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You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Intervet UK Ltd v Merial R.'s University of Belfast the University of Saskatchewan [2010] EWHC 294 (Pat) (23 February 2010)
URL: http://www.bailii.org/ew/cases/EWHC/Patents/2010/294.html
Cite as: [2010] EWHC 294 (Pat)
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CHANCERY DIVISION
PATENTS COURT
Strand, London, WC2A 2LL |
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B e f o r e :
____________________
| INTERVET UK LIMITED |
Claimant |
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| - and - |
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| MERIAL THE QUEEN'S UNIVERSITY OF BELFAST THE UNIVERSITY OF SASKATCHEWAN |
Defendants |
____________________
Simon Thorley QC and Justin Turner QC (instructed by Bird & Bird LLP) for the Defendants
Hearing dates: 3-5, 8-9, 11-12 February 2010
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Crown Copyright ©
- The Defendants (who I shall refer to as "the Patentees") are the joint proprietors of European Patent (UK) No. 1 386 617 entitled "Method for the in vitro diagnosis of type II porcine circovirus infection and diagnostic reagents" ("the Patent"). The Patentees allege that the Claimant ("Intervet") has infringed claim 18 of the Patent by marketing a vaccine known as Porcilis PCV. Intervet denies infringement and seeks revocation of the Patent.
- The Patent has three claimed priority dates. The first is 3 October 1997 and the second is 22 January 1998. The first major issue on validity is whether the Patent is entitled to the first priority date. For brevity, I shall refer to this as "the priority date" and the first priority document, French Patent Application No. 9712382, as "the Priority Document". The Patentees contend that the Patent is entitled to the priority date. In the alternative, they seek to amend the claims into a form which they say is entitled to priority. Intervet disputes that the proposed amendments achieve that objective.
- If the Patent is not entitled to the priority date, the Patentees do not contest Intervet's case that the Patent is invalid over two items of intervening prior art, namely: (i) a submission containing a polynucleotide sequence for porcine circovirus by A.L. Hamel, L.L. Lin and G.P.S. Nayar to GenBank on 26 September 1997, Accession No. AF027217, which was published on the National Center for Biotechnology Information website on 17 December 1997 ("the Hamel GenBank submission"); and (ii) International Patent Application No. WO 99/29717 ("Wang 717") filed on 11 December 1998, which claims priority from US Patent Application No. 60/069,750 filed on 16 December 1997 ("Wang 750").
- The second major issue on validity is whether, even if it is entitled to the priority date, the Patent is obvious in the light of an article by G.P.S. Nayar, A. Hamel and L. Lin, "Detection and characterization of porcine circovirus associated with postweaning multisystemic wasting syndrome in pigs", Can. Vet. J., 38, 385-386, published in June 1997 ("Nayar").
- The dispute on infringement turns primarily on the construction of claim 18.
- For reasons that will appear, it is relevant to note that there have already between proceedings between Intervet and two Merial companies concerning the Dutch counterpart of the Patent in the Netherlands, which resulted in a judgment of the District Court of the Hague dated 9 December 2009. There have also been proceedings between Intervet and Merial and others concerning a corresponding US patent, which resulted in two opinions of the United States District Court for the District of Columbia dated 28 November 2007 and 12 August 2009. In addition, the Patent is under opposition before the European Patent Office.
- Porcine circovirus ("PCV") is a small virus containing a circular single-stranded DNA genome. It was first isolated from a porcine kidney cell line called PK/15 and characterised by Tischer and co-workers in 1982 (Tischer et al, Nature, 295, 64-66). In January 1997 Dr Brian Meehan from The Queen's University of Belfast together with co-workers from the Veterinary Sciences Division of the Department of Agriculture for Northern Ireland published a paper, "Sequence of porcine circovirus DNA: affinities with plant circoviruses", J. Gen. Virol, 78, 221-227, in which they reported the complete nucleotide sequence of the genome of PCV from PK/15 cells ("Meehan").
- In the mid 1990s a new disease of pigs was recognised. Its clinical presentation and epidemiology were first described by Dr John Harding, a Canadian veterinarian, in a short paper presented to a meeting of the Western Canadian Association of Swine Practitioners in 1996 (Proc. Western Can. Assoc. Swine Pract., 1996, 21). Dr Harding termed the new disease post-weaning multisystemic wasting syndrome ("PMWS"). Dr Harding reported that PMWS was a widespread disease affecting numerous herds in Saskatchewan and Alberta, and was probably undiagnosed in additional herds across the prairies. He described PMWS as a chronic, insidious disease in young pigs whose predominant clinical signs included weight loss, tachypnea, dyspnea and jaundice. Morbidity was relatively low, but case fatality high. PMWS had been diagnosed in both PRRS (porcine reproductive and respiratory syndrome) positive and negative herds. Diagnosis was based on the presence of suspicious clinical signs and pathognomonic histopathologic lesions which had been found in most tissues, but were most common in the lung, lymph system, liver and kidney. A causative agent had not been identified, but it was believed to be a virus.
- In March 1997 Dr Harding and Dr Edward Clark presented papers about PMWS to a meeting of the American Association of Swine Practitioners in Quebec. Dr Harding's paper (Proc. Am. Assoc. Swine Prac., 1997, 503, which I shall refer to simply as "Harding") largely repeated the contents of his 1996 paper, with a few additional details. He concluded that "Gaining a better understanding of the etiology, epidemiology and pathogenesis of the disease is a priority", and reported that collaborative studies were in progress involving the Veterinary Infectious Diseases Organisation, Western College of Veterinary Medicine and several swine practitioners. Dr Clark's paper (Proc. Am. Assoc. Swine Prac., 1997, 499-501, which I shall refer to as "Clark") contained postmortem and histopathologic findings based on examinations of about 150 pigs. In the histopathological section of the paper he described the lesions associated with the disease in some detail. He also reported that "preliminary electron microscopic and immunohistochemical studies suggest porcine circovirus may be responsible for these lesions".
- Following the reports by Clark and Harding, several groups set out to isolate and characterise PCV, and/or the genome thereof, from PMWS-affected pigs.
- One such group was Nayar's group at the Virology Laboratory, Veterinary Services Branch, Manitoba. Nayar will be examined in more detail below, but in summary Nayar and his co-workers reported the use of a polymerase chain reaction ("PCR") test to detect PCV DNA in tissue from about 100 pigs. They detected PCV DNA in 15 cases. They compared the nucleotide sequence with that of PCV from PK/15 cells and that reported by Meehan, and found differences. They concluded that "specific strains or variants of PCV can be pathogenic and may be associated with PMWS".
- By late September 1997 the Nayar group had succeeded in sequencing the entire genome of a strain of PCV from PMWS-affected pigs. They submitted the sequence to GenBank on 26 September 1997: this is the Hamel GenBank submission. On 27 October 1997 they submitted a paper containing the details of their work, which was published in June 1998 (A. Hamel, L. Lin and G. Nayar, J. Virol., 72, 5262-5267).
- A second group was based at the College of Veterinary Medicine at Iowa State University. They set out to isolate and characterise PCV from PMWS-affected pigs and the genome thereof using both PCR and traditional virus isolation techniques. They started work in July 1997, shortly after the publication of Nayar, and finished in October 1997. In January 1998 they submitted a paper reporting their work, which was published in September 1998 (Morozov et al., J. Clin. Microbiol., 36, 2535-2541).
- Meanwhile, Dr Clark and Dr Harding together with collaborators from The University of Saskatchewan, The Queen's University of Belfast (including Dr Meehan) and Merial were also seeking to isolate and characterise PCV from PMWS-affected pigs and the genome thereof. By 3 October 1997, when they filed the Priority Document, they had succeeded in isolating three strains and in producing an imperfect sequence of the genome of one of these strains. By 22 January 1998, when they filed the second priority document for the Patent, they had isolated and sequenced two more strains, completed and corrected the sequence in the Priority Document and sequenced the genome of another of the original strains.
- Another group at the University of Saskatchewan was also engaged in the exercise of isolating and characterising PCV from PMWS-affected pigs and the genome thereof. By December 1997 they had succeeded in isolating and sequencing three such strains, and on 16 December 1997 they filed Wang 750 which led to Wang 717.
- Finally, on 20 December 1997 the Veterinary Record published a letter from a group at the Centre National d'Etudes Vétérinaires et Alimentaires in Ploufragan, France disclosing that they had isolated PCV DNA from the lymph nodes of animals suffering from a very similar disease to PMWS, cloned and sequenced it (LeCann et al., Vet. Rec., 143, 660). The sequence differed by 19 nucleotide substitutions from that reported by Meehan and by 30 nucleotide substitutions from another sequence reported by another group. PCV major polypeptide produced by the baculovirus expression system could be used to detect antibodies in the sera of affected animals.
- During the International Congress of Virology in Paris in July 2002 the International Committee for the Taxonomy of Viruses ("ICTV") decided to recognise "PCV1" and "PCV2" as separate species of virus. PCV1 is the species found in PK/15 cells. PCV2 is the species associated with PMWS. Even now, however, it has not been proved that PCV2 causes PMWS, if the criterion of proof of causation is fulfilment of Koch's postulates. A meta-analysis published in 2008 suggests that there are additional factors which increase the likelihood of a pig infected with PCV2 developing PMWS (A. Tomás et al, Vet. Microbiol., 132, 260-273). Since PCV1 and PCV2 were only recognised as separate species after the dates that are relevant to the present dispute, I shall refrain from using that terminology.
- Since there is a dispute as to priority, it is convenient to consider the disclosure of the Priority Document before considering that of the Patent. The Priority Document is in French, but the trial was conducted using a certified translation filed by the Patentees with the US Patent and Trademark Office.
- The Priority Document begins at page 1 lines 1-5:
- The Priority Document then describes PCV in general terms at page 1 lines 9-24. At page 1 lines 25-35 it continues:
- At page 1 line 36 – page 2 line 8 the Priority Document briefly describes PMWS, citing Clark, Nayar and two other publications.
- The Priority Document then states in an important passage at page 2 lines 9-38:
- provisional accession No. V97100219 (called here Imp. 1008PCV)
- provisional accession No. V97100218 (called here Imp. 1010PCV)
- provisional accession No. V97100217 (called here Imp. 999PCV).
- At page 3 lines 1-15 the Priority Document states that the viral strains may be cultured on PK/15 cell lines, enabling the production of virus or antigen, in particular for the production of inactivated vaccine. Immunogenic active ingredients and vaccines of the invention are described at page 3 line 28 – page 5 line 31.
- At page 5 lines 32-34 the Priority Document states that the applicant has obtained the genomic sequence of the Californian circovirus, identified as SEQ ID NO: 1. The Priority Document continues at page 5 lines 35 – page 6 line 9:
- At page 6 lines 10-24 the Priority Document says that these sequences and their fragments may be used for the in vitro or in vivo expression of polypeptides. At page 6 lines 25-33 it is stated that the subject of the invention includes such polypeptides produced in vitro. Further discussion of the production of vaccines is to be found at page 6 line 34 - page 7 line 30.
- The Priority Document goes on at page 7 line 31 – page 11 line 20 to discuss diagnostic tests and methods. At page 7 line 36 – page 8 line 7 the Priority Document states:
- At page 11 line 21-35 the Priority Document describes the Figures. Figure 1 is the DNA sequence of the genome of the Im.999 strain, identified as SEQ ID NO. 1. It can be seen from Figure 1 that a number of bases are unresolved. Figure 2 is an alignment of this sequence with the sequence of the PK/15 strain i.e. the sequence published in Meehan.
- At pages 12-23 the Priority Document describes a number of examples. Example 1 describes the culture and isolation of the PCV strains. This involves the collection of tissue samples from the lung and lymph nodes of piglets with PMWS and the culture of viruses from such samples on uncontaminated PK/15 cells followed by superinfection with lysates obtained after freeze/thaw cycles.
- Examples 2-4 describe the detection of PCV sequences and PCV antigens by immunofluorescence and in situ hybridization.
- Example 5 describes the results of an experiment where the PCV genome was used in an in situ hybridisation experiment. Nucleic acid was detected inter alia in mononuclear cells infiltrating the lungs, in pneumocytes, bronchiolar epithelial cells and follicular lymphocytes. The Priority Document states that no such signals were observed when tissues of healthy pigs were similarly probed, but no details of this are given.
- Example 6 explains that, when the three deposited strains were grown in cell cultures, no cytopathic effect was observed. When some of the tissue preparations were fixed with acetone, they bound polyclonal sera and immunofluoresced.
- Examples 7 and 8 describe the extraction of viral genomic DNA from the new strains of PCV and report differences in the restriction map of the DNA extracted from the Imp.999 strain to that reported by Meehan.
- Examples 9 and 10 describe the cloning and sequencing of the viral genome of the Imp.999 strain.
- Example 11 reports that, when the sequence from the Imp. 999 strain was used to test for homology with sequences contained in GenBank, the only significant homology detected was a homology of about 76% with the sequence of the PK/15 strain i.e. the Meehan sequence. At page 21 lines 9-13 the authors state:
- Example 12 describes the use of a plasmid containing the genome of the Imp.999 strain to infect uninfected PK/15 cells. Viral protein was then detected by immunofluorescence, showing that the plasmid was capable of inducing the production of infectious virus.
- Examples 13 to 16 describe the production of vaccines from isolated PCV.
- After Example 16, there is a further unnumbered example reporting the results of an immunofluorescence experiment reacting the PK/15, US and French strains of PCV with hyperimmune sera prepared from the PK/15 strain and the Canadian strain as well as a panel of monoclonal antibodies prepared from PK/15.
- The Patent is a divisional of European Patent No. 1 281 760 ("760") which in turn is a divisional of European Patent No. 1 019 510 ("510"). The effect of these divisionals is to separate the subject matter of the original application into three parts: 510 relates to vaccines against PCV infection, 760 to PCVs themselves, and the Patent to diagnostic reagents and methods. A further divisional application is still pending.
- The specification of the Patent is again in French, but the trial was conducted using the translation filed by the Patentees with the UK Intellectual Property Office pursuant to section 77(6)(a) of the Patents Act 1977. The Patent contains a number of passages which were not present in the Priority Document and other changes. The principal changes are as follows.
- The passage at page 2 line 1 to page 3 line 5 of the Patent corresponding to the passage at page 2 lines 9-38 of the Priority Document quoted in paragraph 22 above contains three changes. First, it refers to five novel strains (rather than three), which now include two strains deposited at ECACC on Friday 16 January 1998, namely Accession No. V98011608 (termed Imp.1011-48285) and Accession No. V98011609 (termed Imp.1011-48121).
- Secondly, it includes the following new paragraphs:
- Thirdly, the final paragraph of the passage has been altered by the addition of the words "under stringent conditions such that there is no hybridisation with the PCV PK/15 strain". This requirement thus qualifies the definition of the third class of circovirus which I identified in paragraph 22 above.
