“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.”
“In the light of the fact that HCV infection has reached epidemic levels worldwide, and has tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat hepatitis C that have low toxicity to the host. Further, giving the rising threat of other flaviviridae infections, there remains a strong need to provide new effective pharmaceutical agents that have low toxicity to the host. Therefore, it is an object of the present invention to provide a compound, method and composition for the treatment of a host infected with hepatitis C virus. It is another object of the present invention to provide a method and composition generally for the treatment of patients infected with pestivirus, flaviviruses or hepaciviruses.”
“2' and 3'-prodrugs of 1', 2', 3' or 4'-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 antiFlaviviridae antibody or Flaviviridae-antigen positive or who have been exposed to a Flaviviridae. 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 2' or 3'- prodrug of a biologically active 1', 2', 3' or 4'-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 2'-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 2'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. 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.”
“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 invention as disclosed herein is a compound, a method and composition for the treatment of a Flaviviridae infection in humans and other host animals. The method includes the administration of an effective anti-Flaviviridae treatment amount of a 2' and/or 3'-prodrug of a 1', 2', 3', or 4'-branched βD or β-L nucleoside as described herein or a pharmaceutically acceptable salt, derivative or prodrug thereof, optionally in a pharmaceutically available carrier. The compounds of the invention either possess antiviral (i.e. anti-HCV) activity, or are metabolized to a compound that exhibits such activity. HCV is a member of the Flaviviridae famil. HCV has been placed in a new monotypic genus, hepacivirus. Therefore, in one embodiment, the Flaviviridae is HCV. In an alternate embodiment, the Flaviviridae is a flavivirus or pestivirus.”
“R 1, R 2, and R 3 are independently H; phosphate; straight chained, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; sulfonate ester; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; or a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound where R 1, R 2, and/or R 3 is independently H or phosphate; X is O, S, SO 2 CH 2; Base* is a purine or pyrimidine base; R 12 is C(Y 3)3; Y 3 is independently H, F, Cl, Br, or I; and R 13 is fluoro. In one subembodiment X is O, and Y 3 is H. In another subembodiment, when X is O and Y 3 is H, R 1, R 2 and R 3 are also H.”
“The term ‘pharmaceutically acceptable salt or prodrug’ is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a nucleoside compound which, upon administering to a patient, provides the nucleoside compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. The compounds of this invention possess antiviral activity against a Flaviviridae, or are metabolized to a compound that exhibits such activity.” 200. Section IV begins (at page 107 lines 21-30): “The active compound can be administered as any salt or prodrug that upon administration to the recipient is capable of providing directly or indirectly the parent compound, or that exhibits activity itself. Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as ‘physiologically acceptable salts’), and a compound, which has been alkylated, acylated, or otherwise modified at the 5’position, or on the purine or pyrimidine base (a type of ‘pharmaceutically acceptable prodrug’). Further, the modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the salt or prodrug and testing its antiviral activity according to the methods described herein, or other methods known to those skilled in art.” skilled in art.”
“The nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside. A number of nucleotide prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the mono-, di-or triphosphate of the nucleoside reduces polarity and allows passage into cells. Examples of substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischoferger, Antiviral Research, 1995, 27:1-17. Any of these can be used in combination with the disclosed nucleosides to achieve a desired effect.”
“The key starting material for this process is an appropriately substituted sugar with a 2'-OH and 2'-H, with the appropriate leaving (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 2CAN, NaOCI in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and Nbromosuccinimide. 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.”
“In vitro anti-viral activity was tested in the following cell lines: MT-4 for HIV; Vero 76, African green monkey kidney cells for SARS; BHK for Bovine Viral Diarrhea Virus; Sb-1 for poliovirus Sabin type-1; CVB-2, CVB-3, CVB-3, CVB-4, and CVA-9 for Coxsackieviruses B-2, B-3, B-4 and A-9; and REO1 for double-stranded RNA viruses. Note: BVDV = bovine viral diarrhea virus; YFV = yellow fever virus; DENV = dengue virus; WNV = West Nile virus; CVB-2 = Coxsackie B2 virus; Sb-1 = Sabin type 1 poliomyelitis virus; and REO = double-stranded RNA Reovirus. ”
“A compound of Formula (IX) or a pharmaceutically acceptable salt thereof, wherein: R 1, R 2 and R 3 are independently H; phosphate; straight chained, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; COalkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; sulfonate ester; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; or a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1, R 2 and/or R 3 are independently H or phosphate; X is O, S, SO 2 or CH 2; Base* is a purine or pyrimidine base; R 12 is C(Y 3)3; Y 3 is independently H, F, Cl, Br or I; and R 13 is fluoro.”
