GE Healthcare Ltd v Perkinelmer Life Sciences (UK) Ltd & Anor [2006] EWHC 214 (Pat)

[2006] EWHC 214 (Pat)Case No HC 04 C02688
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Venue Royal Courts of Justice, Strand, London, WC2A 2LLDate 17 February 2006
Before
THE HONOURABLE MR JUSTICE KITCHIN
Between
GE HEALTHCARE LIMITEDClaimantPERKINELMER LIFE SCIENCES (UK) LIMITEDDefendantPERKINELMER LAS (UK) LIMITEDDefendantAnd between :
Between
PERKINELMER LIFE SCIENCES (UK) LIMITEDPart 20 ClaimantsPERKINELMER LAS (UK) LIMITEDClaimantPERKINELMER LAS, INC.ClaimantGE HEALTHCARE LIMITEDPart 20 Defendant
Mr Christopher Floyd QC and Ms Kathryn Pickard (instructed by Mayer Brown Rowe & Mawe LLP) for Claimants / Part 20 DefendantMr Richard Arnold QC and Dr Heather Lawrence (instructed by Field Fisher Waterhouse) for Defendants / Part 20 ClaimantsHearing Hearing dates: 1-2, 5-9, 12-14, and 20-21 December 2005
Judgment

Introduction

[1]This is an action for infringement of European Patent (UK) No 1,007,971 entitled “Scintillation Proximity Test” (“the Patent”). The claimant patentee is GE Healthcare Limited but at the time of the events to which this action relates it was known as Amersham, and I will refer to it by that name in this judgment. The defendants to the infringement action are PerkinElmer Life Sciences (UK) Limited and PerkinElmer LAS (UK) Limited, who market an imaging system in the United Kingdom called ViewLux. The defendants, and a US corporation called PerkinElmer LAS Inc (“PLI”), counterclaim for revocation of the Patent or for a declaration that PLI is entitled to the Patent. I will refer to the defendants and Part 20 claimants as “PerkinElmer”.[2]PerkinElmer’s primary case is that the Patent is invalid because it lacks novelty or inventive step. If, however, the Patent is not invalid on these grounds, PerkinElmer’s secondary case is that the Patent rightfully belongs to PLI as successor in title to Packard Instrument Co. Inc. or Packard Bioscience Ltd (“Packard”) and / or Cambridge Imaging Ltd (“CIL”) and that Amersham is liable for breach of confidence.[3]The priority date of the Patent is the 18 August 1997. Independent validity is asserted for claims 1, 4 and 8, and each of these claims is alleged to be infringed.

Scientific Background

[4]Much of the scientific background was not in dispute between the parties and may be summarised as follows.

Scintillation Proximity Assays

[5]The Patent concerns scintillation proximity assay (“SPA”) technology. In such an assay, a surface carrying a phosphor is contacted with a body of fluid containing a radioisotope. When some of that radioisotope becomes bound next to the surface carrying the phosphor, the radioactivity emitted by the radioisotope causes the phosphor to be excited and emit light. The amount of light produced is proportional to the quantity of radioisotope bound to the surface and can be measured by a scintillation counter. The radioactivity emitted by the radioisotope which remains in solution is absorbed by the fluid. In this way, bound radioisotope gives rise to a scintillation signal but unbound radioisotope does not, and this has the benefit that there is no need to separate the one from the other as is the case with conventional radioimmunoassays. For this reason, SPAs are known as homogenous assays as opposed to heterogeneous assays, which involve a separation step.[6]The Patent has coined the term scintillation proximity test (“SPT”) to describe a general scintillation proximity assay procedure. It defines an SPT as follows:
“[0011] A scintillation proximity test is a test in which a surface carrying a phosphor is contacted with a body of fluid containing a radioisotope. Part of the radioisotope becomes immobilised adjacent the surface; the remainder of the radioisotope remains dispersed or dissolved in the fluid. The mean free path of electrons or other particles or radiation resulting from radioactive disintegrations of the radioisotope are small relative to the dimensions of the body of fluid, whereby that part of the radioisotope immobilised adjacent the surface is capable of exciting phosphor carried by the surface, but that part of the radioisotope dispersed or dissolved in the fluid is generally too far from the surface to be capable of exciting phosphor carried by the surface. [0012] The surface may be massive, as for example a wall of a vessel or wells of a multiwell or microtitre plate; or particulate, as for example, threads or beads. The phosphor may be present as a coating applied on a pre-formed surface; or may be dispersed in or constitute or form part of the surface. [0013] The test may be a chemical or biochemical assay, for example a competition assay such as an immunoassay or immunometric assay. Or the test may involve a study of living cells which are, or which become, attached to the surface carrying the phosphor. Any test system in which a radioisotope becomes partitioned between a solid phase and a liquid phase is in principle suitable for the method of the invention. [0014] A radioisotope may be present in free form or combined form, e.g. as an atom or ion; this may be useful for example when it is desired to monitor the take up of the radioisotope by cells adhering to the surface carrying the phosphor. Or the radioisotope may be used to label an assay reagent; this may be useful for example when a labelled reagent is caused to compete with an unlabelled reagent for binding to another reagent immobilised on the surface carrying the phosphor. [0015] A scintillation proximity test may be carried out in a qualitative or more usually in a quantitative manner. For example, measurements may be performed in a static mode, as when the result of a competition assay is determined after a fixed time or at equilibrium. Alternatively a scintillation proximity assay may be performed in a dynamic mode, as when radiolabel uptake by cells is monitored in real time. WO 94/26413 describes a scintillating microtitre plate and methods for studying cellular processes in real time. The scintillating microtitre plate is marketed by Amersham Lifescience under the name Cytostar-T. [0016] The fluid is generally an aqueous or other liquid. The radioisotope is preferably one which emits electrons having a mean free path up to 2000 m in aqueous media. These include isotopes commonly used in biochemistry such as 3H, 125I, 14C, 35S, 45Ca, 33P and 32P, but does not preclude the use of other radioisotopes such as 55Fe, 86Rb, 109Cd, 51Cr which also emit electrons within this range. [0017] The scintillation proximity test is preferably performed in the wells of a multiwell plate e.g. a microtitre plate. The phosphor may be provided as beads dispensed into the wells of such a plate. Or the phosphor may be incorporated into the plate itself, either by direct incorporation into the plastic of the plate, or by coating, together with a binding agent. Examples of possible binding agents are calcium sulphate, as used in the manufacture of tic plates, and low-melting plastics such as polystyrene or copolymers of -methylstyrene and vinyltoluene. These devices may have 24, 96 or 384 wells as in existing plates or may have higher densities of wells such as 864, 1536, 2400, 3456 or indeed any desired number. They can be used to perform cell-based or ligand binding assays in conjunction with CCD camera based imagers.”
Luminescence [0017] The scintillation proximity test is preferably performed in the wells of a multiwell plate e.g. a microtitre plate. The phosphor may be provided as beads dispensed into the wells of such a plate. Or the phosphor may be incorporated into the plate itself, either by direct incorporation into the plastic of the plate, or by coating, together with a binding agent. Examples of possible binding agents are calcium sulphate, as used in the manufacture of tic plates, and low-melting plastics such as polystyrene or copolymers of -methylstyrene and vinyltoluene. These devices may have 24, 96 or 384 wells as in existing plates or may have higher densities of wells such as 864, 1536, 2400, 3456 or indeed any desired number. They can be used to perform cell-based or ligand binding assays in conjunction with CCD camera based imagers.”[7]Luminescence is the emission of light by a luminescent label, sometimes called a reporter, upon excitation with energy. If the energy comes from a chemical reaction the process is referred to as chemiluminescence. If the energy comes from a radioactive disintegration event, the process is referred to as radioluminescence or scintillation. If the energy comes from light, typically UV light, the process is referred to as photoluminescence. Photoluminescence can be subdivided into phosphorescence and fluorescence. Phosphorescence is a relatively slow process, whereas fluorescence is generally more prompt but may be delayed and comparable to phosphorescence.