- There are three changes on page 5 of the Patent. First, the Patent states that the Applicant has obtained the genome of four of the isolates (rather than one), identified as "SEQ ID NOs: 1 to 4, and optionally 6".
- Secondly, the paragraph at page 6 lines 5-9 of the Priority Document (quoted in paragraph 24 above) has been altered by the addition of the words "and which belong to group II as defined hereinabove".
- Thirdly, a new paragraph has been inserted after the first references to the use of sequences and fragments in vitro or in vivo as follows:
- At page 7 of the Patent a new passage has been inserted describing the inclusion of valencies corresponding to other pig pathogens in vaccines.
- At page 11 of the Patent, five new Figures are referred to. Figures 1-4 are respectively the DNA sequences of the genomes of strains Imp.1011-48121, Imp.1011-48285, Imp.999 and Imp.1010, identified as SEQ ID NOS 1-4. Figure 5 shows the alignment of these four sequences with the sequence of the PCV PK/15 strain, identified as SEQ ID NO 5. Figures 6 and 7 are what were Figures 1 and 2 in the Priority Document. The sequence disclosed for the Imp.999 strain in Figure 3 of the Patent is a completed and corrected version of the sequence disclosed in the Priority Document, now to be found in Figure 6 of the Patent. It can be seen from this that the originally disclosed sequence was not merely incomplete but also contained errors.
- Examples 1-9 of the Patent are unchanged from the Priority Document. Example 10 contains some new material describing the optimisation of the sequence of the Imp.999 strain and the determination of the sequence of the three other isolates. Example 11 is again unchanged.
- Examples 12 and 13 in the Patent are completely new examples. Example 12 describes a comparative analysis of the sequences of the four strains and of PCV PK/15. It includes a homology matrix for the five strains. After setting out the matrix, the specification continues at page 21 lines 2-17 as follows:
- Example 13 describes the analysis of proteins coded by the genome of the new PCV strains. It includes details of 13 open reading frames.
- Examples 14-18 in the Patent correspond to Examples 12-16 in the Priority Document and are unchanged apart from the numbering. Example 19 in the Patent corresponds to the unnumbered example after Example 16 in the Priority Document and is unchanged apart from the number.
- The only claims in issue are Claims 1, 13 and 18. As contingently proposed to be amended, these are as follows:
- A patent specification is addressed to those likely to have a practical interest in the subject matter of the invention, and such persons are those with practical knowledge and experience of the kind of work in which the invention is intended to be used. The addressee comes to a reading of the specification with the common general knowledge of persons skilled in the relevant art, and he or she reads it knowing that its purpose is to describe and demarcate an invention. The skilled person is unimaginative and has no inventive capacity. In an appropriate case the patent may be addressed to a team of persons with different skills.
- By the end of the trial it was common ground between the parties that the Patent is addressed to a team interested in the cause of PMWS and comprising a veterinary clinician and/or pathologist and people with the skills needed to isolate and characterise infectious agents, in particular viruses, and to design and make diagnostic reagents and vaccines.
- Intervet's sole expert witness was Dr Alan Radford. He is currently a Senior Lecturer in Small Animal Studies at the School of Veterinary Science in the University of Liverpool. He is a member of the Royal College of Veterinary Surgeons, a member of the Society of General Microbiology and a member of the Association of Veterinary Teachers and Research Workers. He started work for a PhD on feline calicivirus (FCV) in 1994 and completed it in 1998. Since then he has worked in the field of veterinary pathology with a focus on viruses, in particular FCV. During his PhD, Dr Radford designed PCR assays for use as tools to detect strains of FCV. He identified regions of the FCV genome which were conserved between the known strains and designed PCR assays to exploit that conservation, so that they would detect not only the known strains, but also as many unknown strains as possible. He has also helped design PCR assays for a variety of other viruses, including squirrelpox virus, canine parvovirus and canine coronavirus. Dr Radford has also grown (or supervised others growing) various viruses in cell culture, for example FCV, feline herpesvirus and canine coronavirus.
- Dr Radford was an excellent expert witness: he was thorough, careful and fair. As counsel for the Patentees pointed out, Dr Radford was clear as to the limits of his expertise. He had no experience as a pig vet. He was not a pathologist or a bacteriologist. Most importantly, he was not an expert on PMWS or circoviruses. Indeed, he acquired his knowledge of PCV during his work on this case. Counsel submitted that it followed that Dr Radford was not in position to assist the court with regard to common general knowledge. I accept that up to a point, but in my judgment the submission goes too far. It is quite true that Dr Radford was not able to assist me with regard to the common general knowledge of those who were interested in PMWS in October 1997, but in my view his qualifications and skills as a virologist were such that he could well have been recruited as a member of the skilled team described above. Thus I consider that he was able to assist me with regard to the common general knowledge of the virologist, and hence with regard to what the skilled team would do in the light of Nayar.
- An important point to note about Dr Radford's evidence is that Intervet's solicitors showed him Nayar and asked for his opinion as to how an averagely skilled team of scientists in the field of veterinary pathology in 1997 would have reacted to Nayar. Only after he had given his opinion was Dr Radford shown the Patent. Thus Dr Radford's opinion with respect to Nayar was unaffected by knowledge of the Patent. On the other hand, he had seen the Patent by the time that he came to design his primers (as to which, see below).
- The Patentees called no fewer than three experts, and it emerged in evidence that they had engaged a fourth. Their principal expert was Dr Kenneth McCullough. He is head of the Research Department of Immunology and Molecular Virology at the Institute of Virology and Immunoprophylaxis ("IVI"), which is part of the Swiss Federal Veterinary Office. He obtained a PhD from the Queen's University of Belfast in 1979 after studying the means by which measles virus established and maintained persistent infections. Between 1980 and 1986, he was based at what is now the Institute for Animal Health in England. Between 1986 and 1989, he worked for Ciba-Geigy in Switzerland, where he was responsible for the virology and immunology laboratory research of the Biovet Unit, which focused on bovine and porcine respiratory diseases. He joined the IVI in 1989 as the Deputy Head of the Vaccine department, where he worked on isolation and identification of various animal viruses including classical swine fever virus and PRRS virus. In 1992, he became head of the Cell Biology (later Immunology) department. In 2000 he began working on PCV type II. In 2005, the Immunology and Molecular Virology departments were amalgamated into the Research Department of which he is now the head.
- Dr McCullough had the advantage over Dr Radford of having worked on PCV and therefore of having expertise in it. As counsel for the Patentees accepted, however, his knowledge was acquired some time after the priority date and therefore he was not in a position to assist me with regard to the common general knowledge of those interested in PMWS at that date.
- Dr McCullough was a good witness, although his oral evidence differed in certain respects from his report. As counsel for Intervet pointed out, Dr McCullough described himself as a viral immunologist. He was not as well placed as Dr Radford to express views on molecular virology issues such as PCR. As counsel submitted, it is not without significance that the Patentees sent Professor Stephen Bustin, a PCR specialist, rather than Dr McCullough to observe the repeats of Intervet's experiments. Despite that, Dr McCullough was asked to comment on the experiments in his report, and no report from Professor Bustin was served.
- The Patentees' second expert was Professor Christopher Chase. He is a Professor in the Department of Veterinary Science and the Animal Disease Research and Diagnostic Laboratory in the College of Agriculture and Biological Sciences at South Dakota State University. He holds an adjunct Professor position in the Department of Biology/Microbiology at South Dakota State University. He is also an associate consulting veterinarian at the Flandreau Veterinary Clinic. He is the President of Rural Technologies, Inc., a company which performs contract research for a number of animal health companies. He also has a consulting business with clients in that field. He qualified as a veterinarian in 1980. He received a Ph.D. in veterinary science with a specialisation in virology/immunology in 1990 from the University of Wisconsin-Madison. His doctoral work included studies of animal viruses using molecular biology techniques. He was a Veterinary Medical Officer at the Arthropod-borne Animal Disease Laboratory at the United States Department of Agriculture's Agricultural Research Service in Laramie, Wyoming from 1990 to 1992. At the same time he was an adjunct assistant professor in the Department of Molecular Biology at the University of Wyoming in Laramie. He then took up his Professorship in South Dakota.
- Professor Chase is a member of the American Association of Swine Veterinarians formerly the American Association of Swine Practitioners. He has 29 years of experience in swine clinical veterinary medicine. His clinical experience has included swine herd health and working with herds with porcine circovirus. As counsel for the Patentees emphasised, he was the only expert with an interest in PMWS and PCV in October 1997.
- I regret to say that Professor Chase did not impress me as a witness. A key aspect of his evidence was the theory that, viewed as at 1997, PMWS could be some form of manifestation of PRRS or caused by a form of the PRRS virus, but he had not mentioned this theory in his evidence in the parallel Dutch proceedings. He had considerable difficulty in justifying certain passages both in his report for these proceedings and in his Dutch declaration. He also raised points during cross-examination which he had not seen fit to mention in either his report or his Dutch declaration. Accordingly, I have approached Professor Chase's evidence with caution.
- The Patentee's third expert was Dr Chad Kitchen. He is a patent agent and scientific advisor at Merial Ltd. He has a PhD from Emory University in molecular and systems pharmacology. Dr Kitchen's report exhibited a declaration of the same date which the Patentees have filed in the parallel EPO opposition proceedings. In that declaration Dr Kitchen explained that he had carried out a computerised restriction enzyme analysis of published PCV1 sequences (most of which dated from after the priority date). The analysis is contained in Annex 1 to his declaration. The first page of Annex 1 after the cover page states (emphasis added):
- Furthermore, in cross-examination Dr Kitchen was unable to defend the conclusion expressed in Annex 1 that:
- In my judgment Dr Kitchen's evidence is not proper expert evidence and is valueless. In saying this I am not criticising Dr Kitchen personally. I think he was placed in an impossible position by his employer.
- Intervet called Dr Igor Morozov as a witness of fact. He obtained a Doctor of Veterinary Medicine degree from the Moscow Veterinary Academy in 1983, and a PhD from the Institute of Experimental Veterinary Medicine in Moscow in 1991. From 1993 to 1998 he worked in the laboratory of Dr P.S. Paul at the Laboratory of Enteric and Respiratory Swine Viruses in the Veterinary Medical Research Institute ("VMRI"), Iowa State University as a Post Doctoral Research Associate. During his work at VMRI he was involved in several projects on a variety of viral pathogens of swine, including transmissible gastroenteritis virus (TGEV), porcine respiratory coronavirus (PRCV), PRRS virus (PRRSV), and PCV. His major areas of interest were the molecular virology of viruses, including genetic characterization, the expression of recombinant proteins, viral genome replication, and the development of new detection methods based on molecular biology techniques. During that period he was part of the team which obtained the DNA sequence of a PCV variant described in the Morozov et al paper. Dr Morozov's evidence was barely challenged in cross-examination.
- Intervet also served two short witness statements from Dr Paulus Sondemeijer and Dr Rolf Apweiler. Neither was required to attend for cross-examination, and the issues to which their evidence was relevant are no longer live.
- After the conclusion of the oral evidence, on 9 February 2010, the Patentees applied for permission to serve two notices of intention to rely upon hearsay evidence which they had served out of time on 4 and 6 February 2010. CPR r. 33.2(4)(a) provides that a party intending to rely on hearsay evidence must serve such a notice no later than the latest date for serving witness statements. In the present case, the case management order made by Mann J on 7 May 2009 provided that such notices were to be served no later than 6 weeks before trial, two weeks after service of experts' reports and witness statements. Intervet opposed the application. Having heard argument, I reserved my decision.
- Failure to give notice in due time does not of itself mean that the hearsay evidence in question is inadmissible, but it is relevant to (i) the court's exercise of its case management powers and (ii) the weight to be given to the evidence. So far as (i) is concerned, CPR r. 32.1 gives the court a discretion to exclude admissible evidence. That discretion may properly be exercised to refuse to admit hearsay evidence where there is a failure to comply with the specified time limit. Although CPR r. 3.9 does not apply in such circumstances, r. 3.9 sets out all the factors to which the court will wish to have regard: see Cottrell v General Cologne Re UK Ltd [2004] EWHC 2402 (Comm).
- The first hearsay notice concerns certain documents emanating from the inventors. The Patentees wish to rely upon these documents as evidence of collaboration between the inventors and other groups working on the characterisation of PCV in 1997-1998. In exercising my discretion as to whether to admit this evidence, I consider that the following points are particularly relevant.
- First, Intervet made it clear that it was relying upon the work of the other groups both in its opposition to the Patent which was filed at the EPO in December 2008 and in its statement of case in the Dutch proceedings filed in June 2009. Furthermore, in paragraph 4.30 of its judgment, the Dutch court accepted that the work of the other groups supported Intervet's case of obviousness. Thus the Patentees can have had no doubt as to the potential significance of the point from at the latest 9 December 2009.
- Secondly, expert reports and witness statements were exchanged by the parties on 30 December 2009 after an extension of time requested by the Patentees. Dr Radford's (first) report summarised the work of the other groups and expressed the view that it supported his opinion on obviousness. Dr Morozov's (first) statement described the work that his group did. It must have been clear to the Patentees from this that Intervet was running the same case in this regard as it had in the Netherlands.
- Thirdly, the Patentees did not at any stage serve on Intervet a notice to admit setting out the facts on which they relied and requesting Intervet to admit them.
- Fourthly, it appears that all the documents on which the Patentees wish to rely were disclosed on discovery in the US proceedings.
- Fifthly, on 26 January 2010 the Patentees served a supplemental disclosure statement disclosing some, but not all, of the documents in question. The disclosure statement stated that the Patentees now considered these to be relevant in the light of section 6 of Dr Radford's (first) report, which is the section in which he considered the work of the other groups. Thus the Patentees had clearly appreciated the relevance of such documents by then, if not before. They did not serve a hearsay notice at that stage, however.
- Sixthly, the Patentees served no evidence in reply to Dr Radford's first report or Dr Morozov's first statement, whether expert or factual. In particular, they did not serve any witness statements from any of the inventors, who are the authors of the documents in question. Nor did they ask Dr McCullough to comment on the documents.
- Seventhly, all of the inventors (with the possible exception of Dr Meehan) were deposed during the US proceedings. The Patentees have not sought to rely upon any transcripts of those depositions.
- Eighthly, on 1 February 2009 the Patentees' solicitors sent Intervet's solicitors a bundle of documents for use in cross-examination which Dr Radford and Dr Morozov were asked to read before giving evidence. This bundle included all of the documents which are now the subject of the first hearsay notice. At that stage the Patentees did not serve any hearsay notice, however. Intervet did not object to Dr Morozov and Dr Radford being asked to read the documents, nor did Intervet object to Dr Morozov and Dr Radford being asked questions about the documents. Neither Dr Morozov nor Dr Radford had any knowledge of the contents of the documents, however.