“The term ‘leaving group’ used in claim 1 is vague and unclear and leaves the reader in doubt as to the meaning of the technical feature to which it refers, thereby rendering the definition of the subject-matter of said claim unclear (Article 84 EPC).”
“In reply to the clarity objection raised by the Examining Division, and solely to expedite allowance of the present claims, the term objected to by the Examining Division has been deleted.”
“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 antiFlaviviridae 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 Lamino acid, preferably an L-amino acid.”
“A compound of Formula (IX) or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently H; phosphate; straight chained, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; COalkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; sulfonate ester; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; or a cholesterol; X is O; Base* is a purine or pyrimidine base; R 12 is C(Y 3)3; Y 3 is H; and R 13 is fluoro.”
“2. The compound of claim 1, wherein R 1 and R 2 are H. 5. The compound of any one of claims 1-4, wherein Base* is cytosine, uracil, guanine, adenine, or thymine. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a host infected with a Flaviviridae, virus. 7. The compound for use of claim 6, wherein the virus is hepatitis C. 21. A pharmaceutical composition comprising an effective amount to treat a Flaviviridae infection of a compound, or a pharmaceutically acceptable salt thereof, of any of claims 1 to 5 in a pharmaceutically acceptable carrier. 24. The composition of claim 21, wherein the Flaviviridae virus is hepatitis C.”
“straight chained, branched or cyclic alkyl” and “benzyl, wherein the phenyl group is optionally substituted with one or more substituents”
“I have read a copy of the report of Dr Glenn, in which he addresses the virology aspects of HCV. From the Medicinal Chemist’s perspective, research on nucleoside analogues against HCV infection started in the late 1990s. Around the beginning of the 2000s, certain 2'-modified nucleoside analogues were known to have anti-HCV activities. The research activity in the area is reflected in International Patent Application WO 01/90121 published on29 November 2001 which reports anti-HCV activities of 2'-methyl-up nucleoside analogues; and in WO 99/043691 published on2 September 1999 , which reports 2'-fluoro nucleoside analogues having anticancer activities and antiviral activities against several viruses including HCV. Further, other 2'-modified nucleoside analogues were reported to be active against other members of the Flaviviridae virus. For example, WO 01/92282 published on the6 December 2001 reports 2'-methyl-up nucleoside analogues showing antiviral activities against BVDV and YFV. The existence of these patents illustrates the type of work that was being undertaken with respect to 2'-modified nucleoside analogues as anti-Flaviviridae agents.”
“The NS5B gene product is the viral RNA-dependent RNA polymerase [65]. This enzyme is required for both of the RNA synthesis steps necessary for viral replication: the synthesis of the negative-stranded RNA intermediate, complementary to the viral genome, and the synthesis of positive-stranded RNA genomes complementary to the negative-stranded intermediate. Obviously, inhibition of this pivotal enzymatic activity would lead to suppression of the HCV replication in infected cells. The enzymatic reaction catalysed by NS5B, RNA-dependant RNA synthesis, is moreover a reaction not normally carried out in noninfected cells [119]. It is therefore possible that specific inhibitors of this enzyme could be found that block HCV replication with negligible associated toxicity.”
“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 265. (Fig 6, compound 13) was found to be phosphorylated in cultured cells and orally bioavailable in primates [133]. 266. Interestingly, the only nucleoside analogue that thus far was shown to be therapeutically useful against HCV infection is the broad-spectrum antiviral agent D-ribavirin …”
“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 HCVencoded 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.”
