2015 FC, 2015 FC 1156

Date: 20151102 Docket: T-1156-12 Citation: 2015 FC 1156 Ottawa, Ontario, November 2, 2015 PRESENT: The Honourable Mr.

Justice Annis BETWEEN: GILEAD SCIENCES, INC AND GILEAD SCIENCES CANADA, INC Plaintiffs (Defendants to the Counterclaim) and IDENIX PHARMACEUTICALS, INC, UNIVERSITA DEGLI STUDI DI CAGLIARI, L'UNIVERSITÉ MONTPELLIER II AND CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE Defendants AND BETWEEN: IDENIX PHARMACEUTICALS, INC, Plaintiff to the Counterclaim and GILEAD PHARMASSET LLC, GILEAD SCIENCES, INC, AND GILEAD SCIENCES CANADA, INC Defendants to the Counterclaim AND UNIVERSITA DEGLI STUDI DI CAGLIARI, L'UNIVERSITE MONTPELLIER II AND CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE Third Parties to the Counterclaim PUBLIC JUDGMENT AND REASONS (Confidential Judgment and Reasons issued October 9, 2015) I.

Introduction [ 1 ] Gilead Sciences, Inc and Gilead Sciences Canada, Inc, (together with the Defendant by counterclaim Gilead Pharmasset LLC, hereinafter referred to collectively as [ Gilead ] , seek a declaration that Canadian Patent No 2,490,191 [ the ‘191 Patent ] is invalid.

They initiated the claim as interested persons under section 60 (1) of the Patent Act , RSC 1985, c P-4, as amended, s 27 [ the Act ] . [ 2 ] The Defendant, Idenix Pharmaceuticals Inc [ Idenix ] and the other defendants in the main action are the owners of the ‘191 Patent. [ 3 ] Gilead Sciences, Inc through its subsidiary, Gilead Pharmasset LLC, is the owner of Canadian Patent 2,527,657 [the ‘657 Patent] filed on April 21, 2004 and issued June 14, 2011.

The ‘657 Patent includes claims to a novel compound, “sofosbuvir”, for the treatment of Hepatitis C viral infections. [ 4 ] Gilead claims to be an interested person as having a reasonable basis to believe that the manufacture, use or sale of sofosbuvir would be impugned by the Defendants as an infringement of the ‘191 Patent. This has proved an accurate assumption, as evidenced in this matter by the counterclaim of Idenix. [ 5 ] Gilead Sciences Canada, Inc filed a New Drug Submission for sofosbuvir on or about May 21, 2013.

Sofosbuvir was approved for sale in Canada through the issuance of a Notice of Compliance on December 13, 2013. Gilead Sciences Canada, Inc now sells sofosbuvir in Canada under the brand name SOVALDI.

[ 6 ] SOVALDI is a “revolutionary” drug. It represents a significant breakthrough in the treatment of the Hepatitis C virus [ HCV ] , which is said to infect more than 2.2% of the world’s population. It is an oral treatment that is highly effective with few side effects when compared with other treatments. [ 7 ] Gilead seeks to invalidate the ‘191 Patent on the grounds of insufficient disclosure, lack of demonstrated utility/sound prediction and overbreadth.

It does so on the basis that Idenix has claimed a huge number of compounds and their use which lack sufficient disclosure, utility on any basis in the specification of the’ 191 Patent, or in light of the common general knowledge at the relevant date. Idenix filed its patent application before it had made or tested any compound within the ‘191 Patent’s scope, despite more than 18 months of effort to do so. [ 8 ] Conversely, Idenix claims to be the inventor of the novel nucleoside inhibitor that provides the anti-viral activity in sofosbuvir.

It advances the claim, in part, on the basis that the novel nucleoside was an analogue of one of its earlier inventions. [ 9 ] It denies the claim that its inventors did not soundly predict the utility of the novel nucleoside in sofosbuvir. It notes that the novel nucleoside is differentiated by only one substituent with similar stereochemical characteristics to that disclosed in Idenix’s earlier invention, which has demonstrated antiviral activity. [ 10 ] Idenix also denies that the ‘191 Patent does not disclose how to make the novel nucleoside. It claims that the synthesis of the compound was not novel.

Based upon the disclosure in the ‘191 Patent, it could be made by the chemist of ordinary skill in the art, having recourse to the common general knowledge and routine experimentation. It claims the named inventor of the ‘657 Patent synthesized the novel compound with little difficulty, whereas the Idenix chemist assigned the task, similarly made the compound, but without knowing so because he was not acting like a skilled discovery chemist, but rather a process chemist. [ 11 ] Idenix counterclaims that the novel nucleoside in sofosbuvir was anticipated by the ‘191 Patent.

It seeks a declaration that the ‘657 Patent is invalid and that Gilead has infringed certain claims of their patent, along with other remedies of a permanent injunction, damages etc. Idenix has no product, either on the market or pending authorisation by Health Canada, which is covered by the ‘191 Patent. [ 12 ] Idenix argues in the alternative, that to the extent that it does not have priority of a valid invention, the ‘657 Patent is invalid under

section 53 of the Act for knowingly omitting naming Lieven Stuyver as an inventor; a misrepresentation that it claims was made willfully for the purpose of misleading. [ 13 ] After careful consideration of the evidence and submissions of the parties, for the reasons that follow, I allow Gilead’s claim. I declare the ‘191 Patent to be invalid and dismiss Idenix’s counterclaim in its entirety. II. Background Facts A. Idenix and its Patents [ 14 ] Idenix is a pharmaceutical company founded in the late 1990s.

It was interested in discovering, developing and commercializing innovative therapeutics in areas of unmet medical needs. [ 15 ] Idenix had collaboration agreements with the Universita Degli Studi Di Cagliari [ Cagliari ] , L’Université Montpellier II [ Montpellier ] , and Centre National de la Recherche Scientifique [ CNRS ] .

In particular, Idenix established with Montpellier and CNRS a collaborative chemistry laboratory located in Montpellier, France that was overseen by Dr Gilles Gosselin (an employee of CNRS) and by Dr Richard Storer, Idenix’s Executive Director of Chemistry. [ 16 ] Idenix also established with Cagliari a collaborative biological testing laboratory located in Cagliari, Italy that was overseen by Professor Paolo La Colla of Cagliari. [ 17 ] On November 29, 2001, WO 01/90121 [ US ‘121 ] was published disclosing the D-ribose 2’-Methyl (up), 2’-Hydroyl (down) [hereinafter referred to as “2’-C-Me/OH”] nucleoside structures and derivatives for antiviral activity against HCV.

On December 6, 2001, WO 01/92282 [ US ‘282 ] was published similarly disclosing the 2’-C-Me/OH structures for antiviral activity against flaviviruses and pestiviruses. These compounds were the precursors that led to the development of the claimed novel invention, which claims coverage for D-ribose 2’-Methyl (up), 2’- Fluorine (down) [hereinafter referred to as “2’-C-Me/F”] nucleoside structures and their derivatives. [ 18 ] On June 28, 2002, Idenix filed US application 60/392,350 [ US ‘350 ] and US Patent Application 60/392351 [US ‘351], both of which are referred to in the ‘191 Patent.

US ‘350 contained, among its extensive claimed compounds, 2’-C-Me/F compounds. Conversely, the US ‘351 omitted reference to any 2’-C-Me/F compounds. US ‘351 is no longer relied upon by Idenix as a priority application for the ‘191 Patent. [ 19 ] On 31 March 2003, it was announced that Novartis was to acquire a majority stake in Idenix, together including the right to jointly develop its 2’-C-Me/OH nucleoside candidate NM283 to treat HCV. [ 20 ] On April 28, 2003, Idenix filed the US application 60/466,194 [ US ‘194 ] . On May 14, 2003, Idenix filed US application 60/470,949 [ US ‘949 ] .

Both are priority applications for the ‘191 Patent. [ 21 ] On June 27, 2003, Idenix filed a Patent Cooperation Treaty [ PCT ] Patent Application for its Canadian Patent ‘191, naming the academic institutions as co-proprietors of the Patent. They claimed several broad genera of nucleoside alleged analogues of the 2’-C- Me/OH nucleoside. However, of its 49 claims, 32 of the claimed analogues were for 2’-C-Me/F compounds. The application was based on priority documents: US ‘350, US ‘351 (no longer relied upon) US ‘194 and US ‘949.

[ 22 ] On or about September 22, 2008, the Canadian Intellectual Property Office [ CIPO ] issued a Requisition objecting to the ‘191 Patent Application because of; inter alia , a lack of unity of invention. Regarding the various genera claimed by Idenix, the examiner identified 15 different classes of compounds.

The examiner requested that Idenix restrict the claims of the patent application to one class of compounds. [ 23 ] On March 23, 2009, Idenix submitted amended claims to the CIPO deleting 17 of the claims and narrowing the scope to one class of “Formula IX” compounds, consisting of 32 claims of the 2’-C-Me/F genus.

