“Added matter – the law 46. The objection is founded upon Article 123(2) EPC : ‘A European patent application or a European patent may not be amended in such a way that it contains subject matter which extends beyond the content of the application as filed.’ 47. The test for added matter was stated by Aldous J in Bonzel v Intervention (No 3)[1991] RPC 553 at 574 in these terms: ‘The decision as to whether there was an extension of disclosure must be made on a comparison of the two documents read through the eyes of a skilled addressee. The task of the Court is threefold: (1) To ascertain through the eyes of the skilled addressee what is disclosed, both explicitly and implicitly in the application. (2) To do the same in respect of the patent, (3) To compare the two disclosures and decide whether any subject matter relevant to the invention has been added whether by deletion or addition. The comparison is strict in the sense that subject matter will be added unless such matter is clearly and unambiguously disclosed in the application either explicitly or implicitly.’ 48. In Case G 2/10,30 August 2011 , the Enlarged Board of the EPO explained in similar terms that an amendment can only be made “within the limits of what the skilled person would derive directly and unambiguously, using common general knowledge, and seen objectively and relative to the date of filing, from the whole of the application as filed”. 49. In Vector Corp v Glatt Air Techniques Ltd[2007] EWCA Civ 805 ,[2008] RPC 10 , Jacob LJ elaborated aspects of the test to be applied and drew together various statements of principle from earlier cases at [4]-[9]: ‘4. In Richardson-Vicks' Patent[1995] RPC 568 at 576 I summarised the rule in a single sentence: ‘I think the test of added matter is whether a skilled man would, upon looking at the amended specification, learn anything about the invention which he could not learn from the unamended specification.’ I went on to quote Aldous J in Bonzel. His formulation is helpful and has stood the test of time. 5. The reason for the rule was explained by the Enlarged Board of Appeal of the EPO in G1/93 ADVANCED SEMICONDUCTOR PRODUCTS/Limiting feature [1995] EPOR 97 at [Reasons 9]: “With regard to Article 123(2) EPC , the underlying idea is clearly that an applicant shall not be allowed to improve his position by adding subject-matter not disclosed in the application as filed, which would give him an unwarranted advantage and could be damaging to the legal security of third parties relying upon the content of the original application.” 6. Mr Richard Arnold Q.C. provided a clear articulation as to how the legal security of third parties would be affected if this were not the rule: “The applicant or patentee could gain an unwarranted advantage in two ways if subject-matter could be added: first, he could circumvent the “first-to-file” rule, namely that the first person to apply to patent an invention is entitled to the resulting patent; and secondly, he could gain a different monopoly to that which the originally filed subject-matter justified.” 7. Kitchin J has recently helpfully elaborated upon the Bonzel formulation in European Central Bank v Document Security Systems[2007] EWHC 600 (Pat) ,26th March 2007 : “[97] A number of points emerge from this formulation which have a particular bearing on the present case and merit a little elaboration. First, it requires the court to construe both the original application and specification to determine what they disclose. For this purpose the claims form part of the disclosure (s. 130(3) of the Act), though clearly not everything which falls within the scope of the claims is necessarily disclosed. [98] Second, it is the court which must carry out the exercise and it must do so through the eyes of the skilled addressee. Such a person will approach the documents with the benefit of the common general knowledge. [99] Third, the two disclosures must be compared to see whether any subject matter relevant to the invention has been added. This comparison is a strict one. Subject matter will be added unless it is clearly and unambiguously disclosed in the application as filed. [100] Fourth, it is appropriate to consider what has been disclosed both expressly and implicitly. Thus the addition of a reference to that which the skilled person would take for granted does not matter: DSM NV's Patent[2001] RPC 25 at [195]-[202]. On the other hand, it is to be emphasised that this is not an obviousness test. A patentee is not permitted to add matter by amendment which would have been obvious to the skilled person from the application. [101] Fifth, the issue is whether subject matter relevant to the invention has been added. In case