Phosphor

[8]A phosphor is a reporter molecule that can convert radioactive radiation or UV light to light in the visible spectrum. Two kinds of phosphor were referred to in these proceedings. A scintillant is a molecule which can convert radioactive radiation to light in the visible spectrum. A fluor is a molecule which can convert UV light to light in the visible spectrum.

Wavelengths

[9]The visible spectrum stretches from a wavelength of approximately 380 nm to 740 nm and from violet to red. The spectrum can be divided into three broad bands: blue, green and red. Blue covers wavelengths up to about 500 nm; green approximately 500 to 580 nm; and red approximately 580 nm to 740 nm. Colour quenching[10]Colour quenching is the absorption of light emissions from luminescent material by the medium through which the light travels. Depending upon the composition of the medium, light emissions will be quenched to different extents. There are certain general rules with regard to colour quenching. There will be least absorption of light at the wavelength matching the colour of the medium. So, for example, a blue fluid will absorb less blue light than red light, and a red medium will absorb less red light than blue light. Biological assays are often brown or yellow in colour and so tend to absorb more blue light than red light. Further, the higher the energy of the emissions the greater the likelihood that the light being emitted will be absorbed by the medium. Blue light has a shorter wavelength and higher energy than red light and is therefore more likely to be absorbed than red light. By 1997, it was known to calibrate detection instruments to take into account colour quenching.

Scintillation Counter

[11]A scintillation counter is any device which detects and measures radiation by counting the flashes of visible light that are produced when radiation excites a phosphor. One of the ways that such light flashes can be detected and counted is using a photomultiplier tube(“PMT”).

Photomultipliers

[12]A PMT is an electronic device for the detection of low levels of light. A flash of light strikes the sensitive surface of a photocathode in the PMT and causes the emission of a number of primary electrons. In a series of stages this initial current is multiplied by about a millionfold. Nevertheless, the amplitude of the output of the PMT remains proportional to the intensity of the light that is detected. The sensitivity of a PMT to various different wavelengths (that is to say colours) of light is determined by the photocathode. Depending upon the range of wavelengths that need to be detected, a particular photocathode may be selected. Thus, for example, a photocathode sensitive to light in the blue region of the spectrum would be used to detect blue light.

Charge Coupled Device

[13]A charge coupled device (“CCD”) is a complex solid state camera comprising a semiconductor chip consisting of a matrix of photosensitive elements called pixels. When photons fall upon a pixel they cause an electric charge to be liberated. This charge can be read out and used to create an analogue TV picture or a digital image.[14]CCD cameras can be subdivided into two broad categories: intensified CCD cameras and cooled CCD cameras. Intensified CCD cameras use a photomultiplier tube to amplify the signal to increase the sensitivity of the instrument at low light levels. Cooled CCD cameras detect low light signals by integrating the signals for long periods of time, sometimes up to hours. Cooling is necessary to reduce the thermal noise of the system. In general, cooled CCD cameras have a spectral response that has a greater efficiency in the green and red part of the visible spectrum. With intensified CCD cameras, the spectral response differs depending upon the particular photocathode used. Best results are achieved by matching the spectral response to the spectral input.

High throughput screening and miniaturisation

[15]One of the advantages of SPA technology as of the date of the Patent was that it was capable of being used for high throughput screening which is valuable in the case of drug or sample screening applications. At the date of the Patent SPAs were routinely carried out in 96 well microtitre plates counted approximately six wells at a time. There was, however, a search for higher throughput leading to a desire to increase the number of wells on each plate and, correspondingly, to decrease the size of the wells themselves.

Transition Metals

[16]Transition metals are the 38 elements in groups 3 through to 12 of the periodic table. Of particular relevance to these proceedings are the rare earth metals which are composed of the lanthanide and actinide series, which are all found in group 3 of the periodic table, and the sixth and seventh periods. The lanthanide series comprises 15 elements.