These became the claims to the ‘191 Patent as finally issued on August 3, 2010 and which are similar to the claims of compounds covered by the ‘657 Patent of Gilead. [ 24 ] In amending its claims, Idenix did not remove the extensive information relevant to the 2’-C-Me/OH nucleosides that are no longer relevant to the 2’-C-Me/F nucleosides. As a result, the ‘191 Patent as issued on its face is a highly confusing document.

In addition, the ‘191 Patent discloses no information with respect to the fluorination step to create the 2’-C-Me/F nucleoside, as Idenix never succeeded in synthesizing the compound, to its knowledge at least, prior to filing its application. [ 25 ] During this litigation, Idenix amended its statement of defence “solely for Canada and for the purpose of simplifying the issues to be determined at trial in this proceeding in Canada, without making any admission” , to state that “Idenix will not be defending nor asserting a claim of infringement in respect of Claim 1 of the ‘191 Patent.” The effect of this amendment is a matter of contention in this dispute.

B. Initial Development of the 2’-C-Me/OH Compounds by Idenix [ 26 ] Up to late 2004, the Montpellier site conducted all of Idenix’s discovery chemistry efforts, while the Cagliari site carried out most of the biological testing (viral screening). Starting in 2004, Idenix’s facilities in Cambridge, Massachusetts also conducted process chemistry and development biology work. [ 27 ] In the late 1960’s scientists developed a class of 2’-C-Me/OH nucleosides.

In the early 2000s, Idenix discovered that some known nucleoside analogues, which have a 2’-C-Me/OH structure, had activity in in vitro [performed in the laboratory] assays of certain Flaviviridae viruses. Idenix filed patent applications US ‘121 and US ‘282 in respect of these compounds. One of these compounds (known as NM283) was a prodrug of a nucleoside analog having a 2’-C-Me/OH sugar ring and cytosine base. [ 28 ] Idenix (then Novirio) held a chemistry retreat in Maui in December 2001.

Dr Gosselin, Professor La Colla, Dr Sommadossi, Dr Standring and Dr Storer attended, along with the members of its chemistry discovery team. Among other subjects discussed at that meeting, the Idenix chemists identified several nucleoside analogues of the 2’-C-Me/OH compounds that they would attempt to synthesize, one of which was the 2’-C-Me/F nucleoside. [ 29 ] On March 28, 2002, Idenix assigned the synthesis of the 2’-C-Me/F nucleosides to Dr Jean François Griffon, a chemist located in Montpellier who had previous experience with fluorination of nucleosides.

Dr Griffon and his team, which included Ms Audrey Chappe and Ms Elodie Pecheux, attempted to make 2’-C-Me/F nucleosides for two years without success. [ 30 ] Dr Alistair Stewart and Jingyang Wang, Idenix chemists located in Cambridge Massachusetts, continued to work on the synthesis of the 2’-C-Me/F compounds in late 2004-early 2005. They claim to have succeeded in or around January 2005 at a time when Idenix had received information from a former Pharmasset employee about its successful synthesis of the 2’-C-Me/F compound. Idenix clearly successfully synthesized the 2’-C-Me/F nucleoside in March 2005.

Idenix did not test a 2’-C-Me/F nucleoside until March 2005, after the publication date of the Gilead ‘657 Patent. [ 31 ] Idenix contends that Dr Griffon was responsible for its inability to demonstrate that it had successfully synthesized the 2’-C- Me/F compound. It argues that he did not meet the standards of a skilled discovery chemist in many respects. [ 32 ] Idenix contends that he succeeded in synthesizing a 2’-C-Me/F nucleoside without knowing it.

It argues that Albany Molecular Research Inc. [ AMRI ] synthesized the molecule in tests it carried out in 2014 using the same intermediate compound, fluorination reagent, Deoxo-Fluor®, and conditions followed by Dr Griffon during his February 2003 experiments. [ 33 ] Idenix argues that because Dr Griffon did not characterize the products of the reaction he failed to realize his success.

It adds that because Dr Griffon misrepresented to his superiors that only one new compound was formed during the experiment, which was not the target compound, it then failed to pursue the most obvious and only known methodology that could successfully synthesize the 2’-C- Me/F nucleoside. C.

Gilead Parties and their Patents [ 34 ] Gilead Sciences Inc is an American biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. [ 35 ] Gilead Sciences Canada, Inc [ Gilead Canada ] is a wholly owned subsidiary of Gilead Sciences Inc Gilead Canada sells pharmaceuticals in Canada for use in the treatment of diseases such as HIV, cystic fibrosis and Hepatitis. [ 36 ] Pharmasset Inc, under different changing names and country of origin, was a small biopharmaceutical company formed in the late 1990s.

Its mandate was to discover and develop new compounds for the treatment of HIV, Hepatitis B virus [HBV] and HCV. [ 37 ] On 30 May 2003, Pharmasset filed US Provisional Patent Application 60/474,368 [US ‘368] for a 2’-C-Me/F compound, supported by replicon testing data showing anti-viral activity. [ 38 ] On 21 April 2004, Pharmasset filed the Pharmasset PCT application W0 2005/003147 claiming priority from US ‘368. It was

subsequently published on January 13, 2005 [W0 Clark]. The US ‘368 application and the Pharmasset PCT disclose, inter alia , the synthesis of a 2’-C-Me/F cytosine compound and the activity of this compound against HCV in a replicon assay. This synthesis was subject matter of a paper by Clark et al, Design, Synthesis and Antiviral Activity of 2'-Deoxy-2'-fluoro-2'-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication , J. Med.

Chem., 48, 5504-5508 (2005) [the Clark Paper]. [ 39 ] On June 14, 2011, after extensive testing and trials, the Canadian‘657 Patent was issued. [ 40 ] In November 2011, Gilead Sciences Inc purchased Pharmasset. Following the acquisition, Pharmasset became known as Gilead Pharmasset LLC. As noted, Gilead Pharmasset LLC is the current owner of the ‘657 Patent. [ 41 ] Gilead filed its statement of claim on June 15, 2012, with Idenix filing its defence and counterclaim on November 19, 2012. The parties have since amended their pleadings on several occasions. D.

Pharmasset Synthesizes the 2’-C-Me/F Nucleoside [ 42 ] During the 2003 period when Idenix was attempting to synthesize the 2’-C-Me/F compound, Pharmasset was engaged in a similar endeavor. According to Dr Patterson, one of the chemists working with Pharmasset at the time, he believed that Pharmasset set about synthesizing 2’-C-Me/F compounds after Jeremy Clark, a recently hired chemist, discovered that either Idenix’s US ‘121 or US ‘282 Patent omitted them from their coverage. Pharmasset chemists thereafter identified the patent with the omission in coverage as the “Idenix” Patent.

Dr Stuyver claims that he found the omission of coverage for the 2’-C-Me/F compound in an Idenix patent which partly qualifies him a co-inventor. [ 43 ] Dr Patterson testified that, Mr Clark, having found the coverage omission in the Idenix patent, was assigned the task of attempting to synthesize the 2’-C-Me/F compound. After a few months of effort, in or around May 2003, Mr Clark succeeded in making the 2’-C-Me/F nucleoside with a cytidine base (identified as PSI-6130).

Pharmasset biologists, overseen by Lieven Stuyver, tested PSI- 6130 and found it to have anti-HCV activity. [ 44 ] On or about May 30, 2003, following the testing of PSI-6130, Pharmasset filed the US ‘368 Application in respect of 2’-C- Me/F nucleosides. The US ‘368 application included no claims. It named Jeremy Clark and Lieven Stuyver as the inventors. E.

Dr Stuyver Contests his Removal from the Pharmasset Patent [ 45 ] On April 21, 2004, Pharmasset filed the PCT application for the ‘657 Patent naming only Jeremy Clark as the inventor. [REDACTED] [ 46 ] Dr Stuyver contends that he found the omission in the Idenix patent and that he gave Mr Clark the idea of synthesizing the 2’- C-Me/F compound based on his work in other patents involving fluorine at the 2’ (down) position. He claims that Pharmasset removed his name out of spite because he left to move back to Europe and that he signed the declaration under duress, applied by Dr Otto. III. The Witnesses A.

Expert Witnesses

(1) Gilead’s Experts [ 47 ] Gilead called three experts to testify at trial: a nucleoside chemist (Dr Wnuk), a virologist (Dr Seeger) and a pharmaceutical scientist (Dr Krise). (

a) Dr Stanislaw Wnuk [ 48 ] Dr Wnuk is a Professor of Chemistry at Florida International University, a position he has held since 2002. Dr Wnuk obtained a PhD in organic chemistry from Mickiewicz University in Poznan, Poland. From 1985 until 1986, he completed postdoctoral research at the University of Alberta, specializing in the synthesis of modified nucleoside analogues and novel fluorination reactions. Dr Wnuk has worked in the area of nucleoside chemistry, including fluorination of nucleosides, for thirty years.