G1/93, Advanced Semiconductor Products, the Enlarged Board of Appeal of the EPO stated (at paragraph [9] of its reasons) that the idea underlying Art. 123(2) is that that an applicant should not be allowed to improve his position by adding subject matter not disclosed in the application as filed, which would give him an unwarranted advantage and could be damaging to the legal security of third parties relying on the content of the original application. At paragraph [16] it explained that whether an added feature which limits the scope of protection is contrary to Art. 123(2) must be determined from all the circumstances. If it provides a technical contribution to the subject matter of the claimed invention then it would give an unwarranted advantage to the patentee. If, on the other hand, the feature merely excludes protection for part of the subject matter of the claimed invention as covered by the application as filed, the adding of such a feature cannot reasonably be considered to give any unwarranted advantage to the applicant. Nor does it adversely affect the interests of third parties. [102] Sixth, it is important to avoid hindsight. Care must be taken to consider the disclosure of the application through the eyes of a skilled person who has not seen the amended specification and consequently does not know what he is looking for. This is particularly important where the subject matter is said to be implicitly disclosed in the original specification.” 8. When amendment of a granted patent is being considered, the comparison to be made is between the application for the patent, as opposed to the granted patent, and the proposed amendment (see the definition of ‘additional matter’ in s.76(l)(b)). It follows that by and large the form of the granted patent itself does not come into the comparison. This case was to some extent overcomplicated by looking at the granted patent, particularly the granted claim 1. 9. A particular, and sometimes subtle, form of extended subject matter (what our Act calls ‘additional matter’) is what goes by the jargon term ‘intermediate generalisation’. Pumfrey J described this in Palmaz's European Patents[1999] RPC 47 , 71 as follows: “If the specification discloses distinct sub-classes of the overall inventive concept, then it should be possible to amend down to one or other of those sub-classes, whether or not they are presented as inventively distinct in the specification before amendment. The difficulty comes when it is sought to take features which are only disclosed in a particular context and which are not disclosed as having any inventive significance and introduce them into the claim deprived of that context. This is a process sometimes called “intermediate generalisation”.” ‘A European patent application or a European patent may not be amended in such a way that it contains subject matter which extends beyond the content of the application as filed.’ ‘The decision as to whether there was an extension of disclosure must be made on a comparison of the two documents read through the eyes of a skilled addressee. The task of the Court is threefold: (1) To ascertain through the eyes of the skilled addressee what is disclosed, both explicitly and implicitly in the application. (2) To do the same in respect of the patent, (3) To compare the two disclosures and decide whether any subject matter relevant to the invention has been added whether by deletion or addition. The comparison is strict in the sense that subject matter will be added unless such matter is clearly and unambiguously disclosed in the application either explicitly or implicitly.’ ‘4. In Richardson-Vicks' Patent[1995] RPC 568 at 576 I summarised the rule in a single sentence: ‘I think the test of added matter is whether a skilled man would, upon looking at the amended specification, learn anything about the invention which he could not learn from the unamended specification.’ I went on to quote Aldous J in Bonzel. His formulation is helpful and has stood the test of time. 5. The reason for the rule was explained by the Enlarged Board of Appeal of the EPO in G1/93 ADVANCED SEMICONDUCTOR PRODUCTS/Limiting feature [1995] EPOR 97 at [Reasons 9]: “With regard to Article 123(2) EPC , the underlying idea is clearly that an applicant shall not be allowed to improve his position by adding subject-matter not disclosed in the application as filed, which would give him an unwarranted advantage and could be damaging to the legal security of third parties relying upon the content of the original application.” 