- Ninthly, the first hearsay notice was served when Dr Radford was giving evidence, about a day before Intervet closed its case.
- Turning to the factors in CPR r. 3.9, I do not consider that (a) adds anything to (h) and (i) in the present situation. As to (b), the application for permission was not made promptly, but at the last moment. So far as (b), (c) and (f) are concerned, the explanation for the lateness of the application given by counsel for the Patentees was that they did not appreciate how Intervet were relying on the work of the other groups until they received Intervet's skeleton argument on 28 January 2010. That explanation does not hold water for the reasons given above. As to (e), the Patentees are not in default of any other rules. So far as (g) is concerned, neither side suggested that the trial should be adjourned either way. As to (h), the effect of the Patentees' failure to comply with the time limit was that Intervet was deprived of the opportunity of (1) applying to cross-examine the authors of the documents on the hearsay statements under CPR r. 33.4, (2) speaking to the authors to see if they would volunteer witness statements and (3) speaking to third parties to see if they could give relevant factual evidence. So far as (i) is concerned, the effect of permitting late service of the notice is to enable the Patentees to rely upon hearsay evidence at an extremely late stage of the proceedings in circumstances where neither the delay nor the Patentees' failure to adduce first-hand evidence has been justified and to deprive Intervet of the means properly to deal with that evidence.
- Weighing all these factors, I do not consider it appropriate to permit late service of the first hearsay notice and I therefore decline to admit the hearsay evidence to which it is directed. Even if I were to grant an extension of time for service of the notice and admit the evidence, I would give the evidence no weight having regard to the matters set out above, and in particular the Patentees' unexplained failure to adduce first-hand evidence from the authors of any of the documents.
- The second hearsay notice concerns certain documents emanating from Intervet. The Patentees wish to rely upon these documents as evidence that Intervet encountered difficulties when trying to isolate PCV and detect it by PCR in 1998. In exercising my discretion as to whether to admit this evidence, I consider that the following points are particularly relevant.
- First, the evidence in question forms part of the Patentees' positive case as to the non-obviousness of the claimed inventions in the light of Nayar. Its potential relevance must have been relevant to the Patentees at an early stage of these proceedings.
- Secondly, the documents in question were disclosed by Intervet both on discovery in the US proceedings and in these proceedings.
- Thirdly, although the documents were disclosed in the US proceedings, the Patentees did not have the opportunity to depose relevant witnesses about the matters in question during those proceedings. Accordingly they were not able to adduce transcripts of depositions as hearsay evidence.
- Fourthly, the Patentees did not at any stage serve on Intervet a notice to admit setting out the facts on which they relied and requesting Intervet to admit them.
- Fifthly, when witness statements and experts' reports were exchanged on 30 December 2009, the Patentees will have noted that none of Intervet's witnesses discussed its own work on PCV.
- Sixthly, the Patentees asked Intervet whether Dr Sondemeijer, who is employed by Intervet, was involved in that work, to which the answer was no. In the light of that answer, the Patentees decided not to cross-examine Dr Sondemeijer. Thus the Patentees knew at that point that Intervet was not calling any witness with knowledge of the matters in question. Yet the Patentees did not serve a hearsay notice in relation to the documents. The explanation given by counsel for the Patentees was that the documents were technical documents which required expert evidence for their interpretation. I accept that point, but I do not see that it excuses the Patentees' failure to serve a hearsay notice. Even with the benefit of expert evidence to explain them, the factual content of the documents remains hearsay. Moreover, service of a hearsay notice would have forewarned Intervet of the Patentees' intention to rely upon that evidence, which is precisely the function of a hearsay notice.
- Seventhly, as noted above, the Patentees did not serve any reply evidence. Even though the Patentees had asked Dr McCullough to read and comment on the Intervet documents, they did not serve any report from him setting out his understanding of what they disclosed. When I asked counsel for the Patentees why not, he said that they did not wish to compromise Dr McCullough's objectivity. I do not understand why Dr McCullough's objectivity would have been compromised. Given that the Patentees wanted to rely upon what the documents disclosed, and given that the documents contained technical matters which required expert explanation, it would have been perfectly appropriate for the Patentees to ask Dr McCullough to prepare a report setting out his understanding of the technical disclosure of the documents. I am surprised that the Patentees sought to adduce evidence from Dr Radford in cross-examination as to his understanding of the documents when they had not led such evidence from Dr McCullough.
- Eighthly, Intervet had not asked Dr Radford to read its disclosure documents. At the same time that the Patentees' solicitors served the bundle of cross-examination documents referred to above, they also served two substantial bundles containing 65 tabs of copies of Intervet disclosure documents. They did not explicitly request that Dr Radford be asked to read them, and Intervet's solicitors did not understand that was in fact what the Patentees wanted. I have to say that I consider that it would in any event have been burdensome for Dr Radford to have to read all of these documents, in addition to the other bundle, at such short notice. Be that as it may, the upshot was that Dr Radford was confronted with the documents for the first time in cross-examination in circumstances where (a) he had no personal knowledge of their contents and (b) he had not been forewarned of the points of interest whether by reading a report from Dr McCullough or otherwise. Understandably, he found it hard to comment upon their contents. I observed at the time that I saw little value in such evidence, but nevertheless I allowed the cross-examination to proceed.
- Ninthly, the second hearsay notice was served after Intervet had closed its case. I should make it clear that the hearsay notice relates to a small selection of the documents contained in the two bundles referred to above.
- Turning again to the factors in CPR r. 3.9, I again consider that (a) adds nothing to (h) and (i). As to (b), the application for permission was not made promptly, but at the last moment. So far as (b), (c) and (f) are concerned, no acceptable reason was given by the Patentees as to the delay in serving the notice, in particular the delay after they knew that Dr Sondemeijer could not speak to the contents of the documents in question. As to (e), the Patentees are not in default of any other rules. So far as (g) is concerned, neither side suggested that the trial should be adjourned either way. As to (h), the effect of the Patentees' failure to comply with the time limit was that Intervet was deprived of the opportunity of adducing first-hand evidence on these matters. On the other hand, Intervet made no application for an adjournment to enable it to adduce such evidence, and I doubt whether Intervet would have adduced such evidence in any event. So far as (i) is concerned, the effect of permitting late service of the notice is to enable the Patentees to rely upon hearsay evidence at an extremely late stage of the proceedings in circumstances where the delay has not been justified. On the other hand, the Patentees were not in a position to adduce first-hand evidence about these matters, and the delay probably made no difference to Intervet's position.
- Weighing all these factors, I consider that it is appropriate to permit late service of the second hearsay notice and I shall therefore admit the hearsay evidence to which it is directed. Nevertheless, it is difficult for me to attach much weight to the contents of the documents. As counsel for the Patentees himself submitted, they are technical documents. They do not speak for themselves, even when read with the benefit of the technical education I have received during the course of this trial. The Patentees chose not to adduce evidence from Dr McCullough to explain them, and they failed to get themselves into a position where they could get much useful evidence from Dr Radford about them.
- The law as to what constitutes common general knowledge is set out in the decisions of the Court of Appeal in General Tire & Rubber Co v irestone Tyre & Rubber Co Ltd [1972] RPC 457 at 482-483 and Beloit Technologies Inc v Valmet Paper Machinery Inc [1997] RPC 489 at 494-495. Counsel for the Patentees emphasised that, in order to constitute common general knowledge, it is not enough that information is generally known to the relevant skilled persons: it must also be, in the words of the Court of Appeal in General Tire, "generally regarded as a good basis for further action". Laddie J put the same idea in slightly different words in Raychem Corp's Patents [1998] RPC 31 at 40 when he said "generally regarded as sufficiently reliable to use a foundation for further work".
- By the end of the trial there was a considerable degree of common ground between the parties as to the common general knowledge of the skilled team. Such differences as there were related to PMWS and its cause(s). In what follows I shall mainly use the present tense, but I am describing the position as at October 1997. My account is largely drawn from Dr Radford's first report with some additions from Dr McCullough's report.
- Viruses were first described in the 1890s when workers showed that tobacco mosaic disease could be transmitted by sap that had been filtered to remove all larger known pathogens. Viruses are obligate intracellular parasites, and can only replicate inside cells of their host. In doing so, they 'hijack' various components of the cell's own biological reactions to ensure that their own genome is transcribed, translated and replicated.
- Unlike unicellular micro-organisms such as fungi and bacteria, viruses are not cells. They possess no functional organelles and are completely dependent on their host for the machinery of energy production and synthesis of macromolecules. Accordingly, viruses have two clearly defined phases in their life cycle: an inert phase, when they are outside the host cell (i.e. during transmission); and an active phase inside the host cell, where the viral genome will exploit the machinery of the host cell to produce progeny "virions" (complete virus particles).
- Virions consist of two or three main parts. All virions possess a nucleocapsid: the viral genetic information (genes) is contained within a genome, comprised of DNA or RNA (but not both), which is encapsidated (surrounded by) one or more capsid proteins. This nucleocapsid structure protects the genome, and in some viruses, wherein the composition of the nucleocapsid includes one or more viral polymerase proteins, may also be involved in initiating viral replication. With certain viruses – the so-called "enveloped viruses" – the nucleocapsid is surrounded by a lipoprotein envelope, into which are inserted one or more different viral proteins which are often glycosylated. A diverse range of additional components are also found in the more complex viruses.
- Viruses can only survive in nature if they can be transmitted from one host to another and ultimately into the cells of the host. Transmission requires the virus to enter the host, infect host cells which are referred to as "permissive" for the virus and its replication, replicate (virus propagation), be released from the host cell and then be shed from the individual host to spread to the next individual. Transmission can be vertical (i.e. from mother to offspring via the placenta) or horizontal (i.e. between animals via respiratory droplets, faeces or blood). Horizontal transmission can be direct (e.g. through physical contact) or indirect (through fomites, any inanimate object or substance capable of carrying infectious organisms e.g. a shared eating container) or through a common vehicle e.g. fecal contamination of water supplies. It may also be airborne (via respiratory droplets), vector-borne (e.g. via a mosquito) or iatrogenic (caused by a veterinarian by for example using non-sterile equipment). Some viruses (zoonotic viruses) may spread naturally between different species of animals (including humans). Some viruses may be transmitted via several different routes whilst others are restricted to just one.
- Viral ecology is very diverse, which is in part a reflection of their long evolutionary history with their hosts. Some viruses are very stable. Other viruses are very mutable, and often cause outbreaks of new disease as a result of mutations.
- Taxonomy of viruses. Viruses can be classified in different ways based on the structure of their genome, on the tissue they infect, on the host they infect, or on their morphology (as seen by electron microscopy). The classification system most favoured by virologists is based on genome structure and is known as the Baltimore scheme. Virus genomes can be DNA or RNA, single-stranded or double-stranded, linear or circular or segmented. The main morphological features of viruses are whether or not they have a lipid envelope and the shape of the capsid.
- Viruses are classified by order (names ending in –virales), family (names ending in –viridae), subfamilies (names ending in –virinae), genera (names ending in –virus) and species.
- One family of viruses is the Circoviridae, whose members have small single-stranded DNA circular genomes. In 1997 the family Circoviridae was known to include a number of animal and plant virus species. The animal viruses included chicken anaemia virus, psittacine beak and feather disease virus and PCV. The plant viruses included banana bunchy top virus, subterranean clover stunt virus and coconut foliar decay virus.
- The lowest level of virus classification routinely recognised is the species. The ICTV has adopted the definition of a virus species as "a polythetic class [ie a class sharing many properties] of viruses that constitute a replicating lineage and occupy a particular ecological niche." Virus species can be differentiated based on some of the following characteristics: relatedness of genome sequence, natural host range, cell and tissue tropism, pathogenicity and cytopathology, mode of transmission, physicochemical properties of virions, and antigenic properties of viral proteins.
- The classification of viruses below the rank of species can be difficult, and the ICTV has no formally recognised broadly applicable classification method at this level. Sub-species classification may be important, but the words that are used are usually developed gradually by consensus by those scientists working in a particular field. Many terms are used (e.g. serotype, genotype, genogroup, lineage, clade, strain, isolate) and their meanings may be quite different depending on the context.
- In order to start to classify viruses below the species level, a representative sample of that species is needed to ascertain the level of diversity within that species. Until one has identified and characterised a number of members of a virus species, it is not possible to sub-classify individuals accurately into a category below species. Sometimes it is possible to identify groups or types of viruses of a particular species which are distinct from each other (in terms of degree of sequence homology or otherwise), but that requires a number of individual strains or isolates to have been characterised. How many is sufficient is not defined, but clearly more than two members of the species (one from each group) are needed to know that there are two distinct groups.
- Virus isolation and culturing. Isolation and culturing is a technique of obtaining many copies of a virus. In order to isolate and culture a virus, the researcher generally starts with clinical material infected with the virus and simply mixes infected material into a cell culture. Assuming one has chosen a suitable cell line as host, the virus will multiply in the culture. It is usually possible to determine whether a virus is multiplying in the culture because the virus particles start to affect the cells' physiology, leading to a change in their morphology which can be viewed under a microscope. This is called a "cytopathic effect" (CPE). For those viruses that do not cause a CPE, other methods such as immunostaining, in situ hybridisation or PCR can be used to demonstrate the growth of virus.
- Virus isolation in cell culture is commonplace in virology labs. Since viruses are obligate parasites and only replicate in certain host cells, the most important thing that is needed to grow a virus in the laboratory is the right host. This can be whole animals (these are rarely used now for ethical reasons), tissues or eggs, but it is most commonly cell cultures derived from tissue samples. There are many cell cultures available to grow a novel virus in, but as a general rule variant or related viruses tend to grow in the same type of cell culture. It is therefore usually obvious what type of cell culture to try to culture a virus in, and the skilled team would have a fairly high expectation that a virus would grow in a cell culture type known to permit growth of a variant of that virus. That expectation may sometimes be wrong, so that a virus will refuse to grow in a particular type of cell culture, but this is uncommon.
- Whilst virus isolation is very useful for developing diagnostic assays and vaccines, it is not essential. For example, before October 1997 noroviruses (recognised as the most common cause of vomiting and diarrhoea in people) had been sequenced, recombinant antigens expressed and antibodies produced, even though the virus had not been isolated.
- Restriction endonuclease ("RE") type mapping is a routine technique for differentiating between similar DNA sequences using restriction endonucleases and gel electrophoresis.
- A restriction endonuclease is a type of enzyme which cuts, or cleaves, double-stranded DNA strands at specific DNA sequences. For example the restriction endonuclease EcoRI cuts at the sequence GAATTC. Digesting a DNA molecule with EcoRI results in the molecule being cut, or cleaved, at each GAATTC in its sequence. The original molecule is then present in several fragments, the sizes of which depend on the frequency and position of the GAATTC motif in the original sequence.