The Patent

[17]At paragraph [0001] the Patent states that the invention concerns SPTs involving the scintillation proximity principle. This principle is simply that when a radioactive particle is in close association with a phosphor, low energy radiation emitted by the particle is captured by the phosphor and converted into light. When the radioactive particle is not in close association with the phosphor, then the radiation is not captured and is dissipated in the environment.[18]The Patent then proceeds to describe the prior art. In paragraph [0002] it explains that current SPA technology involves the use of scintillant beads made from either yttrium silicate doped with cerium (Y 2SiO 5:Ce) or polyvinyltoluene (PVT) containing an organic scintillant such as PPO (2,5-diphenyloxazole). Yttrium silicate is an example of an inorganic host material and cerium is a lanthanide. Such assays were carried out in aqueous buffers using radioisotopes such as 3H that emit low energy radiation which is easily dissipated in an aqueous environment. The electrons emitted by such isotopes have a very short path length and will only activate the scintillant and produce light if a molecule labelled with one of these isotopes is actually bound to the bead surface either directly or by interaction with another molecule previously coupled to the bead.[19]At paragraphs [0003] and [0004] two prior art documents are referred to, namely PCT W0 91/08489 (“Van Cauter”) and WO 94/26413 (“Cook”). Cook is one of the documents cited against the validity of the Patent and is considered later in this judgment. At paragraph [0005] the Patent indicates the suitability of SPTs for high throughput screening and miniaturisation. It explains that SPAs have been carried out routinely in 96 well microtitre plates counted 6 wells at a time and that the search for higher throughput has led the manufacturers of these counters to produce instruments capable of counting 12 wells at a time and has also seen the advent of 384 well plates. However these larger plates could still only be counted 12 wells at a time.[20]At paragraph [0006], the Patent explains that a problem associated with SPAs is that of colour quenching which attenuates the signal and decreases the signal to noise ratio. It also explains that many of the samples being screened by SPA assays are coloured and that the majority of these are yellow or brown in colour and absorb light in the blue region of the visible spectrum. It points out that both PVT and yttrium silicate : cerium based SPA beads emit light in the blue region and so are susceptible to this effect.[21]The Patent then proceeds to describe the CCD as an alternative detection system suitable for use in low to ultra-low light imaging applications in the biological and biomedical sciences. At paragraph [0007], it explains that the CCD has been used in assays which involve chemiluminescent, bioluminescent and fluorescence detection. Further, applications have included immunoassays. It points out thatthe benefit of this technology is that it is quantitative and fast and that the new generation of imaging instruments using CCD cameras can image the whole of the plate at once and so have great potential for increasing sample throughput compared with microtitre well plate scintillation counting techniques. It explains that area imaging (the simultaneous imaging by a CCD of all wells in a microtitre well plate) is considered to be particularly advantageous when used in conjunction with high well density plates containing 96, 384, 864, or more wells, since the time required to make measurements is significantly reduced compared with conventional scintillation counting techniques.[22]The Patent then refers at paragraph [0009] to a paper by Englert published in 1996 in which, it is said, CCD detection of SPA counts was reported using PVT based microspheres. However, the Patent says, the photon count from the SPA wells was not sensitive enough to enable usable results to be obtained due to low-light output of the beads, sub-optimal signal detection capability of the system, as well as quenching by coloured samples. The Patent continues that the number of photons detected per disintegration was insufficient to enable the determination of quenching levels and quench correction was not possible.[23]Against this background the Patent explains the invention at paragraph [0010] as follows:
“[0010] The present invention seeks to overcome the dual problems of low sensitivity of current CCD-based detection as well as colour quench in conventional SPA bead technology. The invention provides use in a scintillation proximity test of a phosphor that has an emission maximum of 480 nm – 900 nm, and of a charge coupled device for detecting radiation emitted by the phosphor.”
[24]The Patent continues by defining SPT in paragraphs [0011] to [0017] which I have largely set out above. It is notable that at paragraphs [0012] and [0013] it explains that the surface to which the phosphor is attached may be the wall of a vessel or the well of a microtitre plate or be particulate, for example in the form of beads. It may be applied as a coating to the surface or be dispersed in or form part of the surface.[25]At paragraph [0017], the Patent explains that the phosphor preferably has an emission maximum of 500 nm to 700 nm, that is to say in the green, yellow or red regions of the spectrum and that these phosphors generally have a higher light output than the conventional SPA beads using PVT or cerium-doped yttrium silicate. The Patent also claims that the longer wavelength green or red emissions alleviate the colour quenching problem which is at its greatest in the blue region of the spectrum. In paragraph [0018] the Patent continues by noting that some such phosphors are commercially available and refers to Blasse and Grabmaier, Luminescent Materials, and an article by Beverloo et al, Cytometry, 13, 561-570 (1982). Beverloo is another of the citations relied upon in support of the allegation of obviousness and I refer to it in more detail later in this judgment.[26]The Patent continues with a discussion of available suitable phosphors in paragraphs [0019] to [0021]. It explains that there are many suitable phosphors that may be used. Some consist of an inorganic host material doped with an activator and the Patent mentions as examples of such host materials the prior art yttrium silicate and yttrium oxide. It explains the activator is generally a lanthanide or actinide moiety. Other suitable phosphors are organic chelates of lanthanide or actinide moieties and that examples of phosphors of this kind are described in EPA 556005 (“Bell”). Finally, it explains the identity of the lanthanide or actinide moiety determines the emission wavelength of the phosphor and the preferred moieties are selected from, for example, terbium and europium, generally in the form of +2 or +3 ions.[27]The Patent then proceeds to describe a series of ten examples. Attention was particularly focused on examples 1, 2 and 3.[28]In example 1 a CCD imager is used to detect the signal from an assay for 3H-labelled biotin using various streptavidin coated beads in accordance with the invention. Three inorganic phosphors were used, namely: Y 2O 2S:Eu; Y 2O 3:Eu, and YAG:Tb. In addition organic chelate beads were made from polystyrene containing particular Amersham light emitting polymers (described as ALPs), namely tris(2,2,6,6,-tetramethyl-3,5-heptanedionato)terbium III-diphenyl-phosphonimido-triphenyl phosphorane (referred to as ALP-1) and tris(napthoyltrifluoroacetonato)europium III-(diphenyl-phosphonimido-triphenyl phosphorane)1 or 2 (referred to respectively as ALP-7 and ALP-7-diphos). These six phosphors were compared to prior art PVT SPA beads and streptavidin coated Y 2SiO 5:Ce particles. The results are shown in figures 1 and 2, and are said to show that the “CCD imager signal” generated by the phosphors of the invention is up to 10 times higher than the signal generated by the prior art phosphors.[29]In paragraph [0024] the Patent explains the materials and methods used in example 1. It points out that the inorganic phosphors used in the experiment are known materials obtained from commercial suppliers in modified forms to facilitate their use in SPAs. The organic chelate beads were prepared by traditional methods known to those skilled in the art. The Patent therefore assumes that the addressee is familiar with the inorganic phosphors used and with the production methods needed to make the organic chelate beads.[30]It is also to be noted that the Patent assumes that the reader understands and is familiar with the methods needed to coat the particles with proteins, such as streptavidin and other bioreactive species.[31]Very little detail is given as to the CCD imager. The Patent explains that the imager used in the examples is a prototype system supplied by Molecular Devices Inc and incorporates a liquid nitrogen cooled CCD camera supplied by Princeton Instruments Inc. It continues by pointing out that alternative CCD imager detection systems which are under development are expected to give a similar relative response. Accordingly, once again, the Patent assumes that the reader is familiar with CCD cameras and, in particular, how to acquire, set up and operate them or has access to suppliers with that knowledge.[32]The results for experiment 1 are shown in figures 1 and 2. The data depicted demonstrate that the CCD imager signals generated from the new phosphors were significantly higher than the old ones. The Patent does not, however, explain whether the improved results are attributable to the new phosphors emitting more light than the old ones, or rather to the fact that the wavelength of the light emitted by the new phosphors matches more closely the spectral response of the detector. In this regard no details are given of the spectral response of the camera employed. However, it may reasonably be inferred from the fact that the camera was a liquid nitrogen cooled CCD camera that it had an optimal efficiency in the green-red part of the spectrum.[33]Examples 2 and 3 address the issue of colour quench. In example 2, four different dyes, namely acid yellow, tartrazine, methyl orange and neutral red were added to the assays of example 1. The experiment demonstrated that dyes with an absorption spectrum overlapping with the emission spectrum of the scintillants in conventional PVT SPA beads or yttrium silicate SPA particles could cause quenching of the emitted light, whereas the CCD detected signal from the beads and particles containing europium or terbium was not significantly quenched. Experiment 3 compared the concentration dependent quenching of signal from the particles as detected by a CCD imager and a conventional scintillation counter. Four different concentrations of tartrazine were used. Again it was found that the signals from the phosphors of the invention were not quenched or were quenched to a lesser degree than the old phosphors.

The claims

[34]PerkinElmer suggested the following breakdown of the claims, which Amersham was content to adopt.[35]Claim 1: a) Use in scintillation proximity test b) of a phosphor c) that has an emission maximum of 480nm-900nm, d) and of a charge coupled device e) for detecting radiation emitted by the phosphor.[36]Claim 4 limits claim 1 as follows: f) wherein the phosphor has an emission maximum of 500nm-700nm.[37]Claim 8: g) A method of performing a scintillation proximity test, by providing h) a solid surface comprising a phosphor i) in a fluid medium, j) causing a radiolabelled reagent to become divided into two fractions one bound to the solid surface and the other in the fluid medium, k) and detecting the fraction of the radiolabelled reagent bound to the solid surface, l) using a phosphor that has an emission maximum of 480nm-900nm m) and a charge coupled device n) for detecting radiation emitted by the phosphor.

The addressee

[38]It is well established that 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: Catnic Components Ltd v Hill and Smith Ltd [1982] RPC 183 at 242-243. It was submitted on behalf of Amersham that the Patent is addressed to those interested in performing assays, for the purposes of drug or sample screening. As such, it was submitted, the Patent is addressed to skilled biochemists and chemists or those in related fields, such as biochemistry, who have an interest in performing biological or biochemical assays. PerkinElmer submitted, on the other hand, that the Patent is primarily addressed to those who devise, manufacture and market SPTs and detectors suitable for SPTs, and only secondarily to users of SPTs, such as pharmaceutical companies. In my judgment the submission advanced on behalf of PerkinElmer is essentially correct. It was the reagent and detector manufacturers and suppliers who were working to develop scintillants and detectors, not the users of the assays. Further, it is the manufacturers and suppliers who need to understand and implement the teaching of the Patent. It is also to be noted that the invention extends to the use of any SPT format, any phosphor with an emission maximum of 480 nm to 900 nm and any CCD device. Yet the specification provides very little assistance as to how the invention is to be implemented and assumes that the reader has expertise in the three areas of SPTs, phosphors and detection systems. Thus, for example, in paragraph [0023], the specification assumes the reader understands how to make or obtain SPA beads and yttrium silicate particles and how to coat them with proteins, such as streptavidin and other bioreactive species. Further, in paragraph [0024], the specification assumes that the reader is aware of the inorganic phosphors used and how they may be obtained in modified forms to facilitate their use in scintillation proximity assays. This paragraph further assumes the reader knows the traditional methods of preparing organic chelate beads. Finally, the specification assumes that the reader is familiar with CCD imagers, will recognise the description of the liquid nitrogen cooled CCD camera supplied by Princeton Instruments Inc used in the experiment, and will know how to set up such a camera and use it for an SPT assay. In this regard the specification also assumes that the reader knows that cooled CCD cameras generally speaking have their peak response in the green to red part of the spectrum. If the reader did not have this understanding and tried, for example, to put the invention into effect using an intensified camera with its maximum response in the blue part of the spectrum, then he would not be able to reproduce the experimental results described in the example. All of these matters point to the manufacturers and suppliers of SPTs and detectors as the primary addressees. These companies, rather than the users of the assays, had the required knowledge.