6. Mr Richard Arnold Q.C. provided a clear articulation as to how the legal security of third parties would be affected if this were not the rule: “The applicant or patentee could gain an unwarranted advantage in two ways if subject-matter could be added: first, he could circumvent the “first-to-file” rule, namely that the first person to apply to patent an invention is entitled to the resulting patent; and secondly, he could gain a different monopoly to that which the originally filed subject-matter justified.” 7. Kitchin J has recently helpfully elaborated upon the Bonzel formulation in European Central Bank v Document Security Systems[2007] EWHC 600 (Pat) ,26th March 2007 : “[97] A number of points emerge from this formulation which have a particular bearing on the present case and merit a little elaboration. First, it requires the court to construe both the original application and specification to determine what they disclose. For this purpose the claims form part of the disclosure (s. 130(3) of the Act), though clearly not everything which falls within the scope of the claims is necessarily disclosed. [98] Second, it is the court which must carry out the exercise and it must do so through the eyes of the skilled addressee. Such a person will approach the documents with the benefit of the common general knowledge. [99] Third, the two disclosures must be compared to see whether any subject matter relevant to the invention has been added. This comparison is a strict one. Subject matter will be added unless it is clearly and unambiguously disclosed in the application as filed. [100] Fourth, it is appropriate to consider what has been disclosed both expressly and implicitly. Thus the addition of a reference to that which the skilled person would take for granted does not matter: DSM NV's Patent[2001] RPC 25 at [195]-[202]. On the other hand, it is to be emphasised that this is not an obviousness test. A patentee is not permitted to add matter by amendment which would have been obvious to the skilled person from the application. [101] Fifth, the issue is whether subject matter relevant to the invention has been added. In case G1/93, Advanced Semiconductor Products, the Enlarged Board of Appeal of the EPO stated (at paragraph [9] of its reasons) that the idea underlying Art. 123(2) is that that an applicant should not be allowed to improve his position by adding subject matter not disclosed in the application as filed, which would give him an unwarranted advantage and could be damaging to the legal security of third parties relying on the content of the original application. At paragraph [16] it explained that whether an added feature which limits the scope of protection is contrary to Art. 123(2) must be determined from all the circumstances. If it provides a technical contribution to the subject matter of the claimed invention then it would give an unwarranted advantage to the patentee. If, on the other hand, the feature merely excludes protection for part of the subject matter of the claimed invention as covered by the application as filed, the adding of such a feature cannot reasonably be considered to give any unwarranted advantage to the applicant. Nor does it adversely affect the interests of third parties. [102] Sixth, it is important to avoid hindsight. Care must be taken to consider the disclosure of the application through the eyes of a skilled person who has not seen the amended specification and consequently does not know what he is looking for. This is particularly important where the subject matter is said to be implicitly disclosed in the original specification.” 8. When amendment of a granted patent is being considered, the comparison to be made is between the application for the patent, as opposed to the granted patent, and the proposed amendment (see the definition of ‘additional matter’ in s.76(l)(b)). It follows that by and large the form of the granted patent itself does not come into the comparison. This case was to some extent overcomplicated by looking at the granted patent, particularly the granted claim 1. 9. A particular, and sometimes subtle, form of extended subject matter (what our Act calls ‘additional matter’) is what goes by the jargon term ‘intermediate generalisation’. Pumfrey J described this in Palmaz's European Patents[1999] RPC 47 , 71 as follows: “If the specification discloses distinct sub-classes of the overall inventive concept, then it should be possible to amend down to one or other of those sub-classes, whether or not they are presented as inventively distinct in the specification before amendment. The difficulty comes when it is sought to take features which are only disclosed in a particular context and which are not disclosed as having any inventive significance and introduce them into the claim deprived of that context. This is a process sometimes called “intermediate generalisation”.”