Dr Wnuk is an author of over 180 publications, 80% of which relate to nucleosides or nucleotides, and 30% of which relate to fluorination. [ 49 ] Dr Wnuk is qualified by the Court to provide expert opinion evidence in the following areas: organic chemistry, medicinal chemistry and nucleoside chemistry; synthesis of nucleosides, nucleotides, fluorothioethers, and analogues thereof; fluorination methodologies to synthesize fluorinated nucleosides; developing methods for the fluorination of thioethers, alcohols, sugars, nucleosides and nucleotides, including methods for the introduction of fluorine at the 5’ and 2’ positions of purine and pyrimidine nucleosides; and analytical and purification methods used in the synthesis of organic compounds. (

b) Dr Christoph Seeger [ 50 ] Dr Seeger has been a Professor of Virology in the Department of Microbiology at the Fox Chase Cancer Center since 1990. Dr Seeger obtained a PhD in Microbiology from the University of Basel in 1982, focusing on the study of retroviruses. Dr Seeger’s laboratory has produced cell lines that are used to study the lifecycle of Hepatitis B and Hepatitis C viruses and screen for antiviral compounds. Dr Seeger’s laboratory was the second in the United States and the third worldwide to publish on the HCV replicon assay and its use to evaluate and screen antiviral compounds. Dr Seeger’s work has been funded for over thirty years by the National Institues

of Health and his publications have been cited over 3500 times.

Dr Seeger has more than thirty years’ experience in research in the field of virology, including extensive experience studying the HCV. [ 51 ] Dr Seeger was qualified to provide expert opinion evidence in the following areas: molecular biology and virology with an emphasis on human pathogenic viruses including Hepatitis viruses (Hepatitis B virus, Hepatitus C virus) and relevant animal model systems belonging to the Hepadnaviridae and Flaviviridae family of viruses, assessment of usefulness of nucleosides and nucleotides for the treatment of infections caused by these viruses, model systems and cell lines for screening antiviral compounds, including enzyme assays, plaque assays, cell-based assays, replicon assays, and high-throughput screens for the discovery and development of antiviral compounds,

interpretation of results from in vitro assays and animal studies to assess the activity and toxicity of antiviral compounds. (

c) Dr Jeffrey Krise [ 52 ] Dr Krise is an Associate Professor of Pharmaceutical Chemistry at the University of Kansas. His research focus is on the optimization of drug properties in order to maximize the drug’s therapeutic usefulness. Dr Krise completed his undergraduate degree in Pharmacy in 1993 and obtained his PhD in Pharmaceutical Chemistry with Honours in 1998 at the University of Kansas under the tutelage of Valentino Stella, a foremost expert in prodrugs.

Dr Krise synthesized, evaluated, and wrote papers on a novel prodrug approach that employed phosphates for improving water solubility barriers of drugs. Dr Krise was qualified to provide expert opinion evidence in the following areas: pharmaceutical sciences; pharmacokinetics (absorption, distribution, metabolism and elimination); drug formulation; prodrugs, including nucleoside and nucleotide prodrugs; metabolism of sofosbuvir; and drug discovery and development. Dr Krise was the only prodrug expert to testify in this case.

(2) Idenix’s Experts [ 53 ] Idenix called three experts to testify at trial: a chemist (Dr Damha); a second chemist (Dr Barrett); and a virologist (Dr Lamarre). (

a) Dr Masad Damha [ 54 ] Dr Damha is Chair of the Chemistry Department and James McGill Professor of Chemistry at McGill University, previously serving as Professor of Chemistry and other positions in the Chemistry Department at McGill since 1992. He has been Director, Graduate Program, Department of Chemistry, 2000-2004, 2006-2008, and 2010.

He holds senior positions in various societies including President, Oligonucleotide Therapeutics Society, Board of the International Society of Nucleosides, Nucleotides & Nucleic Acids; sits on editorial advisory boards; and is the recipient of various scientific awards and honours. He has published approximately 155 papers in peer-reviewed journals and book chapters, many of which include the synthesis of nucleoside analogues.

He has made more than 80 invited presentations at national and international meetings in the area of bio-organic chemistry, including the synthesis of nucleosides, nucleotides and oligonucleotides. He was an organizer of the 2012 International Roundtable on Nucleosides, Nucleotides and Nucleic Acids in Montreal. [ 55 ] Dr Damha was qualified to provide expert opinion evidence in the following areas: medicinal chemistry and bio-organic chemistry, including the design, synthesis and analysis of nucleosides and nucleoside analogues for use as antiviral agents including via prodrug strategies. (

b) Dr Anthony Barrett [ 56 ] Dr Barrett is the Glaxo Professor of Organic Chemistry and the Director of the Wolfson Centre for Organic Chemistry in Medical Science in the Department of Chemistry at Imperial College of Science, Technology and Medicine [ IC ] in London, England. He is also the Sir Derek Barton Professor of Synthetic Chemistry and Head of the Synthesis

Section in the Department of Chemistry at IC. He is a Fellow of the Royal Society and a fellow of the Academy of Medical Sciences. He trained 127 PhD graduate students and 192 postdoctoral research associates in connection with a variety of research topics in the organic chemistry field, including synthetic organic chemistry and medicinal chemistry. He has published 408 peer-reviewed articles relating to various aspects of organic chemistry. These include 29 publications on the synthesis of carbohydrates and nucleosides, which appear relevant to these proceedings.

He is the recipient of prizes from various organizations such as the Royal Society of Chemistry and the American Chemical Society for his contributions to organic chemistry. [ 57 ] Dr Barrett was qualified to provide expert opinion evidence in the following areas: organic and medicinal chemistry, including the synthesis in nucleosides and carbohydrates, analytical chemistry techniques and procedures as used in synthetic chemistry, including the techniques used in the

interpretation of the results received and the standard laboratory practices of synthetic chemists. (

c) Dr Daniel Lamarre [ 58 ] Dr Lamarre is Professor of Biochemistry and a director of the Molecular Research Laboratory lmmunovirology at Université dé Montreal. He previously held a number of senior research-based positions at Boehringer Ingelheim, in Laval Québec, with a focus on HCV and the discovery of antiviral compounds. He has held numerous fellowships, awards, and research chairs. He supervised three separate teams of approximately 25 scientists in a screening for biological activity of molecules against HCV via inhibition of the NS3 protease, NS3 helicase, and NS5B polymerase.

He has been involved in several important discoveries, including the antiviral drug, ciluprevir and the discovery and development of other significant HCV/HIV drug candidates. [ 59 ] Dr Lamarre was qualified to provide expert opinion evidence in the following areas: in biochemistry with a particular expertise in virology, industrial drug discovery and development, and structure-based rational drug design. His expertise includes a specific focus in HCV and the Flaviviridae family of viruses.

(3) Comments on the Witnesses [ 60 ] As between the nucleoside synthesis witnesses, Gilead submitted that Dr Wnuk is the only expert in this case who is qualified to give opinion evidence in the area of fluorine chemistry. Conversely, they argued that neither Dr Damha nor Dr Barrett is qualified by the Court to provide expert opinion evidence in relation to fluorine chemistry or the fluorination of nucleosides. [ 61 ] I would disagree that neither Dr Damha nor Dr Barrett is qualified to speak to the topic of chemical fluorination of nucleosides.

It is apparent however, that Dr Wnuk focused his career on the synthesis of nucleosides, including an extensive amount of time dealing with the fluorination of nucleosides. I weigh this as a factor in the evidence of the contending experts that favours Gilead with respect to the fluorination issues. [ 62 ] Gilead further submits that Dr Wnuk is the only expert who had personal experience with fluorination during the relevant period and is therefore qualified to express an opinion on this topic from first-hand experience in the 2003-4 period. This appears to be an accurate assessment.

Dr Barrett acknowledged that the chemistry at issue in this case was not of interest to him at the relevant time. Similarly, Dr Damha did not have experience with the fluorination of nucleosides in the 2003-4 period. [ 63 ] This is a fair submission, as there is an advantage to having an expertise in fluorination of nucleosides at the relevant time.

This is particularly germane in being able to describe the limits of common general knowledge on the subject matter and the nature of experimentation at the time, as opposed to providing opinions based on ex post facto reviews of written materials provided to the witnesses or obtained through searches conducted a decade after the events. [ 64 ] Gilead was also critical of both Dr Damha and Dr Barrett concerning the superior qualities they attributed to the skilled chemist. Dr Damha testified that the skilled person had problem-solving and reasoning skills that would not be uncreative.

He attributed this to the fact that by the time they graduate these persons would have made a contribution to some aspect of the knowledge in the field. [ 65 ] I agree with Gilead’s submission that this view could lead to a greater attribution of knowledge and skills than the imaginary skilled chemist would possess.