The experts

[39]Dr Oldenburg gave evidence on behalf of Amersham. He trained as a biochemist and from 1992 to 1996 was employed by Affymax as a scientist researching into the development of techniques to screen large numbers of peptides for specified biological activity. In 1996 he became Director of High Throughput Screening and Drug Discovery at DuPont Pharmaceuticals. There he was responsible for drug discovery and the development of new screening techniques. While at DuPont, he investigated ways in which existing assays, particularly fluorescence and luminescence based assays, but also SPAs, could be miniaturised. So far as miniaturisation was concerned, his interest was focused on developments in microtitre plates, designer liquid handling techniques and automation, but he was not concerned with developments in assay reagents or in assay detectors. He frankly accepted that he was not an expert in camera technology and that he was not equipped to say what a person or a team involved in devising, manufacturing and marketing SPTs and detectors for such tests knew. Nevertheless, I found Dr Oldenburg’s evidence helpful and have no doubt that he was throughout doing his best to assist the court. It was suggested that he occasionally slipped into acting as an advocate for Amersham rather than giving a wholly impartial and objective view. I have no hesitation in rejecting that suggestion. In my judgment he gave his evidence throughout in a balanced and fair way and recognised the limitations to his knowledge and expertise.[40]Professor Tanke gave evidence on behalf of PerkinElmer. He is the head of the Department of Molecular Cell Biology at Leiden University Medical Centre in the Netherlands. He graduated with a degree in biochemistry and gained a PhD in cytometry, that is to say the measurement of properties of cells. After the completion of his PhD in 1982, he continued his research at the Laboratory of Chemistry and Cytometry at Leiden. From 1982 to 1997 his main research interest was the development and use of flow cytometry and, in particular, fluorescence microscopic procedures. By August 1997 he had experience of using CCD cameras for luminescence detection and phosphor detection of immunoassays. He had not conducted SPTs himself but was aware of and understood the principles of SPT technology. I found Professor Tanke’s evidence of great assistance and have no doubt that throughout he too did his best to assist the Court. Common general knowledge[41]The notional skilled addressee lacks inventive capacity but is deemed to be equipped with the common general knowledge in the field to which the invention relates. The law as to what constitutes common general knowledge was explained by the Court of Appeal in Beloit Technologies Inc v Valmet Paper Machinery Inc [1997] RPC 489 at 494 - 495: “It has never been easy to differentiate between common general knowledge and that which is known by some. It has become particularly difficult with the modern ability to circulate and retrieve information. Employees of some companies, with the use of libraries and patent departments, will become aware of information soon after it is published in a whole variety of documents; whereas others, without such advantages, may never do so until that information is accepted generally and put into practice. The notional skilled addressee is the ordinary man who may not have the advantages that some employees of large companies may have. The information in a patent specification is addressed to such a man and must contain sufficient details for him to understand and apply the invention. It will only lack an inventive step if it is obvious to such a man. It follows that evidence that a fact is known or even well-known to a witness does not establish that that fact forms part of the common general knowledge. Neither does it follow that it will form part of the common general knowledge if it is recorded in a document. As stated by the Court of Appeal in the General Tire case at page 482, line 33: "The two classes of documents which call for consideration in relation to common general knowledge in the instant case were individual patent specifications and 'widely read publications'. As to the former, it is clear that individual patent specifications and their contents do not normally form part of the relevant common general knowledge, though there may be specifications which are so well known amongst those versed in the art that upon evidence of that state of affairs they form part of such knowledge, and also there may occasionally be particular industries (such as that of colour photograph) in which the evidence may show that all specifications form part of the relevant knowledge. As regards scientific papers generally, it was said by Luxmoore, J in British Acoustic Films (53 RPC, 221 at 250): "In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art." And a little later, distinguishing between what has been written and what has been used, he said: "It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art." Those passages have often been quoted, and there has not been cited to us any case in which they have been criticised. We accept them as correctly stating in general the law on this point, though reserving for further consideration whether the words 'accepted without question' may not be putting the position rather high: for the purposes of this case we are disposed, without wishing to put forward any full definition, to substitute the words 'generally regarded as a good basis for further action'.” "The two classes of documents which call for consideration in relation to common general knowledge in the instant case were individual patent specifications and 'widely read publications'. As to the former, it is clear that individual patent specifications and their contents do not normally form part of the relevant common general knowledge, though there may be specifications which are so well known amongst those versed in the art that upon evidence of that state of affairs they form part of such knowledge, and also there may occasionally be particular industries (such as that of colour photograph) in which the evidence may show that all specifications form part of the relevant knowledge. As regards scientific papers generally, it was said by Luxmoore, J in British Acoustic Films (53 RPC, 221 at 250): "In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art." "It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art."[42]Further, as Laddie J explained in Raychem Corp.’s Patents [1998] RPC 31 at 40, the general knowledge is not limited to material which the skilled person has memorised and has at the front of his mind. It includes all that material in the field in which he is working which he knows exists, which he would refer to as a matter of course, if he cannot remember it, and which he understands is generally regarded as sufficiently reliable to use as a foundation for further work.[43]There was a certain amount of common ground between the parties as to the common general knowledge. In other areas, however, and in particular in relation to CCDs and phosphors, there was a substantial measure of disagreement. It is convenient to consider the matter by reference to the various heads of common general knowledge relied upon by PerkinElmer.

SPTs

[44]The parties were in agreement that the skilled person would have known of the SPA principle, what an SPA is and of the availability of SPA products from Amersham. The skilled person would have been aware that SPA was a technique which had been shown to be widely applicable to radioimmunoassays, receptor binding assays and enzyme assays.[45]The skilled person would also have appreciated that scintillating microplates used in SPAs were available from Amersham and from New England Nuclear (NEN). Those available from Amersham were called Cytostar T Plates and those from NEN were called FlashPlates. The rights to the FlashPlate technology were derived from Packard.[46]The skilled person would also have known that the amount of light generated from an SPA sample is orders of magnitude less than that generated by fluorescence or chemiluminescence techniques. Exposure times for SPAs were in the order of a few minutes, whereas for fluorescence or chemiluminescence assays they were in the order of a few seconds.