“1.6.3 Deletion of elements from lists – shrinking the lists without singling out a combination of features According to the boards' consistent case law, the guiding principle is that deleting meanings of residues in a generic chemical formula must not lead to the selection, in the respective lists, of a particular combination of single, specific but originally undisclosed meanings of residues (see T 615/95 and T 859/94). In T 615/95 there were three independent lists of sizeable length specifying distinct meanings for three residues in a generic chemical formula in a claim. One originally disclosed meaning was deleted from each of the three independent lists. The board stated that the present deletions did not result in singling out a particular combination of specific meanings, i.e. any hitherto not specifically mentioned individual compound or group of compounds, but maintained the remaining subject-matter as a generic group of compounds differing from the original group only by its smaller size. Such a shrinking of the generic group of chemical compounds was not objectionable under Art. 123(2) EPC 1973, since these deletions did not lead to a particular combination of specific meanings of the respective residues which was not disclosed originally or, in other words, did not generate another invention. (See also T 948/02, which refers in detail to this case law and which did not allow the amendment of a generic chemical formula. For another decision distinguishing its case from T 615/95, see T 1150/15; see also T 894/05, T 888/08). In T 50/97 the board explained that in the case at issue the shrinking of the lists of alternative definitions disclosed in the application as filed was not objectionable as that limitation did not result in singling out a particular combination of specific definitions, i.e. a hitherto not specifically mentioned sub-class of compounds, but maintained the remaining subject-matter of claim 1 as generic lists of alternative definitions differing from the original lists only by their smaller size (with reference to T 615/95 and T 859/94). In T 942/98 the board held that, through the deletion of all other meanings, residues X1, X2 and R5 had been narrowed down to a single meaning, leading to a combination of specific meanings of residues not disclosed in the application as filed. Consequently, claim 1 as filed did not in itself provide adequate support for claim 1 as amended (cited by T 2013/08 in connection with the established case law concerning "singling out"). In T 1506/13 the board, referring to T 948/02, summarised that a deletion of genes from a list of specific genes was allowable if it fulfils two conditions: First, the deletion must not result in singling out any hitherto not specifically mentioned individual compound or group of compounds, but maintains the remaining subject-matter as a generic group of compounds differing from the original group only by its smaller size. Second, the deletion does not lead to a particular combination of a specific meaning which was not disclosed originally, i.e. it does not generate another invention, or in other words it merely restricts the required protection but does not provide any technical contribution to the originally disclosed subject-matter. In T 98/09, which concerned the "singling out" of combinations of active ingredients not originally disclosed from lists, the board held that, contrary to the appellant's view, a deletion from a list could also constitute an inadmissible extension if the singling out of one individual ingredient led to a selection of combinations which, even if conceivably covered by the application as filed, had not been specifically disclosed. It was the boards' settled case law that such a selection is to be regarded as an inadmissible extension and so as an infringement of Art. 123(2) EPC (see e.g. T 727/00 and T 686/99). The case at issue concerned two lists (six elements and 47 elements). The applicant sought to individualise one of the lists to one element. The board held that this selection was contrary to Art. 123(2) EPC. For a similar case, in which the board found that the deletion of elements of two lists led to an unallowable selection, see T 1808/08. In T 10/97 not all the compounds listed in the original claim were included in amended claim 1. However, since the claimed group of compounds was obtained not by restricting an originally disclosed generic definition of a substituent in a generic formula to a specific one selected from worked examples, but by deleting some members from a list of individualised equally useful compounds in order to improve the chances of patentability over the available prior art, the board found that such deletions must be considered admissible in accordance with the case law of the boards of appeal (see T 393/91). For the remaining compounds, no particular technical effect was either disclosed or alleged. In T 783/09 the board referred to T 10/97. All forty-four combinations resulting from the combination of the elements of the two lists (one list with two elements, the other list with 22 elements) were directly and unambiguously disclosed. However, a further issue was whether or not the claiming of only three of the forty-four combinations disclosed extended the content of the application as filed in an unallowable way. The forty-four combinations were referred to as "very preferred embodiments"; by this statement the skilled person was taught that each of the forty-four combinations had the same quality, i.e. they were all very preferred combinations in the context of the invention. Nothing else was derivable from the remainder of the application, i.e. a particular quality, for example a particular technical effect, was attributed neither to the three combinations of claim 1 nor to the remaining forty-one. Hence, the group of claim 1 was to be considered as the result of the deletion of forty-one elements from a list of forty-four qualitatively equal elements (see T 10/97). In summary, the subject-matter of claim 1 complied with the requirements of Art. 123(2) EPC. In T 1075/12 the patent proprietor restricted the definitions of groups to lists of specific substituents. The board held that the more precise definitions of the groups did not result in a particular combination of specific meanings of the respective groups being singled out, namely no particular structural feature of the compounds concerned was now claimed which was not disclosed originally. The board distinguished its case from T 859/04 and T 801/02, in which more than one variable in the respective chemical formulae had been individualised.”
