Gilead Sciences, Inc. v. Idenix Pharmaceuticals Inc.

Gilead Sciences, Inc. v. Idenix Pharmaceuticals Inc.
Court (s) Database
Federal Court Decisions
Date
2015-11-02
Neutral citation
2015 FC 1156
Decision Content
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 al