Luminescence

[47]The skilled person would have known about the various different types of luminescence and, in particular, chemiluminescence, bioluminescence, radioluminescence, phosphorescence and fluorescence and would have been familiar with assay techniques based upon those different types of luminescence. As to fluorescence, the skilled person would have been aware of techniques such as time resolved fluorescence (“TRF”). In TRF a molecule is labelled with a fluor that exhibits delayed fluorescence. The presence of the labelled molecule in an assay is determined by exposing the assay to a flash of light and, after an appropriate delay, detecting the emission of light from the fluor. This addresses the problem of autofluorescence, that is to say background fluorescence due to the emission of light by molecules that naturally occur in the sample following excitation by light. The fluorescence of interest is measured after the autofluorescence has died away. The skilled person would have been aware of, in particular, the Wallac DELPHIA assay marketed in the mid 1980s, and homogenous TRF (“HTRF”) assays such as the Packard-CIS Bio HTRF assay. This latter assay, being a homogenous assay, did not require any separation step. He would also have been aware that fluorescence assays frequently employed green or red emitting fluors, such as europium chelates.

Characteristics of low light level detectors

[48]The skilled person would have been aware that low light level detectors have a number of characteristics which need to be considered when deciding how best to optimise a particular detector for a particular assay and, in particular, signal to noise ratio, quantum efficiency, sensitivity and the wavelength over which the instrument has to be sensitive. Further, he would have been aware the detector does not care how the light is produced but only how much of it is present.

Matching the detector to the assay

[49]The skilled person would have known that the best results are achieved by matching the wavelength of light emitted by the scintillant to the spectral response of the detector; put shortly, the emitted light needs to be somewhere in the sensitive region of the camera. I am satisfied that this accounted for the choice of yttrium silicate doped with cerium and PVT incorporating first, PPO and then butyl-PBD/DPA as the scintillants in Amersham’s SPA beads. All these scintillants emit light in the blue region of the spectrum and were adopted because they were readily detectable by conventional scintillation counters incorporating PMTs which were most efficient in detecting blue light.

Scintillation counters incorporating PMTs

[50]The skilled person would have known about scintillation counters incorporating PMTs and how to use them to detect luminescence in different kinds of assays, including SPAs. He would also typically have had some familiarity with either the Packard TopCount or the Wallac MicroBeta detectors. He would also have known that such instruments counted 6 or 12 wells at a time and also that the physical size of the PMTs in such instruments meant that they could count wells on 96 well plates or, at a stretch, 384 well plates, but were not practical for miniaturisation beyond that.

High throughput screening and miniaturisation

[51]The skilled person would have been well aware there was an increasing trend towards high throughput screening and miniaturisation. In the mid 1990s the 96 well plate was a standard format and increasingly 384 well plates were being used. Moreover, people who were buying new detectors such as imagers wanted to use them for as many applications as possible.

Phosphors

[52]There was some agreement between the experts as to the extent that the skilled person would have known about phosphors. In particular, they both agreed that the skilled person would know what phosphors, scintillants and fluors were, and would know the wavelength of light that common biological phosphors emitted. If he did not know the wavelength of a particular biological phosphor, then he would know where to look it up. It was also agreed that the skilled person would have had a familiarity with, at least, organic phosphors and would have been aware of DELPHIA and that red emitting europium chelates were used in that assay. This apart, however, the experts were not in agreement, reflecting, in my judgment, their different backgrounds. For example, Dr Oldenburg knew nothing about the wavelength at which the scintillants in the beads and scintillating microplates used for SPA emitted light because this information was of no importance to him. Nevertheless, in the light of my assessment of the identity of the persons to whom the Patent is addressed, I am satisfied that the skilled person would have known the colour and wavelength of the light emitted by the scintillants used in SPA beads and scintillating microplates. On the evidence it is clear that these are matters which would have been well known to the manufacturers of beads, plates and detectors. Further, in the light of the evidence of Professor Tanke, I am satisfied that the skilled person would have known of the use in connection with TRF and HTRF of a number of organic chelates of lanthanides or inorganic materials doped with lanthanides. In particular, the skilled person would have been aware of the use of terbium (Tb3+) and europium (Eu3+) and that terbium was known to have its strongest emission in the green part of the spectrum and europium to have its strongest emission in the red part of the visible spectrum. I am also satisfied that the skilled person would have been aware that he could look up information relating to the emission properties of inorganic crystals doped with lanthanides in reference books such as Blasse & Grabmaier. An important reason to use lanthanides was that they showed a large Stokes’ shift, that is to say a difference between the excitation wavelength (UV) light and the emission wavelength (green or red).

Colour quenching

[53]The experts were agreed that the skilled person would have been aware of the phenomenon of colour quenching and its causes. Many of the samples screened by SPA assays are coloured, and the majority of these are yellow or brown. The skilled person would have been aware that the degree of quenching would depend upon the overlap between the absorption spectrum of the coloured sample and the emission spectrum of the scintillant. Further, the skilled person would have been aware that colour quenching gave rise to three problems, namely a reduction in signal and hence sensitivity to detection, false negatives or false positives, and an error in the quantitative results obtained. As a result of all these problems, scintillation counters adopted systems of colour quench correction although these were not wholly accurate and did not deal with the problem of loss of signal.

CCD cameras

[54]There was a marked difference between the experts on this issue. Dr Oldenburg had very little knowledge of the use or potential use of CCD cameras by 1997. Nevertheless, he accepted that CCD cameras were established devices in the fluorescence field by 1993 and that, by the same date, such cameras were widely available for cell microscopy. From Professor Tanke’s perspective, much more was known about these cameras. As I have identified the skilled person, I am satisfied that Professor Tanke’s evidence on this issue is to be preferred. In the light of that evidence, I consider that the following matters were common general knowledge. First, CCD cameras could be used and had been used to detect fluorescence, including TRF and fluorescence based immunoassays. Secondly, he would have known, or reference to a manufacturer would have revealed, the differences between intensified and cooled CCD cameras. It was known that cooled CCD cameras were particularly sensitive to light in the green and red parts of the visible spectrum. By contrast, the spectral sensitivity of intensified CCD cameras varied depending upon the intensifier or photocathode being used. Although intensified CCD cameras could be optimised to have a peak sensitivity at different wavelengths, the performance of the camera in terms of the signal to noise ratio tended to be higher for blue light than for green or red light. Further, intensified CCD cameras tended to be more sensitive than cooled CCD cameras. In addition, intensified CCD cameras could image faster than cooled CCD cameras but cooled cameras provided the highest spatial resolution. Thirdly, in the mid 1990s, sensitivity of CCD cameras was improving rapidly and their cost was coming down. Fourthly, it was known that they were capable of taking a two dimensional image of the assay, providing quantitative measurements and spatial resolution and enabling a larger area to be observed at any given time than was the case with conventional detectors. Finally, the principle of matching the emission maximum of a luminescent molecule to the peak sensitivity of the detector applied as much to CCD cameras as to any other detectors.

