“107. … The skilled person in June 2003 would have known that, in general, activity of a nucleoside analogue against one virus species was not predictive of the nucleoside’s activity against other virus species. Cross-reactivity of some direct acting nucleoside analogues between related viral species has been shown: for example, 3TC works against both HIV and HBV, and this has also been demonstrated for tenofovir. It is more common, however, for a nucleoside analogue that is effective therapeutically to be specific for a particular virus. For example, AZT works in HIV, but not in HBV. Furthermore, in general, if a compound is able to target structurally different viral polymerases, it may also target cellular polymerases and cause toxicities. 108. The nucleoside analogues that were active against HIV RT, which is a DNA polymerase, could not be predicted to be effective at preventing HCV replication. Deoxyribonucleosides, like the aforementioned HIV drugs, are structurally distinct from ribonucleosides that are the natural substrates for RNA polymerases.”
“109. … By June 2003, the skilled person would have been aware that various research groups were interested in the potential of using nucleoside analogues for treating HCV by directly inhibiting NS5B activity. They would have been aware of the successful use of nucleoside analogues in the treatment of HIV, HBV, CMV and herpes virus infections. They would also have known that the efficacy of direct acting nucleoside analogues against Flaviviridae infections, and in particular HCV, had not been demonstrated in the clinic and that therefore no direct acting nucleoside analogues were on the market. It was not until sofosbuvir was approved that a direct acting nucleoside analogue was approved for use in the treatment of HCV.”
“110. In June 2003 (and still today) it was not possible to determine from a molecule’s structure whether it would be effective in inhibiting HCV NS5B, and, in turn, in treating HCV. This is especially so because, as noted above, the ternary crystal structure of NS5B is not yet known and NS5B is a highly mobile molecule which undergoes conformational change as it catalyses the addition of ribonucleotides to the RNA chain. The development of nucleoside analogues to inhibit NS5B therefore was (and still is) largely empirical. 111. Generally, the approach to the discovery of novel nucleoside analogues for HCV infection involved the synthesis and testing of these compounds in order to discover which compounds had activity without toxicity. In theory, nucleoside analogues can be altered at most positions on the sugar ring and the base by the addition of a range of substituents. But to have antiviral activity, they still need to be recognised by cellular enzymes to phosphorylate the nucleoside analogue to the active triphosphate form and be recognised by the viral polymerase to catalyse its incorporation into the viral RNA chain. It was appreciated that even small changes in the nucleoside analogue can lead to significant changes in its activity. These changes can give rise to toxicity, inactivity or antiviral therapeutic potential. Once a promising candidate compound has been found, studies can be carried out to try to understand how its structure affects its mechanism of action. Typically, this involves making small changes to the structure and seeing how these affect its activity, enabling a picture to be built up of the structure-activity relationship.”
“133. … by 2003, nucleoside analogues had attracted a great deal of interest as potential candidates for the treatment of various diseases including cancer and viral infections. In general, these compounds contain chemical modifications in either the sugar or the nucleobase of the nucleoside or both. The aim of the modifications when developing antiviral compounds is to ensure that the biosynthesis of DNA and RNA of the target virus is affected, but this needs to be done without causing harm to healthy host cells (which produce their own DNA or RNA). The identification of such highly selective compounds was (and still is) a significant and challenging scientific task. 134. The skilled person approaching the synthesis of a nucleoside analogue in 2003 would have had a number of options for doing so, and the details of his approach would depend on the particular target nucleoside in question. In general, he would start by looking to see if the particular molecule was reported in the scientific literature and, if so, whether the details of its synthesis were given in any report. If there were no reports of the exact nucleoside analogue targeted, then the skilled person would examine whether related compounds had been reported, and determine whether reported syntheses of such compounds would provide guidance for a synthetic strategy. Key textbooks might also be consulted. 135. The skilled person might also carry out further, broader, literature searches relating to the structure of the desired compound. The skilled person would then use any helpful information in the key textbooks and the literature, as well as his common general knowledge, to consider how he might attempt a synthesis of the desired nucleoside analogue by carrying out a retrosynthetic analysis. 136. In very general terms, nucleoside analogue synthesis might be approached by modifying an existing nucleoside, that is, a sugar with the desired base already attached (often known as the “nucleoside route”), or by first preparing a sugar with the desired modifications before attaching the base by glycosylation (often known as the “sugar route”). The sugar route itself might involve either modifying a sugar which was already readily available, or starting with small molecules which could be used to build up the sugar with the desired modifications in place. 137. The skilled person would have known that the synthesis of nucleosides is often complicated, as a result of the number of chiral centers in the sugar ring and the number of reactive functional groups attached to the sugar (which might give rise to unwanted reactions and which would therefore need masking with suitable protecting groups, as to which see below). There would also be the need (in the case of the nucleoside route) to carry out the reaction on a molecule containing a sensitive functional group (the nucleobase) or the need (in the case of the sugar route) to carry out a glycosylation step to attach the nucleobase to the sugar and it was known in 2003 that in some circumstances this could be a difficult step.”
“The invention is in the area of pharmaceutical chemistry, and is in particular, a 2' and/or 3' prodrug of a 6-modified, 1', 2', 3', or 4'-branched pyrimidine nucleoside or 8-modified 1', 2', 3' or 4'-branched purine nucleoside for the treatment of a Flaviviridae infection, such as a hepatitis C virus infection.”
“Idenix Pharmaceuticals discloses the use of branched nucleosides in the treatment of flaviviruses (including HCV) and pestiviruses in International Publication Nos. WO 01/90121 and WO 01/92282. Specifically, a method for the treatment of hepatitis C infection (and flaviviruses and pestiviruses) in humans and other host animals is disclosed in the Idenix publications that includes administering an effective amount of a biologically active, 1', 2', 3' or 4'-branched ß-D or ß-L nucleosides or a pharmaceutically acceptable salt or derivative thereof, administered either alone or in combination with another antiviral agent, optionally in a pharmaceutically acceptable carrier. Other patent applications disclosing the use of certain nucleoside analogs to treat hepatitis C virus include: PCT/CA00/01316 (WO 01/32153; filed November 3, 2000) and PCT/CA01/00197 (WO 01/60315; filed February 19, 2001) filed by BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT/US02/01531 (WO 02/057425; filed January 18, 2002) and PCT/US02/03086 (WO 02/057287; filed January 18, 2002) filed by Merck & Co., Inc., PCT/EP01/09633 (WO 02/18404; published August 21, 2001) filed by Roche, and PCT Publications Nos. WO 01/79246 (filed April 13, 2001), WO 02/32920 (filed October 18, 2001) and WO 02/48165 by Pharmasset, Ltd. PCT Publication No. WO 99/43691 to Emory University, entitled ‘2'-Fluoronucleosides’ discloses the use of certain 2'-fluoronucleosides to treat HCV. Eldrup et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.)) described the structure activity relationship of 2'-modified nucleosides for inhibition of HCV. Bhat et al. (Oral Session V, Hepatitis C Virus, Flaviviridae, 2003 (Oral Session V Hepatitis C Virus, Flaviviridae; 16th International Conference on Antiviral Research (April 27, 2003, Savannah, GA.); p A75) describe the synthesis and pharmacokinetic properties of nucleoside analogues as possible inhibitors of HCV RNA replication. The authors report that 2'-modified nucleosides demonstrate potent inhibitory activity in cell-based replicon assays. Olsen et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16th International Conference on Antiviral Research (April 27, 2003, Savannah, GA.) p A76) also described the effects of the 2'-modified nucleosides on HCV RNA replication.”