- Gel electrophoresis is used to separate DNA molecules of different sizes. Due to its negative electrical charge, DNA can be moved through a medium (preferably a gel) by applying an electrical field to the medium. Smaller molecules move faster than large molecules, and so it is possible to separate differently-sized DNA fragments from one another. DNA labelling techniques permit the researcher to visualise the DNA and therefore compare the sizes of the DNA molecules in different samples.
- RE type mapping consists of digesting DNA samples using restriction endonucleases, and then analysing the sizes of the fragments produced by gel electrophoresis. If there is more than one variant of the sequence in the sample, and if a difference between the two variants falls at an endonuclease target site, then the digestion of the two variants with that endonuclease will result in a different set of fragments. This will result in a different pattern, or RE map, when the samples are visualised after gel electrophoresis.
- Nowadays, it is possible to do virtual RE mapping using computer software which analyses published DNA sequences. It was software of this kind that Dr Kitchen used for his analyses.
- The polymerase chain reaction (PCR) is a method by which small amounts of a specific sequence of DNA can be amplified exponentially. Starting with say 10 copies of a particular DNA sequence in a sample (e.g. of blood), PCR can multiply those 10 copies into many millions of copies. This amplification permits the researcher to conduct further analysis on the sample which may not have been possible on the original sample due to an insufficient number of copies of the particular sequence.
- All that is required to perform a PCR experiment is a kit of reagents to extract template DNA from the source sample, a thermal cycling machine, thermostable polymerase (this is the enzyme that catalyses the replication of DNA molecules) and primer DNA sequences (known as primers). In 1997 there were several kits available for extracting template DNA and RNA from a range of tissues using routine techniques. Thermal cycling machines were commercially available, as were thermostable polymerases. The primers necessary for amplification could be purchased from commercial laboratories and were inexpensive.
- A primer is a 17-30 base single-stranded DNA molecule that acts as a start-point for the polymerase enzyme. A primer binds (anneals) to a particular point on the single-stranded template DNA because its sequence is designed to be complementary to the template (using the base-pair binding rules of DNA, i.e. T binds to A, and G binds to C). In order to amplify a particular sequence, one would use two primers, with one at either end of the target sequence.
- Processing of PCR amplification products is typically carried out on ethidium bromide-stained agarose gels which enable the experimenter to visualise the result of the experiment. PCR amplification products (amplicons) can readily be sequenced either in the lab, or by third parties, using routine techniques.
- The PCR technique works by separating double-stranded template DNA into single-stranded DNA molecules. This permits the primers to bind to the single-stranded DNA, so acting as a starting point for the polymerase enzyme to replicate the single-stranded template DNA. The polymerase enzyme converts single-stranded molecules into double-stranded molecules by starting at the primer and then adding nucleotides to pair with the base on the template strand. These newly created double-stranded molecules are then again separated into single-stranded molecules. The polymerase enzyme again, prompted by the primers, converts them into double-stranded molecules. Where before there was one double-stranded DNA molecule, there are now four (after two iterations). The process is repeated until the reaction is stopped or runs out of a reagent, typically after 30-40 cycles.
- The section of amplified DNA between the primers which results from the experiment is known as an "amplicon" and often obtaining the amplicon is the aim of the experiment. Sometimes, however, the initial amplicon is only the start of the process. For example, if the object is to obtain the sequence of a circular DNA molecule, it is a simple matter to sequence the amplicon and then design primers facing outwards and sequence the product of that reaction. It is slightly more laborious to obtain the sequence either side of an amplicon from a linear DNA molecule.
- The most obvious variable between PCR reactions is the sequence of the primers. In order to amplify a particular DNA sequence, one must use a primer at the start and a primer at the end of a sequence. Primer design is therefore crucial in PCR. If the sequence of the primer is not a good enough match to the sequence of the template DNA, then the reaction will not work. If one is using PCR to amplify a known sequence, then there is no problem because an exact match can be guaranteed. If one is using PCR to "fish" for a novel sequence, then the conservative approach is to use part of the sequence which is known to be conserved across other related organisms, or other genes in the same gene family.
- There are various rules for primer design that should ideally be observed. The primer should be 17-30 nucleotides in length, with a GC content of about 50% and no self-complementarity. Sequences with long runs of a single nucleotide should be avoided. Ideally, the two primers used in a particular reaction should have similar melting temperatures.
- It is also possible to use "degenerate" primers. These are used to increase the likelihood of a primer binding to a target DNA. They are particularly useful where you are trying to amplify regions where the precise DNA sequence is not known, but where you expect the amino acid sequence to be conserved. Instead of a defined single sequence, a primer mixture is made with many variable, but closely related, sequences within it. The mixtures are denoted by the use of additional letters in the primer other than the usual A, G, C and T. For example, R = A or G, Y = C or T, and N = A or G or C or T. If one designs a short hypothetical degenerate primer that has the sequence ARGY, this primer when manufactured will be a mixture of the following four sequences: AAGC, AGGC, AAGT and AGGT. The disadvantage of degenerate primers is that they come with an increased risk of binding to other unrelated sequences, and that it can be slightly harder to sequence any resulting amplicons. They can, however, be extremely useful when trying to amplify a poorly defined target sequence, particularly one that fails to amplify with conventional, non-degenerate primers. Degenerate primers can be used in various circumstances, in particular to search for variant members of a known related group of genes.
- Uses of PCR. As well as amplifying known templates, PCR has also been extensively used to fish for related novel DNA sequences. It is possible to fish for novel DNA sequences because DNA sequences exist in related groups, the result of mutations and gene duplications. Regions of a DNA sequence may therefore be conserved across a gene family or virus family – usually because that DNA sequence has an important function. These conserved sequences are useful when using PCR to fish for novel genes or novel viruses. The researcher simply designs primers based on the most conserved region of the DNA sequence. Multiple primer pairs are commonly used to maximise the chances of obtaining an amplicon.
- Confidence in PCR. If a skilled person was trying to amplify a known sequence, then he would be highly confident of being able to do so. He would design a pair of primers and run the experiment using the manufacturer's recommended conditions. Usually this would work first time. Sometimes, for unknown reasons, a particular primer pair just fails to work, even when all the rules have been followed. In the event it does not work at all then, he would change the primers. The change could either be small – starting or ending the primer a few bases upstream or downstream of the failed primer; or it could be more radical – basing the primer on a different part of the target sequence. If the experiment worked, but only partially (for example, in the event there was not enough amplicon, or additional amplicon or the wrong size amplicon) then it is routine to manipulate the conditions (such as annealing temperature, magnesium concentration, primer concentration) to improve the results of the experiment.
- If the skilled person was trying to amplify a sequence known to be related to another sequence, then his confidence would depend on how closely related the sequences were believed to be. It would be normal in these circumstances not to rely on one pair of primers, but to design a handful and to test them all in various combinations so as to maximise the chances of amplifying target DNA.
- Hybridisation refers to binding complementary strands of DNA or RNA. For present purpose there are two main types, in situ hybridisation and Southern blot hybridisation.
- In situ hybridisation uses a labelled complementary DNA or RNA strand (called a "probe") to localise a specific DNA or RNA sequence in a portion or section of tissue (in situ). Sample cells and tissues are first treated to fix the DNA or RNA in place and to increase access of the probe. The probe hybridises to the target sequence and excess probe is washed away. The probe is labelled with either radio-, fluorescent- or antigen-labelled bases. This enables it to be localised and quantified in the tissue using either autoradiography, fluorescence microscopy or immunohistochemistry, respectively.
- In Southern blot hybridisation the DNA or RNA is extracted from the tissue, separated on agarose gel and blotted on to a nitrocellulose filter where the probe is applied.
- The strength of the binding between the strands depends on a number of factors, including the length of the region of homology, the extent of homology in that region and the percentage of GC content. In addition, solution parameters such as temperature, salt and/or detergent concentration can be manipulated to alter the extent of non-identical interactions. Hybridisation can be carried out such that only exact sequence matches will remain bound. Alternatively, hybridisation can be carried out such that sequences with a low degree of homology will remain bound. Conditions which result in only sequences with a high degree of homology remaining bound are referred to as "high stringency" conditions. This is a relative term, however, and does not denote a particular set of conditions or a particular degree of homology.
- An antigen (antibody generator) is a substance which is capable of eliciting an immune response from an animal. Antigens may have multiple epitopes (parts of an antigen recognised by an antibody), and so generate multiple antibody specificities.
- Antibodies can be cross-reactive, meaning that a particular antibody might bind to more than one antigen, either because the antigens share the same epitope with precisely the same sequence of amino acids, or because they contain very similar epitopes.
- Antibodies remain in an animal's system long after the antigen that prompted their production has been removed. Therefore the presence of antibodies to an antigen is not necessarily an indicator that the antigen is also present in the animal, it may only be that the antigen has been in the animal in the past.
- Vaccines are designed to protect against infection by stimulating the body's immune system. They generally contain protein components from the organism that you are trying to protect against. The proteins are most commonly obtained by growing the whole organism. Such preparations can either be applied whilst the organism is still capable of replication, or the organism may be inactivated before injection. In the former case, the organism needs to be attenuated so it no longer causes disease itself. The process of attenuation usually involves growing the organism repeatedly in the lab such that the organism mutates and becomes adapted to culture, and less efficient at growing in its normal host.
- An alternative approach to producing the pathogen is to use recombinant DNA technology, such that fragments of the pathogen's protein are expressed in vitro by some other organism. These fragments of the pathogen's protein are then used as the antigenic unit in the vaccine. These engineered vaccines (generally referred to as "subunit vaccines") are becoming more common as they allow the response to the vaccine to be subtly manipulated, and in theory may be safer. Since sequences can be obtained for such vaccines by PCR, it is not necessary to be able to grow the virus for such vaccines. These types of vaccines have been available since the 1980s.
- There are many approaches to developing diagnostic tests for infectious organisms. They can be broadly divided into those that rely on proteins (antibody and antigen tests) and those that detect nucleic acids (PCR). To detect antibodies you need an antigen which, as for a vaccine, can be produced either by growing the organism or by recombinant DNA technology. To detect an antigen, you need antibodies, usually raised in experimental animals by injecting them with a source of antigen (again this can be the whole organism, or a part of the organism expressed by recombinant DNA technology). For PCR, you need to know something of the genetic sequence of the organism you are trying to identify, either its exact sequence, or the sequence of related organisms.
- For both vaccine and diagnostic design and production, there are many potential routes available. Many routine, if somewhat laborious, protocols employing the above principles were available in 1997.
- By the end of the trial, there was no real dispute between the parties as to the skilled team's common general knowledge regarding PCV. This can be summarised as follows:
- In addition, the skilled team would have appreciated that it was likely that other strains of PCV existed in pigs which were different from PCV PK/15. The skilled team would understand there was no reason why other strains of PCV should not be pathogenic just because pathogenicity had not been observed for the PK/15 strain. On the contrary, it was logical to expect that a wild type PCV related to the PK/15 strain could be pathogenic, for two reasons. First, because the PK/15 strain had been attenuated. Secondly, because mutant viruses can be pathogenic and cause an outbreak of a new disease. Indeed, counsel for the Patentees accepted that the skilled team would have been aware that there had been two reports that suggested that PCV could be pathogenic (B. Daft et al, Interstitial Pneumonia and Lymphadenopathy Associated with Circoviral Infection in a Six Week-Old Pig, Proc. Am. Assoc. Vet. Lab. Diagnos. 1996, 32; R.K. Hines and P.D. Lukert, Porcine Circovirus as a Cause of Congenital Tremors in Newborn Pigs, Proc. Am. Assoc. Swine Pract., 1994, 344-345).
- The principal area of dispute between the parties as to the skilled team's common general knowledge concerns PMWS and its cause(s).
- It is common ground that PMWS was a new disease which had been recognised as widespread and which was causing considerable concern in the pig industry. As a result, gaining a better understanding of the etiology, epidemiology and pathogenesis of the disease was regarded as a priority.
- Intervet contend that the contents of Harding and Clark were common general knowledge. The Patentees' final position was to accept that the information contained in those papers was generally known, but to dispute that it was all generally accepted. In particular, the Patentees say that it was not generally accepted that PMWS was caused by a virus, still less that it was caused by PCV: that was merely a theory advanced by Harding and Clark.
- In my judgment Intervet are right to say that the contents of Harding and Clark were common general knowledge. As at October 1997, the study of PMWS was an extremely small and specialised field. Harding and Clark were the seminal papers in that field, and indeed the primary source of information. It is clear that everyone who was interested in PMWS read them, cited them, and treated the information they contained as sufficiently reliable to form a good basis for further action. Dr Radford, Dr McCullough and Professor Chase all agreed that the contents of these publications were common general knowledge.
- So far as the cause of PMWS is concerned, neither Harding nor Clark purported to have identified the causative agent or agents. Rather, Clark postulated that PCV "may be responsible" for the unique lesions found in PMWS-affected pigs. This was not pure theory, since Clark said that "preliminary immunohistochemical and electron microscopic" results supported the theory, although he gave no details. In my judgment the evidence demonstrates that the hypothesis that PCV was responsible for PMWS was generally accepted by those in the field as a plausible hypothesis which merited investigation. Indeed, as outlined above and considered in more detail below, a number of teams immediately set about carrying out such investigations. Thus the hypothesis was generally regarded as sufficiently reliable to form a good basis for further action even though it was not generally accepted to be an established fact. In that sense, it was common general knowledge, as Dr McCullough accepted.
- Professor Chase suggested in his report that the "prevailing theory" at the priority date was that PMWS was a manifestation of or related to PRRS, but he back-tracked from this position in oral evidence in chief. His qualified position was that PRRS was just one of several competing theories about the cause of PMWS, the others being PCV and environmental/nutritional factors. It was not established on the evidence, however, that the skilled team at the priority date was even aware that this theory existed. Thus Dr Morozov had not heard of it. There was no mention of it in any of the contemporaneous documents from which the skilled team would have acquired their knowledge about PMWS. Nor did any of the publications cited by Professor Chase in his report support the theory, and he could not point to any that did. It is telling that Professor Chase himself did not refer to the theory in his evidence in the Netherlands. Professor Chase said that he had heard about the theory at meetings, but that does not establish that it was generally known. In my judgment, it has not been established that the theory that PMWS was a manifestation of PRRS or caused by PRRSV was common general knowledge.
- Even if some workers in the field did think that PRRS might play a role in PMWS, Professor Chase accepted it would not have excluded a role for PCV or have stopped the skilled team at the priority date from looking at PCV as a potential cause of the disease. Moreover, he agreed that PCV was certainly a high suspect on the list of potential causative agents of PMWS in 1997.