Novelty

[55]The House of Lords has recently reviewed the law of novelty in Synthon BV v SmithKline Beecham plc [2005] UKHL 59. Lord Hoffmann explained that there are two requirements for the objection of lack of novelty to succeed: prior disclosure and enablement. As to disclosure, Lord Hoffmann summarised the position as follows: the matter relied upon as prior art must disclose subject matter which, if performed, would necessarily result in an infringement of the patent: [20]-[25].[56]PerkinElmer relied upon two documents in support of its objection that the Patent lacks novelty:- a) “Developments and Applications of Photon Imaging for Biomolecular Screening” by Hooper et al.; The Society for Biomolecular Screening (1995) (“Hooper”); b) WO95/11461 (“Rushbrooke”). Hooper[57]Hooper is a paper presented at the first conference of the Society for Biomolecular Screening (“SBS”) in November 1995. It was written by four authors from Cambridge Imaging Limited (“CIL”), including Dr Claire Hooper and Dr John Rushbrooke.[58]Hooper discloses the use of an intensified CCD camera for carrying out photoimaging in a range of assay applications using isotopic and non-isotopic labels. The abstract explains that these include radioisotopic applications such as 3H SPA detection in 384-well microplates and autoradiography of 3H and 14C. Non-isotopic assays include measurement of alkaline phosphatase with fluorescent (Attophos) and chemiluminescent (Lumiphos) substrates.[59]On the second page of the paper, it is explained that low noise intensified CCD cameras provide ultimate sensitivity for low light level detection and that single photon events can be counted and integrated in images over a wide dynamic range. This sensitive combination has made it possible to image single scintillation events from radioisotopic labels and to discriminate very effectively against most sources of noise.[60]The paper then proceeds to describe two types of radioisotope imaging. The first mode, autoradiography, involves the placing of samples on a thin sheet of scintillant which in turn is imaged in direct contact with the fibre optic input of the camera. Hooper explains that even low energy radioisotopes such as 3H can be effectively imaged at high resolution.[61]The second radioisotope imaging mode is used when the sample and scintillant are dispersed in a solution as in the case of the imaging of SPA. The authors describe the use of 3H labelled PVT test microspheres in a 384-well microplate. The results were apparently satisfactory and the authors state that they estimate that up to 96 wells could be counted simultaneously. They further note that the results suggest that it may be possible to miniaturise SPAs in dense arrays and improve analysis throughput.[62]The authors then proceed to describe the use of the CCD camera for non-radioisotopic imaging, in particular chemiluminescence and fluorescence detection. As to fluorescence, they explain that they have imaged arrays by fluorescence detection by using Attophos. Attophos emits green light and it has an emission maximum of 560 nm.[63]It is apparent from this description that Hooper discloses the suitability of an intensified CCD camera for SPT imaging, albeit that the authors used test beads rather than an actual SPT. The beads used were traditional Amersham PVT beads emitting blue light between 350 and 450 nm, and accordingly outside the claimed range. Nevertheless, Professor Tanke explained that it was his belief that the skilled person would find it implicit in the paper that a green or red, rather than a blue emitting phosphor could be used, especially so given the reference to the same system being used to image Attophos with a wavelength of 560 nm in relation to fluorescence. Similarly, as I will explain when addressing the issue of obviousness, Dr Oldenburg agreed that it was implicit that a phosphor of similar emission characteristics to Attophos could be used in an SPT with the CCD detector described.[64]In my judgment it is clear that Hooper does not constitute an anticipation of the Patent. It does not contain a description or disclosure of subject matter which, if performed, would necessarily result in an infringement of the Patent. The actual description of SPT involves the use of a phosphor with an emission maximum falling outside the claimed range. There is, accordingly, no clear and unmistakeable direction to use in an SPT feature c), f) or l). Rushbrooke[65]Rushbrooke is a patent application entitled “Improved Imaging Method and Apparatus”. The applicants were CIL and Packard. It was published on 27 April 1995 and claims priority from two earlier applications filed on 20 October 1993 and 23 March 1994.[66]The abstract explains that the invention is directed to a method of detecting the presence and position of radioisotope material in a sample and comprises the steps of exposing the sample to a phosphor, repetitively imaging the phosphor onto an image intensified CCD camera and then scanning the camera CCD array and interrogating the charge pattern upon it following each exposure.[67]The field of the invention is described on page 1. There the specification explains:- “This invention concerns methods and apparatus for detecting radioisotope labelled materials which emit radiation such as beta particles. The invention is an application in the field of radioisotopic diagnostics and analysis and for performing measurements and analysis on labelled immunoassays, tissue sections, microbiological specimens, cellular specimens, cellular monolayers, reporter genes, DNA and / or protein gels and blots.” Conventionally, these applications used a photographic plate, for example an X-ray film, to detect the location or amount of radioactivity contained within a sample. Rushbrooke explains that, instead of a photographic plate, an intensified CCD camera may be used.[68]The primary application that Rushbrooke describes is autoradiography. Typically in this application, a sample of tissue is brought into proximity with a phosphor screen and radiation emitted from any isotope present in the sample produces an image on an X-ray film. Rushbrooke explains that when a radioactive tissue sample is placed against a phosphor screen, emitted light can be captured with an intensified CCD. Thus, for example, figure 1 depicts an apparatus for detecting radioactive beta particle disintegration in a radioisotope labelled sample. The sample is carried by a glass microscope slide which is placed face down in contact with a phosphor layer. The phosphor layer is in turn carried by the input window of an image intensifier and an image intensified representation of the incident light is then transferred to a CCD array. It is notable that Rushbrooke nowhere mentions SPT expressly.[69]Professor Tanke expressed the view that the passage in Rushbrooke set out in paragraph 67 above discloses the use of a CCD camera in connection with an SPT because it refers to the method of the invention as being of wide application, including to radioimmunoassays. He reasoned that Rushbrooke applies to all fields where radioisotopes are used as labels, and that although many formats exist, radioimmunoassays form by far the largest and most important group of assays in the field. Since the vast majority of SPTs use antibodies or other immunospecific ligands and are therefore radioimmunoassays, he took it that Rushbrooke applied to SPTs.[70]Dr Oldenburg did not accept this analysis and in my judgment he was right not to do so. As he explained, a radioimmunoassay generally involves the mixing of an experimental sample of unlabelled antigen with a constant, known amount of the same antigen which has been radioactively labelled. To this mixture is added a limited amount of rabbit antibody prepared against the antigen being measured. Since the system is antibody limited, the amount of labelled antigen bound to the rabbit antibodies is inversely proportional to the quantity of non radioactive antigen present. The antigen-antigen complexes are then separated from free antigen. A variety of methods are available for this purpose but the one most widely used experimentally is immunoprecipitation.[71]Some SPTs adopt the format of a radioimmunoassay in which an antibody is attached to the SPT bead and the antigen of interest is free in solution along with the radiolabelled analog. There are many SPTs, however, that are not radioimmunoassays. Further, there are many radioimmunoassays that are not SPTs. There is no clear direction in this passage to apply the method to SPTs.[72]Various other matters were relied upon in support of the contention that Rushbrooke gives clear directions to carry out an SPT. First, Professor Tanke relied upon the fact that, on various occasions, Rushbrooke explains that the radiolabelled sample should preferably be “in contact” with a film of phosphor. So, he contended, the reader would understand that a radioimmunoassay conducted using a film of phosphor which is in contact with the radiolabelled sample, where the sample is a fluid, is a form of SPT. Further, he explained under cross examination that the conditions Rushbrooke describes are “very similar” to those disclosed in Cook. There is no doubt that Cook does indeed disclose SPTs but again, in my judgment, it does not advance the matter. As I have explained, contact between phosphor and sample is a feature of autoradiography. It does not amount to a clear direction to use an SPT.[73]It is right to say that Rushbrooke discloses the use of yttrium silicate doped with cerium as a phosphor, this being one of the phosphors the skilled person would be likely to recognise as being used in SPT, and also the use of P20 as a phosphor, which has an emission maximum of 560 nm. Moreover, Rushbrooke discloses the imaging of low energy beta particles and the use of a very similar list of isotopes to that given in the Patent at paragraph [0016]. As might be expected, Rushbrooke explains that the sample usually needs to be in contact with the phosphor in order to ensure that the phosphor is within the mean free path of the low energy beta particles and that the phosphors are generally supported on thin films. I accept all these matters but they are equally consistent with autoradiography. They do not constitute clear and unmistakeable directions to carry out an SPT. For the same reason I am unable to accept Professor Tanke’s opinion that the disclosure on page 1 of Rushbrooke, paragraph 4, in the definition of “phosphor”, of polymer media doped with rare earth chelates constitutes a direction to carry out SPTs. Polymer media doped with rare earth chelates can be used as phosphor sheets in autoradiography.[74]Finally, it was suggested that Dr Oldenburg accepted in principle that there was no difference between growing a cellular monolayer on a plastic sheet containing a rare earth chelate, which is described in Rushbrooke, and using a scintillating microplate such as Cytostar T which had a plastic bottom containing a scintillant. This is a matter to which I will revert in considering obviousness. Once again, however, it does not constitute a clear and unmistakeable direction to carry out an SPT.