“The β-D and β-L nucleosides of this invention may inhibit Flaviviridae polymerase activity. Nucleosides can be screened for their ability to inhibit Flaviviridae polymerase activity in vitro according to screening methods set forth more particularly herein. One can readily determine the spectrum of activity by evaluating the compound in the assays described herein or with another confirmatory assay.”
“The key starting material for this process is an appropriately substituted sugar with a 2'-OH and 2'-H, with the appropriate leaving group (LG), for example an acyl group or a halogen. The sugar can be purchased or can be prepared by any known means including standard epimerisation, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins’s reagent (dipyridine Cr(VI) oxide, Corey’s reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO 2,ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, CI 2-pyridine, H 2O 2-ammonium molybdate, NaBrO 2-CAN, NaOCI in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide. Then coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkylcopper or R 6 –SIMe 3 in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the 2'-alkylated sugar. The alkylated sugar can be optionally protected with a suitable protecting group, preferably with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The optionally protected sugar nucleoside can then be coupled to the BASE [sic] by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium tetrachloride or a trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base with the presence of trimethylsilyltriflate. Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition 1991. In a particular embodiment, the 2'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 3. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonnucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction.”
“The invention is in the area of pharmaceutical chemistry, and is in particular, a 2'-branched pyrimidine nucleoside or 2'-branched purine nucleoside as defined in the claims. The invention is also a pharmaceutical composition comprising the nucleoside, and the nucleoside for use in a method for the treatment of a Flaviviridae infection, such as a hepatitis C virus infection.”
“[0029] This invention relates to 2'-branched nucleosides, compositions thereof, and the nucleosides for use in methods as defined in the claims. [0030] 3'-prodrugs of 2'-branched β-D or β-L nucleosides, or their pharmaceutically acceptable salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of Flaviviridae infections and other related conditions such as anti- Flaviviridae antibody positive and Flaviviridae - positive conditions, chronic liver inflammation caused by HCV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-Flaviviridae antibody or Flaviviridae-antigen positive or who have been exposed to a Flaviviridae. [0031] A method for the treatment of a Flaviviridae viral infection in a host, including a human, is also disclosed that includes administering an effective amount of a 3'- prodrug of a biologically active 2'-branched β-D or β-L nucleoside or a pharmaceutically acceptable salt thereof, administered either alone or in combination or alternation with another anti-Flaviviridae agent, optionally in a pharmaceutically acceptable carrier. The term 3'-prodrug, as used herein, refers to a 1', 2', 3' or 4'-branched β-D or β-L nucleoside that has a biologically cleavable moiety at the 3'-position, including, but not limited to acyl, and in one embodiment, a natural or synthetic D or L-amino acid, preferably an L-amino acid.”
“straight chained, branched or cyclic alkyl” and “benzyl, wherein the phenyl group is optionally substituted with one or more substituents”
“[245] The medicinal chemist would be experienced in the synthesis of organic compounds for medicinal applications. He would be likely to have some experience in the synthesis of nucleoside analogues. 246. The virologist would have expertise in the biology of the Flaviviridae virus family, and a particular interest in the antiviral activity of nucleoside analogues against Flaviviridae. He or she would be familiar with (and able to carry out) standard molecular- and cell-biological techniques, as well as activity assays.”
“It has never been easy to differentiate between common general knowledge and that which is known by some. It has become particularly difficult with the modern ability to circulate and retrieve information. Employees of some companies, with the use of libraries and patent departments, will become aware of information soon after it is published in a whole variety of documents; whereas others, without such advantages, may never do so until that information is accepted generally and put into practice. The notional skilled addressee is the ordinary man who may not have the advantages that some employees of large companies may have. The information in a patent specification is addressed to such a man and must contain sufficient details for him to understand and apply the invention. It will only lack an inventive step if it is obvious to such a man. It follows that evidence that a fact is known or even well-known to a witness does not establish that that fact forms part of the common general knowledge. Neither does it follow that it will form part of the common general knowledge if it is recorded in a document. As stated by the Court of Appeal in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd [1972] R.P.C. 457, at page 482, line 33: ‘The two classes of documents which call for consideration in relation to common general knowledge in the instant case were individual patent specifications and “widely read publications”
“In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art.”
“It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art.”
“In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art.”
“It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art.”
“The court is trying to determine in a common sense way how the average skilled but non-inventive technician would have reacted to the pleaded prior art if it had been put before him in his work place or laboratory. The common general knowledge is the technical background of the notional man in the art against which the prior art must be considered. This is not limited to material he has memorised and has at the front of his mind. It includes all that material in the field he is working in which he knows exists, which he would refer to as a matter of course if he cannot remember it and which he understands is generally regarded as sufficiently reliable to use as a foundation for further work or to help understand the pleaded prior art. This does not mean that everything on the shelf which is capable of being referred to without difficulty is common general knowledge nor does it mean that every word in a common text book is either. In the case of standard textbooks, it is likely that all or most of the main text will be common general knowledge. In many cases common general knowledge will include or be reflected in readily available trade literature which a man in the art would be expected to have at his elbow and regard as basic reliable information.”
“Novel series of nucleosides that are candidates for the treatment of HCV are being developed, and some have been described in the recent patent literature [131-133]. In particular the discovery of oral, once-daily nucleosides potentially useful for the treatment of all HCV genotypes was recently reported [134]. Among these, beta-D-2'-methyl-ribofuranosyl-guanosine (Fig 6, compound 13) was found to be phosphorylated in cultured cells and orally bioavailable in primates [133].”
“A myriad of new therapies for treating HCV are in various stages of preclinical and clinical development. As reviewed here, these include nucleic acid-based approaches (antisense and ribozymes), small molecule inhibitors of essential HCV-encoded enzymes (protease, helicase, and polymerase), immune modulation, and immunotherapy. As more details of the HCV life cycle are elucidated, new targets and approaches will be discovered. Drug development is difficult, expensive, and always agonizingly slow for patients in need and their physicians. Nonetheless, a broad effort has been mounted for HCV, and substantial progress has been achieved. The prospects for new HCV treatments are bright. The next few years will be very exciting as the first candidates move through clinical trials and, hopefully, into widespread clinical use.”
“Idenix particularly rely on the passage which mentions compound 13, which is a 2'-methyl-up-2'-hydroxy-down nucleoside analogue. All this passage says about compound 13, however, is that it was “found to be phosphorylated in cultured cells and orally bioavailable in primates”
“265. It follows that, even if the skilled team took a particular interest in compound 13 in the De Francesco and Rice article and chased down the references, they would not know whether compound 13 had any anti-HCV activity. As Dr Brancale accepted, the skilled team would know that, in order to identify whether a nucleoside analogue such as compound 13 was active against HCV, it was necessary to test its activity using at least one of the in vitro assays that were available. I would add that WO 01/90121 is the only one of the references which was mentioned by Dr Brancale in the passage from his first report quoted above, and as previously noted, he did not suggest that the content of that application was common general knowledge. ”
“Thus, the 2'-modifications of natural substrate nucleosides transform these molecules into potent inhibitors of HCV replication.”