“The lack of a highly effective and safe treatment option for the hepatitis C virus (HCV) has spurred aggressive efforts to identify new, more effective therapies. The RNA-dependent RNA polymerase encoded by HCV, which is strictly required for viral replication, has been the focus of intense drug discovery activity. This is in large measure due to successes in targeting the polymerases from other viral systems, coupled with recent advances in experimental systems for studying the HCV polymerase. Both nucleoside and non-nucleoside inhibitors of HCV polymerase have been identified through the innovative use of new screening tools and rational drug design. Some of these compounds have encouraging profiles and could be further developed into therapeutics. Initiation of clinical trials in the near future promises to yield exciting new information on the ability of these compounds to achieve sustained responses in suppressing HCV replication.”
“The absence of a reliably efficacious cure for HCV infection has enticed numerous pharmaceutical companies to enter the frenzied sprint for compounds with superior efficacy and nominal toxicity. The result has been the identification of several compounds with the potential to inhibit various targets encoded by HCV, including the metalloprotease (NS2/3), the serine protease (NS3), the helicase (NS3) and a novel, highly conserved IRES [41●] that mediates cap-independent initiation of translation of viral proteins. However, a primary focus is currently on finding inhibitors of the NS5B polymerase, as is apparent from reviewing the numerous patents filed within the past year laying claims both to new compound entities and to new therapeutic utilities related to HCV treatment. These patents describe compounds that can logically be subdivided into the nucleoside and non-nucleoside inhibitors. These two classes generally differ in specificity, according to their mode of action. Nucleoside inhibitors directly compete with nucleoside substrates for binding to highly conserved active sites. Thus, these inhibitors generally exhibit broader spectrum activity against a class of polymerases. Greater specificity may be achieved by a non-nucleoside inhibitor, which may interact outside of the highly conserved active site at a unique allosteric site common only to structurally related polymerases.”
“The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is essential for the replication of viral RNA and thus constitutes a valid target for the chemotherapeutic intervention of HCV infection. In this report, we describe the identification of 2'-substituted nucleosides as inhibitors of HCV replication. The 5'-triphosphates of 2'-C-methyladenosine and 2'-O-methylcytidine are found to inhibit NS5B-catalyzed RNA synthesis in vitro, in a manner that is competitive with substrate nucleoside triphosphate. NS5B is able to incorporate either nucleotide analog into RNA as determined with gel-based incorporation assays but is impaired in its ability to extend the incorporated analog by addition of the next nucleotide. In a subgenomic replicon cell line, 2-C-methyladenosine and 2'-Omethylcytidine inhibit HCV RNA replication. The 5’- triphosphates of both nucleosides are detected intracellularly following addition of the nucleosides to the media. However, significantly higher concentrations of 2'-C-methyladenosine triphosphate than 2'-O-methylcytidine triphosphate are detected, consistent with the greater potency of 2'-Cmethyladenosine in the replicon assay, despite similar inhibition of NS5B by the triphosphates in the in vitro enzyme assays. Thus, the 2'-modifications of natural substrate nucleosides transform these molecules into potent inhibitors of HCV replication.”
“Any person who has duly filed in or for any State party to the Paris Convention for the Protection of Industrial Property, an application for a patent or the registration of a utility model or for a utility certificate or for an inventor’s certificate, or his successors in title, shall enjoy, for the purpose of filing a European patent application in respect of the same invention, a right of priority during a period of twelve months from the date of filing of the first application.” 326. Article 8 of the PCT provides: “(1) The international application may contain a declaration, as prescribed in the Regulations, claiming the priority of one or more earlier applications filed in or for any country party to the Paris Convention for the Protection of Industrial Property. (2)(a) Subject to the provisions of sub-paragraph (b), the conditions for, and the effect of, any priority claim declared under paragraph (1) shall be as provided in Article 4 of the Stockholm Act of the Paris Convention for the Protection of Industrial Property. (b) The international application for which the priority of one or more earlier applications filed in or for a Contracting State is claimed may contain the designation of that State. Where, in the international application, the priority of one or more national applications filed in or for a designated State is claimed, or where the priority of an international application having designated only one State is claimed, the conditions for, and the effect of, the priority claim in that State shall be governed by the national law of that State.” (2)(a) Subject to the provisions of sub-paragraph (b), the conditions for, and the effect of, any priority claim declared under paragraph (1) shall be as provided in Article 4 of the Stockholm Act of the Paris Convention for the Protection of Industrial Property. having designated only one State is claimed, the conditions for, and the effect of, the priority claim in that State shall be governed by the national law of that State.”
