compounds found by Professor Flower in the defendants' documents have a number beginning C and it is not suggested that Professor Baker was aware of these compounds when he wrote his report. With his C compounds, Professor Flower produces counter-examples to each of these propositions of Professor Baker's. In fact, there is a clear counter-example to (a) in compound C13 as Professor Baker accepted in cross-examination. Professor Baker himself qualified paragraph (b) in the light of compound C9. His evidence was that the results collected in RJF 25 represented an attempt at an SAR for these molecules, which would necessarily require refinement, but this is not one of the facts that the Notice of Experiments was put forward to show. There is no doubt that many of the compounds in question were inactive; others less so. The claimants pointed to C3, C5, C6, C10, C11 and C12 as compounds where there was activity below but close to 50% at 100µM or 1000µM. On the other hand, some compounds were plainly inactive, among which B55 is to be included. The same goes for paragraph (d). The evidence was thin, but the compounds disubstituted at the 2,6 and 3,5 positions actually tested were inactive."
"100. It is possible to draw a number of conclusions from the very extensive evidence which was available in respect of classes F, G and H. The first is that it is quite clear that it is not possible to predict the degree of activity of the compounds in general. The second is that it is likely that the defendants have identified classes of compounds within the claims in which activity is very unlikely. In particular, it seems clear that large substituents at X will be inactive, and this is more likely if there are two X substituents, as the claim permits. Since X may be acyl, a substantially unbounded class of substituents, and aryl, a very large class also, and since both on Professor Baker's unchallenged evidence include substituents equal in size to or bigger than the whole of the rest of the molecule, I am satisfied that what can loosely be called the bulky group point is established. From classes B, C and D I am satisfied that unless there is a 4-methylsulphonylphenyl or 4-sulphamylphenyl substitution at either the 3 or 4 position of the heterocycle, it is very much more likely than not that the compound will be on the patent's own terms inactive. Finally, Class E does establish that disubstitution of the 4-substituted phenyl ring will substantially reduce the prospects of finding an active compound."
"112. The in vivo tests did demonstrate that there were three examples of the patent in suit which failed to demonstrate any anti-inflammatory effect, and a preferred compound (compound 68) which was a gastric irritant. They did not demonstrate that example 1 of the patent in suit was inactive as an anti-inflammatory, but did show that it was certainly not attractive."
"115. In coming to a conclusion on the question of the right criterion to apply in deciding whether or not a compound exhibits activity in the in vitro tests, I have gone over a great amount of the ground covered by the objection of insufficiency. I am satisfied that the experimental evidence shows that the specification provides the skilled man with a class comprising many compounds which may or may not be Cox II selective with diminished side effects. The effect of the experiments taken as a whole is to demonstrate that the class in question is unpredictable in its qualities and contains a substantial number of compounds which do not have one or other or both of these qualities. It is not possible to point to any characteristic which underpins success, and avoids failure. As I have indicated, the feature which immediately distinguishes the compounds of claim 1 from those constituting the state of the art is (subject to the disclosure of Brown) the 3,4 disubstitution of the heterocycle as opposed to the 2,3 disubstitution displayed in, for example, DuP 697. But it is clear that this does not give success on its own; and I am satisfied on the evidence that it has not proved possible to provide a general description of a class having the desired characteristics. As will be apparent when I consider the history of the claimants' development, I do not consider that the work they had done by the priority date nor the later work which they did justify any suggestion that it was a reasonable prediction that the class of claim 1 either as granted or as amended would possess anti-inflammatory properties. 116. The invention of claim 13 must be considered separately. Claim 13 covers "a pharmaceutical composition comprising a therapeutically-effective amount of an anti-inflammatory compound, said compound selected from a compound of Claim 1, or a pharmaceutically-acceptable salt thereof"
"5. – (1) For the purposes of this Act the priority date of an invention to which an application for a patent relates and also of any matter (whether or not the same as the invention) contained in any such application is, except as provided by the following provisions of this Act, the date of filing the application. (2) If in or in connection with an application for a patent (the application in suit) a declaration is made, whether by the applicant or any predecessor in title of his, complying with the relevant requirements of rules and specifying one or more earlier relevant applications for the purposes of this section made by the applicant or a predecessor in title of his and each having a date of filing during the period of twelve months immediately preceding the date of filing the application in suit, then – (a) if an invention to which the application in suit relates is supported by matter disclosed in the earlier relevant application or applications, the priority date of that invention shall instead of being the date of filing the application in suit be the date of filing the relevant application in which that matter was disclosed, or, if it was disclosed in more than one relevant application, the earliest of them; (b) the priority date of any matter contained in the application in suit which was also disclosed in the earlier relevant application or applications shall be the date of filing the relevant application in which that matter was disclosed or, if it was disclosed in more than one relevant application, the earliest of them. … (4) The foregoing provisions of this section shall apply for determining the priority date of an invention for which a patent has been granted as they apply for determining the priority date of an invention to which an application for that patent relates."