“292. Dr Brancale’s evidence was that, although the precise data presented in these presentations would not have been common general knowledge, he thought that the general message conveyed by them, namely that 2'-methyl-up-2'-hydroxy-down nucleoside analogues were showing very promising anti-HCV activity, would have been. Prof Götte disagreed. In my judgment the evidence falls a long way short of showing that even the general message conveyed by these presentations was common general knowledge by27 June 2003 . ”
“37. Neither the European Patent Convention (“EPC”) nor thePatents Act 1977 includes amongst the available grounds of invalidity of a granted patent an objection that the patent does not make a technical contribution to the art. However the “problem and solution” approach adopted by the EPO under the EPC to the ground of lack of inventive step necessarily involves isolating from the patent (in comparison with the prior art) some technical contribution or effect. The EPO adopt this approach in order to formulate a technical problem which is solved by the patent – achieving that technical effect – as a precursor to asking whether the patent solves that problem in an obvious or non-obvious way.”
“39. As with any consideration of obviousness, the technical results or effects must be shared by everything falling within the claim under attack. This follows from the fundamental principle of patent law, which underpins many of the grounds of objection to validity, that the extent of the monopoly conferred by a patent must be justified by the technical contribution to the art. If some of the products covered by a claim demonstrate a particular property, but others do not, then the technical problem cannot be formulated by reference to that property. Either the products which do not exhibit the property must be excised from the claim by amendment, or the problem must be formulated by reference to some other, perhaps more mundane, technical contribution common to the whole claim.”
“12. The appellant filed post-published evidence … establishing that GDF-9 was indeed a growth differentiation factor. This cannot be regarded as supportive of an evidence which would have been given in the application as filed since there was not any. The said post-published documents are indeed the first disclosures going beyond speculation. For this reason, the post-published evidence may not be considered at all. Indeed, to do otherwise would imply that the recognition of a claimed subject-matter as a solution to a particular problem could vary as time went by. Here, for example, had the issue been examined before the publication date of the earliest relevant post-published document, GDF-9 would not have been seen as a plausible solution to the problem of finding a new member of the TGF-Beta superfamily and inventive step would have had to be denied whereas, when examined thereafter, GDF-9 would have to be acknowledged as one such member. This approach would be in contradiction with the principle that inventive step, as all other criteria for patentability, must be ascertained as from the effective date of the patent. The definition of an invention as being a contribution to the art, i.e. as solving a technical problem and not merely putting forward one, requires that it is at least made plausible by the disclosure in the application that its teaching solves indeed the problem it purports to solve. Therefore, even if supplementary post-published evidence may in the proper circumstances also be taken into consideration, it may not serve as the sole basis to establish that the application solves indeed the problem it purports to solve.”
“49. I would summarise the position thus far in the following way: (i) Article 56 of the EPC is in part based on the underlying principle that the scope of the patent monopoly must be justified by the patentee's contribution to the art; (ii) If the alleged contribution is a technical effect which is not common to substantially everything covered by a claim, it cannot be used to formulate the question for the purposes of judging obviousness; (iii) In such circumstances the claim must either be restricted to the subject matter which makes good the technical contribution, or a different technical solution common to the whole claim must be found; (iv) A selection from the prior art which is purely arbitrary and cannot be justified by some useful technical property is likely to be held to be obvious because it does not make a real technical advance; (v) A technical effect which is not rendered plausible by the patent specification may not be taken into account in assessing inventive step; (vi) Later evidence may be adduced to support a technical effect made plausible by the specification; (vii) Provided the technical effect is made plausible, no further proof of the existence of the effect is to be demanded of the specification before judging obviousness by reference to the technical effect propounded.” (i) Article 56 of the EPC is in part based on the underlying principle that the scope of the patent monopoly must be justified by the patentee's contribution to the art; (ii) If the alleged contribution is a technical effect which is not common to substantially everything covered by a claim, it cannot be used to formulate the question for the purposes of judging obviousness; (iii) In such circumstances the claim must either be restricted to the subject matter which makes good the technical contribution, or a different technical solution common to the whole claim must be found; (iv) A selection from the prior art which is purely arbitrary and cannot be justified by some useful technical property is likely to be held to be obvious because it does not make a real technical advance; (v) A technical effect which is not rendered plausible by the patent specification may not be taken into account in assessing inventive step; (vi) Later evidence may be adduced to support a technical effect made plausible by the specification; (vii) Provided the technical effect is made plausible, no further proof of the existence of the effect is to be demanded of the specification before judging obviousness by reference to the technical effect propounded.”
“149 In paras.6–8 of its judgment in ZymoGenetics [T 0898/05] the TBA contrasted a product whose structure was given but whose function was undetermined or obscure or only vaguely indicated with one which was “definitely described and plausibly shown to be usable”
“46. The EPO and domestic cases do, however, indicate that the requirement of plausibility is a low, threshold test. It is designed to prohibit speculative claiming, which would otherwise allow the armchair inventor a monopoly over a field of endeavour to which he has made no contribution. It is not designed to prohibit patents for good faith predictions which have some, albeit manifestly incomplete, basis. Such claims may turn out to be insufficient nonetheless if the prediction turns out to be untrue. A patent which accurately predicts that an invention will work is, however, not lightly to be revoked on the ground that the prediction was based on the slimmest of evidence. Thus, the claims will easily be seen not to be speculative where the inventor provides a reasonably credible theory as to why the invention will or might work. The same is true where the data in the specification is such that the reader is encouraged to try the invention. 47. We heard argument as to whether the invention is only to be treated as plausible if the reader of the specification would be encouraged to try the invention with a reasonable prospect of success, thereby bringing the test for plausibility into line with that sometimes used in the context of obviousness. I do not accept that there is any reason to align the tests in this way. A test designed to prevent speculative claiming need go no further than requiring the patentee to show that the claim is not speculative: the specification does not need to provide the reader with any greater degree of confidence in the patentee’s prediction than that.”
“444. …They could well have covered as many as a trillion compounds. Furthermore, it was common ground between Prof Götte and Dr Brancale that it was not plausible that all the compounds claimed would be effective against Flaviviridae. Counsel for Gilead characterised the Application as a “land grab”, and in my view that is a fair description. It does not necessarily follow that the Patent is invalid, however.”