This requires restraint in some areas when relying on Dr Damha’s opinions about the skilled chemist’s achievements in the synthesis of new compounds. [ 66 ] I find that Dr Barrett similarly overreaches in describing the basic skills of the person skilled in drug discovery, testifying that he or she was “brilliant at reactions, but not inventive” .

The superior laboratory skills attributed to the person of ordinary skill in the art [POSITA/ skilled chemist] by Dr Barrett diminishes somewhat the weight I attribute to his opinion of the skilled person’s ability to synthesize compounds by trial and error experimentation. I also take this into account in tempering the high degree of obviousness that Dr Barrett portrays in synthesizing the 2’-C-Me/F compound and the contrasting harsh criticisms he has of Dr Griffon’s work in his failed attempts to synthesize the target compound. [ 67 ] I make a few comments where I find that the witnesses are overreaching.

Overall, I did not find that their cross-examination played much of a role in the trial. I preferred different witnesses on different issues, based on the content and depth of support for their opinions, rather than how they testified. I also tended to give more weight to the evidence of the witnesses who were involved in the events in 2003-4, when in conflict with the opinions of the experts. B. Fact Witnesses

(1) Gilead’s Fact Witnesses [ 68 ] Gilead did not lead evidence from any fact witnesses in respect of the main claim, but relied on admissions and read-ins from the discovery process. I also gave leave to Gilead to file foreign testimony from a former Idenix chemist, Dr Alistair Stewart. Gilead called one fact witness (Dr Otto) in respect of Idenix’s counterclaim contesting inventorship. (

a) Dr Alistair Stewart [ 69 ] Dr Stewart was the Director of Chemistry, Manufacturing and Controls at Idenix in Cambridge, Massachusetts. Dr Stewart received a PhD in Organic Chemistry from the University of Oxford in 2003, having studied under Professor George Fleet. Dr Stewart joined Idenix in September 2003 as a Research Scientist 1 in the Process Chemistry group. Dr Stewart worked on a project to make 2’-C- Me/F nucleosides from mid-2004 to early 2005, and oversaw the work of Ms Jingyang Wang. Dr Stewart was not called to testify at trial.

However, after hearing parties on a motion in writing, I gave leave to Gilead to file Dr Stewart’s witness statement and related cross- examination transcript from the U.K. Proceeding as evidence in this trial. I provide my reasons for doing so when considering Idenix’s efforts to synthesize the 2’-C-Me/F compounds and the related evidence of Ms Wang from the UK proceedings, which was admitted on consent. (

b) Dr Michael J. Otto [ 70 ] Dr Otto was the Chief Scientific Officer at Pharmasset Inc from 1998 to 2012. His role was to direct the chemistry and biology program, coordinate research efforts, and run the development program for an HIV drug. He holds a PhD in Microbiology from the Medical College of Wisconsin. Dr Otto testified as to the discovery of PSI-6130, the filing of patent applications for PSI-6130, and his recollection of events in respect to allegations made by Dr Lieven Stuyver concerning Dr Stuyver’s alleged role in the discovery of PSI-6130 as one of its inventors.

(2) Idenix’s Fact Witnesses [ 71 ] Idenix called six fact witnesses to testify at trial (Drs Standring, Griffon, Patterson, Clemens, Stuyver, and Professor La

Colla). The parties agreed to the admission of foreign testimony from a seventh witness, Ms Wang in lieu of viva voce evidence at trial. (

a) Dr David Standring [ 72 ] Dr Standring holds a PhD in Bio-organic Chemistry from Harvard University. He was employed by Idenix Pharmaceuticals Inc. in Cambridge, MA in a variety of senior management positions from 2000 until his departure from the company in 2013. Dr Standring is not a listed inventor on the ‘191 Patent. He was not involved in the chemistry in respect of the compounds at issue. (

b) Professor Paolo La Colla [ 73 ] Professor La Colla is a Professor of Microbiology at Cagliari. Professor La Colla acted as the Director of the Department of Biomedical Science and Technology at the University of Cagliari from 2002 to 2008. He oversaw the collaborative work done at the University of Cagliari between the University of Cagliari and Idenix Pharmaceuticals Inc in respect of testing anti-HIV, anti-HBV and anti-HCV compounds. Professor La Colla did not make any decisions in respect of which compounds to test and had no involvement with the synthesis of the compounds.

Professor La Colla was the only named inventor of the ‘191 Patent (out of four named inventors) called as a witness at this trial. (

c) Dr Steven Patterson [ 74 ] Dr Patterson has a PhD in Organic Chemistry with a minor in Biochemistry from Georgia State University. He was employed at Pharmasset between February 2000 and June/July 2004. He became the head of the analytical chemistry group in or around February 2003. Dr Patterson was called to testify by Idenix and spoke about the idea to make 2’-fluoro (down)- 2’-methyl(up) compounds at Pharmasset and how Jeremy Clark was the first person to make such a compound. (

d) Dr Jean François Griffon [ 75 ] Dr Griffon is a Senior Research Scientist at Idenix in Montpellier in the nucleoside analogues group. Dr Griffon obtained a PhD in Organic Chemistry in 1998 from Montpellier in the laboratory of Professor Jean-Louis Imbach under the supervision of Dr Gilles Gosselin. Dr Griffon synthesized a number of 2’- and 3’-fluoro substituted nucleosides during the course of his PhD Dr Griffon joined Idenix in 2001. He was assigned the synthesis of 2’-fluoro (down)-2’-methyl (up) nucleosides on March 28, 2002 and he worked on this project until mid-2004. (

e) Dr Lieven Stuyver [ 76 ] Dr Stuyver received a PhD in Human Genetics in 1992. He was the head of the biology group at Pharmasset from 1998 to 2004. Dr Stuyver was named as an inventor on provisional US ‘368, which is cited as the priority application to the ‘657 Patent, but was not named as an inventor on the PCT patent application that led to the Canadian ‘657 Patent, or the ‘657 Patent itself. (

f) Ms Jingyang Wang [ 77 ] Ms Jingyang Wang is a Principal Research Scientist at Idenix in Cambridge, Massachusetts. Ms Wang received a Bachelor of Science degree in chemistry in 1989 from Nankai University, Tianjin, China; a Master’s of Science in Organic Chemistry in 1995 from University of Manchester, United Kingdom; and a Master’s of Science degree in Organic Chemistry in 1998 from the University of Maine. Ms Wang joined Idenix Pharmaceuticals, Inc in 2002 as Process Chemist and was promoted to the position of Research Scientist in May 2004.

Ms Wang worked on a project to make 2’-fluoro(down)-2’-methyl(up) nucleosides from late 2004 until early 2005 under the direction of Dr Alistair Stewart. The parties agreed to have Ms Wang’s witness statement and related cross-examination from the U.K. proceeding entered into evidence in this trial in lieu of viva voce testimony. (

g) Dr Alexander Clemens [ 78 ] Dr Clemens is a process chemist who works for AMRI. Dr Clemens performed experiments requested by Idenix in June-July 2014, as well as a repeat of those experiments in August 2014 intended to demonstrate that Dr Griffon had synthesized a 2’-C-Me/F nucleoside, without realizing it. Dr Clemens was not involved in the development of the protocols for the experiments. C. The Failure of Jeremy Clark to Testify [ 79 ] Neither party called Mr Clark to testify. Idenix submitted at one point that the Court should draw an inference against Gilead by its failure to call him.

Dr Otto provided evidence of a strained relationship between Mr Clark and Pharmasset (now Gilead). He felt that he had not been appropriately compensated for his invention He sent letters to the company, communicated with the company’s lawyers and filed lawsuits against the company and against Dr Schinazi. While he is a former employee, he is not under Gilead’s control. He did not testify in the United Kingdom case. It is not a surprise that he did not testify in this matter. [ 80 ] Gilead for its part, suggests that Idenix should have called Mr Clark.

Idenix conducted a discovery of Mr Clark and asked a full day of questions relating to his work. It also points out that Idenix made allegations in respect of Clark’s work, and therefore, Idenix assumed the burden of proof on such facts. Gilead asks the Court to infer that Mr Clark’s evidence would not have assisted Idenix. I do not see why Gilead would want to or needed to call Mr Clark because of these facts. Idenix had his evidence from the discovery of Mr Clark and could have called him. In addition, Dr Patterson described Mr Clark as someone with a somewhat idiosyncratic temperament.

I attribute no adverse inference to either party for the failure to call Mr Clark.

IV. Scientific Principles and their Relation to the Issues [ 81 ] The following is a brief introduction to the requisite chemistry and biology principles that inform this decision along with some discussion of their relation to the issues under consideration. The scientific background information is excerpted from the expert reports and parties’ submissions. A. Chemical Notation [ 82 ] The majority of the chemistry at issue is organic chemistry. Organic chemistry is carbon -based chemistry. Each carbon atom in an organic molecule is most commonly capable of forming four bonds to other atoms.