“4.3 The basic principle underlying Article 123(2) EPC, in the jurisprudence of the Enlarged Board The importance and the applicability, without exception, of Article 123(2) EPC was underlined in the jurisprudence of the Enlarged Board of Appeal as early as in its opinion G 3/89 and decision G 11/91 (OJ EPO 1993, 117 and 125, relating to amendments by way of correction). From these rulings it follows that any amendment to the parts of a European patent application or of a European patent relating to the disclosure (the description, claims and drawings) is subject to the mandatory prohibition on extension laid down in Article 123(2) EPC and can therefore, irrespective of the context of the amendment made, only be made within the limits of what a skilled person would derive directly and unambiguously, using common general knowledge, and seen objectively and relative to the date of filing, from the whole of these documents as filed, points 1., 1.3 and 3 of the Reasons.”
“6.3 The Board observes that in accordance with established jurisprudence regarding the deletion of meanings from multiple lists defining variables in a generic formula (see Case Law of the Boards of Appeal, 10th Edition, II.E.1.6.3) it is not sufficient that the remaining subject-matter still relates to a generically defined group of compounds. In order to comply with Article 123(2) the deletion must not result in a particular combination of specific meanings which was not originally disclosed and which thereby generates another invention. In other words the amendment may not lead to a combination that is suitable to provide a technical contribution to the originally disclosed subject-matter as opposed to a mere restriction of the required protection. In the patent as granted the definition of the compounds of formula I had already been limited with respect to the originally disclosed group of compounds by restriction of Y to a single meaning. Whilst such limitation is not objectionable as sole amendment, the combination of this limitation of Y with the further deletion of H in the meaning of X seems to single out those compounds in which Y represents F and in which X does not represent H. The original disclosure does not seem to provide any pointer to such combined limitation. The combined limitation effectively results in a group of compounds which is distinguished from the originally defined group of compounds by not comprising those compounds which are also covered by the teaching of document D36 [Shepard] and seems thereby suitable to provide a technical contribution to the originally disclosed subject-matter.”
“According to a first aspect of the invention there is provided a compound of formula I: wherein: R is selected from the group comprising alkyl, aryl and alkylaryl; R’ and R” are, independently, selected from the group comprising H, alkyl and alkylaryl, or R’ and R” together form an alkylene chain so as to provide, together with the C atom to which they are attached, a cyclic system; Q is selected from the group comprising -O- and -CH 2-; X and Y are independently selected from the group comprising H, F, Cl, Br, I, OH and methyl (-CH 3); Ar is a monocyclic aromatic ring moiety or a fused bicyclic aromatic ring moiety, either of which ring moieties is carbocyclic or heterocyclic and is optionally substituted; Z is selected from the group comprising H, alkyl and halogen; and n is 0 or 1, wherein when n is 0, Z’ is -NH 2 and a double bond exists between position 3 and position 4, and when n is 1, Z’ is =O; or a pharmaceutically acceptable derivative or metabolite of a compound of formula I; with the proviso that when n is 1, X and Y are both H, R is methyl (-CH 3), one of R’ and R” is H and one of R’ and R” is methyl (-CH 3), then Ar is not phenyl.”
“Reference in the present specification to an alkyl group means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.”