“447. … Claim 1 of the Patent is much narrower in scope than the claims in the Application. Nevertheless, it still covers a very large number of compounds, on a conservative estimate at least 50 billion compounds. Gilead contend that, considered as at27 June 2003 , it was not plausible that substantially all the compounds covered by claim 1 would be effective against Flaviviridae. I can deal with this contention quite shortly, because it is Idenix’s own evidence that claim 1 covers classes of compounds which it was not plausible would be effective. Dr Brancale expressed the opinion in paragraphs 201-202 of his first report that compounds of Formula (IX) would not have been thought likely to have antiviral activity where R 1 and R 2 were either “straight chained, branched or cyclic alkyl” or “benzyl, wherein the phenyl group is optionally substituted with one or more substituents”
“451. First, the Patent contains no experimental data to suggest that any of the claimed compounds may be effective. The only experimental data is in Example 26, but that example (i) is expressly acknowledged to relate to a compound which falls outside the claim, (ii) relates to an unidentifiable compound which does not appear to contain fluorine and (iii) does not establish that the compound has any potentially therapeutically useful activity. 452. Secondly, the Patent contains no rationale for the assertion that the claimed compounds may be effective. On the face of the Patent, the assertion appears to be nothing more than speculation. 453. Thirdly, the specification adds nothing to the common general knowledge of the skilled team as to what nucleoside analogues might exhibit Flaviviridae, and in particular anti-HCV, activity. It was known in June 2003 that certain nucleoside analogues could inhibit replication in certain viruses, since such analogues had been used successfully in HIV and HBV therapy. It was also known that NS5B was a potential target for direct acting nucleoside analogues and this was an area of active research. Accordingly, as a matter of common general knowledge, it was plausible that as yet untested nucleoside analogues might exhibit anti-HCV activity through their effect on NS5B. The Patent contains nothing which makes this more plausible. Still less does it contain anything to make it more plausible that the compounds claimed in claim 1 – as opposed to, for example, other compounds claimed in the Application – might exhibit such activity. In particular, the passage at [0022(10)] (corresponding to page 9 line 29 – page 10 line 24 of the Application, quoted in paragraph 181 above) which is relied on by Idenix does not do so. As I have said, it is simply part of the recitation of prior art and it does not identify the 2'-modified nuclesides [sic] which were the subject of the Eldrup, Bhat and Olsen presentations at the Savannah conference. 454. Fourthly, Idenix’s attempt to fill the gaps in the specification by raising the level of the skilled team’s common general knowledge was unsuccessful. Idenix’s case on plausibility as presented in counsel for Idenix’s closing submissions started from the premise that it was common general knowledge that the 2'-methyl-up-2'-hyxroxy-down nucleoside analogues being investigated by Merck which were the subject of the Carroll paper and the presentations at the Savannah conference had activity in the HCV replicon and acted as chain terminators of the HCV RNA-dependent RNA polymerase. I have found that this was not the case. 455. Fifthly, even if Idenix’s attempt to fill the gaps in the specification by raising the level of the skilled team’s common general knowledge had succeeded, it would have been self-defeating. Even if it was correct that, for example, the Carroll paper was common general knowledge, and therefore the skilled team would bring that knowledge to their reading of the Patent, it would remain the case that the Patent added nothing to their knowledge. If it was plausible in the light of the information in the Carroll paper that the claimed compounds would be effective, that would not demonstrate that the Patent had made any technical contribution to the art. 456. Sixthly, counsel for Idenix relied on the fact that Prof Götte had accepted that the compounds claimed in claims 9-11 of the Application were highly structurally related to the Merck 2'-methyl-up-2'-hydroxy-down compounds. This does not assist Idenix, however. Prof Götte was clear that this did not make it plausible that the claimed compounds would be effective against HCV, rather this had to be tested. Furthermore, it was part of the skilled team’s common general knowledge that small structural changes could have a substantial effect on activity and/or toxicity. Still further, as I have explained, Idenix failed to establish that the skilled team would have regarded fluorine as an isostere for a hydroxyl group. On the contrary, the skilled team would have appreciated that substituting fluorine for hydroxyl could seriously affect the properties of the molecule, and in particular its biological activity. 457. Seventhly, counsel for Gilead pointed out that counsel for Idenix had approached his cross-examination of Professor Götte by asking whether compounds with the structure of claim 10 of the Application “would at least be plausible in the sense of worth testing”
“239. The specification must disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these: (i) the first step is to identify the invention and that is to be done by reading and construing the claims; (ii) in the case of a product claim that means making or otherwise obtaining the product; (iii) in the case of a process claim, it means working the process; (iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims; (v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification; (vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim; (vii) the specification must be sufficient to allow the invention to be so performed without undue burden.” (i) the first step is to identify the invention and that is to be done by reading and construing the claims; (ii) in the case of a product claim that means making or otherwise obtaining the product; (iii) in the case of a process claim, it means working the process; (iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims; (v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification; (vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim; (vii) the specification must be sufficient to allow the invention to be so performed without undue burden.”
“97. … the question whether the specification adequately discloses the invention is one of degree. I put it this way in Novartis AG v Johnson & Johnson Medical Ltd[2009] EWHC 1671 in a passage cited by the judge in this case: “236. Whether the specification discloses an invention clearly and completely enough for it to be performed by a person skilled in the art involves a question of degree. It is impossible to lay down any precise rule because the degree of clarity and completeness required will vary depending on the nature of the invention and of the art in which it is made. On the one hand, the specification need not set out every detail necessary for performance. The skilled person must be prepared to display a reasonable degree of skill and use the common general knowledge of the art in making routine trials and to correct obvious errors in the specification, if a means of correcting them can readily be found. Further, he may need to carry out 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. On the other hand, he should not be required to carry out any prolonged research, enquiry or experiment: Mentor Corporation v Hollister Inc. [1993] R.P.C. 7.”” “236. Whether the specification discloses an invention clearly and completely enough for it to be performed by a person skilled in the art involves a question of degree. It is impossible to lay down any precise rule because the degree of clarity and completeness required will vary depending on the nature of the invention and of the art in which it is made. On the one hand, the specification need not set out every detail necessary for performance. The skilled person must be prepared to display a reasonable degree of skill and use the common general knowledge of the art in making routine trials and to correct obvious errors in the specification, if a means of correcting them can readily be found. Further, he may need to carry out 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. On the other hand, he should not be required to carry out any prolonged research, enquiry or experiment: Mentor Corporation v Hollister Inc. [1993] R.P.C. 7.””
