Strand, London, WC2A 2LL
B e f o r e :
| Scinopharm Taiwan Limited
|- and -
|Eli Lilly & Company
Colin Birss QC and Thomas Hinchliffe (instructed by Messrs. Lovells LLP) for the Defendant
Hearing dates: 4, 5, 6, 9, 11, 12 February 2009
Crown Copyright ©
MR. JUSTICE KITCHIN :
i) United States Patent 4,526,988 ("Hertel 1");
ii) European Patent 0,122,707 ("Hertel 2");
iii) A paper entitled "Synthesis of 2-Deoxy-2,2-difluro-D-ribose and 2-Deoxy-2,2-difluoro-D-ribofuranosyl Nucleosides" by L. W. Hertel et al (Journal Organic Chemistry, 1988) ("Hertel 3");
iv) A paper entitled "Stereospecific Synthesis of 2-Deoxy-2,2-difluororibonolactone and Its Use in the Preparation of 2'-Deoxy-2',2'-difluoro-ß-D-ribofuranosyl Pyrimidine Nucleosides: The Key Role of Selective Crystallization" by T. S. Chou et al (Synthesis, 1992) ("Chou");
v) A paper entitled "An Investigation by H NMR spectroscopy into the factors determining the ß:a ratio of the product in 2'-deoxynucleoside synthesis" by A.J Hubbard et al (Nucleic Acids Research, 1984) ("Hubbard");
vi) A paper entitled "The Synthesis of 2'-Deoxy-5- Trifluoromethyluridine Utilizing a Coupling Reaction" by H. Kawakami et al (Heterocycles, 1990) ("Kawakami");
vii) European Patent Application 0,428,109 ("Vemishetti");
viii) A paper entitled "Antiviral Nucleosides. A Stereospecific, Total Synthesis of 2'-Fluoro-2'-deoxy-ß-D-arabinofuranosyl Nucleosides" (Journal Organic Chemistry, 1988) by H.G. Howell et al ("Howell").
The skilled addressee
Common general knowledge
"Finally, the common general knowledge does not include knowledge which does not inform the skilled person's approach from the outset. As Kitchin J said in Generics (UK) v Daiichi Pharmaceutical  EWHC 2413 (Pat):
" I can readily accept that, faced with a disclosure which forms part of the state of the art, it may be obvious for the skilled person to seek to acquire further information before he embarks on the problem to which the patent provides a solution. But that does not make all such information part of the common general knowledge. The distinction is a fine one but it may be important. If information is part of the common general knowledge then it forms part of the stock of knowledge which will inform and guide the skilled person's approach to the problem from the outset. It may, for example, affect the steps it will be obvious for him to take, including the nature and extent of any literature search."
Whether knowledge is common and general depends on the considerations explained by Aldous LJ in Beloit. If information does not satisfy that criterion, it does not become common general knowledge by postulating a set of steps that the skilled team might take to find it if they had already embarked on an attempt to solve a particular problem. That is not to say that it is illegitimate, in assessing an obviousness attack, to take account of material which would inevitably be found and treated as reliable in consequence of a step or steps which it is obvious to take. If the material so found is such as would be accepted, then it may assist in showing obviousness of a further step. But what it cannot be used for is in support of an argument that the series of steps being undertaken were obvious from the start."
Nucleophilic substitution reactions
Nuc: + EL-LG ? EL-Nuc + LG:
Influencing SN1 and SN2 reactions
Some sugar chemistry
Glycosylation and nucleoside synthesis
SN2 glycosylation reactions are rare
Stereochemical control of glycosylation reactions – a challenge
"A great deal of data exists on the anomeric nature of the products formed by the condensation of a sugar derivative and a heterocyclic base. The stereo-specificity of the coupling reaction depends on the method of condensation, and, within a given method, can vary on the choice of solvent, temperature and catalysts, and be very dependent on the structures of the reactants. In spite of the huge amount of effort devoted to the synthesis of nucleosides, there have been essentially no studies specifically directed toward elucidating the detailed mechanism of any of the condensation methods. The stereochemistry of the product provides the best basis for speculation about these mechanisms. "
"The use of acetylated glycosyl halides of 2-deoxy-D-erythro-pentose, which lack a participating group at C-2 give mixtures, as predicted, of a and ß anomers in reactions with heavy metal salts of both purines and pyrimidines"
"Although the syntheses of 2'-deoxynucleosides from suitable derivatives of 2-deoxysugars and salts of acidic heterocyclic bases or silylated heterocyclic bases have already been discussed, the different methods for their preparation are summarized here. These syntheses are among the most difficult in nucleoside chemistry..."