"In Asahi Kasei Kogyo KK's Application [1991] R.P.C. 485 this House decided that for matter to be capable of supporting an invention within the meaning of section 5(2)(a) it must contain an "enabling disclosure", that is to say, it must disclose the invention in a way which will enable it to be performed by a person skilled in the art. This construction has not been challenged by the appellants before your Lordships' House. It is however important to notice the relationship between the requirement of "support" in section 5(2)(a) and certain other provisions of the Act which share the concept of an enabling disclosure. The concept of an enabling disclosure is central to the law of patents. For present purposes, it touches the matters in issue at three different points. First, as we have seen, it forms part of the requirement of "support" in section 5(2)(a). Secondly, it is one of the requirements of a valid application in section 14. And thirdly, it is essential to one of the grounds for the revocation of a patent in section 72. I shall start with section 14. Subsection (3) says: "
"the Act can hardly have contemplated a complete application for a patent lacking some of the material necessary to sustain the claims made"
"The need for an enabling disclosure to satisfy the requirements of support under section 5(2)(a), valid application under section 14 and sufficiency under section 72(1)(c) has, I think, been plain and undisputed since the decision in Asahi . What has been less clear is what the concept of an enabling disclosure means. Part of the difficulty has been caused by a misinterpretation of what the Technical Board of Appeal of the E.P.O. said in Genentech I/Polypeptide expression (T 292/85) [1989] O.J. E.P.O. 275. This was a patent for a plasmid suitable for transforming a bacterial host which included an expression control sequence or "regulon" which could enable the expression of foreign DNA as a recoverable polypeptide. The Examining Division was willing to grant a patent only in respect of the plasmids, bacteria and polypeptides known at the date of application. The Technical Board of Appeal allowed the appeal, saying that the Examining Division had taken too narrow a view of the requirement of enabling disclosure: "
"132. So far as the unamended patent in suit is concerned, on the other hand, at least one methylsulphonyl or sulphamyl substitution, not necessarily on a phenyl ring but on an aryl ring (which includes naphthyl, phenyl substituted with a lower alkyl, and also other two-membered rings, three-membered rings and heteroaryl rings) is a defining feature of the claim. In my judgment, claim 1 of the patent in suit is not entitled to priority for three reasons. First, because there is no disclosure of a sulphamyl substitution in R 2 or R 3 in the priority document other than in the list of Formula I', and certainly no disclosure of it as a defining feature of the invention. Second, there is no disclosure of a methylsulphonyl substitution in R 2 or R 3 as a defining feature of the invention, but only as defining a preferred subclass in combination with a 4-fluorophenyl substitution, a subclass which does not include a hydroxy substitution at X. Third, a monopoly defined by one or other of these substitutions as an invariant feature across the whole width of the claim cannot be fairly based on a disclosure which does not hint at their materiality either textually or as a matter of necessary implication but only, at best, as a result of well-informed assessment of probabilities. 133. The amended claim is no longer open to objection on the ground either that it covers a sulphamyl substituent at R 2 or R 3 , or that it covers R 2 or R 3 substituted with methylsulphonyl other than as 4-methylsulphonylphenyl. The objection that there is no disclosure in the priority document of such a substitution otherwise than in the combination I have already described, and the consequence is the same."