Carbon atoms can be characterized according to the number of other carbons they are attached to. A “primary carbon” is a carbon bonded to a single carbon atom. Carbons that are bonded to two or three carbon atoms can be described as secondary or tertiary carbons. When attached to alcohols, they denote a secondary or tertiary alcohol. B.

Sugar Rings, Nucleosides, Nucleotides and Nucleic Acids [ 83 ] The ‘191 and ‘657 Patents both relate primarily to nucleosides and nucleotides that are modified at what is described as the 2’ carbon position of their sugar ring (also referred to as a carbohydrate ring or in this matter ribose ). Nucleosides and nucleotides are compounds to which a heterocyclic base (also referred to as a “Base” or “Nucleobase” discussed below) is attached to a sugar ring. [ 84 ] Nucleosides and nucleotides are the building blocks of nucleic acids.

Nucleic acid is a general term used to describe a polymer (a large molecule composed of many repeated subunits) of nucleotides linked together by bonds. Deoxyribonucleic acid [ DNA ] and ribonucleic acid [ RNA ] are the primary nucleic acids in cells that serve to encode and carry out genetic information in living organisms. [ 85 ] The HCV genome consists of a single strand of positive-sense RNA. The modified nucleosides or nucleotides are designed to mimic the natural nucleosides that are incorporated by the Hepatitis C virus to form RNA.

When this occurs, analogues nucleotides are useful in the treatment of HCV by their disruption of the replication process that is required for new viruses to be formed.

(1) The Sugar Ring [ 86 ] The Sugar Ring can take the structure of a five membered ring containing an oxygen atom. The sugar rings found in RNA and DNA are “ribose” and “deoxyribose” respectively. They are identical except at the 2’ “down” position. The RNA Ribose contains a hydroxyl group at the 2’-C (down) position, while DNA Deoxyribose contains a hydrogen atom at that position. They may be depicted using a “Haworth projection” as follows: [ 87 ] A Haworth projection is a common way of representing the three-dimensional perspective of sugar rings, nucleosides, nucleotides and prodrugs.

The Haworth projection provides information about whether substituents are attached above [(up )] or below [(down)] the plane of the sugar ring. Hydrogen atoms on the sugar ring are not depicted. Carbon atoms are represented by either a vertex (a point where two or more straight lines meet), or a line without a carbon symbol. The relative positions of the carbons around the sugar ring are denoted using the prime (‘) symbol along with the number of the carbon.

(2) Nucleosides [ 88 ] A “nucleoside” is a chemical compound that consists of a base and a sugar ring. The sugar ring and the base are connected to each other by a chemical bond, known as a “glycosidic bond.” “Glycosylation”, or sugar-base condensation, is the process of coupling the sugar and base. An example of a nucleoside is depicted below. The spatial arrangement of the components on the drawing is illustrated using a wedge and dash drawing with the following bonds: a straight line is a bond in the plane of the paper; a bold wedge is a bond coming out of the page (in the (up) position); a hatched line is a bond coming into the paper (in the (down) position).

[ 89 ] Both DNA and RNA use combinations of bases to perform their coding function. In DNA, these bases are thymine, adenine, cytosine and guanine. In RNA, thymine is replaced by uracil. Adenine and guanine are classified as “purines” and contain a double-fused ring. Cytosine, thymine, and uracil only contain one ring and are classified as “pyrimidines”. These bases are often represented by a single letter (A, C, G, T or U). [ 90 ] The numbering on the atoms in the bases follows standard convention as illustrated below: C.

Stereochemistry [ 91 ] “Stereochemistry” involves the study of the relative three-dimensional spatial arrangement of atoms that form the structure of molecules and their manipulation. Stereoisomers are isomers that differ in spatial arrangement of atoms, rather than order of atomic connectivity. An important branch of stereochemistry is the study of chiral molecules.

A chiral molecule exists in two different forms, which are mirror images of each other. [ 92 ] A chiral molecule and its mirror image are called “enantiomers” of each other. [ 93 ] Enantiomers have identical chemical and physical properties such as boiling point, melting point, density and refractive index. However, they differ in how they interact with polarized light, and may have different biological properties.

A mixture of enantiomers in equal proportions is referred to as a “racemic mixture.” [ 94 ] Diastereoisomers (diastereomers) are stereoisomers of a compound having two or more chiral centers that are not a mirror image of another stereoisomer of the same compound [ 95 ] The distinction between these terms may be seen from the following drawing [ 96 ] The process of applying a Grignard reagent in the schemes in the ‘191 Patent describing how to synthesize the 2’-C-Me/OH compounds would result in a racemic mixture of diastereomers of both the 2’-C-Me/OH and 2’-C-OH/Me compounds.

These can be separated to obtain the desired 2’-C-OH/Me enantiomer as the intermediate used to synthesize the 2’-C-Me/F target compound. D. Fluorination [ 97 ] The term “fluorination” refers to the addition of at least one fluorine atom to a compound. By January 2004, fluorination reactions were understood to generally proceed via two different mechanisms: “electrophilic fluorination” and “nucleophilic fluorination”. Different starting materials and fluorinating reagents were required for electrophilic fluorination reactions as compared to nucleophilic fluorination reactions.

[ 98 ] Electrophilic fluorinating agents that were known as of January 8, 2004 include: F 2 ; SelectFluor; N-flurobenzenesulfonimide; and ClO 3 F. Nucleophilic fluorinating agents that were known as of January 8, 2004 include: HF and HF-based reagents (e.g. HF- pyridine, HF-pyridine/ AlF 3 , anydrous HF, HF/Fe (AcAc) 3 ; AgF and AgF-based reagents (AgF/NH 4 F); Et 3 N ● 3HF; KF and KF-based reagents (e.g.

KHF 2 ); DAST; Deoxo-Fluor®; tetrabutylammonium fluoride (TBAF); tris(dimethylamino)sulfonium difluorotrymethylsilicate (TASF); Bu 4 NH 2 F 3 ; Bu 4 NHF 2 /Fe(AcAc) 3 ; and perfluoro-1-butanesulfonyl fluoride (PBSF). [ 99 ] The 2’-C-Me/F compounds were first synthesized using the nucleophilic fluorination agent of DAST, and thereafter using a more stable version of it sold under the trademark of Deoxo-Fluor®. E.

Nucleophilic substitution reactions [ 100 ] A “nucleophile” (nucleophilic fluorinating agents such as DAST) is an electron rich species that reacts with electron deficient species, termed “electrophiles,” to generate new molecule. A reaction between a nucleophile and an electrophile is called a “nucleophilic substitution reaction.” In such reactions, the nucleophile reacts with the electrophile, while another moiety, termed a leaving group, is released.

(1) Mechanisms of nucleophilic substitution reactions [ 101 ] Nucleophilic substitution reactions can proceed by two different reaction mechanisms. These are called S N 1 and S N 2 mechanisms, and have different stereochemical consequences. [ 102 ] A “SN2 mechanism” proceeds with complete inversion of stereochemistry and gives rise to a single product. This is illustrated in the scheme below.

The starting material with a hydrogen atom above the plane and a hydroxyl group below the plane; the product has a hydrogen atom below the plane and a fluorine atom above the plane: an inversion. [ 103 ] In contrast, a “S N 1 mechanism” gives a mixture of stereoisomers.

This is illustrated in the scheme below: [ 104 ] Whether a nucleophilic substitution reaction will occur via a S N 1 or S N 2 mechanism depends on a number of factors, such as the degree and type of substitution, the steric hindrance of the substrate, the strength of the nucleophile, the stability of the leaving group, and the solvent used, among others. [ 105 ] The synthesis of the 2’-C-Me/F nucleoside by Gilead was carried out on the 2’-C-OH/Me compound by a S N 2 fluorination of the tertiary alcohol in that compound with inversion of the stereochemistry resulting to synthesize the 2’-C-Me/F compound. F.

Protecting Groups [ 106 ] A nucleoside (and sugar) has multiple potential reaction sites. During a synthetic sequence, some of these reaction sites may need to be blocked from chemical reactions so that a selective chemical transformation can occur at the targeted reaction site. A “protecting group” is a functional group that is temporarily placed on a potentially reactive site of the nucleoside to block it from undergoing unwanted reactions. A protecting group can be removed once the desired transformation is achieved. Certain protecting groups are more compatible with certain reaction conditions than others. G.