“Preferably, X and Y are, independently, selected from the group comprising F, H and OH. When n is 1, preferably each of X and Y is H. When n is 0, preferably each of X and Y is F, or X is OH and Y is H, or X is H and Y is OH.”
“When Z is F, Q is O, n is 1 and X and Y are each H, the base moiety of the compound of formula I corresponds to that of fluorodeoxyuridine i.e. compound (1) above. When Z is H, Q is O, n is 0 and X is OH and Y is H, the base moiety of the compound of formula I corresponds to that of cytarabine i.e. compound (2) above. When Z is H, Q is O, n is 0 and X and Y are each F, the base moiety of the compound of formula I corresponds to that of gemcitabine i.e. compound (3) above. When Z is H, Q is O, n is 0 and X is H and Y is OH, the base moiety of the compound of formula I corresponds to that of cytidine.”
“Compounds of formula I wherein n is 0 and X and Y are F are preferred. Particularly preferred are compounds of formula I wherein n is 0, X and Y are F, Q is O and Z is H, corresponding to phosphoramidated gemcitabine. Also preferred are compounds of formula I wherein n is 0 and X is OH and Y is H. Particularly preferred are compounds of formula I wherein n is 0, X is OH, Y is H, Q is O and Z is H, corresponding to phosphoramidated cytarabine. Also preferred are compounds of formula I wherein n is 0 and X is H and Y is OH. Particularly preferred are compounds of formula I wherein n is 0, X is H, Y is OH, Q is O and Z is H, corresponding to phosphoramidated cytidine.”
“Preferably Z is selected from the group comprising H, F, optionally substituted C1-6 alkyl particularly Me (-CH 3), optionally substituted C1-6 alkenyl and optionally substituted C1-6 alkynyl, the optional substituents being as recited immediately above. When n is 1, Z’ is O, Q is O and X and Y are each H, preferably Z is a substituted C 2 alkenyl (i.e. ethenyl or vinyl) moiety (-CH=CH-); more preferably, Z is bromovinyl (-CH=CHBr) or methylpropenoate (-CH=CHCO 2Me); and most preferably, Z is -CH=CHBr.”
“16. A compound according to any one of the preceding claims wherein n is 1, each of X and Y is H. 17. A compound according to any one of claims 1 to 15 wherein n is 0, each of X and Y is F. 18. A compound according to any one of claims 1 to 15 wherein n is 0, X is OH and Y is H. 19. A compound according to any one of claims 1 to 15 wherein n is 0, X is H and Y is OH.”
“The general principles are: (i) The patent must disclose “a practical application” and “some profitable use” for the claimed substance, so that the ensuing monopoly “can be expected [to lead to] some ... commercial benefit” (T 0870/04, para 4, T 0898/05, paras 2 and 4); (ii) A “concrete benefit”, namely the invention’s “use ... in industrial practice” must be “derivable directly from the description”, coupled with common general knowledge (T 0898/05, para 6, T 0604/04, para 15); (iii) A merely “speculative” use will not suffice, so “a vague and speculative indication of possible objectives that might or might not be achievable” will not do (T 0870/04, para 21 and T 0898/05, paras 6 and 21); (iv) The patent and common general knowledge must enable the skilled person “to reproduce” or “exploit” the claimed invention without “undue burden”, or having to carry out “a research programme” (T 0604/04, para 22, T 0898/05, para 6)”
“something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true”
“[NuCana’s] contention is that all or substantially all [the claimed] compounds are characterised by improved intracellular delivery (compared to that of the corresponding bare nucleoside analogues) and/or cytotoxic activity. As a consequence of said improved intracellular delivery, the Patents disclose that the phosphoramidate pro-drug approach devised by Professor Christopher McGuigan can be successfully applied to gemcitabine and all or substantially all the gemcitabine-like nucleosides defined in the claims. Further, as a consequence of said improved intracellular delivery and/or cytotoxic activity, all or substantially all the claimed compounds (i) have the potential to be used as therapeutic agents and/or (ii) have utility in non-therapeutic applications, including as research tools in scientific research.”