“103. … the Boards of Appeal of the EPO have recognised that in the case of a claim to the use of a product to make a medicine for a particular therapeutic purpose it would impose too great a burden on the patentee to require him to provide absolute proof that the compound has approval as a medicine. Further, it is not always necessary to report the results of clinical trials or even animal testing. Nevertheless, he must show, for example by appropriate experiments, that the product has an effect on a disease process so as to make the claimed therapeutic effect plausible. It was put this way in T609/02 Salk at [9]: “…It is a well-known fact that proving the suitability of a given compound as an active ingredient in a pharmaceutical composition might require years and very high developmental costs which will only be borne by the industry if it has some form of protective rights. Nonetheless, variously formulated claims to pharmaceutical products have been granted under the EPC, all through the years. The patent system takes account of the intrinsic difficulties for a compound to be officially certified as a drug by not requiring an absolute proof that the compound is approved as a drug before it may be claimed as such. The boards of appeal have accepted that for a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application (T 241/95, OJ EPO 2001, 103, point 4.1.2 of the reasons, see also T 158/96 of28 October 1998 , point 3.5.2 of the reasons) or, as decision T 158/96 also put it, if there is a “clear and accepted established relationship” between the shown physiological activities and the disease (loc. cit.). Once this evidence is available from the patent application, then post-published (so-called) expert evidence (if any) may be taken into account, but only to back-up the findings in the patent application in relation to the use of the ingredient as a pharmaceutical, and not to establish sufficiency of disclosure on their own.”” “…It is a well-known fact that proving the suitability of a given compound as an active ingredient in a pharmaceutical composition might require years and very high developmental costs which will only be borne by the industry if it has some form of protective rights. Nonetheless, variously formulated claims to pharmaceutical products have been granted under the EPC, all through the years. The patent system takes account of the intrinsic difficulties for a compound to be officially certified as a drug by not requiring an absolute proof that the compound is approved as a drug before it may be claimed as such. The boards of appeal have accepted that for a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application (T 241/95, OJ EPO 2001, 103, point 4.1.2 of the reasons, see also T 158/96 of28 October 1998 , point 3.5.2 of the reasons) or, as decision T 158/96 also put it, if there is a “clear and accepted established relationship” between the shown physiological activities and the disease (loc. cit.). Once this evidence is available from the patent application, then post-published (so-called) expert evidence (if any) may be taken into account, but only to back-up the findings in the patent application in relation to the use of the ingredient as a pharmaceutical, and not to establish sufficiency of disclosure on their own.””
“98. … it is permissible to define an invention using general terms provided the patent discloses a principle of general application in the sense that it can reasonably be expected the invention will work with anything falling within the scope of these terms. As Lord Hoffmann said in Biogen Inc. v Medeva plc [1977] R.P.C. 1 at pp.48–49: “If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them. Thus if the patent has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect: see May & Baker Ltd v Boots Pure Drug Co. Ltd. (1950) 67 R.P.C. 23, 50. On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.” 99 . In Kirin-Amgen Inc v Hoechst Marion Roussel Ltd[2004] UKHL 46 , [2005] R.P.C. 9 Lord Hoffmann further explained the concept of a principle of general application in this way: “112. In my opinion there is nothing difficult or mysterious about [a principle of general application]. It simply means an element of the claim which is stated in general terms. Such a claim is sufficiently enabled if one can reasonably expect the invention to work with anything which falls within the general term. For example, in Genentech I/Polypeptide expression (T 292/85) [1989] O.J. EPO 275, the patentee claimed in general terms a plasmid suitable for transforming a bacterial host which included an expression control sequence to enable the expression of exogenous DNA as a recoverable polypeptide. The patentee had obviously not tried the invention on every plasmid, every bacterial host or every sequence of exogenous DNA. But the Technical Board of Appeal found that the invention was fully enabled because it could reasonably be expected to work with any of them. 113. This is an example of an invention of striking breadth and originality. But the notion of a ‘principle of general application’ applies to any element of the claim, however humble, which is stated in general terms. A reference to a requirement of ‘connecting means’ is enabled if the invention can reasonably be expected to work with any means of connection. The patentee does not have to have experimented with all of them.” 100. It must therefore be possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. The products and methods within the claim are then tied together by a unifying characteristic or a common principle. If it is possible to make such a prediction then it cannot be said the claim is insufficient simply because the patentee has not demonstrated the invention works in every case. 101. On the other hand, if it is not possible to make such a prediction or if it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee has made to the art and the claim will be insufficient. It may also be invalid for obviousness, there being no invention in simply providing a class of products or methods which have no technically useful properties or purpose.” “If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them. Thus if the patent has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect: see May & Baker Ltd v Boots Pure Drug Co. Ltd. (1950) 67 R.P.C. 23, 50. On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.” “112. In my opinion there is nothing difficult or mysterious about [a principle of general application]. It simply means an element of the claim which is stated in general terms. Such a claim is sufficiently enabled if one can reasonably expect the invention to work with anything which falls within the general term. For example, in Genentech I/Polypeptide expression (T 292/85) [1989] O.J. EPO 275, the patentee claimed in general terms a plasmid suitable for transforming a bacterial host which included an expression control sequence to enable the expression of exogenous DNA as a recoverable polypeptide. The patentee had obviously not tried the invention on every plasmid, every bacterial host or every sequence of exogenous DNA. But the Technical Board of Appeal found that the invention was fully enabled because it could reasonably be expected to work with any of them. 113. This is an example of an invention of striking breadth and originality. But the notion of a ‘principle of general application’ applies to any element of the claim, however humble, which is stated in general terms. A reference to a requirement of ‘connecting means’ is enabled if the invention can reasonably be expected to work with any means of connection. The patentee does not have to have experimented with all of them.”
“102. … patentees not infrequently seek to avoid the possibility that a claim covers products or methods which do not work by inserting a functional limitation. Such a claim may be allowed by the EPO if the invention can only be defined in such terms or cannot otherwise be defined more precisely without unduly restricting its scope. But, it must still be possible to perform the invention across the scope of the claim without undue effort. As I said in Novartis v Johnson & Johnson at [244]: “…In the case of a claim limited by function, it must still be possible to perform the invention across the scope of the scope of the claim without undue effort. That will involve a question of degree and depend upon all the circumstances including the nature of the invention and the art in which it is made. Such circumstances may include a consideration of whether the claims embrace products other than those specifically described for achieving the claimed purpose and, if they do, what those other products may be and how easily they may be found or made; whether it is possible to make a reasonable prediction as to whether any particular product satisfies the requirements of the claims; and the nature and extent of any testing which must be carried out to confirm any such prediction.”” “…In the case of a claim limited by function, it must still be possible to perform the invention across the scope of the scope of the claim without undue effort. That will involve a question of degree and depend upon all the circumstances including the nature of the invention and the art in which it is made. Such circumstances may include a consideration of whether the claims embrace products other than those specifically described for achieving the claimed purpose and, if they do, what those other products may be and how easily they may be found or made; whether it is possible to make a reasonable prediction as to whether any particular product satisfies the requirements of the claims; and the nature and extent of any testing which must be carried out to confirm any such prediction.””