"the ratios of the desired natural ß anomer to the undesired a anomer are often difficult to control and to reproduce".
"In fact control of the stereochemical outcome of nucleophilic substitution at this position is one of the most difficult tasks faced by a synthetic organic chemist".
"Although conceptually extremely simple, this operation has in fact been frustrating chemists for nearly a hundred years ….".
"Although a completely general approach to total stereocontrol of the formation of any glycosidic bond remains as yet unrealised, we shall see that in many specific cases high levels of stereocontrol may be achieved by judicious choice of reaction conditions and protecting groups".
"The continued interest in the synthesis of 2'-deoxyfluoronucleosides and their analogues is predicated on their successful use as therapeutic agents for treating viral and cancerous diseases. A compound of particular interest is gemcitabine; see European Patent Specification No. 211354 and U.S. Patent No. 4,526,988. Since these compounds are beta nucleosides, there is a need to provide such compounds in high yield. "
And second, the problem with existing processes:
"A critical step in the synthesis of 2'-deoxyfluoronucleosides is the condensation or glycosylation of the nucleobase and carbohydrate to form a N-glycoside bond. However, processes for synthesis of 2'-deoxynucleosides are typically non-stereoselective forming mixtures of alpha and beta nucleosides. For instance, U.S. Patent 4,526,988 [Hertel 1] did not stereoselectively produce 2-deoxy-2,2-difluoro- beta -nucleosides but instead produced a 4:1 alpha to beta anomer ratio of 2-deoxy-2,2-difluoronucleoside. Even optimizing the protecting groups could not increase the alpha to beta ratio beyond 1:1; see U.S. Patent No. 4,965,374 [a patent in the name of Chou, but which is not cited as prior art in this case] which utilized benzoyl blocking groups on the carbohydrate. "
A process of preparing a ß anomer enriched nucleoside of the formula (I)
wherein R is a nucleobase selected from the group consisting of…
where R1 is…hydrogen; R2 is… primary amino [NH2]..
(i) conducting the SN2 displacement optionally in a suitable solvent of a
sulfonyloxy group (Y) from an a anomer enriched carbohydrate of the formula (II)
wherein X is independently selected from hydroxy protecting groups;
(ii) with at least a molar equivalent of a nucleobase (R") selected from the group consisting of…..
wherein R1… are as defined above and; Z is a hydroxyl protecting group; W is an amino protecting group;…and
(iii) deblocking to form the compound of formula (I).
"The phrase "anomer enriched" alone or in combination refers to an anomeric mixture wherein the ratio of a specified anomer is greater than 1:1 and includes substantially pure anomer."
"A key feature of the present invention is the discovery that novel a anomer enriched carbohydrate intermediate of formula (III) … can be reacted under nucleophilic displacement conditions which favor inversion (i.e. SN2) to provide the ß anomer enriched nucleosides of formula (I).
To obtain an efficient reaction between the nucleobase and the a anomer enriched carbohydrate of formula (II), an appropriate leaving group (Y) must be stereoselectively attached to the lactol to activate the lactol and generate the a anomer enriched carbohydrate of formula (II). However, the leaving group selected depends on the nucleobase chosen and the glycosylation conditions selected."
"80. These are the main groups of recipes in the Examples in the Patent:
(i) The a-enriched mesylate with the silylated cytosine typically (Example 5 on p. 16) at 115-120 °C for 7 hours in anisole giving a ß: a ratio of 7.3:1 and a yield of 79.5%.