- The task for the court when construing a patent claim is to determine what the person skilled in the art would have understood the patentee to have been using the language of the claim to mean: see Kirin Amgen Inc v Hoechst Marion Roussel Ltd [2004] UKHL 46, [2005] RPC 9 at [30]-[35]. In that case the list of principles to be found in the judgment of Jacob LJ in Technip France SA's Patent [2004] EWCA Civ 381, [2004] RPC 46 at [41] was approved subject to one point.
- As the Court of Appeal recently held in Virgin Atlantic Airways Ltd v Premium Aircraft Interiors UK Ltd [2009] EWCA Civ 1062, the skilled reader is taken to know about certain aspects of patent law and practice that bear upon the interpretation of the claim, including the practice of filing divisional applications.
- Intervet suggested that there were two possible interpretations of the expression "type II porcine circovirus". The first is that this means the class of PCVs consisting of the five deposited strains identified in the Patent. The second is that it means the class of PCVs the DNA sequences of which are more than 96% homologous with the four sequences disclosed in the Patent and about 76% homologous with the sequence of the PK/15 strain of PCV.
- The Patentees contend that neither of these interpretations is correct, and that "type II porcine circovirus" means a novel type of PCV of which the five deposited strains are representative. Furthermore, they say that the criterion by which the skilled readers can determine that a particular PCV is of type II is that type II PCVs have a significant serological relationship with the five deposited strains and/or cross-hybridise with the five deposited strains under stringent conditions such that there is no hybridisation with the PCV PK/15 strain.
- It is common ground that skilled persons reading the Patent, whether in October 1997 or January 1998, would not have encountered the expression "type II porcine circovirus" before. It was not a term which had been used to describe PCVs previously. On the contrary, it was coined by the Patentees in the Patent. Accordingly, the skilled reader would look to the Patent for an understanding of what it meant.
- In my judgment it is clear that the invention described in the Patent is not limited to the five deposited strains. On the contrary, the passages at page 2 lines 10-12 and page 21 lines 12-14 expressly state that the five novel strains are representative of a novel type of PCV which the inventors call "type II". Consistently with this, the claims are drafted by reference to type II PCV, that is to say, any PCV of the type of which those five strains are representative. The claims are not drafted by reference to the five novel strains. More generally, the clear message of the specification read as a whole is that the Patentees anticipate that there are likely to be other strains which are also representative of type II. Intervet has not identified any technical reason why the skilled readers of the Patent would think that the claims were limited to just the five deposited strains.
- Page 2 line 14 expressly states that type II PCV (strictly group II, but the terms are used interchangeably in the specification) is "defined above". Similarly page 5 line 24 states that it is "defined hereinabove". In my judgment skilled readers would understand this to mean that the paragraph at page 2 lines 7-12 defines what is meant by "type II" PCV.
- I do not consider that the skilled readers would understand that the definition referred to was merely the statement that type II "denoted" a novel type of PCV. This is not merely a question of semantics. That statement on its own does not define what type II PCV is. Moreover, it must be read in context. As indicated by the word "Thus", the context is provided by the preceding two sentences. It is only when the paragraph is read as a whole that it provides a definition of type II PCV.
- Although the paragraph does not in terms say that type II PCVs are those which have greater than 96% nucleotide homology with the deposited strains and about 76% homology with PK/15 PCV, that is the clear message. Exactly the same message is conveyed by the passage in Example 12 at page 21 lines 2-17, which forms the basis for the earlier passage.
- The Patentees' interpretation of "type II porcine circovirus" amounts to treating the paragraph at page 3 lines 1-5 of the Patent as defining what is meant by "type II porcovirus". In my view there a number of reasons why this paragraph does not support the Patentees' interpretation.
- First, it does not purport to define the term "type II porcine circovirus". Indeed, the words "type II" are not even mentioned.
- Secondly, it comes after the reference to "group II porcine circovirus as defined above" at page 2 line 14. Moreover, by contrast with that passage, it does not refer back to the earlier definition.
- Thirdly, I do not consider that the skilled readers would read it as either providing a definition or broadening the definition which had already been provided. If the skilled readers thought about it, they would appreciate that, as noted above, the paragraph in question contemplates three classes of PCVs. The first embraces any PCV from a pig with PMWS. Counsel for the Patentees accepted that the skilled readers would not think that "type II" was intended to be that broad, and submitted that they would mentally cross the first alternative out. But if the skilled readers would not read the first alternative as defining "type II", why should they think that the second or third alternatives did so? Furthermore, the second alternative is completely uncertain as to its scope. As noted above, the Patent does not define what is meant by "a significant serological relationship". The nearest it comes is Example 19, but that does not come close to providing a criterion for what counts as "significant". For these reasons, I think that the skilled readers would read the passage in question merely as describing certain broad characteristics of PCVs associated with PMWS, but not as defining what constituted a type II PCV.
- Fourthly, if the claims were to be interpreted as the Patentees suggest, for the reasons just given they would be indefinite. It would not be possible for skilled persons to determine whether they were inside or outside the claims. Accordingly, the claims would be invalid on the ground of insufficiency. I shall elaborate on this point below.
- Counsel for the Patentees also relied on the paragraph at page 5 lines 21-24. In my view this provides no assistance to the Patentees. It suffers from similar problems as page 3 lines 1-5, in that the Patent does not define what is meant by "high homology with the strains of the invention" unless this is understood as meaning greater than 96%. Furthermore, it concludes with the words "and which belong to group II as defined hereinabove". Indeed, it seems to me that this paragraph tends to contradict the Patentees' interpretation, since it indicates that "belonging to group II as defined hereinabove" is an additional qualification to hybridisation under high stringency conditions and/or high homology.
- Finally, although claim construction is a matter for the Court when properly instructed as to the common general knowledge, it is telling that when Dr McCullough was asked to consider in his report whether the Patent enabled the skilled readers to determine whether a PCV was a "type II porcine circovirus", the only characterising feature he mentioned was sequence homology. He did not mention serological relationships or suggest that either the passage at page 3 lines 1-5 or Example 19 would enable the skilled persons to determine whether a PCV was a type II PCV. Furthermore, he readily accepted in cross-examination that the reader of the Patent would understand from page 2 lines 1-15 and Example 12 that what characterises "type II porcine circovirus" is its greater than 96% nucleotide homology to the four sequenced strains and about 76% homology to the PK/15 strain. Dr Radford's evidence was to the same effect (although Dr Radford considered that even that definition left some uncertainty with regard to PCVs that were, say, 90% homologous to the sequenced strains).
- For all these reasons, I conclude that Intervet's second construction is the correct interpretation of this feature.
- It is common ground that the skilled readers would not understand the words "responsible in pigs for PMWS" as meaning that it must be shown that type II PCVs cause PMWS. Dr Radford, Dr McCullough and Professor Chase all agreed that the most that the Patent suggests is that type II PCV is associated with lesions in PMWS-affected pigs.
- Counsel for the Patentees submitted that type II PCV by definition was something which was responsible for PMWS. Indeed, he went so far as to say that the words "responsible in pigs for PMWS" in the claims could be disregarded as surplusage.
- Counsel for Intervet submitted that it was not right to treat the claims as if these words were not present. Thus he argued that, if someone found a type II PCV (meaning a PCV which satisfied the nucleotide homology criteria set out at page 2 lines 8-10) which was not responsible for PMWS (meaning that it was not associated with lesions in PMWS-affected pigs e.g. because it was found to be widespread in healthy pigs), then it would not fall within the claims.
- In principle, I consider that counsel for Intervet is correct. The practical difference between these interpretations in the terms of the scope of the claim is slight, however. What is more important is that Patent does not disclose, and therefore the claims cannot be interpreted as requiring, anything more than association between type II PCV and PMWS. In particular, the Patent does not describe a case control study involving type II PCV. Nor does it exclude PRRSV as a potential cause of PMWS. Still less does it exclude other causative agents such as bacteria. This is of significance when it comes to the inventive concept of the claims (as to which, see below).
- It is common ground that a "type II porcine circovirus specific antibody" would be understood as meaning an antibody which demonstrably binds to type II PCV antigens, and not with other antigens which may be found in pigs such as type I PCV antigens, and a "type II porcine circovirus specific antigen" would be understood to mean an antigen which only binds antibodies produced following exposure to type II PCV and will not generate antibodies which cross-react with other antigens which are found in pigs such as type I PCV antigens.
- Intervet contends that claim 18 requires the specific antigen to "[allow] the diagnostic of type II PCV infection" in the state in which it is present in the "isolated antigenic preparation". Accordingly, Intervet says that the claim does not extend to preparations which contain antigens which might be useful as diagnostic tools if extracted from the preparation and put into some other context.
- The Patentees contend that claim 18 is not limited to antigenic preparations which are used for diagnostic purposes, but extends to antigenic preparations which contain an antigen which is suitable for use as a diagnostic for type II PCV. Accordingly, the Patentees say that the claim extends to a subunit vaccine that contains an antigen which could be used as a diagnostic.
- It is convenient to consider the Patentee's argument in stages. Counsel for the Patentees submitted that the starting point for the construction of claim 18 is to recognise that it is a product claim and not a method claim. Although the final integer of claim 18 appears at first blush to have a method flavour to it, it would not be correct to construe the claim as if were a method claim. Counsel for Intervet did not dispute this.
- Counsel for the Patentees next submitted that claim 18 does not limit the purpose for which the isolated antigenic preparation is to be used. Again, Counsel for Intervet did not dispute this.
- Counsel for the Patentees next submitted that the comma in claim 18 indicates that it is the antigen which must allow the diagnostic of type II PCV and not the isolated antigenic preparation. Counsel for Intervet accepted this, but subject to the qualification that it is the antigen when comprised in the isolated antigenic preparation which must allow this. I agree with that qualification.
- Finally, counsel for the Patentees submitted that "allowing the diagnostic of" meant much the same as "suitable for diagnosing". I am prepared to accept this. As counsel for Intervet submitted, however, it does not follow that the claim covers products which cannot be used for that purpose without modification. As is stated in the EPO's Guidelines for Examination in section C chapter III paragraph 4.13:
- Reading claim 18 in the context of the Patent as a whole, I consider that the skilled readers would understand it clearly to be directed to a diagnostic reagent and not to a subunit vaccine. After all, as counsel for Intervet pointed out, the title of the Patent is "Method for … in vitro diagnosis … and diagnostic reagents". Furthermore, the specification only discusses specific antigens and specific antibodies in the context of diagnostic reagents, not vaccines. As Dr Radford explained, specificity is important for the purpose of a diagnostic reagent but not for a vaccine.
- Counsel for the Patentees sought to support the Patentees' construction by pointing out that page 6 lines 1-15 of the Patent discloses subunit vaccines comprising at least one polypeptide obtained by expression of sequences of type II PCVs. Such a polypeptide would constitute an antigen which could be used as a diagnostic tool. In my view that would not lead the skilled readers to think that claim 18 was directed to subunit vaccines when everything else points in the opposite direction.
- Finally, counsel for Intervet argued that Intervet's construction was also supported by the fact that, as the skilled readers were to be taken to be aware, the Patent was a divisional and one of the other patents in the family, namely 510, contained claims directed to vaccines. Counsel for the Patentees riposted that the claims of 510 were confined to vaccines containing inactivated virus and did not include subunit vaccines. I am unimpressed with that point, particularly in circumstances where a further divisional is still pending. In my view, the knowledge that the Patent in suit is a divisional application, and that at least one other divisional contained claims to vaccines, would reinforce the skilled readers' natural reading of claim 18 as being directed to diagnostic reagents and not vaccines.
- For all these reasons I prefer Intervet's construction.
- In order for a claimed invention to be entitled to priority from an earlier application, it must, in the words of section 5(2)(a) of the 1977 Act, be "supported by matter disclosed" in that earlier application. Article 87(1) of the European Patent Convention expresses the requirement as being that priority can only be accorded in respect of "the same invention" as one in the earlier application. Section 5 is one of the sections which is declared to be intended to have the same effect as the corresponding provision of the EPC: see section 130(7).
- In case G2/98 [2001] OJEPO 413, [2002] EPOR 167 the Enlarged Board of Appeal of the European Patent Office equated "the same invention" in Article 87(1) with "the same subject-matter" in Article 87(4). It expressed the requirement for claiming priority as follows:
- The Court of Appeal explained this requirement in Unilin Beheer NV v Berry Floor NV [2004] EWCA Civ 1021, [2005] FSR 6 at [48] as follows:
- As Kitchin J observed in Abbott Laboratories Ltd v Evysio Medical Devices plc [2008] EWHC 800 (Pat), [2008] RPC 23 at [228], after citing G2/98 and Unilin v Berry:
- In his closing submissions, counsel for the Patentees conceded that, if Intervet's construction of the claims was correct, then they were not entitled to priority for the Priority Document. It is nevertheless worth explaining why I consider that that concession was correctly made.
- Although the burden of proof lies upon the Patentees to establish that the claims in issue are entitled to priority (see Evans Medical's Patent [1988] RPC 517 at 532-533), it is convenient to begin by summarising Intervet's challenge to priority. In short, Intervet contends that the first priority document did not disclose either the existence or the characteristics of the class of PCVs referred to in the claims as "type II porcine circovirus", which is a fundamental aspect of the claimed inventions in the Patent. There was no way, says Intervet, that the existence and characteristics of that class, and hence the claimed inventions, could be derived directly and unambiguously from the disclosure of the Priority Document.
- Counsel for the Patentees submitted in his opening submissions that the mere fact that the Patent contains additional information which was not present in the Priority Document does not mean that the claims in issue are not entitled to priority. I accept that. Counsel for the Patentees also submitted that the mere fact that the Patent uses a new label to denote a class of viruses does not mean that the claims are not entitled to priority if that class was disclosed in the Priority Document. Again, I accept that.
- The question, therefore, is whether, as a matter of substance, not terminology, the Priority Document disclosed the existence and characteristics of the class of viruses which the Patent refers to as type II PCVs. In my judgment there can only be one answer to that question. The Priority Document does not begin to disclose the existence of that class, let alone its characteristics. The Priority Document does imply that the three strains may be representative of up to three classes of PCVs, but those classes are very broadly and imprecisely defined. The Priority Document only discloses the sequence of one strain, Imp.999. It is fair to say that the Priority Document does disclose that the sequence of Imp.999 is about 76% homologous to that of PK/15 PCV. The skilled readers of the Priority Document have no idea, however, whether the other two deposited strains are more homologous to PK/15 PCV than that, and if so how much more, still less whether other strains that might be isolated from PMWS-affected pigs would be more homologous, and if so how much more. There is no hint in the Priority Document of the criterion of greater than 96% homogeneity. That is not surprising, because the Patentees had not done the sequencing work which enabled them to devise that criterion by the time of the Priority Document.