“Any person who has duly filed an application for a patent, or the registration of a utility model, or of an industrial design, or of a trademark, in one of the countries of the Union, or his successor in title, shall enjoy, for the purposes of filing in the other countries, a right of priority during the periods hereinafter fixed.”
“93. So art.4 specifies a person is to enjoy a right of priority if he has filed a relevant application for a patent or if he is the successor in title to such a person. Successor in title here must mean successor in title to the invention, as the parties before me agreed. Further, any person wishing to take advantage of the priority of such a filing must be required to make an appropriate declaration. 94. Both elements of art.4 are reflected in s.5 of the Act which requires a declaration made by the applicant which complies with the relevant rules and specifies one or more earlier relevant applications made by the applicant or a predecessor in title. 95. In my judgment, the effect of art.4 of the Paris Convention and s.5 of the Act is clear. A person who files a patent application for an invention is afforded the privilege of claiming priority only if he himself filed the earlier application from which priority is claimed or if he is the successor in title to the person who filed that earlier application. If he is neither the person who filed the earlier application nor his successor in title then he is denied the privilege. Moreover, his position is not improved if he subsequently acquires title to the invention. It remains the case that he was not entitled to the privilege when he filed the later application and made his claim. Any other interpretation would introduce uncertainty and the risk of unfairness to third parties. In reaching this conclusion I derive a measure of comfort from the fact that the Board of Appeal of the EPO has adopted the same approach to the interpretation of art.87 EPC in two cases: J19/87 and T62/05.”
“69. I would add that, even if it was not effective to convey the legal title to the invention, paragraph 3 of the Confidentiality Agreement was plainly effective to transfer the entire beneficial interest in the invention, including the right to file patent applications in respect of it, from Mr Lina to KC Inc. KC Inc would have been entitled to demand that Mr Lina convey the bare legal title to the invention to itself at any time, and to compel Mr Lina to do so if he failed or refused to do it. If necessary, I would hold that that was sufficient to make KC Inc Mr Lina’s ‘successor in title’ for the purposes of a claim to priority under Article 87(1) of the EPC and Article 4(A)(1) of the Paris Convention even if KC Inc had not acquired the bare legal title at the relevant date. 70. I am encouraged so to hold by the decision of the Legal Board of Appeal in Case J19/87 Burr-Brown/Assignment [1988] EPOR 350 that an assignment of an invention and a patent application from A to B with a covenant of further assurance was sufficient to entitle B to claim priority from an application filed by A even though the assignment of the patent application was ineffective because it was not signed by B contrary to section 30(6) of the 1977 Act as it then stood. In holding that the priority claim was a good one, the Board (two of whose members were Peter Ford, later His Honour Judge Ford, and Gerald Paterson, later the author of The European Patent System) accepted an opinion from English counsel (Nicholas Pumfrey, later Pumfrey J) stating that (i) the assignment of the invention (which post-dated the making of the invention) was effective in law even though the assignment of the patent application was not, and (ii) although the assignment was ineffective in law B had acquired an equitable interest in the patent application which was a proprietorial interest. Although it could well be argued that point (i) was enough, the Board seems to have regarded point (ii) as significant as well. 71. To my mind, this makes sense. 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 legal formalities, that matter.”
“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 or Alan 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.”
“Whenever an inventor refuses to execute an application for patent, or cannot be found or reached after diligent effort, a person to whom the inventor has assigned or agreed in writing to assign the invention or who otherwise shows sufficient proprietary interest in the matter justifying such action, may make application for patent on behalf of and as agent for the inventor on proof of pertinent facts and a showing that such action is necessary to preserve the rights of the parties or to prevent irreperable damage, and the Director may grant a patent to such inventor upon such notice to him as the Director deems sufficient, and on compliance with such regulations as he prescribes.”