Isolating Molecules [ 107 ] After performing reactions, chemists must isolate and purify the products of their reaction for analysis and identification. Most commonly, chemists use chromatography to separate and purify reactions. [ 108 ] Chromatography involves the separation of compounds based on different partitions between the mobile phase and the stationary phase. The mobile phase is usually a solvent or mixture of solvents and the stationary phase is usually an inorganic solid like

silica or alumina. Chromatography generally proceeds by allowing a solution containing the mixture of products to flow through the stationary phase. Due to the differences in partition, the products of the mixture progress (elute) at different rates through the stationary phase and are collected separately and evaporated. [ 109 ] Three main forms of chromatography bear consideration for the purposes of this case: thin layer chromatography [TLC], column chromatography, and high-performance liquid chromatography [HPLC].

(1) Thin Layer Chromatography [ 110 ] TLC is commonly used to monitor progress of a reaction. TLC provides a chemist with a simple, inexpensive, efficient and relatively fast determination to analyze a reaction mixture and to monitor the progress of a reaction and the extent of conversion of starting material into product. It also provides an empirical and approximate measure of the purity of the product or products. [ 111 ] In TLC, usually a glass or alumina plate is covered with a stationary phase, usually silica or alumina. The solutions of interest are spotted on the plate at a set distance from the bottom.

The reaction mixture is spotted on the plate, and the bottom of the plate is placed in a small amount of solvent or solvent mixture which migrates up the plate by capillary action. The compounds in the reaction mixture are dragged along with the mobile phase at different speeds depending on how avidly they interact with the silica or alumina.

The compounds in the reaction mixture are separated based on differences in solubility, polarity and absorption of compounds. [ 112 ] While monitoring an organic synthesis, a chemist can place the starting material in the left-hand lane on a TLC plate, and the reaction mixture in the right hand lane. If both lanes show exactly the same spots on the TLC plate, then the chemist would usually assume that no reaction has occurred. If there was a different spot on the TLC, when compared to the original lane, this would imply that there is one reaction product.

If there were multiple additional spots on the new lane, the inference would be that multiple reaction products were formed in the reaction. [ 113 ] A TLC plate may be employed after the separation of the reaction products to assist in determining whether it contains a sugar, such as a 2’-C-Me/F nucleoside. The TLC plate is stained with sulphuric acid, which preferentially charcoals carbohydrates, such as sugars. Spots containing sugars char darkly under UV light. Compounds that do not contain carbohydrates (such as a base that was not successfully coupled to a sugar) will not char as darkly.

(2) Purification by Chromatography [ 114 ] Various forms of chromatography are used to separate mixtures of different compounds for analytical purposes. These include: column chromatography, HPLC and reverse phase HPLC. [ 115 ] In column chromatography, the mobile phase – the reaction mixture – is poured on top of a stationary phase – a column that is typically made of silica gel. Additional solvent is continuously added and fractions are eluted from the base of the column. Different compounds from the reaction mixture flow through the stationary phase at different speeds.

The reaction product is collected manually in vails that are combined into similar reaction products, which can be further analyzed. [ 116 ] HPLC is similar to column chromatography. It is a more sophisticated chromatographic technique in which the solution mobile phase is pumped under pressure through a finely divided stationary phase and the eluted solution monitored for composition change by a detector. HPLC is usually much more efficient in separations than column chromatography. H. Characterizing Molecules [ 117 ] Chromatography is used to separate reaction products, but not characterize them.

Many methods of characterization of molecules exist. The two relevant methods in this matter are mass spectrometry [ MS ] and nuclear magnetic resonance [ NMR ] .

(1) Mass Spectrometry [ MS ] [ 118 ] MS analysis provides a mass spectrum that may provide the molecular composition of the compound as well as providing some information on its structural features. MS can also be coupled with HPLC allowing for separation and characterization using one procedure.

(2) Nuclear Magnetic Resonance [ NMR ]

[ 119 ] NMR spectroscopy is a frequently employed technique that is used for the structural characterization of compounds. It determines either completely or partially, the structure of a compound by giving information on the types of groups of atoms present and their connectivities. [ 120 ] NMR can also be used to authenticate a sample of a compound by comparisons of the NMR spectra with those from an authentic sample. NMR spectroscopy is the primary method used by chemists to characterize unknown compounds and to authenticate other samples.

(3) High-pressure Liquid Chromatography Attached to a Mass Spectrometer [LC/MS] [ 121 ] HPLC attached to a mass spectrometer is a more recent technology to separate and characterize reaction compounds. It operates by a small amount of reaction mixture being introduced into to an HPLC column. After leaving the column, the eleunt immediately passes into a mass spectrometer, allowing the chemist to monitor, in real time on an on-going basis, the molecular weights of the compounds leaving the column. I.

Nucleotides and the Formation of Ribonucleic acid [ RNA ] and Deoxyribonucleic acid [ DNA ] [ 122 ] Nucleosides are precursors of nucleotides. Nucleotides are nucleosides that contain a phosphate bonded to the oxygen atom of the alcohol (hydroxy) unit of the sugar. A nucleotide is defined as a nucleoside having a mono-, di-, or triphosphate group attached to the sugar ring at the 2’, 3’ and/or 5’ position, with the 5-carbon site the most common as is the situation in this matter.

The nucleotide in sofosbuvir, i.e. a prodrug of a 2’-C-Me/F is a nucleotide with a monophosphate at the 5’ position. [ 123 ] An example of the three forms of a nucleotide is depicted below. [ 124 ] The conversion of a nucleoside into a nucleotide by the attachment of the phosphate (for example PO 3 5- ) to the C-5 alcohol unit is a chemical process that can occur naturally in vivo (inside the cell). Their formation starts after the nucleoside or monophosphate nucleotide enters the cell.

The entry into the cell is facilitated by the use of “prodrugs,” which are discussed below. [ 125 ] Once inside the cell, the nucleoside, or a mono or di-phosphate nucleotide, undergo up to three consecutive phosphorylation steps at the hydroxyl group attached to the 5’-carbon to form 5’-nucleotide mono-, di and triphosphates respectively. “Phosphorylation” is a metabolization process that may occur in vivo whereby a phosphate group is naturally added to a nucleoside or to a mono or di- phosphate nucleotide to become a nucleotide.

It is catalyzed by enzymes called “kinases”. [ 126 ] A polymerase is an enzyme which can take the nucleotide building blocks and couple them together to make strands of DNA or RNA. For a polymerase to link one nucleotide to the next, it is necessary for the nucleotide to be in a triphosphate form (having three phosphate groups at the 5’ position of the sugar ring). For ribonucleosides, a hydroxyl group at the 3’ position (the 3’ OH group) of one nucleotide will be coupled with a 5’ phosphate group at the next nucleotide to result in the phosphate bridge.

By this process the triphosphate is converted back to a monophosphate, which forms the phosphate bridge to the next nucleotide. [ 127 ] In

summary, as part of the DNA and RNA replication machinery of cells, a nucleoside triphosphate is the required starting material for forming a phosphate bridge to an adjoining nucleotide to form a growing strand of RNA or DNA. Kinase enzymes are responsible for phosphorylating nucleosides and mono and diphosphate nucleotides. Polymerases are enzymes that are responsible for synthesizing the growing strands of RNA or DNA. J. Viruses

[ 128 ] “Viruses” are the smallest of all self-replicating organisms. While self-replicating, they have no metabolism of their own, but rather are obliged to invade cells and direct subcellular machinery to produce more viruses. All viruses carry a genome composed of viral nucleic acid (either RNA or DNA) enveloped in a protein coat, called a capsid. Viruses infect living things and make use of their host’s cellular reproduction mechanisms to reproduce themselves. Like normal cells, nucleic acids are the genetic material of viruses. Viruses carry their own polymerase called viral polymerase.

Viruses can be classified based upon whether they contain RNA or DNA as their genetic material. [ 129 ] Viruses are categorized into families. A family of viruses can include 10, 20 or 30 viruses. The Flaviviridae family encompasses numerous viruses of significant global concern that affect both humans and animals. [ 130 ] The Flaviviridae virus family includes three types: flavivirus, hepacivirus and pestivirus.

Some examples of these types include: [ 131 ] Flaviviridae show similarity in their genome (their genetic code, which provides the blueprint for the proteins required to replicate the virus), which includes the viral RNA polymerase. All Flaviviridae viruses have viral RNA polymerase enzymes (flavivirus - NS5, pestivirus - NS5B, hepacivirus - NS5B) that replicate RNA in the same way by building RNA using nucleoside triphosphates.

(1) Hepatitis C [ 132 ] HCV is one of the most important viruses of the Flaviviridae family because of its significant impact on human health. HCV is a disease of the liver. It is transmitted by blood-to-blood contact, including through contaminated blood and blood products. Once an individual is infected, HCV continuously replicates and spreads within hepatocytes (liver cells).

About 185 million people, roughly 2.2% of the human population, are infected with HCV, and virus transmission remains a significant public health concern. [ 133 ] The most notable feature of HCV infections is that they typically persist, often for decades, with more than 70% of cases with acute Hepatitis C progressing to chronic Hepatitis. Patients with chronic Hepatitis are predisposed to developing chronic active Hepatitis, cirrhosis of the liver, and hepatocellular carcinoma, all of which are responsible for hundreds of thousands of deaths each year.