(ii) The same reagents but neat (without solvent) typically (Example 48 on p. 31) at 130 °C for 1 hour giving a ß:a ratio of 3.9:1 and a yield of 43%.
(iii) The same reagents but in acetonitrile with added salts typically (Example 26 on p. 24) potassium trifluoromethansulfonate at 75 °C for 45 hours giving a ß:a ratio of 7.2:1 and a yield of 62.4%. A direct comparison of a salt-catalysed and an uncatalysed reaction is reported in Examples 27 (6.7:1, 59.3%) and 28 (3.4:1, 77%), respectively.
(iv) The a-enriched triflate, carefully made and kept at or below –65°C, with the silylated cytosine in dichloromethane typically (Example 17 on p. 22) at 23 °C for an unspecified time giving a ß: a ratio of 2.5:1 and a yield of 68%.
(v) The a-enriched p-bromobenzenesulfonate with the potassium salt of N-pivaloylcytosine (Example 49 on p. 32) at 65 °C for 5.5 hours in acetonitrile giving a ß: a ratio of 3.9:1 and a yield of 20%.
81. In addition, other Examples record the use of the potassium salts of variously protected purines (Examples 30-42, 54-55), silylated uracil (Example 44), the sodium salt of a purine (Example 53) and of benzylcytosine (Example 56), triazole salts (Examples 51, 52 and 57) and chloropurines (Example 58), and as electrophiles the a-iodide (Examples 50 and 56) and bromide (Example 51).
82. Most of the Examples, i.e. 1-6, 8-11, 13-29, 43, 45 and 48 give blocked gemcitabine straightforwardly, and 12, 46, 47, 49, 50 and 56 give differently blocked versions which could easily be converted to gemcitabine."
"The numerous examples show that ß-selectivity can be accomplished by employing the following reaction conditions:
(a) an excess of nucleobase favors the production of the ß-anomer (see example 7)
(b) using mesylate or tosylate as a leaving group requires the use of very apolar solvents (such as xylenes) and requires the reaction to be carried out at high temperatures (105-135oC)
(c) using triflate as a leaving group requires the use of a solvent such a dichloromethane and a much lower reaction temperature (many of the examples are between -60 and 20 oC )
(d) the addition of non-nucleophilic salts appears to improve the ß- selectivity
(e) fusion conditions can be employed to prepare ß-enriched nucleosides."
(1) (a) Identify the notional "person skilled in the art".
(b) Identify the relevant common general knowledge of that person.
(2) Identify the inventive concept of the claim in question or, if that cannot readily be done, construe it.
(3) Identify what, if any, differences exist between the matter cited as forming part of the "state of the art" and the inventive concept of the claim or the claim as construed.
(4) Ask whether, when viewed without any knowledge of the alleged invention as claimed: do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?
"In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent  RPC 479, by saying that the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case. As Kitchin J said in Generics (UK) Ltd v H Lundbeck A/S  RPC 32 , para 72:
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.""
"23. Mr Thorley also submitted that the judge had wrongly rejected his submissions that were recorded by the judge as paragraph 46 of his judgment. He submitted that an invention would not be obvious unless there was some motivation to implement the disclosure in the prior art and to take the steps required to arrive at the invention. In certain cases that can be right. Such cases are usually those where the invention lies in the idea of taking a step. However, motivation may not be a requirement. The fact that nobody would dream of making a plate one inch bigger than the standard size does not mean that there would be invention in making one. In Pharmacia Corporation v Merck & Co Inc  EWCA Civ 1610, I cited this passage from the speech of Laddie J in Hoechst v Celanese Corp v BP Chemicals Ltd  FSR 547at 573:
"Before a step from the prior art can be held to be obvious there must be some reason why the man skilled in the art would wish to take it. If he has a problem and the step would occur to him as a solution to it, then he has a reason. But there is no requirement that it be demonstrated that the step would have been expected to produce significant commercial advantages. The problem might be very small. The courts will assume that he may just want an alternative way of achieving essentially the same result as in the prior art. Thus were workshop modifications, none of which would be expected to produce significant technical or commercial benefits are still obvious. To adopt an example sometimes given by Jacob J., if it is known to make a 5-inch plate, it is obvious to make a 5¼ -inch plate. Technicians and businessmen frequently want to make trivial variations in established or known products. Similarly if the prior art discloses two wooden parts held together by screws it would be obvious to glue them, even if so doing would not be expected to advance the industry. The notional addressee is likely to want to use materials readily at hand to make essentially the same thing as is disclosed in the prior art. That is sufficient motivation and the use of those materials is, accordingly, obvious. When the defendants argue that Hingorani or any of his readers is entitled to use any "natural extension" or "obvious variant" of his concept, they are correct if by that they mean the type of workshop modification or alternative discussed above. But it was not and could not be suggested by any witness that changing the medium from aqueous to organic and changing the resin was a mere workshop variant of what is set out in Hingorani."