“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 397. … 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. 400. … ARTICLE III GRANT OF RIGHT TO USE INTANGIBLE PROPERTY 401. … 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. 403. … 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. 406. …. ARTICLE VIII MISCELLANEOUS PROVISIONS 407. … 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. 409. ... 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. 411. …”
“Hepatitis C Virus (HCV) Project: Drug discovery in nucleoside analogs to treat HCV involving: A. Development and production of novel compounds; B. Assays, active and proposed, of compounds; C. Further evaluation of promising compounds using preclinical models.”
“Employee hereby assigns and agrees to assign to [Pharmasset Georgia], its successors, assigns, or designees, all of Employee’s rights to inventions …”
“2.4.2 … it has for long been a generally accepted legal principle that the extent of the patent monopoly should correspond to and be justified by the technical contribution to the art …. Now, whereas in both the above decisions this general legal principle was applied in relation to the extent of the patent protection that was justified by reference to the requirements of Articles 83 and 84 EPC, the same legal principle also governs the decision that is required to be made under Article 56 EPC, for everything falling within a valid claim has to be inventive. If this is not the case, the claim must be amended so as to exclude the obvious subject-matter in order to justify the monopoly. Moreover, in the Board’s judgment, it follows from this same legal principle that the answer to the question what a skilled person would have done in the light of the state of the art depends in large measure on the technical result he had set out to achieve. In order words, the notional ‘person skilled in the art’ is not to be assumed to perform a particular act without some concrete technical reason; he must, rather, be assumed to act not out of idle curiosity but with some specific technical purpose in mind.”
“… if the claimed compounds were to be assumed not to have any technically useful property, then it could be postulated that the technical problem which is solved by the claimed compounds … would be the minimalist one in such a situation, namely the mere provision of further (or alternative) chemical compounds as such, regardless of their likely useful properties.”
“… the Board holds that, contrary to the appellant's submission, the assessment of the technical contribution to the art must take account of the actual technical reason for providing the very compounds now being claimed, as distinct from the host of other theoretically possible modified chemical compounds. In this respect, the description (see page 3, lines 1 and 2) asserts that all claimed compounds do have herbicidal activity. Herbicidally active chemical compounds which are structurally similar to the claimed ones, since they are also triazole derivatives, are known from D3, D7 and D8 (see point 2.3.1 and 2.3.2 above). Any one of these documents may therefore serve as the 'closest state of the art' in the present case. In view of this state of the art the technical problem which the present patent application asserts to solve is the provision of further (alternative) chemical compounds with herbicidal activity. However, in the light of the Board's finding in point 2.4.3 above, this technical problem could only be taken into account if it could be accepted as having been solved, that is, if, in deciding the issue under Article 56 EPC, it would be credible that substantially all claimed compounds possessed this activity (see also point 2.5.4 above). Accordingly, the Board has examined whether this requirement is fulfilled.”
“2.6.2 In the present case, the appellant's submission that the test results contained in the description show that some of the claimed compounds are indeed herbicidally active cannot be regarded as sufficient evidence to lead to the inference that substantially all the claimed compounds possess this activity. The reason for this is that there is no proven common general knowledge to show that the type of substituent that may be present in the claimed compounds would be irrelevant to the existence of the alleged herbicidal activity. On the contrary, the Board accepts the appellant's own submission that the structural differences between the compounds disclosed, for example, in D3, D7 and D8 on the one hand, and the claimed compounds on the other hand, are such that a person skilled in the art would have been unable to predict on the basis of his common general knowledge that the claimed compounds would have herbicidal activity …., and that it can therefore be accepted as undisputed common general knowledge that even small structural modifications may cause major differences in biological activity. Nevertheless, it is also well accepted that the properties of chemical compounds do indeed largely depend on their chemical structure, and that a skilled person would therefore normally expect that the properties of two compounds would become the more similar the more similar their chemical structures became …. In view of all the above considerations, the Board finds that reasonable predictions of relations between chemical structure and biological activity are in principle possible, but that there is a limit beyond which no such prediction can be validly made. 2.6.3 In the Board's judgment, this limit has to be established on the basis of the available facts and the evidence submitted for this purpose in each particular case … … 2.6.5 In the tests which are reported on pages 37 to 40 of the description, a great number of compounds was used. However, in all these compounds R 1 was always either unsubstituted phenyl or 2-pyrimidinyl optionally substituted by methyl groups and R 3 was always phenyl substituted by halogen atoms or methyl groups. Thus, despite the number of tested compounds, these test results do not support the alleged herbicidal activity of compounds in which, for example, the phenyl ring in position R 3 may be substituted by absolutely anything, having regard to the common general knowledge relied on by the appellant himself, namely that the influence of structural modifications on the desired herbicidal activity is unpredictable. 