The death rate from HCV will continue to climb for at least 10 years, because of the decades-long lag time between acute infection and liver failure.

(2) The HCV genome [ 134 ] The HCV genome consists of a single strand of positive-sense RNA. The organization of the HCV genome is illustrated below: [ 135 ] The non-structural [ NS ] proteins that are encoded by this genome are involved in viral replication and protein synthesis. For example: (

a) NS3 - a protease which helps process the polyprotein to generate mature proteins by cleaving it at specific target sequences; and (

b) NS5B - a polymerase that is responsible for the multiplication of the viral genome. It is the enzyme that connects the nucleotides together to make a chain of viral RNA.

(3) HCV replication [ 136 ] An understanding of the HCV lifecycle is an important aspect of antiviral drug discovery since antiviral drugs often inhibit virus-specific functions that are essential for replication. The HCV lifecycle includes the following steps, as illustrated in the figure below:

[ 137 ] The steps are as follows: (

a) The HCV particle attaches itself to (Step 1), and enters, the host liver cell (i.e. hepatocyte) (Step 2); (

b) Once inside the cell, the outer shell of the HCV particle falls apart (uncoating) to expose the RNA strand that the virus carries and will use to make copies of itself (Steps 3 and 4); (

c) The virus uses the host cell’s components to read the information present on the RNA strand and produce proteins such as NS5B (the viral protein responsible for making new copies of the HCV RNA strand, also called the HCV polymerase) (Step 5); (

d) NS5B recognizes and binds to specific nucleotide triphosphates that are found in the cell, and incorporates them into the new strand of RNA (RNA replication) (Step 6). [ 138 ] To synthesize RNA (either the replicative negative strand or the positive strand viral RNA), nucleotides triphosphates are specifically required, which are used by the NS5/NS5B polymerase to incorporate ribonucleotides to a growing nascent chain based on the template RNA. K. Nucleoside analogues to treat viral infections [ 139 ] When developing nucleoside analogues to treat viral infections, cytotoxic effects must be avoided.

The aim is to kill the virus, not the host cell. Thus, the requirements known in 2003 for direct acting nucleoside and nucleotide analogues for HCV infections should have the following properties: be able to enter infected cells without harming them; be able to convert into nucleotide triphosphates; be recognized in their triphosphate form by the HCV NS5B polymerase protein; be incorporated into the new growing HCV RNA strand in place of a naturally-occurring nucleotide; and possess some property that, once incorporated into the new RNA strand, inhibits the complete replication of the growing HCV RNA strand. L.

Evaluating HCV Treatments [ 140 ] The study of HCV and the development of anti-HCV therapies have been hindered by difficulties in developing appropriate model systems. This is because HCV is a species-selective virus that infects only humans and chimpanzees. Instead, various in vitro model systems were used in 2003. These are discussed below.

(1) Phosphorylation assay [ 141 ] The phosphorylation assay is not used to measure direct antiviral activity. As set out above, nucleoside analogue inhibitors need to be converted to their triphosphate form in vivo to be recognized by a polymerase. The phosphorylation assay simply determines whether a nucleoside analogue inhibitor can be phosphorylated in vitro . This assay uses normal cells that are not infected with a virus, and therefore, this assay must be done in conjunction with additional assays to fully test antiviral activity.

(2) Polymerase assay

[ 142 ] As discussed above, a nucleoside analogue used in the treatment of HCV should inhibit the activity of NS5B. The HCV polymerase assay may be used by the skilled virologist to assess anti-HCV activity (i.e. it can be used to determine the ability of different test compounds to inhibit the HCV polymerase’s activity). [ 143 ] However, like the phosphorylation assay, the polymerase assay is not ideal. First, it involves the large-scale production of soluble viral polymerase in bacteria or insect cells. Second, it can only be used if the test compound is in its tri-phosphorylated form.

Third, it does not provide data about cytotoxicity. In 2003, a skilled virologist would have been aware of the drawbacks of the polymerase assay.

(3) BVDV, (Bovine Viral Diarrhea Virus) surrogate model [ 144 ] In 2003, there was no HCV cell culture system or a convenient small animal model in which to screen potential anti-HCV compounds. Therefore, prior to the development and adoption of the HCV replicon assay, some scientists used an in vitro assay system based on the pestivirus BVDV as a surrogate model for testing nucleoside analogues for anti-HCV activity. [ 145 ] Madin-Darby bovine kidney [ MDBK ] cells are first seeded onto a monolayer of cultured cells and then infected with BVDV, followed by the addition of serial dilutions of test compounds.

After several rounds of viral replication, the initial infection gives rise to visible structures called plaques through the diffusion of the virus from the original site of infection to new sites. The number of plaques on each plate is compared to a control plate that was not tested with any test compound. If a compound inhibits BVDV RNA replication, it will reduce the number of plaques formed as compared to the control.

(4) The replicon assay [ 146 ] The replicon assay was first reported in 1999 by Lohmann et al in the preeminent “Science” journal. A replicon is a portion of the HCV genome that is able to mimic HCV RNA replication in human hepatocytes. A replicon cell culture system can be used to directly measure the ability of a compound to prevent successful replication of the HSV RNA. After adding a test compound to the cell culture, the cells are incubated for a given period of time to allow for viral replication, and then the amount of replicon RNA in the cells is measured.

By comparing the amount of replicon RNA in the cells that received the test compound to the amount of replicon RNA in control cells, it is possible to quantify the anti-HCV effect of the test compound.

(5) Measures of antiviral activity and toxicity [ 147 ] In order to be an effective antiviral compound for HCV treatment, a nucleoside analogue must act selectively against the HCV virus, but also be non-toxic to HCV-infected or uninfected cells. A compound’s antiviral activity is expressed in the following ways. [ 148 ] The “Effective Concentration 50%” [ EC50 ] is a measure of a compound's antiviral activity, i.e. the amount of a given compound required to reduce virus titer or RNA or protein in virus infected cells by 50%.

EC50 is often used interchangeably with a measure of Inhibition Concentration 50% [ IC50 ] , which refers to the concentration of a drug that is required for 50% inhibition of the RNA polymerase activity in vitro . By determining the amount of test compound required to reduce viral replication (i.e. plaque number) by 50%, the test compound's EC50 can be determined.

The lower the EC 50 value, the more potent the compound. [ 149 ] The “Cytotoxic Concentration 50%” [ CC 50 ] on the other hand, is a measure of a compound's cellular toxicity, and refers to the concentration of the compound required to reduce the number of cells by 50%. The larger the CC 50 value, the less toxic the compound. [ 150 ] The “Therapeutic index” is used to assess EC 50 values in relation to their CC 50 values through a ratio [ CC 50:EC 50 ] .

Since a high CC 50 value indicates low toxicity, and a low EC 50 value indicates high anti-viral activity, a preferred compound would have a significantly higher CC 50 value than an EC 50 value. A higher therapeutic index is preferable over a lower one. [ 151 ] In order to assess a therapeutic index, the EC and CC values must be obtained for the same cell line as that in which the virus is tested. This is because different cell lines show different sensitivities to different nucleoside analogues. M.

Prodrugs [ 152 ] A “prodrug” is a biologically inactive derivative of a drug that upon administration to the human body is converted into its active form by some chemical or enzymatic pathway. Generally, a prodrug is a compound that metabolizes to the active compound at some point in vivo . [ 153 ] The negative charge of an unmasked nucleoside mono, di, or triphosphate, i.e. a nucleotide, presents a barrier to cellular uptake, thus preventing drugs from reaching their desired target.

The negatively charged mono-, di, or triphosphate has difficulties passing through the cell membrane because the lipid bilayer of the cell membrane resists charged molecules. To overcome this issue, nucleotide prodrugs can be prepared to mask the negative charge on the phosphate groups to increase the passage through a cell’s membrane. [ 154 ] Once inside a cell, the prodrug components of the nucleoside/nucleotide are removed. This may involve the cleaving of the leaving group in one, or a number of steps, in the metabolization process.

In the case of a nucleotide monophosphate prodrug, the nucleotide monophosphate is then inside the cell and, as it is already monophosphorylated, it is in an excellent position to be converted to its di and triphosphate forms. V. The Person Skilled in the Art and Common General Knowledge

A. The Skilled Person [ 155 ] Patent specifications are addressed to a hypothetical person possessing the ordinary skill and knowledge to which the patent relates and a mind willing to understand the specification ( Apotex Inc v Sanofi-Synthelabo Canada Inc , 2008 SCC 61 para 25 ). [ 156 ] The Federal Court of Appeal has compared the notional person of ordinary skill in the art to the “reasonable person” in the context of negligence law.