- Counsel for Intervet submitted that the claims were not entitled to priority from the Priority Document even on the Patentees' construction. Since I have rejected that construction, I shall only deal with this briefly. The Patentees' construction defines "type II porcine circovirus" as including viruses which "cross-hybridize with the strains of the invention under stringent conditions such that there is no hybridisation with the PCV PK/15 strain". The Priority Document merely referred to viruses "having cross-hybridisation with the strains of the invention". The first point is that "the strains of the invention" means different things in the two documents: in the Priority Document it is the three originally deposited strains, whereas in the Patent it is the five strains. Furthermore, the addition of the words "under stringent conditions such that there is no hybridisation with the PCV PK/15 strain" changes the class of viruses referred to. Merely saying that strains "cross-hybridise", as the Priority Document does, says nothing about the stringency of the conditions, or the degree of homology of the sequences. By contrast, skilled persons reading the Patent would understand that they are supposed to choose their conditions by increasing stringency until the strain of the invention no longer cross-hybridises with the PK/15 strain, and then use those conditions to see whether the strain of interest cross-hybridises with the strains of the invention. Thus even on the Patentees' construction the Priority Document does not disclose the same invention as is claimed in the Patent.
- I therefore conclude that the unamended claims are not entitled to priority from the Priority Document.
- I would add that in my view this conclusion supports the construction of the claims I have adopted. If the claims were to be entitled to priority, it could only be on the basis that "type II porcine circoviruses" denoted a class of PCVs the existence and characteristics of which (albeit not the label for which) were disclosed in the Priority Document. That would mean that the criteria for determining whether a PCV fell within or outside that class would have to be based exclusively on the disclosure of the Priority Document. That would mean that skilled readers of the Patent would have to rely solely upon the incorrect first sequence of Imp.999 and its 76% homology to PK15, and for what it is worth the serological experiment, for that purpose. There is nothing in the Patent to suggest to skilled readers that that information was sufficient to determine whether a PCV was type II or not. On the contrary, the clear message of the Patent is that the four sequences disclosed in it are key to that determination.
- In his closing submissions counsel for the Patentees substantially conceded that, if Intervet was right on priority, the proposed amendments did not assist the Patentees. Accordingly, I shall deal with them briefly. They restrict claim 1 to a diagnostic method involving a diagnostic reagent that recognises a type II PCV selected from the three deposited the day before the Priority Document was filed and claim 18 to an antigenic preparation comprising an antigen recognised by antibodies specific to a type II PCV selected from those three.
- Three points may be noted. First, no amendment is proposed to claim 13. Accordingly, the amendments cannot save claim 13's entitlement to priority.
- Secondly, the amendments to claims 1 and 18 do not simply limit those claims to diagnostic reagents that recognise one of the three deposited strains and antigenic preparations comprising antigens from one of the three deposited strains.
- Thirdly, the amendments do not actually address the problem, since the claims continue to refer to "type II porcine circovirus". This confirmed by two matters. First, counsel for the Patentees submitted in opening that "the amendments meet the theoretical objection that the mere depositing of additional sequences may have subtly affected the scope of the term 'type II porcine circovirus' antigen". As he ultimately accepted, however, that is not Intervet's objection. Secondly, counsel for the Patentees himself contended that the amendments had very little effect on the scope of the claims.
- Accordingly, I shall not allow the amendments since they do not entitle the claims to priority and therefore do not save the Patent from invalidity.
- Intervet relies upon insufficiency as a squeeze on construction. Counsel for Intervet accepted that, if the claims were construed as contended for by Intervet, then the claims were not insufficient. He submitted, however, that, if the claims were construed as contended for by the Patentees, then the Patent did not disclose the invention clearly and completely enough for it to be performed by skilled persons. As I indicated above, I accept that submission. I shall elaborate upon my reasons here.
- As mentioned above, the Patent does not attempt to define what amounts to a "significant serological relationship". Although Example 19 of the Patent reports the results of a serological comparison, the Patent does not attempt to relate these results to "significant serological relationship". It was put to Dr Radford, and he accepted, that the test in Example 19 was a conventional test which was not difficult to perform, but that is beside the point. Even if the skilled readers guessed that "significant serological relationship" was intended to reflect the results reported in Example 19, neither those results nor anything else in the Patent provide a criterion which the skilled persons can apply in order to determine whether something is within the claim or not. As noted above, it is telling that Dr McCullough did not suggest in his report that serological similarity could provide a basis for characterising type II PCV.
- Counsel for the Patentees submitted, and counsel for Intervet accepted, that the words "circoviruses which cross-hybridise with the strains of the invention such that there is no hybridisation with the PCV PK/15 strain" did provide a workable test. As Counsel for Intervet submitted, however, that does not assist the Patentees. Even on the assumptions that (a) the skilled readers treat the passage at page 3 lines 1-5 as providing a working definition of "type II porcine circovirus" and (b) the skilled readers mentally cross out the first class identified, it remains the case that this passage clearly presents "circoviruses having a significant serological relationship with the strains of invention" as one of the classes of virus embraced by the term "type II porcine circovirus". Counsel for the Patentees did not suggest that skilled readers would mentally cross that one out as well.
- A patent will be invalid for lack of inventive step if the invention claimed in it was obvious to a person skilled in the art having regard to the state of the art at the priority date. The familiar structured approach to the assessment of allegations of obviousness first articulated by the Court of Appeal in Windsurfing International Inc v Tabur Marine (Great Britain) Ltd [1985] RPC 59 was re-stated by Jacob LJ in Pozzoli v BDMO SA [2007] EWCA Civ 588, [2007] FSR 37 at [23] as follows:
- In both H. Lundbeck A/S v Generics (UK) Ltd [2008] EWCA Civ 311, [2008] RPC 19 at [24] and Conor Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] UKHL 49, [2008] RPC 28 at [42] Lord Hoffmann approved without qualification the following statement of principle by Kitchin J at first instance in the former case:
- When considering the fourth Pozzoli step, a relevant consideration is whether what is claimed arises from taking steps which were obvious to try with a fair expectation of success. As Lord Hoffmann said in Conor at [42]:
- The primary evidence on the question of obviousness is that of properly qualified expert witnesses. Secondary evidence must be kept firmly in its place: Mölnycke AB v Procter & Gamble Ltd [1994] RPC 49 at 112. As Laddie J explained in Pfizer Ltd's Patent [2001] FSR at [63]-[64], evidence of what actual researchers in the field were doing at the time may be persuasive, but must be examined with care to see if it sheds light on what the notional skilled person with common general knowledge and the prior art would do.
- I have already identified the skilled team and their common general knowledge above.
- Jacob LJ has recently cautioned in Actavis UK Ltd v Novartis AG [2010] EWCA Civ 82 at [19]-[20] that strictly what matters is the claim and that attempting to identify the inventive concept can be a distraction, particularly where it is disputed. In the present case, however, I consider that it is of assistance to identify the inventive concept.
- It is common ground that there is no material difference between the inventive concept of claim 1, 13 and 18 so far as the issue of obviousness over Nayar is concerned. It is also common ground that, although the claims are directed to diagnostic methods and reagents, developing these would be a matter of routine once type II PCV and/or its genome was isolated and characterised. Accordingly, counsel for Intervet submitted, and I agree, that the inventive concept is the identification and characterisation of a PCV and/or its genome which is of the class which the Patent calls type II.
- Counsel for the Patentees submitted that the inventive concept was (a) the identification and characterisation of the class of strains which together form type II porcine circovirus (b) as the causative agent of PMWS. I do not accept either limb of this formulation. So far as (a) is concerned, the claim is obvious if anything falling within it is obvious. It follows that it is not necessary for Intervet to show that the characterisation of the class was obvious provided that it was obvious to characterise a member of the class. With regard to (b), as discussed above, the Patent does not disclose that type II PCV is the causative agent of PMWS, merely that it is associated with PMWS.
- I have summarised Nayar in paragraph 11 above. In more detail, Nayar begins by briefly describing PMWS, citing Harding and Clark. It then describes PCV, making the points that it is "ubiquitous" in pigs and that PCV PK/15 is non-pathogenic. Nayar and his colleagues then say that they have tested 100 pigs with clinical signs and pathology consistent with PMWS for PCV using a PCR test. PCV DNA was detected in 15 cases. Three of these were also positive for PRRSV and two for Mycoplasma hyopneumoniae. All were negative for swine influenza virus. The DNA products of PCR amplification from the 15 cases were then subjected to RE cleavage map analysis. At least three different RE types were found. Nayar concludes (emboldening in the original):
- Nayar discloses four points of significance to the skilled team. First, it provides further support for Clark's hypothesis that PCV may be responsible for PMWS. Secondly, it suggests for the first time that specific strains or variants of PCV could play a pathogenic role in the disease. Thirdly, it says that these strains or variants had measurable genetic differences from the Meehan sequence. Fourthly, it indicates that routine laboratory techniques were used to obtain these results.
- On the other hand, Nayar is a short publication which omits a number of matters. First, it does not include details of the experimental methodology and in particular the primers which were used, although the reference to Meehan suggests that they were based on the PCV PK/15 sequence Meehan disclosed. Secondly, it does not include the actual results obtained, in particular the sequences and RE maps. Thirdly, Nayar does not report any results from controls, in particular negative controls from clinically normal pigs.
- The difference between Nayar and the inventive concept is that the inventors have actually isolated, and sequenced the whole genome of, strains of type II PCV from PMWS-affected pigs.
- Intervet's case that the invention is obvious over Nayar is simple and straightforward. It is an "obvious to try" case which can be summarised as follows:
- The Patentees take issue with each of points (i), (ii) and (iii). There is quite a lot of evidence on these issues. I shall concentrate on what seem to me to be the salient points, but I have taken all the evidence into account.
- What would the skilled team have done in the light of Nayar? Dr Radford's opinion as expressed in his reports was that the skilled team would have regarded Nayar as an exciting disclosure and that it would have been obvious for them to try either of the two routes discussed above. So far as PCR was concerned, there were two obvious possibilities, namely to design primers based on the Meehan sequence which either targeted likely conserved regions of the genome (Dr Radford's preferred approach) or were randomly positioned along the genome. Dr Radford was not shifted from this opinion in cross-examination.
- The Patentees contend that the skilled team would not have done anything at all in the light of Nayar. It was this case that the reports of Dr McCullough and Professor Chase were served to support. It failed to withstand cross-examination, however.
- Dr McCullough's evidence was that he would have expected the skilled team to seek to characterise PCV in the lesions of pigs with PMWS even without Nayar:
- Dr Cullough accepted that Nayar would reinforce this:
- In his report Dr McCullough raised a number of points about Nayar, but these boiled down to one, namely the absence of any reported controls. He accepted, however, that this would not deter the skilled team from repeating Nayar but with proper controls. Professor Chase's evidence was to the same effect.
- In his closing submissions, counsel for the Patentees went so far as to submit that the skilled team would have regarded Nayar as a step backwards from Clark and Harding. Leaving aside the fact that it is hardly consistent with how the Patent itself treats Nayar at page 1 lines 19-23, in my judgment the submission is contrary to the evidence. Counsel also submitted that Nayar had not excluded other potential causes of PMWS, such as PRRSV, a bacterium or even nutrition. That is true, but it does not detract from the fact that, as Dr Radford and McCullough agreed, Nayar added to the evidence that PCV was responsible for PMWS. The Patent does not exclude other causes either, and all it adds to Nayar in terms of evidence for causation is the bare statement that healthy pigs tested negative for type II PCV.
- Given that the skilled team would have taken Nayar forward, Dr Radford's opinion that PCR with either primers for conserved regions or random primers and virus isolation were obvious things to try was not directly challenged. Nor did Dr McCullough suggest that they were not obvious to try. On the contrary, it can be seen from the extracts quoted above that he accepted that they were both obvious approaches.
- Would the skilled team have had a reasonable expectation of success? It is convenient to consider the two routes separately.
- So far as virus isolation is concerned, as set out above, culturing PCV PK/15 using the PK/15 cell line was part of the common general knowledge at the priority date. Dr Radford said in his first report that it was obvious to use the same cell line and same set of conditions to try to culture PCV from the lesional tissue of PMWS-affected pigs. Furthermore, the skilled team would have been reasonably confident of success. This evidence was reinforced by Dr Radford's cross-examination. He said that the skilled team would not know if virus culture and isolation would work, but it was easy to try and it would have been worth trying.
- Dr McCullough did not suggest that the skilled team would not have had a reasonable expectation of success. On the contrary, as can be seen from the extracts quoted above, his evidence was that virus isolation would have been their preferred route.
- Furthermore, Dr Radford's opinion is supported by the following points:
- As for the PCR route, Dr Radford's evidence was that, whether they used primers randomly positioned along the genome or based on expected conserved regions, the skilled team would have had a reasonable expectation that this would work to produce a variant PCV amplicon. The amplicon would then be sequenced and new primers made to amplify the remainder of the genome. The skilled team could then examine its etiological role, and design and make diagnostic tools and vaccines. Dr Radford's evidence that the skilled team would have a reasonable expectation of success was not directly challenged in cross-examination. Rather, the cross-examination concentrated on difficulties that they might face, which I shall consider below.
- Dr McCullough agreed that the skilled team would have expected to succeed:
- Would the skilled team have been likely to succeed? Again, it is convenient to consider the two routes separately.
- So far as virus isolation is concerned, Dr Radford's evidence was that it was likely to work. Dr McCullough did not suggest otherwise. The evidence considered in paragraph 223 above confirms that success was likely.
- The only evidence the other way comes from the Intervet disclosure documents. It appears from these that in March 1998 Intervet did initial preparatory work relating to virus isolation, and by June 1998 it had succeeded. In the interim, there appear to have been three unsuccessful experiments. In the first case, Dr Radford's evidence was there was something wrong with the negative control; in the second case the experiment seemed to have failed for a reason which was not immediately apparent to him; in the third the positive control failed. It was not put to Dr Radford, however, that the length of time and number of attempts needed by Intervet to achieve success was out of line with the skilled team's expectations or was in any way other than standard in the art. Nor was it put to him that the skilled team would not have embarked on the virus isolation route because of the risk of initial failures, or that success required invention or undue effort. This evidence comes nowhere near displacing the conclusion to be drawn from the evidence considered above.
- As to PCR, Dr Radford designed a set of primers which were used in experiments carried out by Intervet and shown to bind to type II PCVs and to produce amplicons of the expected size in the conserved regions.
- A number of points were put to Dr Radford in cross-examination on this part of the case. First, it was suggested that there might be difficulty in getting hold of samples from PMWS pigs. Dr Radford did not think that that would be a problem. Nor was it suggested by Dr McCullough that getting hold of suitable tissue samples was difficult.