“571. In my judgment, however, the specification gives the skilled person little assistance. First, as Prof Boons pointed out, if the skilled person studied the text accompanying Schemes 3 and 4 (at [0117]-[0121] corresponding to page 123 line 1 – page 124 line 3 of the Application, quoted in paragraph 206 above, and [0122]-[0125]), he would wonder if it was written by someone who knew what they were talking about. The specification describes the production of the ketone by an oxidation step. Among the possible oxidising agents listed in the specification for this reaction, however, are Jones’ reagent, an aggressive mixture of chromic acid and sulphuric acid which one would not use on a nucleoside, Collins’ reagent and Corey’s reagent, which again are aggressive reagents, and Raney nickel, which is a reducing agent, not an oxidising agent. I should say that counsel for Idenix objected in his closing submissions that this evidence was given in response to a question which I asked Prof Boons. I do not accept that objection, since my question arose out of counsel’s cross-examination and Prof Boons’ evidence. More importantly, counsel submitted that Gilead had not taken any point about the oxidation reaction. That is true, but Gilead do contend that the specification does not assist the skilled person to synthesise the claimed compounds. 572. Secondly, organolithium is just one of a list of possible reagents. Furthermore, no specific mention is made of methyl lithium, still less are appropriate reaction conditions given, nor is any reference given to Matsuda II. 573. Thirdly, even if the skilled person proceeds down this path, he is still faced with the problem of how to achieve stereospecific fluorination of the tertiary carbon. The specification gives the skilled person no assistance with this whatsoever. On their face, where R 6 is methyl, Scheme 3 and Scheme 4 produce a 2'-methyl-up-2'-hydroxy-down compound. Fluorinating that compound would require retention of the stereochemistry, which would rule out an SN2 reaction. In fact, however, organolithium reagents are generally not stereoselective, and so the product of the methylation reaction would be expected to be a mixture of isomers. It should then be possible to separate out the 2'-methyl-down-2'-hydroxy-up compound, which in principle it should be possible to fluorinate with inversion of the stereochemistry by an SN2 reaction. But the specification says nothing about this, and the skilled person is left to work it out for himself. The skilled person is also left to find a fluorinating agent and reaction conditions which will achieve stereospecific fluorination of the tertiary carbon, rather than one of the competing reactions such as elimination.”
“585. Prof Boons’ opinion in summary was that making any of the claimed compounds was a research project which represented a significant synthetic challenge and which was of uncertain outcome. He had conducted a literature search on the synthesis of 2'-methyl-2-fluoro nucleosides, and had found that no such synthesis of such a compound, regardless of stereochemistry, had been reported by June 2003. There was literature relating to 2'-methyl sugars/nucleosides and, separately, to 2'-fluoro nucleosides, but it would not have been thought possible to combine these teachings. A major difference between what had been reported and what needed to be accomplished was the nature of the fluorine at the 2' position: synthesis of a secondary fluorine at the 2' position had been reported, but not the synthesis of a tertiary fluorine at the 2' position. The tertiary fluorine would fundamentally alter the reaction pathways compared to a nucleoside with a secondary fluorine at the 2' position. The skilled person undertaking a retrosynthetic analysis would have been confronted with a number of possible routes, all of which would have had potential difficulties associated with them, and the skilled person would not have known in advance which, if any, might have led successfully to the product. Nucleophilic substitution of a tertiary alcohol was just one possible step on one of these routes, but it was known to be difficult with competing reactions, including elimination and migration reactions. In addition to nucleophilic substitution, it was also known that fluorination could be attempted using electrophilic addition, but again this would be difficult to control. Accordingly, if asked to carry out this project, Prof Boons would have asked for a year’s funding for a post-doctoral worker, would not have considered that success could be predicted and would have considered a successful synthesis worthy of publication in a peer-reviewed journal. Prof Boons formed this view before he knew about the numerous failed attempts by Dr Griffon. He subsequently reviewed various documents relating to these attempts, and concluded that they reflected a project of significant complexity with numerous failures, very much along the lines he had anticipated.”
“Having tried and failed with his first five strategies, Dr Griffon commenced a new approach in February 2003, which involved making a 3'-5'-protected 2'-hydroxy-up-2'-methyl-down nucleoside and then fluorinating it using Deoxo-Fluor (“Strategy 6”), as shown below. Strategy 6”
“492. Dr Griffon first attempted the fluorination step on13 February 2003 . He proceeded to deprotect the hydroxyl groups before attempting to separate and analyse the reaction products. He completed his analysis of the reaction products on17 February 2003 . He monitored the reaction using TLC, first viewing the plate under UV light and then staining it with 10% sulphuric acid in methanol and heating it. He pasted into his laboratory notebook the stained TLC plates for the crude reaction mixture (i) after 5½ hours, (ii) after leaving the reaction overnight and (iii) after deprotection. The last of these three appears to show four main spots which charred with the staining and two very small spots which had been visible under UV, and had been circled in pencil by Dr Griffon, but which did not char. Dr Griffon then analysed the mixture by analytical HPLC. He then separated the crude reaction mixture using silica gel chromatography into three components. The first component he presumed to be the uracil base. The second component, which appeared to be the major product, he analysed by MS, 1H and 19F NMR. This turned out to be the 2' ethenyl derivative i.e. the elimination product. The third component he presumed to be the deprotected starting material. He recorded his work, including the analytical data, on pages 12 and 14 of his laboratory notebook for that period.”
“Question: Due to the synthetic difficulties encountered, is it worthwhile to continue to consider this series as future targets?”
“568. Counsel for Idenix informed me, without contradiction by counsel for Gilead, that Mr Clark was a relatively junior and inexperienced chemist who did not have a PhD. On the other hand, he did not work alone, as can be seen from the fact that the Clark Paper had 14 authors, including Dr Schinazi, who counsel for Idenix not merely accepted, but asserted, was a leader in the field at that time, while Clark II had five authors, including Dr Schinazi. 569. The conclusion that I draw from Mr Clark’s work is that he and his colleagues did succeed in synthesising a 2'-methyl-up-2'-fluoro-down compound much more quickly than the Idenix team. The question is why. In my view, the explanation lies in a combination of skill and luck. When Mr Clark and his colleagues carried out their retrosynthetic analysis, it evidently occurred to them at a reasonably early stage that, if they took the sugar route, there were two key reactions to be achieved: conversion of the ketone to the 2'-hydroxy-up-2'-methyl down compound followed by SN2 fluorination of the tertiary alcohol in that compound with inversion of the stereochemistry to give the 2'-methyl-up-2'-fluoro down compound. When planning the first reaction, it would appear that their literature searches turned up Matsuda II. As for the second reaction, it would appear from their comments in the Clark Paper and Clark II that they appreciated that stereospecific fluorination of the tertiary alcohol was likely to be challenging, but their searches turned up Singh and Shreeve, Wachmeister and Yang. Encouraged by the first two papers, they followed Wachtmeister’s method, but using DAST rather than Deoxo-Fluor and omitting the pyridine. It is unclear why they used DAST and not Deoxo-Fluor. It is also unclear why they omitted the pyridine, whether this would have been expected to make any difference and whether this in fact did make any real difference. Whatever the answers to these questions, it is clear from the Clark Paper and Clark II that the success of the fluorination reaction was considered worthy of specific comment in publications in two high profile journals.”