"144. The first question is accordingly one of construction of the patent in suit. Does the claim allow X to be an aliphatic acid? The argument proceeds in stages. First, the claim expressly contemplates that one of the substituents (or the substituent, so far as the amended claim is concerned) may be an acyl group (feature a(vi) of the claim as I have labelled them) or may be a "lower alkyl group substituted … with a substituent selected from … acylamino, … lower alkyl(acyl)amino, acyl …" (feature a(vii) of the claim). The terms "acyl" and "acylamino" are normally well defined. The primer gives the necessary structural diagrams. The acyl group is shown thus (R is an alkyl group, that is, what is left after removing a single hydrogen atom from a hydrocarbon). The acylamino group is shown thus (R1 is an alkyl group, R2 is an alkyl group or hydrogen): 145. At page 9 line 56 of the specification, the term "acyl" is given an extended meaning: The term "acyl", whether used alone, or within a term such as "acylamino", denotes a radical provided by the residue after removal of a hydroxyl ion from an organic acid. Suitable "acyl" and acyl moiety in the terms "acylamino" and "lower alkyl(acyl)amino" may be carboxy,…"
"145. At page 9 line 56 of the specification, the term "acyl" is given an extended meaning: The term "acyl", whether used alone, or within a term such as "acylamino", denotes a radical provided by the residue after removal of a hydroxyl ion from an organic acid. Suitable "acyl" and acyl moiety in the terms "acylamino" and "lower alkyl(acyl)amino" may be carboxy,…"
"139. … The objection of obviousness assumes that there is no anticipation of the claim, but that nonetheless there has been no inventive activity on the part of the patentee which justifies the grant of a patent. Obviousness is a question of fact, and the factual analysis is habitually approached in the manner described by Oliver LJ in Windsurfing International v Tabur Marine[1985] RPC 59 at 73. There are, we think, four steps which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as [forming part of the state of the art] and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention. There are a number of arguments which are frequently advanced to fend off an attack of obviousness which need to be considered with care. The first (and perhaps the commonest) is that where there is a number of possible courses of action for the skilled man to pursue in the light of a particular disclosure, no particular course is obvious. This is wrong: all of the courses of action which present themselves without the exercise of invention are obvious (see Brugger v Medicaid[1996] RPC 635 ). The second is that the test in such a case is whether the skilled man could, rather than would, adopt the course of action which would bring him within the claim. A test formulated in this way almost invites the tribunal to consider irrelevant considerations, such as commercial attractiveness ( Hallen v Brabantia[1991] RPC 195 ). In each case, the only question is whether something within the claim was technically obvious to the skilled man in the light of the disclosure relied on. Evidence of what was actually done in the art at the relevant time can be of assistance, but what people actually did may be explicable on many grounds having nothing to do with technical obviousness. For this reason it has been said that such evidence has to be kept in its place and it is necessarily valueless unless the persons whose activities are under examination can be shown both to be aware of the prior art and possessed of the common general knowledge (see Molnlycke v Procter & Gamble[1994] RPC 49 and Hoechst Celanese v BP[1997] FSR 547 )."
"157. The substantial allegation of obviousness is based on disclosures of DuP 697 and its properties. A comparison with Example 2 of the patent in suit shows why: DuP 697 is the 2,3 isomer of Example 2 of the patent in suit. The Defendant's case is simple. They say that if one wishes to produce an SAR of DuP 697, then it is obvious to make its 3,4 isomer, which falls within the claim. Routine investigation would also traverse a great number of compounds within the claim."
"164. Professor Baldwin's view of medicinal chemists working in industry was that they basically try to copy. When they get a lead, he suggested that they mounted "some sort of chemical war" on the molecule to make something better. Generally, I think his view was that they take the line of least resistance: that is, they go first for the things that are easy to make. The evidence was that the 2,3 compounds were easier to synthesise than the 3,4 compounds. I do not think that I misrepresent his evidence if I say that his view was that invention might lie in departing from the line of least resistance. I have no doubt that he may be correct. His view was that the change from 2,3 to 3,4 substitution was sufficiently radical that it would not immediately commend itself to a skilled team seeking to make more anti-inflammatory compounds having reduced side effects."