- Secondly, it was suggested his choice of the expected conserved region primers was a hindsight one which was influenced by his reading of the Patent. Dr Radford did not accept this. Moreover, Dr McCullough's evidence was that he would have expected the skilled team to base their primers on the Meehan sequence at regions of consensus amongst other circoviruses.
- Thirdly, it was suggested that one of Dr Radford's primers, primer 4, was unusual since it was based not on the conserved region but on a nearby region containing two consecutive tryptophan residues. Dr Radford replied that the design of that primer was based on a standard textbook and he did not accept that it was clever, although he could not say that a skilled team would necessarily use that primer. In any event, success in the experiments did not depend upon use of primer 4, as one of the primer sets which worked well did not use it, as did other primer sets which worked, albeit less well.
- Fourthly, it was pointed out that Intervet's experiments had used three strains of type II PCV deposited by the Patentees rather than lesional tissue. Dr Radford explained that experiments on lesional tissue could have been done, but there wasn't time. It was put to Dr Radford that he could not be sure that his primers would work on tissue samples, but he said that his expectation was that they would work. Furthermore, I agree with counsel for Intervet that, given that Intervet's experiments succeeded, the evidential onus then shifted to the Patentees to conduct an experiment in reply to show that the same result would not be obtained using tissue samples. No such experiment was done.
- Three reasons were suggested as to why Dr Radford's primers might not work with tissue. Two of these were dealt with by Dr Radford in his second report, were not pursued in cross-examination and were not maintained by Dr McCullough. The only point that was pursued, at some length, was that the samples used by Intervet in its experiments contained much larger copy numbers of PCV than would be found in lesions. I agree with counsel for Intervet that this point went nowhere. Dr McCullough relied on a paper by Liu et al (J. Clin. Microbiol., 38, 3474-3477) which showed the number of type II PCV in serum as averaging 4.6 x 106 copies/ml with 4.6 x 104 copies being used in Liu's PCR experiments. It is quite true that the samples used by Intervet contained several orders of magnitude more PCV copy numbers. As Dr Radford pointed out, however, if the PCR assay is above its threshold of sensitivity, then it does not matter that a vast excess of PCV was used. The quantities in serum which were being detected by Liu are not small quantities for a PCR assay, so there is no reason to think that Liu's PCR was particularly sensitive. Furthermore, there is nothing to suggest that Intervet's PCR assay was anywhere near its level of sensitivity. Not only was no such suggestion put to Dr Radford, but also he said he would be surprised if it did not work on much lower amounts of DNA than were used in the experiments. In any event, the evidence indicates that levels of type II PCV DNA in lesions are likely to be significantly higher than those in serum.
- The Patentees also sought to rely upon Intervet's disclosure documents as showing that Intervet had encountered difficulties in performing PCR tests on tissue. Dr Radford was not able to say much about these documents, and I am unconvinced that they demonstrate that the skilled team would be likely to face significant problems.
- The highpoint of counsel for the Patentees' cross-examination of Dr Radford was the following passage:
- The work of the other groups. Dr Radford analysed in his first report the publications reporting work done by the others in the field in 1997. Neither his analysis, nor his summary of the matters which emerged from the publications by Nayar, Morozov et al and Wang, was challenged. This evidence shows that:
- In addition to Dr Radford's analysis of the published materials, Dr Morozov gave first-hand evidence of the work his group did. In summary, the work was stimulated by the reports associating PCV with PMWS lesions, especially Nayar. Dr Morozov said he was confident that he would find a wild type PCV in samples from PMWS pigs, based on Clark and Nayar. He adopted what seemed an obvious approach of using random primers based on the Meehan sequence, and used standard procedures which led to obtaining the sequence of the genome within two months. The virus was then isolated by Ms Morgan as described above. The whole process took about 3 months, which was standard. It was not put to Dr Morozov that he, or the others in the team who conducted the work, were unusually skilled, or that they were in any way inventive in what they did. Counsel for the Patentees suggested that it was significant that Dr Paul's group had a particular interest in xenotransplantation. It was not suggested, however, that the work would not have been done, or would have been done differently, if the group had not had that interest and instead had only been interested in PMWS.
- As noted above, the Patentees sought to rely upon disclosure documents emanating from the inventors as suggesting that there had been collaboration between the inventors and the other groups. For reasons I have given, I decline to admit this evidence and I would not give it any weight even if it were admitted. In any event, the documents do not establish that there was any transfer of any information from the inventors to any of the other groups or, if there was, that it was material information not available to the skilled team in October 1997.
- I consider that the Nayar, Morozov and Wang groups approximate reasonably closely with the skilled team. Certainly there is no evidence to suggest that they had access to special information (except that the Nayar group will obviously have known more about the work described in Nayar than anyone else) or were inventive. Accordingly, I consider that the secondary evidence in this case lends strong support to the primary evidence that it was obvious to try to isolate and characterise a type II PCV and/or its genome, that the skilled team would have a reasonable expectation of success and that they would be likely to succeed.
- Conclusion. I conclude that it would have been obvious to the skilled team in the light of Nayar to try to isolate and characterise PCV, and/or its genome, from PWMS-affected pigs by each of the two routes discussed above, that they would have had a reasonable expectation of success and that they would have been likely to succeed. Accordingly, the claimed inventions are obvious in the light of Nayar.
- The problem and solution approach. It is worth cross-checking this conclusion using the EPO's problem and solution approach discussed by Jacob LJ in Actavis v Novartis. The closest prior art is Nayar. The objective technical problem is to isolate and characterise a type II PCV, and/or its genome, from PWMS-affected pigs. Would the skilled team solve that problem starting from Nayar without invention? In my judgment they would. The skilled person would have strong motivation to follow up on the findings by Nayar that "specific strains or variants of PCV can be pathogenic and may be associated with PMWS", given the nature of the disease known from Harding and Clark, which even if they were not common general knowledge are incorporated by reference in Nayar. The skilled team would have a good expectation of success, as the required techniques, viral isolation and PCR/sequencing, were well established in the art. Furthermore, there were no difficulties in the application of either technique: PCV was known to replicate on a readily available cell-line, PK/15, and viral DNA could be readily amplified by PCR, cloned and sequenced using well-known techniques.
- The Dutch judgment. I also note that the Dutch court concluded in section 4 of its judgment that the Dutch counterpart of the Patent was obvious for similar reasons to those given above.
- Porcillis PCV is a vaccine for the active immunisation of pigs against PCV in order to reduce the virus load in blood and lymphoid tissues and to reduce weight loss associated with PCV2 infection occurring during the fattening period. It contains as a subunit antigen the major capsid protein encoded by what is known as the ORF2 gene of PCV2. (This is the same gene as is referred to as ORF13 in the Patent.) This protein is expressed in baculovirus infected insect cells. The infected insect cells are then subjected to sonication, inactivation and centrifugation. The centrifugation product, which is used in Porcills PCV, comprises the PCV2 capsid protein as well as insect cell fractions and baculovirus aggregates.
- Porcillis PCV also contains di-alpha-tocopheryl acetate and light liquid paraffin as adjuvants and polysorbate 80, simethicone and water for injection as excipients.
- Dr Radford gave unchallenged evidence that Porcillis PCV cannot be used as a diagnostic tool. He also gave unchallenged evidence that various modifications would have to be made to the product to enable the ORF2 antigen to be used as a diagnostic tool.
- It follows that, on the construction of claim 18 that I have adopted, Porcilis PCV does not fall within claim 18.
- Intervet contend that, if the claim were to be amended as proposed, there would be a further reason why Porcilis PCV would not infringe. This is that there is no evidence that Porcilis PCV ORF2 antigen will be recognised by antibodies specific to one of the three originally deposited strains. Counsel for the Patentees submitted that this was not what the amended claim required, and that it was sufficient if the antibodies were specific to any type II PCV, and not merely to one of the three deposited strains, provided that the antibodies bound to one of those three strains. I cannot accept that submission. As proposed to be amended, the claim requires "antibodies specific to a type II porcine circovirus selected from those deposited [etc]". The Patentees' interpretation involves re-writing the claim and comes close to rendering the words "selected from those deposited [etc]" otiose. Furthermore, even if amended claim 18 were to be interpreted in that way, I agree with counsel for Intervet that it would not assist the Patentees, because there is no evidence that the Porcillis PCV ORF2 antigen is an antigen found on any of the three deposited strains. It is encoded by the same gene, but that gene could easily differ by one or more nucleotides and thus encode a different protein.
- I therefore conclude that Intervet has not infringed claim 18.
- The Patent is invalid and must be revoked. In any event, Intervet has not infringed claim 18.
MR. JUSTICE ARNOLD :
Contents
| Topic | Paragraphs |
| Introduction | 1-6 |
| Background to the dispute | 7-17 |
| Porcine circovirus | 7 |
| PMWS | 8-9 |
| Characterisation of PCV associated with PMWS | 10-16 |
| Subsequent events | 17 |
| The Priority Document | 18-37 |
| The Patent | 38-51 |
| The claims | 52 |
| The skilled team | 53-54 |
| The witnesses | 55-68 |
| The Patentees' hearsay notices | 69-94 |
| The first hearsay notice | 71-82 |
| The second hearsay notice | 83-94 |
| Common general knowledge | 95-147 |
| Viruses | 97-110 |
| Taxonomy of viruses | 102-107 |
| Virus isolation and culturing | 108-110 |
| RE mapping | 111-115 |
| PCR | 116-127 |
| Uses of PCR | 125 |
| Confidence in PCR | 126-127 |
| Hybridisation | 128-131 |
| Antigens and antibodies | 132-134 |
| Vaccines and diagnostics | 135-138 |
| PCV | 139-140 |
| PMWS and its cause(s) | 141-147 |
| Construction | 148-179 |
| Type II porcine circovirus | 150-164 |
| Responsible in pigs for PMWS | 165-168 |
| Type II porcine circovirus specific antigen and type II porcine circovirus specific antibody | 169 |
| Allowing the diagnostic of type II porcine circovirus | 170-179 |
| Priority | 180-190 |
| Amendment | 191-195 |
| Insufficiency | 196-198 |
| Obviousness | 199-243 |
| The law | 199-202 |
| The skilled team and the common general knowledge | 203 |
| The inventive concept | 204-206 |
| Nayar | 207-209 |
| The difference | 210 |
| Was it obvious? | 211-243 |
| What would the skilled team have done in the light of Nayar? | 213-219 |
| Would the skilled team have had a reasonable expectation of success? | 220-225 |
| Would the skilled team have been likely to succeed? | 226-236 |
| The work of the other groups | 237-240 |
| Conclusion | 241 |
| The problem and solution approach | 242 |
| The Dutch judgment | 243 |
| Infringement | 244-249 |
| Conclusion | 250 |
Introduction
Background to the dispute
Porcine circovirus
PMWS
Characterisation of PCV associated with PWMS
Subsequent events
The Priority Document
"The present invention relates to new porcine circovirus (PCV for Porcine CircoVirus) strains responsible for the PMWS syndrome (Porcine Multisystemic Wasting Syndrome also called Post-Weaning Multisystemic Wasting Syndrome) to reagents and methods allowing their detection, to methods of vaccination and to vaccines, as well as to methods of producing these reagents and vaccines."
It is clear from various passages in the Priority Document that the authors are using the word "strain" to refer to individual virus isolates.
"The PCV derived from the PK/15 cells is considered not to be pathogenic. Its sequence is known from [Meehan]. It is only very recently that some authors have thought that strains of PCV could be pathogenic and associated with the PMWS syndrome ([Nayar and Clark]). Nayar et al have detected PCV DNA in pigs having the PMWS syndrome using PCR techniques. No wild-type PCV strain has however been isolated and purified so far."
"The applicant has succeeded in isolating three new PCV strains from pulmonary or ganglionic samples obtained from farms situated in Canada, the United States (California) and France (Brittany), hereinafter called circoviruses according to the invention. These viruses have been detected in lesions in pigs with the PMWS syndrome, but not in healthy pigs.
The invention relates to any porcine circovirus capable of being isolated from a physiological sample or from a tissue sample, especially lesions, from a diseased pig having the PMWS syndrome, especially following the method described in the examples.
The subject of the present invention is more particularly purified preparations of three strains, which were deposited at the ECACC (European Collection of Cell Cultures …) on Thursday 2 October 1997:
The invention aims to consider the porcine circoviruses isolated from a diseased pig and/or the circoviruses having a significant serological similarity with the strains of the invention and/or the circoviruses having cross hybridization with the strains of the invention."
It can be seen that the last paragraph in this passage that the invention "aims to consider" (whatever that might mean) three classes of circovirus. First, PCVs isolated from a diseased pig, which in context must mean a pig with PMWS. Secondly, PCVs having "a significant serological similarity" with the strains of the invention, which in context must mean the three deposited strains. The Priority Document does not define what is meant by "a significant serological similarity". Thirdly, PCVs which cross-hybridise with the three deposited strains. The Priority Document does not state under what conditions.
"The subject of the present invention is therefore a DNA fragment containing all or part of this sequence. It goes without saying that the invention automatically covers the equivalent sequences, that is to say the sequences which do not change the functionality or the strain specificity of the sequence described or of the polypeptides encoded by this sequence. There will of course be included the sequences differing by degeneracy of the code.
The invention also covers the equivalent sequences in the sense that they are capable of hybridizing with the above sequence under high stringency conditions and/or have a high homology with the strains of the invention."
It can be seen that the second paragraph quoted contemplates two classes of equivalent sequences. First, those which are capable of hybridising with the sequence identified as SEQ ID NO. 1 under "high stringency conditions". Secondly, those which have "high homology" with the three deposited strains. The Priority Document does not define what is meant by "high stringency conditions" or "high homology".
"Knowledge of the sequences of the different circoviruses makes it possible to define common sequences which make it possible to produce reagents capable of recognising all the porcine circoviruses known.
Persons skilled in the art will also be able to select fragments of the sequences corresponding to regions exhibiting little or no homology with the corresponding PK/15 circovirus sequence in order to carry out a specific diagnosis."
The Priority Document does not define what is meant by "little" homology with PK/15.
"Analysis of the sequences obtained from the Imp.999 strain cultured using lesions collected from Californian piglets having clinical signs of the multisystemic wasting syndrome shows clearly that this viral isolate is a new porcine circovirus strain."
The Patent
"The Applicant has also sequenced the genome of four of these strains, namely the strains from Canada and from the United States as well as two French strains. The strains have a very high nucleotide homology which exceeds 96%; it is much lower with the PK/15 strain, at about 76%. Thus, the novel strains can be considered to be representative of a novel type of porcine circovirus, herein denoted type II, type I being represented by PK/15.
The present invention describes group II porcine circovirus as defined above, isolated or in the form of a purified preparation."
In addition, the words "in particular type II circovirus" have been inserted into what was the second paragraph of the passage in the Priority Document.