“57. At paragraph 298, Dr Galmarini states that “in my view, the Patent is directed to a drug discovery team that was interested in developing a NA drug for cancer”
“NuCana’s primary case is that cytotoxic activity is demonstrated by a measurable IC 50/EC 50 etc value in an in vitro cytotoxicity/antiproliferative assay such as the MTT assay. NuCana’s secondary case is that cytotoxicity is demonstrated by a value of 100 μM or less in such an assay.”
“Cytotoxic nucleoside analogues are clinically important anticancer drugs. The newer member of this family, gemcitabine, has shown great activity in solid tumors and thus enlarged the spectra of malignancies treated by this family of molecules. However, the clinical use of nucleoside analogues is limited by important side-effects and primary or acquired drug resistance, and there is an unmet medical need for the development of new molecules and technologies allowing a suitable treatment of cancer patients with these agents.”
“These first two phases [identifying compounds for testing and in vitro testing] represented a significant challenge. The chemical space (i.e. the number of possible compounds that could be made and tested) is vast. The medicinal chemist seeking to develop new nucleoside analogues is faced with an almost infinite number of choices in terms of the structure of potentially useful compounds, even if factors such as the ease of synthesis and druggability of the compounds are taken into account. The identification of a defined class of new compounds with cytotoxic activity would therefore have represented a valuable technical achievement at the Priority Date, as it still does today.”
“[The skilled person] must seek success. He may need to carry out the ordinary methods of trial and error, which involve no inventive step and generally are necessary in applying the particular discovery to produce a practical result. In each case, it is a question of fact, depending on the nature of the invention, as to whether the steps needed to perform the invention are ordinary steps of trial and error which a skilled man would realise would be necessary and normal to produce a practical result.”
“Even though a reasonable amount of trial and error is permissible when it comes to the sufficiency of disclosure in an unexplored field or – as it is in this case – where there are many technical difficulties, there must then be available adequate instructions in the specification or on the basis of common general knowledge which would lead the skilled person necessarily and directly towards success through the evaluation of initial failures or through an acceptable statistical expectation rate in case of random experiments.”
“It is not enough if the instructions are such that a number of equally qualified notional addressees can arrive at completely different end points, some within the scope of the claimed invention and some not. If reasonable addressees can come to different conclusions there is a conundrum as to which is right. That is not enablement. This view appears to be consistent with the approach of the Technical Board of Appeal of the EPO in Unilever/Stable bleaches (Decision T226/855) [1988] OJEPO 336, which was referred to with approval by Aldous J and the Court of Appeal in Mentor Corp v. Hollister Inc.”
“247. If I had to personally prioritise routes, based upon my background and experience I would say that routes 3.1-3.2 (nucleophilic fluorination) would be my first preference because they potentially offer the shortest route to the target compound from starting materials which are described in the literature; however, the fluorination step required by these routes is unknown. An attractive feature of these routes is that there is the option of doing each with the base on (i.e. a nucleoside route), or the base off (i.e. a sugar route). Trying the ‘base on’ reactions first would be slightly more attractive to me, because if the fluorination works ‘base on’ would mean a smaller number of steps to make the final molecule for the biologist to test. If the base has to be added, then there are potential problems with the stereocontrol for the addition of the base (discussed in paragraph 203). The sugar routes would remain a fall-back option if there were problems with the nucleoside routes, that would have been my initial preference. 248. In contrast, Routes 1.1 and 1.2 are probably the best precedented of all the routes have discussed above because the plan would be to essentially follow the Hertel synthesis if the initial step could be achieved. Routes 1.1-1.2 also avoid the need for difficult and unknown fluorination reactions on complex molecules. The downsides are that routes 1.1-1.2 involve a larger number of unknown steps than Routes 3.1-3.2.”