“594. Drawing these threads together, the conclusion I have reached is that the Patent does not enable the skilled person to make the claimed compounds without undue burden. The specification gives the skilled person no meaningful assistance, and so the skilled person has to rely upon his common general knowledge. The skilled person would undertake a retrosynthetic analysis, and would be immediately confronted with the problem that his target compound contained a tertiary fluorine with a particular stereochemistry. He would appreciate that making such a compound would be difficult and challenging, and there would a large number of potential routes to consider. The skilled person’s prospects of success would depend on both skill and luck. If he was skilled and lucky, he could hit upon a successful synthesis fairly quickly, as Mr Clark and his colleagues did. If he was skilled but unlucky, he could spend many months on the problem without success, as Dr Griffon did. ”
“591. In addition, counsel for Idenix cross-examined Prof Boons at some length on the scientific literature regarding DAST. The purpose of the cross-examination was to try to establish that the statement in March was supported by the literature. But counsel did not put to Prof Boons the primary reference given by March for his statement, reference 1158, which is W.J. Middleton, “New Fluorinating Reagents. Dialylaminosulfur Fluorides”
“Gilead allege that the Patent does not enable the skilled team to perform the invention in claim 1 without undue burden because it does not enable them to synthesise the 2'-methyl-up-2'-fluoro down compounds claimed. The allegation is focused upon the 2'-methyl-up-2'-fluro-down substitutions on the ribose ring; Gilead do not contend that the skilled team would have any difficulty with regard to the other substitutions covered by Markush formula in claim 1 … ”
“517. The picture which emerged in cross-examination was somewhat different. Although Dr Griffon repeatedly said that he was seeking yields of 20-30%, or even 30-50%, it is clear from his laboratory notebooks that he sometimes isolated and characterised products at lower yield, including ones at 15% and 16%. Furthermore, Dr Griffon started multiple experiments with amounts of starting material in the region of 50-100 mg, where getting 100-200 mg of product would simply have been impossible. Still further, Dr Griffon’s Progress Reports make no mention of him only seeking high yields and do not use language which suggests that only major reaction products were considered. Yet further, Dr Griffon accepted that he had pursued his research with great persistence: his attitude to his experiments had been “never give up”.”
“518. Above all, it is clear that Dr Griffon was not so poor a synthetic chemist that he did not ask himself what the minor products of reactions were. This is demonstrated in particular by the very evidence that Idenix rely upon and which formed the basis for their Experiments. As discussed above, Dr Griffon’s TLC analysis of the crude deprotected reaction mixture revealed the presence of a number of products. Dr Griffon separated three of these. It is true that he only characterised one of them, which he hoped might be the fluorinated compound, but turned out not to be; but he still thought about what the other two were. Because he believed he knew what they were, he did not characterise them. (I should make it clear that Idenix do not suggest that Dr Griffon was mistaken in his belief as to the identity of the other two products.) I do not believe that, having got as close to his goal as he had by then, if Dr Griffon had thought that one of the other minor products of the reaction was 2'-fluoro-2'-methyl uridine, he would not have attempted to separate and analyse it. 519. Furthermore, there is another, and in my view more plausible, reason, why at the time he did not think that the small spot which he ultimately suggested was 2'-fluoro-2'-methyl uridine was the target compound. As Prof Boons explained, that spot did not char when stained with the sulphuric acid, indicating that it did not contain a carbohydrate moiety.”
“522. Furthermore, Dr Griffon was not working on his own, but received extensive advice from relevant experts. Counsel for Idenix sought to downplay the assistance Dr Griffon had received from others by arguing that there was no evidence that they were aware of his idiosyncratic approach. I do not accept this argument for two reasons. First, I do not accept that Dr Griffon’s approach was idiosyncratic. Secondly, the evidence indicates that Dr Griffon explained to experts such as Prof Fleet and Dr Coe what approaches he had tried and what the results had been. If they had thought that he ought to have succeeded with a reaction that had apparently failed, I am sure they would have suggested that he try it again.”
“… His point was a different one, namely that the 2'-hydroxy-up-2'-methyl-down compound is only one possible precursor and that one only arrives at that precursor working backwards in the retrosynthetic analysis if and when one has solved the problem of fluorinating the tertiary alcohol. Unless the skilled person perceives a solution to that problem, his retrosynthetic analysis will be likely to work back by other routes.”
“593. … The question is whether the skilled person carrying out a retrosynthetic analysis would have (i) planned to follow a route in which the final step (i.e. the first step in the retrosynthetic analysis) involved nucleophilic fluorination of a tertiary alcohol, (ii) thought of using DAST to carry out that step and (iii) had a reasonable expectation that the reaction to work. Prof Boons’ evidence was clear that he did not think it likely that the skilled person would plan such a route, or that the skilled person would have been likely to use DAST (he said that he himself would not have used it), or that the skilled person would have had a reasonable expectation of success. As I have indicated, I consider that Prof Boons’ evidence is supported by Dr Griffon’s work. But it is also supported by the fact that Prof Fleet did not suggest the use of DAST to Dr Griffon (he proposed electrophilic substitutions) and by the fact that Dr Coe’s comments on the use of DAST made it clear that he expected it to lead to elimination and migration reactions. ”
“596. … Gilead contend that the Patent does not enable the skilled team to perform the invention across the breadth of claim 1 without undue burden. The basis for this contention is simple: even once the medicinal chemist has made one of the compounds, the virologist has to test it for antiviral activity. There is no dispute that testing a compound for anti-Flaviviridae activity would be routine work which in itself would not be unduly burdensome. But the claim covers billions of compounds and the Patent gives the skilled team no clue as to where to start. Dr Brancale accepted that it would take 3-6 days to synthesise a straightforward nucleoside analogue and that a more complicated case might take 2-3 months. As discussed above, the Patent suggests using BVDV assays to identify active compounds, but 2'-deoxy-2'-fluoro-2'-C-methylcytidine is inactive in the BVDV assay. Admittedly, the virologist would know from his common general knowledge that the gold standard assay was the replicon assay, and 2'-deoxy-2'-fluoro-2'-C-methylcytidine turns out to be active in the replicon assay. But what this emphasises is that the Patent is setting the skilled team a substantial research project to select, synthesise and test the claimed compounds relying upon their own common general knowledge and claiming the results if they are successful. 597. Idenix’s answer to this contention is that Gilead have not established that any of the claimed compounds do not work. Accordingly, Idenix say that the invention can be performed across the breadth of the claims without undue burden, because the medicinal chemist can make the compounds without undue burden and the virologist can test them without undue burden.”
“598. The Patent does not suggest that all of the claimed compounds have an anti-Flaviviridae activity, however. On the contrary, all it says is that they can be screened for such activity. Even if it is plausible that the claimed compounds do have such activity, it is clear from the evidence that they may turn not to do so [sic] when tested. Accordingly, I agree with Gilead that the Patent does not enable the skilled team to perform the invention across the breadth of the claim without undue burden because it sets the skilled team a research project and claims the results.”
“605. I do not accept this argument. Although I agree that the Application is of stupendous breadth, one of many of the classes of compounds which it specifically identifies as a preferred embodiment of the invention is the subclass identified on page 100. Furthermore, the message that that subclass is one of the classes of particular interest is reinforced by claims 9-11. I do not consider that the skilled team would learn anything new about that embodiment of the invention as a result of claim 1 as granted being restricted to that subclass and claims to the other classes of compounds being abandoned. Accordingly, I reject the allegation of added matter in relation to claim 1.”