"In particular, open reading frames forming the DNA fragments of the invention which can be used for this purpose have been identified on the genomic sequence of type II circoviruses. The invention describes any polypeptide containing at least one of these open reading frames (corresponding amino acid sequence). Preferably, the invention describes a protein essentially formed by ORF4, ORF7, ORF10 or ORF13."
"The homology between the two French strains Imp.1011-48121 and Imp.1011-48285 was over 99% (0.9977).
The homology between the two North American strains Imp.999 and Imp.1010 was also over 99% (0.9949). The homology between the French strains and the North American strains was just above 96%.
The homology of all of these strains with PK/15 fell to a value of between 75% and 76%.
It can be deduced therefrom that the strains of the invention are representative of a novel type of porcine circovirus, distinct from the type represented by the PK/15 strain. This novel type, isolated from pigs presenting with PMWS, is termed type II porcine circovirus, PK/15 representing type I. The strains belonging to this type II had a remarkable nucleotide sequence homogeneity, even though they were isolated in regions very far apart geographically."
The claims
"1. Diagnostic method of the infection by a type II porcine circovirus responsible in pigs for Post-Weaning Multisystemic Wasting Syndrome (PMWS), wherein a sample of physiological fluid or a porcine tissue sampling and a diagnostic reagent specific to type II circovirus that recognises a type II circovirus selected from those deposited at the ECACC with accession No. V97100217, V97100218 and V97100219 are put together, and the potential presence of specific type II porcine circovirus antigen, antibody or nucleic acid is revealed within this sample or sampling.
13. Isolated preparation of type II porcine circovirus responsible in pigs for the Post-Weaning Multisystemic Wasting Syndrome (PMWS) specific antibodies, obtainable from a type II porcine circovirus or from an antigenic fragment of a type II porcine circovirus or from a polypeptide encoded by a fragment of the sequence SEQ ID NO:6.
18. Isolated antigenic preparation comprising a type II porcine circovirus responsible in pigs for the Post-Weaning Multisystemic Wasting Syndrome (PMWS) specific antigen, this antigen being recognized by antibodies specific to a type II porcine circovirusspecific antibodiesselected from those deposited at the ECACC with accession No. V97100217, V97100218 and V97100219 and allowing the diagnostic of type II porcine circovirus infection."
The skilled team
The witnesses
"Summary of Argument
It is alleged that the June 1997 Nayar Report describes the discovery of PCV2 by use of the Restriction Enzyme mapping technique.
Herein, we use computerised sequence analysis to provide evidence that Restriction Enzyme mapping could support an argument that:
Nayar's samples contained multiple variants of PCV1 DNA Sequences, which resulted in the identification of multiple 'RE Types' of PCV1."
As this makes plain, Dr Kitchen's evidence was argumentative.
"Based on these computerised analyses, it is probable that the samples in the Nayar Report would have contained a comparable diversity of PCV1 sequences, thus accounting for the mention of multiple RE types in the Nayar report. In other words, based on these computerised analyses, it is entirely plausible that the multiple RE types of PCV mentioned in the Nayar Report were all variants of PCV1."
As the cross-examination demonstrated, the analyses do not make this plausible, let alone probable. In fact, in all of Dr Kitchen's virtual RE digests, the majority, and in many cases the vast majority, of the sequences showed the same RE pattern as that of the Meehan sequence, whereas Nayar reported that all his strains had different RE patterns from that of the Meehan sequence.
The Patentees' hearsay notices
The first hearsay notice
The second hearsay notice
Common general knowledge
Viruses
RE mapping
PCR
Hybridisation
Antigens and antibodies
Vaccines and diagnostics
PCV
i) PCV was a contaminant of laboratory cell line PK/15 (a porcine kidney cell line). Most of the publications about PCV related to this PCV, PCV PK/15, which Tischer had described how to isolate and culture.
ii) PCV PK/15 was generally considered not to be pathogenic.
iii) Antibodies cross-reactive to PCV PK/15 had been found to be widespread in pig herds in both Europe and North America.
iv) PCV PK/15 was known to be a non-enveloped circovirus, with a circular single-stranded DNA genome of about 1.76 kb.
v) Meehan had published the sequence of PCV PK/15.
PMWS and its cause(s)
Construction
Type II porcine circovirus
Responsible in pigs for PMWS
Type II porcine circovirus specific antigen and type II porcine circovirus specific antibody
Allowing the diagnostic of type II porcine circovirus
"If a claim commences with such words as: 'Apparatus for carrying out the process etc...' this must be construed as meaning merely apparatus suitable for carrying out the process. Apparatus which otherwise possesses all of the features specified in the claims but which would be unsuitable for the stated purpose or would require modification to enable it to be so used, should normally not be considered as anticipating the claim. Similar considerations apply to a claim for a product for a particular use…."
Having considered these guidelines, and earlier domestic authorities, in Zeno Corp v BSM-Bionic Solutions Management GmbH [2009] EWHC 1829 (Pat) at [26]-[34] Lewison J was prepared to accept that something is "suitable for" a specified purpose if it is capable of being used for that purpose without modification (although he expressed doubts as to whether this was not too broad a construction of such a claim). Thus claim 18 does not extend to antigenic preparations comprising antigens which are suitable for diagnosis unless they are capable of being used for that purpose without modification.
Priority
"The requirement for claiming priority of 'the same invention', referred to in Article 87(1) EPC, means that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the skilled person can derive the subject-matter of the claim directly and unambiguously, using common general knowledge, from the previous application as a whole."
"The approach is not formulaic: priority is a question about technical disclosure, explicit or implicit. Is there enough in the priority document to give the skilled man essentially the same information as forms the subject-matter of the claim and enables him to work the invention in accordance with that claim?"
"So the important thing is not the consistory clause or the claims of the priority document but whether the disclosure as a whole is enabling and effectively gives the skilled person what is in the claim whose priority is in question. I would add that it must "give" it directly and unambiguously. It is not sufficient that it may be an obvious development of what is disclosed."
Amendment
Insufficiency
Obviousness
The law
"(1)(a) Identify the notional 'person skilled in the art';
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the 'state of the art' and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?"
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
"In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case."
The skilled team and the common general knowledge
The inventive concept
Nayar
"We are continuing our efforts to characterise more RE types by RE mapping and to determine the complete nucleotide sequence of the PCV genome obtained from clinical PMWS cases.
Using RE mapping results, the nucleotide sequence of PCV from pigs with PMWS was also compared with that of PCV from PK-15 cell lines and from a PCV isolate reported by Irish workers [Meehan]. We concluded that the RE types of PCV from pigs with PMWS were different from the RE types of PCV isolated from other sources and which were not considered pathogenic. We further concluded that specific strains or variants of PCV can be pathogenic and may be associated with PMWS."
The difference
Was it obvious?
i) Having read Nayar in the light of the common general knowledge, it would have been obvious to the skilled team to try either (a) to do precisely what Nayar and his colleagues indicated that they were doing in the first sentence quoted above, namely to use PCR to sequence the genome of PCV from PMWS-affected pigs, or (b) to isolate and culture PCV from such pigs.
ii) Either way, the skilled team would have a reasonable expectation of success.
iii) Following either route would in fact have been likely to lead to success.
"Q. Part of the common general knowledge, I think you have agreed, would be the knowledge that PCV has been seen in the lesions of PMWS pigs and that Clark has proposed that it is responsible for those lesions.
A. Yes, I would agree with that.
Q. Surely the skilled team would follow up on that proposal and seek to characterise the PCV in lesions of pigs with PMWS.
A. Yes, that would be one certainly and a very important approach to actually understand more about what this PCV was doing in those lesions.
Q. And what you would want to do would be to isolate the virus.
A. That would certainly be the choice that I would follow and the route which I believe many virologists would follow.
….
Q. So one option is to isolate the virus. That might be your preferred option.
A. Yes, that would be correct.
Q. And another obvious option for the skilled team in 97 would be to determine the sequence of the genome of the virus.
A. That would certainly be an approach to look for the DNA of the virus. I think the sequence would be certainly one aspect. Into what depth they could go would really depend upon how much DNA they could isolate and the tools available to them.
Q. And one tool available was the PCR technique.
A. That was one method, yes.
Q. We will come on to talk about that. You would agree, therefore, that the skilled team, given the common general knowledge in 1997, would set out to either isolate this virus or to use a technique such as PCR to determine, to obtain, and sequence the genome.
A. I am not so sure I would agree with the very last phrase. Certainly they would wish to isolate the virus. That is certainly an aim when it comes to virus etiology. Looking at the sequence of the virus, or looking at the virus DNA, I would put it that they would perhaps be looking to understand or confirm that this was the PCV that they thought it was. I would put it that way. I hope I am not being too unspecific in what I am saying. I am not sure that the sequencing would have been the only thing in their minds on looking.
Q. Of course, doctor, I am sure that is right. One of the reasons for wanting the genome is to find out what this virus is.
A. Yes. I would say, from the point of view of determining, 'Is this really porcine circovirus or is it something else?' certainly looking at the DNA material available, and trying to characterise that DNA by the methods available, that would be an approach.
Q. And you would want to know how related it was to the PCV that you already knew of from PK/15 cells.
A. I would agree with that.
…
Q. What Nayar has done is he has set out, has he not, to answer this question, or to try to answer this question, that has been raised of the etiological association?
A. That seems to be his rationale, yes, certainly.
Q. And he has done it by looking for PCV DNA in relevant tissues from pigs with clinical signs of PMWS.
A. Yes, I would agree with that.
Q. Would you agree there is nothing clever about doing that in 1997?
A. No, certainly not.
Q. Given Clark's suggestion that PCV might be responsible for the lesions seen in PMWS pigs, it would have been obvious for the skilled team to do what Nayar did.
A. Yes, to look into the lesion to further characterise the PCV material which was present, yes.
Q. And to use PCR to try and amplify up the PCV DNA.
A. That would be one approach, yes.
Q. It would have been an obvious approach for the skilled team, would it not?
A. Yes, but it would not have been the only approach.
Q. No, not the only obvious approach.
A. No.
Q. It would have been virus isolation as well?
A. Yes, which certainly I would have thought that that would have been the favoured approach."
"Q. If we look at what Nayar concludes at the end of the article, the last sentence, their conclusion is that specific strains or variants of PCV can be pathogenic and may be associated with PMWS. So Nayar is supporting what Clark said about a link between PCV and PMWS.
A. Yes, he was going in that same direction.
Q. And in particular he is saying that there appeared to be specific strains or variants which may be associated with PMWS.
A. Yes, he is going a little further.
Q. A little further than Clark.
A. Yes.
Q. If you are a skilled team in '97, you are interested in searching for the cause of PMWS and you have read Nayar, PCV would have been an obvious candidate for investigation.
A. Yes, certainly I would say that the information was growing that one should look more closely at PCV, yes.
Q. And one would have done it in either of the ways we have discussed by Nayar's approach of PCR or virus isolation.
A. Yes, and one could also have continued in the direction that Clark had started, which was the antibody based analyses, histochemistry, but he could also have done electron microscopy, which would have further enhanced his results.
Q. Following Nayar, you would be looking for strains or variants which differed from the PK/15 strain?
A. That is an assumption that the virus was changing rather than the conditions in which the virus could cause disease where it was changing, but it is certainly a logical approach to take.
Q. Well, one would not be expecting the PK/15 strain to be causing the pathogenicity?
A. It would seem unlikely.
Q. So you would be looking for strains or variants which differed from PK/15, yes?
A. Yes, I would be looking for that.
Q. That is what the skilled team would have done.
A. Yes, I agree with that."
i) Dr Morozov gave unchallenged evidence that Marsha Morgan (a senior technician) followed the protocol described by Tischer because it was obvious to use the same cell line and follow a protocol that had already been shown to work with a PCV strain. Dr Morozov said that he was not aware that Ms Morgan encountered any problems with her virus culture and isolation, which he described as a "routine experiment". His evidence was that the virus isolation experiments were carried out within about a month.
ii) The Patent discloses use of the same virus culture technique in Example 1, which cites Tischer. The Patent does not suggest that the protocol is anything other than routine, and demonstrates that it will work for type II PCV. Furthermore the Patent says at page 3 lines 7-16 that type II PCV grows well on PK/15 cells in culture.
iii) Wang's group appear to have used the same approach, again with success.
"Q. OK. Are you saying that the skilled team in 97 would not be able to design primers and choose conditions to do their own PCR to amplify PCV DNA from lesions from PMWS pigs?
A. I would say that the skilled person, like we presume Nayar had done, would be able to perform that task, yes.
Q. They would expect to be able to do so.
A. Yes, certainly, but they would believe in themselves that they could do that until maybe they failed repeatedly. They have to believe to start, yes.
Q. So they might hit unexpected problems along the way, but they would set off expecting to succeed.
A. Eventually to succeed, yes."
"Q. Having reviewed the material, on the assumptions I have given you, I want you to consider this very carefully. We have to consider the position of the unimaginative skilled team at the priority date of the patent. Can I get you at least to accept this, that that skilled team, if they were sent off by their supervisor with Nayar in their hand to obtain the viral genome of pathogenic PCV II, the project would not be straightforward and would represent a challenge?
A. The project has a chance of failing, if that is what you mean. The steps involved, I would not expect people to be inventive in what they tried to do. As you said, they are not inventive people so they are following protocols that are generally published apart from having to design their primers. If that means it is not straightforward, if that is what you mean by not straightforward, then I am happy to accept that that is the case.
Q. Properly described, this is a research project, is it not?
A. Yes.
MR. JUSTICE ARNOLD: What do you understand by the expression a 'research project'?
A. It is a series of experiments, I guess. You conduct experiments and test hypotheses and move forward from there. It is a research project. It is trying to find out something new...."
Counsel for the Patentees submitted that Dr Radford's acceptance that this was a research project showed that the invention was not obvious. I disagree. What Dr Radford accepted was that experiments were required and that success was not guaranteed. As discussed above, however, he maintained that both routes were obvious to try, easy to try and worth trying and that the skilled team would have a reasonable expectation of success and would have been likely to succeed.
i) Various groups were interested in trying, and thought it worthwhile to try, to isolate and/or characterise the causative agent of PMWS.
ii) Each of the groups appears to have thought it likely that a PCV was involved which was related to PK/15 PCV and proceeded on that basis.
iii) The Nayar, Morozov and Wang groups all proceeded by using PCR and designing primers based on the PCV PK/15 sequence.
iv) The approaches adopted by Nayar and Morozov of primers designed based on the PCV PK/15 genome, but situated randomly along it, led to success in obtaining the DNA sequence of the entire genome of a new PCV strain. So too did Wang's more directed approach to primer design. In the case of Morozov's group, they also isolated their virus.
v) All three groups identified, and sequenced, PCV strains with high degrees of similarity to each other and to the strains whose sequences are disclosed in the Patent.
Infringement
Conclusion