[75]For all these reasons, I am satisfied that Rushbrooke does not anticipate any of the claims in issue. There is no disclosure of subject matter which, if performed, would necessarily result in an infringement of any of these claims. In particular, there is no disclosure of subject matter which would necessarily involve features a) or g); nor (and for like reasons) is there disclosure of subject matter which would necessarily result in the use in connection with an SPT of a phosphor with an emission maximum of 480 nm to 900 nm and consequently of features c), f) or l). Obviousness[76]PerkinElmer contended that the invention described and claimed in the Patent was obvious and did not involve any inventive step having regard to the common general knowledge, Hooper, Rushbrooke and the following further four citations: a) Scintillation Proximity Assay, N. Bosworth and P. Towers, Nature 341:167-168 (14 September 1989) (“Bosworth”). b) Preparation and Microscopic Visualization of Multicolour Luminescent Immunophosphors, Beverloo et al., Cytometry 13:561-570 (1992) (“Beverloo”). c) CCD Camera Imaging for the Chemiluminescent Detection of Enzymes Using New Ultrasensitive Reagents, Akhavan-Tafti et al., J Biolumin Chemilumin 1994; 155-164 (“Tafti”). d) WO 94/26413 (“Cook”).[77]The general principles to be applied in considering the question of obviousness are well established. In the present case the following are particularly relevant. First, it is convenient to address the question using the structured approach explained by the Court of Appeal in Windsurfing International Inc. v Tabur Marine (Great Britain) Ltd [1985] RPC 59. This has been summarised as follows: i) Identify the inventive concept of the claim; ii) Identify the common general knowledge of the skilled team; iii) Identify the difference(s) between the prior art under consideration and the inventive concept of the claim; iv) Ask whether the difference(s) would have been obvious or required invention.[78]Secondly, the primary evidence is that of the expert witnesses. All other evidence is secondary to that primary evidence. Secondary evidence has its place and the weight to be attached to it will vary from case to case. However, such evidence must be kept firmly in its place: Mölnlycke v Procter & Gamble Ltd (No 5) [1994] RPC 49 at 113.[79]Thirdly, a decision on obviousness does not require a conclusion as to whether or not the skilled person would be slightly, moderately or particularly interested in any document. Any prior document relied on must be deemed to be read properly and in that sense with interest: Asahi Medical Co Ltd v Macopharma(UK) Ltd [2002] EWCA Civ 466 at [21]-[25].[80]Fourthly, what matters is whether the inventive concept is technically obvious over the prior art, not whether it is commercially obvious to take that step: Hallen Co v Brabantia UK Ltd [1991] RPC 195.[81]Fifthly, if a particular route is an obvious one to take, it is not rendered any less obvious from a technical point of view merely because there are a number, and perhaps a large number, of other obvious routes as well: Brugger v Medic-Aid Ltd [1996] RPC 635 at 661.[82]Further, I was cautioned by Amersham to be wary of any submission that the invention in the present case was one which was obvious to try. The “obvious to try” doctrine needs to be applied with caution. As Jacob LJ said in St Gobain v Fusion Provida [2005] EWCA Civ 177 at [35]:
“Mere possible inclusion of something within a research programme on the basis you will find out more and something might not turn up is not enough. If it were otherwise there would be few inventions that were patentable. The only research which would be worthwhile (because of the prospect of protection) would be into areas totally devoid of prospect. The “obvious to try” test really only works where it is more-or-less self-evident that what is being tested ought to work.”
Inventive concept[83]The parties were agreed as to the inventive concept of the claims in issue. The inventive concept is the use in an SPT of a phosphor with an emission maximum within the claimed ranges and a CCD detector.[84]As I have already noted, the claims are very broad. They cover the use of all SPT formats, all CCD cameras and all phosphors with an emission maximum within the claimed ranges. There is no limitation in the claims to any particular level of performance. Nor is there any limitation to particular phosphors which, for example, will produce the results shown in the examples. This is of some importance. As Laddie J explained in Brugger v Medic-Aid [1996] RPC 635 at 656:
“For this purpose it is necessary to bear in mind that the relevant inventive step must apply to all embodiments falling within the claims which are said to have independent validity. It is not legitimate to define the inventive step as something narrower than the scope of the relevant claims. In particular, it is not legitimate to identify a narrow sub-group of embodiments falling within the claim and which have certain technical advantages and then to define the inventive step in terms which apply to that sub-group but not the rest of the claim.”
[85]Paragraph [0010] of the Patent is set out in paragraph 23 above. It explains that the invention seeks to overcome the dual problems of low sensitivity of current CCD-based detection as well as colour quench in conventional SPA bead technology. Each of these suggested problems merits a little consideration.[86]As to the sensitivity of current CCD-based detection, this appears to be based upon the statement in the preceding paragraph [0009] of the Patent concerning a paper by Englert. He was part of the team at CIL and presented his paper at the second SBS conference in 1996. The Patent suggests Englert reported CCD-detection of SPA counts using PVT based microspheres, but that the photon count from the SPA wells was not sensitive enough to enable useful results to be obtained due to low light output of the beads, sub-optimal signal detection capability of the system, as well as quenching by coloured samples. Englert does indeed disclose the use of an intensified CCD camera in connection with an SPA. This was the same camera system disclosed in Rushbrooke and Hooper. However, contrary to the suggestion in the Patent, Englert explains that the count rate obtained from a 384 well plate with his camera – called the Contact Imager – was twice that obtained using a scintillation counter. This, Dr Oldenburg agreed, was a pretty useful result. Similarly, as I have explained, Hooper had also demonstrated the successful use of the same Contact Imager camera in connection with SPAs at the first SBS conference one year earlier.[87]In any event, however, and more importantly, the Patent gives no teaching at all as to how the suggested sub-optimal signal detection capability of the system is to be remedied. That is not a feature of the disclosure of the body of the specification and not a feature of any claim. There is no teaching in the Patent as to how to make an improved CCD camera. The Patent assumes, on the contrary, that the invention can be implemented with a cooled or an intensified camera and that the addressee will either know of such instruments himself or be able to ascertain all necessary information about such instruments from suppliers such as Molecular Devices Inc. or Princeton Instruments Inc.[88]The Patent also suggests in paragraph [0009] that the low sensitivity of current detection was due to low light output of the beads. However, as Dr Oldenburg accepted, the Patent does not suggest that all phosphors with an emission maximum in the claimed range of 480 to 900 nm emit more light than all phosphors with an emission maximum below 480 nm. Moreover, if the Patent did suggest that, then Dr Oldenburg believed that it would not be true. The phosphors which are claimed do not therefore solve the problem because they emit more light. Nor does a change in phosphor from one that emits at less than 480 nm to one that emits at more than 480 nm affect the performance of the detector as such. The detector has no interest in what has generated the light. It is only concerned with the amount of light and its wavelength. It is important that the sensitivity of the detector and the emission maximum of the phosphor are matched. That is so whether the emission maximum is above or below 480 nm and was, in any event, well known. For all these reasons I conclude that even if the sensitivity of current CCD based detection systems was a problem, the invention does not solve that problem.[89]As to the second problem, namely that of colour quench in conventional SPA bead technology, this again appears to be based upon the suggestion in paragraph [0009] of the Patent that first, Englert had experienced quenching by coloured samples, and secondly, in the case of CCD detection using conventional SPA beads under normal assay conditions, the number of photons detected per disintegration was insufficient to enable determination of quenching levels, and quench correction was not possible. As to this, colour quenching was, as I have already explained, a well known phenomenon and it was one which was addressed in a conventional SPA assay by the adoption in scintillation counters of colour quench correction programs or by the use of colour quench correction curves. It was a particular issue for customers screening natural products and the more miniaturised the system the greater the potential problem. Secondly, changing from a conventional scintillation counter to a CCD detector makes no difference to the degree of colour quenching that occurs in any particular assay. Thirdly, it was technically perfectly clear to the skilled person that the degree of quenching depends on the overlap between the absorption spectrum of the coloured sample and the emission spectrum of the scintillant. A brown coloured sample will more readily absorb blue light than red light. Fourthly, the Patent contains no teaching as to how to solve the issue of colour quenching other than adopting a red shifted scintillant. I consider later in this judgment the issue of whether or not that was obvious to the notional addressee.[90]There are two other points which I should mention at this stage. First, the experts agreed that a red shifted scintillant does not totally solve the problem of colour quench in any event. Although the majority of samples are yellow or brown in colour, a significant number are not and in relation to these samples a red shift of the wavelength does not reduce the problem of colour quench but increases it. Further, even though many biological samples are brown or yellow in colour, the actual tones of particular samples vary one to another. It is therefore still necessary to correct for colour quenching even if a red shifted scintillant is adopted. Overall therefore, red shifting the scintillant ameliorates the problem of colour quench but does not solve it. Secondly, the experts were agreed that, contrary to the statement in the Patent, Englert did not state that colour quench correction was not possible with CCD detection.[91]In summary, I agree with the submission advanced by PerkinElmer that the claims are directed to the bare idea of using a red shifted scintillant in an SPT with a CCD regardless of whether or not that yields any improvement in the efficiency of signal production or detection. Obviousness over