"A. Yes. I think my characterization from my contact with these people, as consultant for the pharmaceutical industry, is that they basically try to copy. They find something that someone else has discovered and that gives them what they call a lead. Then they mount some sort of chemical war on that molecule to change it into something that is better. The theme that they largely follow, as I have observed, is the route of least work, of least effort, which is actually understandable because many of the substances that they may wish to make are actually not very easy to make. Their job is to produce compounds that can be tested in a screen that some other people are running to see if they can improve on the so-called lead structure. I am not criticizing them, but it is inevitable that they take the path of least resistance and they follow the small changes. If they do not work out, they are forced to do more and more difficult things until eventually they do something that actually leads to an invention of a new structure. They do not do that initially. They initially try to, if you like, massage what is there with modest changes and test them to see if they can see a route leading away from the first activity to improved activity. … I would have thought a medicinal chemist, when confronted with that data would say, "
"171. Structurally, there is a clear similarity between DuP 697 and its close 3,4 disubstituted ana logues. It is a matter of reasonable prediction that they will have similar activity. I think that a medical chemist wishing to investigate the structure/activity relationship of DuP 697 would think of making its 3,4-diaryl analogues, with a view to seeing whether they are active. I also think that confronted with DuP 697 and required to develop a novel compound of similar activity, the 3,4-diaryl substitution is one of the first things which would occur to the medical chemist. The claimants point to DuPont. Why, they say, if it was so obvious to use the 3,4-diaryl substitution, did not DuPont do so. The answer to this is, I think, threefold. First of all, DuP 697 was a good compound: it was not commercialised not because it had poor bioavailability but because it has too long a lifetime in the body. Second, it was comparatively straightforward to synthesise. Third, Dr Galbraith's evidence suggests that there was a degree of inertia in this field, which was only dissipated with the discovery of the inducible Cox II enzyme. All the evidence gave me the clear picture that the 3,4 diaryl compounds were obvious to try for any skilled person knowing of DuP 697, and the ones which were most obvious to try (Examples 1 and 2 of the specification) are both Cox II selective, anti-inflammatory, and gastric sparing. It follows that in my judgment claim 1 both as granted and as sought to be amended is obvious in the light of Dr Galbraith's disclosure, which provides the impulse to test for Cox II selectivity. Given also that the existence of the inducible isoform of the COX enzyme was in my view common general knowledge at the priority date, it was obvious to investigate the compound of Gans, which was said to be gastric sparing, to see why."
"154. Against this, the claimants submit that the disclosure is a disclosure of a less-preferred method. This is, of course, irrelevant. It cannot matter if the disclosure is less preferred, since we are here concerned with a description of the compounds themselves, not with determining whether there are clear and unambiguous directions to do or make something within the claim. Second, they submit that there is no disclosure of the 4– substitution of the methylsulphonyl group. This is correct. I do not think that the 4– substitution is expressly disclosed, but it is plainly obvious, since any person wishing to substitute one of the Ar rings of Brown with a methylsulphonyl group in accordance with Brown's specific teaching will, on Professor Baldwin's evidence, go for the easiest substitution, which is at the 4 position. It is not suggested that Brown does not give sufficient directions for the intermediates to be prepared."
"18. ….. Section 125 of that Act provides that an invention shall be that specified in the claim "as interpreted by the description and any drawings … shall be determined accordingly."
"Article 69 should not be interpreted in the sense that the extent of the protection conferred by a European Patent is to be understood as that defined by the strict, literal meaning of the wording used in the claims, the description and drawings being employed only for the purpose of resolving an ambiguity found in the claims. Neither should it be interpreted in the sense that the claims serve only as a guideline and that the actual protection conferred may extend to what, from a consideration of the description and drawings by a person skilled in the art, the patentee has contemplated. On the contrary, it is to be interpreted as defining a position between these extremes which combines a fair protection for the patentee with a reasonable degree of certainty for third parties."
"…. care is needed not to stifle further research and healthy competition by allowing the first person who has found a way of achieving an obviously desirable goal to monopolise every other way of doing so (see Merges and Nelson On the Complex Economics of Patent Scope [1990] 90 Columbia Law Review 839)."
"Subject to the following provisions of this section, a person (other than the proprietor of the patent) also infringes a patent for an invention if, while the patent is in force and without the consent of the proprietor, he supplies or offers to supply in the United Kingdom a person other than a licensee or other person entitled to work the invention with any of the means, relating to an essential element of the invention, for putting the invention into effect when he knows, or it is obvious to a reasonable person in the circumstances, that those means are suitable for putting, and are intended to put, the invention into effect in the United Kingdom."
"72. (1) Subject to the following provisions of this Act, the court or the comptroller may on the application of any person by order revoke a patent for an invention on (but only on) any of the following grounds, that is to say- ……. (c) the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art; (d) the matter disclosed in the specification of the patent extends beyond that disclosed in the application for the patent, as filed, ….. "
"2. (1) An invention shall be taken to be new if it does not form part of the state of the art. (2) The state of the art in the case of an invention shall be taken to comprise all matter (whether a product, a process, information about either, or anything else) which has at any time before the priority date of that invention been made available to the public (whether in the United Kingdom of elsewhere) by written or oral description, by use or in any other way."
"A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee."
"3. An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2(2) above (and disregarding section 2(3) (above)."