2.6.6 Such an allegation is likewise not supported by the content of documents D3, D7 and D8, which all disclose classes of herbicidally active compounds with limited substitution possibilities (see point 2.3.1 and 2.3.2 above). 2.6.7 The appellant had been informed about the insufficiency of the evidence submitted by him in the present case, and had also been given ample opportunity either to restrict his claims to such a group of compounds for which the Board was prepared to accept the credibility of their alleged herbicidal activity (see point III above), or to provide further evidence, either by test results or by other means, that in the present case the kind of substitution of the phenyl ring R 3 is not relevant to the herbicidal activity. Despite these clear and helpful leads, which the Board was not obliged to afford, neither appropriate amendments nor further evidence were forthcoming. 2.7 For these reasons, and on the basis of what evidence there is in the case, the Board is not satisfied that substantially all compounds now being claimed are likely to be herbicidally active. Since, as set out above in points 2.4.2, 2.5.4 and 2.6, only those of the claimed chemical compounds could possibly involve an inventive step which could be accepted as solutions of the technical problem of providing further herbicidally active compounds, the subject-matter of the main request extends to compounds which are not inventive and therefore does not meet the requirement of Article 56 EPC.”
“8. Furthermore, as already mentioned above, members of the TGF-Beta superfamily share sequence homology. In the part of the application as filed describing the prior art related to the invention (page 2), it is disclosed that subgroups in the family had been defined according to the percentage of homology between members, the members of a given subgroup being from 70% to 90% homologous. Here, GDF-9 is very far from fulfilling this criteria as its sequence is stated to be significantly divergent from those of other family members (cf. page 28), the maximal percentage of homology which was observed being 34% with the bone morphogenetic protein, BMP-4. This implies that GDF-9 cannot be attributed to any subgroup and, thus, must at best be considered as the first member of a yet unidentified subgroup. This finding and that in point 7 lead to the conclusion that, contrary to GDF-1 in document (3), GDF-9 cannot be clearly and unambiguously identified as a member of the TGF-Beta superfamily by only using a ‘structural approach’. 9. Of course, the situation could most probably be looked at differently if it had been demonstrated in the application as filed that GDF-9 played a role similar to that of the transforming factor-Beta (as was the case for all of the factors which initially served to define the superfamily). Yet, there is no evidence at all in this respect. In fact, the application only discloses that expression of GDF-9 is localised in ovarian tissues, which per se is useful but insufficient information in relation to any function the molecule might have. 10. As already pointed out above (cf. point 8), in the application (page 28), it is admitted that ‘..., the sequence of GDF-9 is significantly diverged from those of other family members’. Yet, functions of members of the TGF-Beta superfamily previously isolated from ovarian follicular fluid (inhibins) or shown to inhibit ovarian cancer (MIS) are recited, and tentatively and presumptively attributed to GDF-9. Further putative roles are also suggested for GDF-9 which cover some of the effects observed with TGF-Beta (paragraphs bridging pages 8 and 9). At oral proceedings, it was argued that speculations of this kind should be permitted because of the ‘first to file approach’ of the European patent system which forced the applicant to cover any and all subject-matter connected with its invention. The board is unable to endorse this reasoning. On the contrary, in a first-to-file system the (earlier) filing date of the application, not the date at which the invention was made determines to whom of several persons having made an invention independently of each other, the right to a European patent belongs (cf. Article 60(2) EPC). Hence, it is particularly important in such a system that the application allows to conclude that the invention had been made, i.e. that a problem had indeed been solved, not merely put forward at the filing date of the application. Therefore, the issue here is rather how much weight can be given to speculations in the application in the framework of assessing inventive step, which assessment requires that facts be established before starting the relevant reasoning. In the board's judgment, enumerating any and all putative functions of a given compound is not the same as providing technical evidence as regard a specific one. 11. Accordingly, as a significant structural feature fails to be identical in TGF-9 and the members of the TGF- Beta superfamily, and no functional characterisation of TGF-9 is forthcoming in the application, it is concluded that the application does not sufficiently identify this factor as a member of this family i.e. that there is not enough evidence in the application to make at least plausible that a solution was found to the problem which was purportedly solved.”