24. I continued:
"124. That statement of the law was, I expect, apt on the facts of that case, but should not be followed generally. A step from the prior art, albeit made without reason, can still be obvious. The judge categorises such a step as workshop modifications and, in so doing, introduces a test not in the statute, namely whether the step from the prior art was a workshop modification. The statutory test is obviousness and any modification which is obvious will not be patentable, whereas one which is not obvious will be. The true test, as made clear in Windsurfing, is to ask whether the invention was obvious. Whether or not there is a reason for taking the step from the prior art may well be an important consideration, but that does not mean that it is an essential requirement of a conclusion of obviousness."
25. The judge did not in paragraph 46 of his judgment fall into the error of principle that Mr Thorley submitted that he had. What he said in that paragraph has to be read in the light of the conclusion he had reached in paragraph 45. The judge concluded that the step from the prior art was a "workshop variation" and therefore was an obvious step. Mr Thorley had submitted that it was not obvious because the skilled person would not in practice have thought of implementing it at all. If the step from the prior art lacked invention, then it mattered not whether anybody would have thought of implementing it. The public are entitled to make obvious modifications. Whether they would want to do so will depend upon a variety of factors which could include such things as cost and the attitudes of users."
"96. I think the Judge erred in principle here. The skilled man has his common general knowledge — the mental tools of his trade — but no more. The law of obviousness supposes that he can be given any individual piece of prior art and read it with that knowledge. The piece of prior art forms part of the "state of the art". What he cannot do is to just link one piece of prior art with another, unless so to do would itself be uninventive. No-one disputes what Lord Reid said in Technograph v Mills & Rockley  RPC 346 at page 355:
"In dealing with obviousness, unlike novelty, it is permissible to make a 'mosaic' out of the relevant documents, but it must be a mosaic which can be put together by an unimaginative man with no inventive capacity.""
Hertel – disclosure
Chou – disclosure
"We believe the reaction proceeds via an SN1 pathway involving an oxonium ion intermediate 15 giving rise to a 1:1 mixture of nucleoside anomers."
"Therefore, we concluded that the observed 1:1 ß/a ratio of nucleosides was not the result of epimerization of either the mesylate starting material or the nucleoside product, but rather a consequence of the predominant reaction mechanism."
i) First that by fractional crystallisation it is possible to obtain analytically pure mesylate;
ii) Second that the reaction proceeds, under the conditions used in the paper, by an SN1 pathway.
Differences between (a) Chou and Hertel and (b) the invention
Was it obvious to carry out a process by the SN2 pathway in light of Chou and Hertel?
"Q. As I understand it, just simply on that, what you say the skilled person would do is take the experimental [conditions] in Chou and add more nucleophile.
A. Yes. The first thing to do is to get it more concentrated because these reactions are done pretty dilute.
Q. Essentially, what you are saying they would is take the experiments in Chou and add more nucleophile.
A. One of the things they would do is that, yes.
Q. First, second?
A. I would cut down the solvent first; but I do not know, you see. This is where the experimentalist does in fact rule because it may turn out that you cannot get them all into solution in less solvent than is here. I do not know what the situation is because I have not handled these compounds myself.