“610. … Counsel for Gilead submitted that, by deleting certain substituents from the list of substituents for R 1 and the list of substituents for R 2, Idenix was creating a narrower sub-class of compounds which was neither disclosed in the Application nor clearly and unambiguously derivable from it. Furthermore, to make matters worse, Idenix’s own evidence was that it was plausible that this new sub-class was effective against Flaviviridae, whereas this was not the case for the broader class. Accordingly, the skilled team would learn something new about the invention from the amended claim …”
“Employee hereby assigns and agrees to assign to [Pharmasset Georgia], its successors, assigns or designees, all of Employees rights to inventions, … patents, …relating to the development … of antiviral and anticancer agents which, during the term of Employee’s employment by [Pharmasset Georgia], Employee makes, develops of conceives … in the course of such employment …”
“WHEREAS, [Pharmasset Barbados] is the owner of all right, title, and interest in certain intangible property in Exhibit A to this Agreement and Know-How relating to the Products (the ‘Intellectual Property’) … ARTICLE I DEFINITIONS … 1.7 Improvements. “Improvements” shall mean any findings, discoveries, inventions, additions, modifications, formulations, or changes made by either [Pharmasset Barbados] or [Pharmasset Georgia] during the term of this Agreement that relate to Intellectual Property or the Project. … 1.11 Project or Projects. ‘Project’ or ‘Projects’ shall mean research project listed in Exhibit D to this Agreement. … ARTICLE III GRANT OF RIGHT TO USE INTANGIBLE PROPERTY 3.1 Grant by [Pharmasset Barbados] [Pharmasset Barbados] grants to [Pharmasset Georgia] the nonexclusive right to use, develop, and enjoy the Intellectual Property for the purpose of completing the Project, subject to the terms and conditions of this Agreement. … 3.3 Grant by [Pharmasset Georgia] [Pharmasset Georgia] grants to [Pharmasset Barbados] an exclusive, irrevocable, royalty-free right to use, develop, and enjoy any Improvements. … ARTICLE V OWNERSHIP 5.1 Intellectual Property Ownership. [Pharmasset Georgia] acknowledges [Pharmasset Barbados]’s exclusive right, title, and interest in and to the Intellectual Property. [Pharmasset Georgia] shall not at any time do or cause to be done, or fail to do or cause to be done, any act or thing, directly or indirectly, contesting or in any way impairing [Pharmasset Barbados]’s right, title or interest in the Intellectual Property. Every use of any Intellectual Property by [Pharmasset Georgia] shall inure to the benefit of [Pharmasset Barbados]. 5.2 Ownership of Rights. [Pharmasset Barbados] shall at all times, during or after the term of this Agreement, be the sole owner of all rights relating to or emanating from Intellectual Property, Know How, Improvements, or other matters developed in, or related to, a Project. …. ARTICLE VI TERM AND TERMINATION … 6.3 Rights and Duties on Termination. On termination of this Agreement [Pharmasset Georgia] shall return all Intellectual Property, Know-How, Improvements, and any and all confidential information disclosed to it by [Pharmasset Barbados] in its possession to [Pharmasset Barbados], and all such aforementioned items shall be the exclusive property of [Pharmasset Barbados]. … ARTICLE VIII MISCELLANEOUS PROVISIONS … 8.6 Further Assurances. Each party hereby covenants that it shall execute and deliver such deeds and other documents as may be required to implement any of the provisions of this Agreement. ... 8.9 Captions. Titles or captions of articles and paragraphs contaned in this Agreement are inserted only as a matter of convenience and for reference, and in no way define, limit, extend, or describe the scope of this Agreement or the intent of any provision hereof. …”
“404. …. it is clear from the surrounding circumstances that it was the parties’ intention that Pharmasset Barbados should own the Improvements, for tax reasons. It is also clear that the parties acted upon the understanding that this was the effect of the R&D Agreement. Thus it was Pharmasset Barbados which obtained confirmatory assignments from inventors like Mr Clark, Pharmasset Barbados which filed patent applications such as the Pharmasset PCT and Pharmasset Barbados which granted licences. Accordingly, to the extent that the R&D Agreement is ambiguous or uncertain, it should be interpreted to give effect to that intention and understanding in accordance with agreed principles (12), (13) and (14).”
“1. Let’s have the PSL/PSI agreement signed and dated (December xx, 1999 – the date the B of D authorized it at the HI meeting). I suggest that it be signed for LTD in Barbados, the next time we have them sign documents. Kathleen [Metzger] or Alan [Roemer] could sign it. … Let’s get all of this together early next week to be sent to PWC Barbados. We do not have to send a signed agreement to PWC, the fact that Board approved it is good enough.”
“342. … Mr Roberts’ recollection of having seen a signed copy bearing the signatures of Mr Pritchard and Dr Schinazi on behalf of Pharmasset Barbados together with two other signatures on behalf of Pharmasset Georgia made by persons whose names Mr Roberts could not recall. Mr Roberts could not recall when this happened, save that it was some time during his tenure at Pharmasset Georgia. Neither signature was particularly distinctive, nor were Mr Pritchard and Dr Schinazi identified by name in the document which Mr Roberts recalls that he saw. Mr Roberts’ evidence was that the reason why this stuck in his mind was that it was the only time he could recall seeing an agreement signed on behalf of Pharmasset Georgia as well as Pharmasset Barbados. Every other document he could recall had only been signed on behalf of Pharmasset Barbados.”
“… how likely is it that a document which was important for tax purposes and which had been specifically requested by PWC for the purposes of an audit was not signed? Furthermore, how likely is it that lightning struck twice i.e. that, having failed to get the R&D Agreement executed following the board meeting on11 December 1999 , Pharmasset again failed to do so following the request from PWC? Finally, how likely is it that, having gone to the trouble of preparing the exhibits to the R&D Agreement so that it could be executed, Pharmasset nevertheless did not get it signed?”
“351. …. Let it be assumed that none of them has any recollection of either signing the R&D Agreement or seeing a signed version. I am still left with the documentary evidence, Mr Roberts’ evidence and the inherent probabilities.”
“352. The most troubling point is the absence of any original or copy of the signed agreement. I agree with counsel for Idenix that, for the various reasons he gave, this is very hard to explain if the R&D Agreement was indeed signed. Nevertheless, it is not impossible. For example, it is possible, if unlikely, that there was only one original, that no copies were made of it and that the original was lost during the archiving project. 353. I am left to weigh the documentary evidence, Mr Roberts’ evidence and the inherent probabilities which favour execution against the improbability of no copy of a signed agreement surviving if it was signed. On the balance of probabilities, I conclude that the R&D Agreement was signed.”
“… Article 4(A) of the Paris Convention and Article 87(1) of the EPC are provisions in international treaties whose operation cannot depend upon the distinction drawn by English law, but not most other laws, between legal and equitable title. When determining whether a person is a ‘successor in title’ for the purposes of the provisions, it must be the substantive rights of that person and not his compliance with the legal formalities that matter.”
“Employee hereby assigns and agrees to assign to [Pharmasset Georgia], its successors, assigns, or designees, all of Employee’s rights to inventions …”
“… clause 5.2 of the R&D Agreement does not use the language of assignment, it uses the language of ownership. I see no reason why this aspect of the agreement cannot take effect through the mechanism of designation rather than the mechanism of assignment. Accordingly, I would if necessary hold that the Pharmasset PCT was entitled to priority through Route 3. It is not necessary to consider Gilead’s alternative case.”