“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 postpublished 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.”
“36. These cases are in my opinion far from the facts of this case. The specification did claim that a taxol coated stent would prevent restenosis and Conor did not suggest that this claim was not plausible. That would have been inconsistent with the evidence of its experts that taxol was just the thing to try. It is therefore not surprising that implausibility was neither pleaded nor argued. …. 37. The Court of Appeal upheld the judgment of Pumfrey J. on the ground that the patent contained no ‘disclosure’ saying that taxol was specially suitable for preventing restenosis. Again, I agree that the description, though offering a theory (its antiangiogenic properties) as to why taxol would prevent restenosis, did not offer any evidence that this would turn out to be true. If it had not turned out to be true, the patent would have been insufficient. But there is in my opinion no reason as a matter of principle why, if a specification passes the threshold test of disclosing enough to make the invention plausible, the question of obviousness should be subject to a different test according to the amount of evidence which the patentee presents to justify a conclusion that his patent will work.”
“50. … The EPO jurisprudence is founded firmly around a fundamental question: has the patentee made a novel nonobvious technical advance and provided sufficient justification for it to be credible? That is the basis of all the reasoning – see e.g. [2.4.2] of AgrEvo. A ‘selection’ (by which I mean the later claimed compound or sub-class) which makes a real technical advance in the art is patentable. 51. More specifically Mr Carr contended that a sub-class or individual member of a prior art published class was taken to be obvious if it was a random selection from the earlier published class. I have no difficulty with that. Such a ‘selection’ provides no technical contribution. Mankind can learn nothing from it. Nor indeed does Lilly dispute that proposition. It said in its skeleton argument: ‘Lilly does not dispute that in relation to obviousness a selection from the prior art cannot be merely arbitrary.’ 52. Of course one has to consider here what is meant by an ‘arbitrary selection’. The answer is to be found in the guiding principle – is there a real technical advance?”
“... the Board's approach in cases such as these is consistent and clear, and it is based on its general approach to patent validity on novelty and obviousness. There is nothing in the 1977 Act (any more than there was in the 1949 Act, it is fair to say) which recognises, or even implies, a special approach to, or even the existence of, selection patents as a special category of patent, which require a different approach when determining validity from other patents… ”
“Where it is suggested that a claimed invention is obvious as being an arbitrary selection, the key question is whether the specification ‘passes the threshold test of disclosing enough to make the invention plausible’ as Lord Hoffmann put it in Conor v Angiotech, that is to say, to make it plausible that the selection has the technical significance claimed for it.”
“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.”
“(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 would not quarrel with Jacob L.J.’s comment, after consulting the Shorter Oxford English Dictionary, that the sense [the word ‘plausibly’] conveys is that there must be some real reason for supposing that the statement is true: para. 111. The important point, however, is that the standard is not any higher than that.”
“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.”
“… 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.’”
“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.”
“Target 9 is an attempt to replace the tertiary OH of the ribo analogue with fluorine. We’ve tried a variety of procedures from the exocyclic methylene analogue in an attempt to effectively add HF across the double bond [cf. Strategies 1 & 2]. We had no success with that. We’re now looking at attempting to take the 2'- methyl anhydro compound and open that with fluoride. I'm not too hopeful for success with that. Appendix 3 shows a summary of this. Your thoughts on how to introduce the tertiary fluoro substituent in compound 9 would be appreciated.”