Q. I see.
A. But those are the directions in which my thinking would go, certainly; or rather, I should say, how I think the skilled person would think.
Q. I understand. Just to be absolutely clear -- I should say I am surprised, but I just want to be clear because I do not want there to be any misunderstanding later -- I had understood your evidence to be that you were saying you would take the Chou conditions and add more nucleophile. As I understand it, you are saying that is one of the things you would do. The other thing you would do is what?
A. Well, you would look at the solvents but decide that there was not very much room for making them less polar than they already are and you would make things concentrated. It is the concentration of the nucleophile that is critical."
"Q. So increasing the concentration of the nucleophile by 10 fold, you ought to increase it 10 times. If it is 10 times of very little, it is still very little, is it not?
A. Yes, but it gives you more beta than alpha if you start with alpha mesylate.
Q. The point that I am trying to put to you is, would you accept this, that there is no evidence in Chou that such a ghostly SN2 reaction is large enough already that speeding it up 10 fold will make enough of a difference that you see a material difference to the anomeric outcome?
A. No, there is no evidence in Chou for that."
"Q. So can I ask you to imagine if you were the skilled person in 1992 with the common general knowledge and so forth that we have, that you set out in your report, and if I can ask you to imagine that Dr. Chou comes to you and says "I had the alpha mesylate. I had stereocontrol at the C-1 position and then I lost it, because it was an SN1 predominant SN1 reaction mechanism", and he says, "What shall I do?"
A. He would give you a simple answer that is also in my report. It is, you can get facial selectivity also in an SN1 mechanism. So if you start playing with your protecting groups, and that is already what the prior art is teaching, if you have trimethyl S, you get mainly alpha, now I change protecting groups and I go to benzoate still an SN1 pathway but now, wow, I get lots more [beta]. I would suggest to Dr. Chou as the skilled person, let us keep playing with protecting groups. If we can go from 4-1 to 1-1 maybe we can go to 1-4 in favour of the beta anomer. That would be the most logical, what I think the skilled person would suggest to Dr. Chou."
"Q. And is one answer that you might give, I mean, not necessarily your first answer, to Dr. Chou in that situation, where he said to you "I had the stereocontrol, I had the alpha mesylate but I lost it because it was an SN1 predominant SN1 reaction mechanism" and he tells you it was a predominant SN1 reaction mechanism, against that background, is not one answer that you might give to Dr. Chou in that situation, "Well, have you thought of trying the SN2 pathway?"?
A. I think that Dr. Chou knew quite a bit of carbohydrate chemistry. I think that Dr. Chou, there is another Dr Chiu who is a famous nucleoside chemist -- would know that SN2 glycosylations by direct nucleophilic substitution in an SN2 pathway are very, very rare. So I think if the skilled person would have suggested that, I think Dr. Chou would have said, "well, that is not really the way to proceed". I do not think the skilled person would have suggested that in the hypothetical world where the skilled person would make a suggestion I think Dr. Chou would have said that there is really no or very little ground to make this work. The prior art basically shows that, yes, these two difluorides might have promoted an SN2, but failed. So why keep banging your hand against a door that does not want to open. A wall, not a door that does not want to open? That sounds strange. I sometimes say strange things. But I think you get the point. It works.
MR. MILLER: All that Dr. Chou has done is to run his glycosylation step with the alpha mesylate and found that he got a predominant SN1 reaction mechanism and lost stereocontrol of the C-1 position. I mean, that is all he has done.
A. That is in accord with what we generally find in glycoside chemistry. So the two fluorides might make me and the skilled person speculate otherwise. The experiment has been done in two very different settings and it is SN1. So why keep -- can I say banging your head against the wall?"
Hubbard with Chou and Hertel 3
i) The chlorosugar is not fluorinated at C-2. The Patent is concerned with 2-deoxy-2,2-difluororibofuranosyl derivatives; and
ii) The anomeric leaving group is chloride whereas the Patent employs a sulfonate-leaving group.
Kawakami, Howell and Vemishetti