This “man in the Clapham omnibus of patent law” has been described in Beloit Canada Ltd v Valmet OY (1986), 8 CPR (3d) 289 at 294 (FCA) as: The technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. [ 157 ] I also find apt the description of the skilled person set out in Valensi v British Radio Corporation [1973] RPC 337 at 377 , as follows: The hypothetical addressee is not a person of exceptional skill and knowledge, that he is not to be expected to exercise any invention, nor any prolonged research, inquiry or experiment.

He must, however be prepared to display a reasonable degree of skill in common knowledge of the art in making trials and correcting obvious errors in the specification as a means of correcting them can readily be found. [ 158 ] The skilled person has the same capabilities whether the issue is construction of the patent, utility and sound prediction, sufficiency of disclosure, or overbreadth. [ 159 ] The ‘191 Patent is to be construed as of its publication date (January 8, 2004) from the perspective of the skilled person. [ 160 ] The parties are in agreement that the skilled person would comprise a team of persons having at least a PhD with about three years of practical work experience, or a Master’s degree with a corresponding increase in work experience. [ 161 ] There is also agreement for the most part, that the skilled team members would comprise: (

a) a chemist with knowledge or experience in the chemical aspects of drug discovery including the synthesis of nucleosides and standard laboratory techniques for synthesising and characterising nucleoside compounds; (

b) a biologist or virologist familiar with the biological aspects of drug discovery particularly as it relates to Flaviviridae infections and particularly HCV with experience conducting relevant in vitro assays, cell culture systems, and interpreting data from in vitro assays, cell culture systems and animal models, and in assessing the activity and toxicity of other models for biological activity and toxicity. [ 162 ] Idenix’s experts contend that the patent does not address a skilled person with a background in pharmacology with knowledge and experience relevant to bioavailability, pharmacokinetics, drug delivery and metabolism.

Their opinion is that the patent is addressed to skilled persons in the art of novel drug discovery comprised in the two groups described above, as opposed to those who work on the after-development of the drug, once invented, which is the field of the pharmacologist. [ 163 ] I agree with this submission and as a result, I give less weight to some of Dr Krise’s evidence, particularly concerning the meaning of “a leaving group” in the ‘191 Patent.

I address this issue below. [ 164 ] I further accept Dr Wnuk’s opinion that the notional person skilled in the art may still need direction and would only be starting to get into independent work. This is corroborated by Dr Krise’s evidence that while recent graduates may have an in-depth knowledge of a very narrow field of study, their knowledge across the remainder of their field remains basic. [ 165 ] I also accept Dr Wnuk’s opinion that the skilled person would have little experience in fluorination synthesis. His opinion was that in 2004 only a small percentage of chemists were trained in this art.

Dr Wnuk had the advantage of being the only expert to testify with personal experience in fluorination in 2004. [ 166 ] I also agree with Idenix’s experts that skilled persons performing the tasks of a discovery chemist must have an awareness of the requirement to characterize compounds resulting from their synthesis experiments. This would require the skilled discovery chemist to employ reasonable means at his or her disposal to characterize the compounds synthesized.

To the extent that there may be constraints on access to technology, these limitations are attributable to the organization responsible for drug discovery and not the competence of the skilled person. B.

Common General Knowledge [ 167 ] Common general knowledge is “knowledge generally known by persons skilled in the relevant art at the relevant time” , Apotex v Sanofi Synthelabo Canada Inc , [2008] 3 SCR 265, 2008 SCC 61 at para 37 (2) [Plavix (SCC)] . [ 168 ] In Eli Lilly and Company v Apotex Inc , 2009 FC 991 at para 97 [ Cefaclor ], Madam Justice Gauthier, adopted with approval the comprehensive description of common general knowledge from General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (1971), [1972] RPC 457 at 480 to 481 (UKCA) which I have summarized without citations as follows: The common general knowledge imputed to such an addressee must be carefully distinguished from what in patent law is regarded as public knowledge.

Common general knowledge is derived from a common sense approach to the practical question of what would in fact be known to an appropriately skilled addressee - the sort of man, good at his job, that could be found in real life.

Individual patent specifications and their contents do not normally form part of the relevant common general knowledge, though there may be some exceptions.

As regards scientific papers generally, • 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 regarded as a good basis for further action [as opposed to 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 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. [ 169 ] A party that asserts that a particular piece of information was part of the common general knowledge at the relevant time must prove this fact with evidence. [ 170 ] Idenix relies on the ability of the skilled person to locate the common general knowledge by the use of search engines commonly available in the chemical discovery and education world.

It makes reference to Justice Gauthier’s decision in Cefaclor from para 104 as follows: The distinction between common general knowledge and prior art which is part of the state of the art for the purpose of assessing anticipation and obviousness tends to diminish in modern times because of the sophistication of search engines and the availability of electronic publications and databases. [ 171 ] This does not mean however, that scientific papers found by searches or otherwise produced at trial can be used to buttress disclosure deficiencies in the ‘191 Patent unless established as meeting the requirements of common general knowledge. [ 172 ] In addition to expert evidence, the Court has heard from several individuals who were actually working on the synthesis of 2’- C-Me/F compounds during the relevant period.

I agree with Gilead’s submission that where the experience of individuals actually working on the problem differs from the theoretical opinions of experts, the contemporaneous factual information should be preferred. VI. Construction of the ‘191 Patent A. Principles of Construction [ 173 ] The claims of the patent are to be construed prior to any assessment of validity or infringement. It is a fundamental rule that “the claims receive one and the same

interpretation for all purposes” Whirlpool Corp v Camco Inc , 2000 SCC 67 , [2000] 2 SCR 1067 at para 49 [ Whirlpool ]. [ 174 ] The modern principles of claim construction were developed by the Supreme Court of Canada in the companion cases of FreeWorld Trust v Électro Santé Inc, [2000] 2 SCR 1024 at para 13 , 2000 SCC 66 [ Freeworld ] and Whirlpool . These principles of claim construction were later summarized by the Federal Court in Biovail Pharmaceuticals Inc v Canada (Minister of National Health & Welfare) , 2005 FC 9 at para 15 as follows: 1.

A patent is construed as a bargain between the inventor and the public. In consideration of disclosing the invention, the inventor is given a temporary monopoly to exploit it. 2. It is a statutory req u irement that the patent contain a specification and end with a claim or claims "defining distinctly and in explicit terms the subject-matter of the invention for which an exclusive privilege or property is claimed".

The specification must be sufficiently full, clear, concise and exact "as to enable any person skilled in the art or science to which it pertains, or to which it is most closely connected, to make, construct, compound or use it". ( Patent Act , R.S.C. 1985, c. P-4, as amended, s. 27 ) 3. The patent is notionally addressed to a person skilled in the art or science of the subject-matter and is to be read as such a person would have read it when it first became public… 4.

The claims are to be read in an informed and purposive way to permit fairness and predictability and to define the limits of the monopoly "[I]ngenuity of the patent lies not in the identification of the desired result but in teaching one particular means to achieve it. The claims cannot be stretched to allow the patentee to monopolize anything that achieves the desired result" ( Free World Trust , paras 31, 32 ). 5.

The claim portion of the patent specification takes precedence over the disclosure portion in the sense that the disclosure is read to understand what was meant by a word in the claims "but not to enlarge or contract the scope of the claim as written and thus understood" ( Whirlpool , para 52 ). 6. It is only such novel features that the inventor claims to be essential that constitute the "pith and marrow" of the claim. "The key to purposive construction is therefore the identification by the Court with the assistance of the skilled reader, of the particular words or

phrases in the claims that describe what the inventor considered to be the "essential" elements of his invention" ( Whirlpool , para 45 ). 7. Some elements of the claimed invention are essential and others are not, based either on common knowledge when the patent was published or according to the intent of the inventor, expressed or inferred from the claims… 8. To overclaim is to lose everything. If the inventor underclaims, the court will not broaden the monopoly in the interests of the "spirit" thereof.

This often, as in this case, results in layers of claims, each limitation serving as a potential safety net so that if the broadest claims fall, the monopoly may be saved in part by the more modest claims. 9. Yet a patent is not an ordinary writing. It meets the definition of a "regulation" in the

Interpretation Act , and must be read to assure the attainment of its objects. "Claims construction is a matter of law for the judge, and he was quite entitled to adopt a construction of the claims that differed from that put forward by the parties." ( Whirlpool , para 52 ) [ 175 ] Claims are to be interpreted in a purposive manner in order to “achieve fairness and predictability and to define the limits of the monopoly” ( Dimplex North America Ltd v CFM Corp , 2006 FC 586 , 54 CPR (4 th ) 435 at para 49 , aff’d 2007 FCA 278 , 60 CPR (4 th ) 277 [ Dimplex ]). [ 176 ] A patent is to be given a “purposive construction”, not a technical or literal construction, taking into account the ent

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