“…in our experience and indeed in that of manner other [sic] particularly the de Clerc group the most viable routes to fluoro nucleosides are by sugar/base condensation methods the anomer problem notwithstanding, for the very reasons you have discovered, in that the leaving groups generated in situ e.g. in DAST reactions are readily attacked by the pyrimidine ring nucleophiles or elimination and/or participation of blocking groups. Further migrations of groups can readily occur: see our papers in JFC 1993 62 145 and 1993 60 239. Having said this some of the route [sic] you have tried are OK except that I think you are using the wrong reagents, leaving groups and reaction conditions.”
“All the strategies that were attempted to introduce the methyl group at the 2'-‘up’ position and the fluorine atom at the 2'‘down’ position starting from different uridine derivatives failed. A ‘sugar strategy’ involving the synthesis of a 2'-methyl ‘up’-2'-fluoro ‘down’-ribofuranose derivative will be proposed.”
“You should not assume the experiments which were the subject of your notice are not in issue. To the extent to you wish to rely on the results obtained in the repeats or the original notice you will need to prove these experiments by serving appropriate evidence on 15 September.”
“This approach to the preparation of experimental evidence consisting, as it does, of presenting to the expert a fait accompli in the form of a completed experimental protocol is in my view always subject to the risk that it will be unhelpful, both in the general case and certainly in any case where anticipation by inevitable result is alleged. Indeed, it is difficult to conceive of any more effective way of leading an expert witness than to place in front of him a protocol for the performance of an experiment and ask a question of the form: That is all right, is it not?”
“… it must be understood that if relevant questions do arise as to how experiments were designed and how they came to be conducted as they were, and if the witnesses attending court are unable to address such questions, then the weight which the court can attach to the experiments may be substantially reduced.”
“The major synthetic challenge for the synthesis of the 2deoxy-2-fluoro-2-C-methyl-D-ribofuranoses (8-12) is the stereoselective introduction of the fluorine atom at the 2position. In the initial synthetic planning, the number of literature examples describing the nucleophilic fluorination of tertiary alcohols, particularly those desiring stereospecificity, were scarce. Of the few literature examples that describe the nucleophilic fluorination of tertiary alcohols, both inversion 10 and retention of configuration 11 were reported. For the synthesis of methyl 3,5-di-O-benzyl-2-deoxy-2-fluoro-2-Cmethyl-β-D-ribofuranoside (8), it was reasoned that the carbohydrate starting material, methyl 3,5-di-O-benzyl-2-Cmethyl-β-D-arabinofuranoside (7), would not only serve to introduce the fluorine in the ribose configuration, but also minimize the number of stereocentres requiring assembly.”
“Hydrogen fluoride does not generally convert alcohols to alkyl fluorides.1156 The most important reagent for this purpose is the commercially available diethylaminosulfur trifluoride (Et 2NSF 3) (DAST),1157 which converts primary, secondary, tertiary, allylic, and benzylic alcohols to fluorides in high yields under mild conditions.1158”
“To sum up, primary and secondary substrates generally react by the SN2 mechanism and tertiary by the SN1 mechanism. However, tertiary substrates seldom undergo nucleophilic substitution at all. Elimination is always a possible side reaction of nuclephilic substitutions (wherever a β hydrogen is present), and with tertiary substrates it usually predominates. With a few exceptions, nucleophilic substitutions at a tertiary carbon have little or no preparative value.”
“Q. … What else do you think the skilled man would understand to be of scientific value in [the application] that you can identify? A. The reasoning on this patent, and on the patent in general, is that very often the essence of the patent is in the claims. So clearly the good idea is there to be protected. If we have to look for science and want to know where the science – to start to look for science we have to start from the claims and I think within the claims to the more specific claims. That is what I said in the report. We have to look at the more specific claims because that is where we might find the actual needle in a haystack where the meat is in these ones. Then you can probably work your way around the patent and try to understand the connection there in terms of the science that it can offer -- well, what science is there to support it in terms of references maybe or in terms of data, if there is any data.”
“A Community patent shall also confer on its proprietor the right to prevent all third parties not having his consent from supplying or offering to supply within the territories of the Contracting States a person, other than a party entitled to exploit the patented invention, with means relating to an essential element of that invention, for putting it into effect therein, when the third party knows, or it is obvious in the circumstances, that these means are suitable and intended for putting that invention into effect.”