Common general knowledge

[92]In my judgment, particular care must be taken to avoid hindsight reasoning when considering an argument that an invention is obvious in the light of common general knowledge. As Aldous LJ noted in Coflexip & Anr v Stolt Connex Seaway MS Ltd and Ors, 31 July 2000, unreported on this point, at [45]: the advantage of starting an attack upon this basis may well be that it is unencumbered by any detail. The court must ensure that points upon which reliance is placed are not taken out of context.[93]It was not known as a matter of common general knowledge to use a CCD camera with a red shifted phosphor for SPTs. The case that it was obvious to do so in the light of the common general knowledge is a very straightforward one.[94]Professor Tanke expressed the opinion in his report that in August 1997 it was obvious to use a CCD camera in connection with SPTs for the following reasons. CCD cameras were known to be capable of detecting low light levels in biomedical assays. In the mid 1990s the sensitivity of the CCD cameras available in the market was improving rapidly and their cost was coming down. They had the advantage of imaging the whole plate at once with high resolution. Consequently, they had the potential to deal with high well density plates and increase throughput.[95]Both cooled and intensified CCD cameras were obvious cameras to use. The skilled person would have known that for optimum results the wavelength of interest from the assay should match the spectral characteristics of the detector. The spectral characteristic of cooled CCD cameras peaked in the green-red part of the visible spectrum and, accordingly, if the skilled person chose a cooled CCD camera it would have been obvious to use a phosphor which emitted light in this part of the spectrum. In particular, it would have been obvious to use organic chelates of lanthanides or inorganic materials doped with lanthanides, and the most obvious lanthanides to use would have been terbium or europium.[96]If the skilled person decided to use an intensified CCD camera, it would have been obvious that he could use these same phosphors and choose an intensified camera which had a matching spectral response.[97]Further, and in any event, the skilled person knew that colour quenching was a problem with SPTs, that the majority of biological samples were coloured yellow or brown and accordingly absorbed blue light. In the circumstances, it was obvious to use a phosphor which emitted green or red light because this would reduce colour quenching. Further, it was obvious to image an SPT using such a phosphor with a CCD camera.[98]Professor Tanke was cross examined on this evidence. He accepted that it was not known from common general knowledge that a CCD camera could detect SPTs and that was something that would need to be investigated. Nevertheless, he explained that it was known that a CCD camera could be used, for instance, to read out a multi well plate on the basis of fluorescence and that it would make sense to have a combined approach and think about the sensitivity of the CCD camera and the phosphors to be used in connection with it.[99]It was also suggested to Professor Tanke in cross examination that someone who was being properly advised on the choice of a CCD camera to image an ultra low light assay such as an SPT would be advised to use an intensified camera, as it was the most sensitive, and SPT was recognised to be a demanding application. Professor Tanke accepted that a number of factors favoured the choice of an intensified CCD camera: for a very low light application there would have been a preference to use an intensified camera to boost the signal; intensified cameras had a high degree of flexibility which would permit the matching of an intensified camera to a blue emitting assay; intensified cameras were faster, and intensified cameras offered “high gain for single photon sensitivity”. In addition he accepted that, in the context of the intensified CCD system, the signal to noise ratio decreased as one moved from blue light to green and red light; that noise is created by thermal photons and these are emitted in the red region of the spectrum, and that blue light has a higher energy and gives a better efficiency. Nevertheless, he maintained that a cooled CCD camera was an obvious if not more obvious choice because it was the first on the market, sufficiently sensitive, cheaper, and because an intensifier could adversely affect the signal to noise ratio. Plainly, if a cooled CCD camera were adopted, then it would be obvious to use a phosphor whose emission maximum matched the peak response of the detector.[100]As to colour quenching, Professor Tanke accepted that colour quenching was conventionally dealt with by quench correction built into the PMT apparatus or a curve which the user applied to his results. He also accepted that, in the end, he would not have advised anyone to shift wavelength simply to deal with colour quench. This was because wavelength shifting does not completely solve the problem. Whatever the shift, there will still need to be some correction. However, this does not seem to me to meet the point that it was technically obvious, as Professor Tanke maintained in his report, that a way of correcting for colour quench caused by yellow and brown samples was to red shift the phosphor. That is all the Patent teaches. The fact that a skilled person might not choose to implement that technically obvious route because he would still have to make a colour quench correction for samples of other colours does not, in my judgment, mean that the route was not technically obvious.[101]I must also refer to the position in relation to alternative phosphors. It was argued by Amersham that the skilled person would need some comparative information on the strength of different phosphors in order to be persuaded to change his phosphor to one which emitted light of a different wavelength. However, there was nothing in the common general knowledge to indicate how efficient red shifted phosphors would be compared to the existing blue emitting phosphors. In this regard Professor Tanke accepted that he was not able to point to any textbook or other literature containing such comparative information. In the circumstances Amersham maintained there was nothing available in the general knowledge to guide the skilled person in favour of red shifted phosphors over phosphors emitting light in the blue region. I accept this is the case. But, in my judgment, it does not meet the point advanced. It was not suggested that it was known, as a matter of common general knowledge, that red shifted phosphors would provide any benefit over the use of conventional phosphors in SPTs, save that they would be obvious phosphors to use to address colour quenching by yellow or brown coloured samples. That such phosphors were available is recognised by the Patent and it was well known that they had been used in other fluorescence assays such as DELPHIA. It is for this reason that Professor Tanke maintained that it was technically obvious to use such phosphors in SPTs.[102]Dr Oldenburg expressed the view in his report that the invention was not obvious in the light of the general knowledge. He considered that it was not obvious to substitute a CCD camera for a scintillation counter and was not obvious to adapt the wavelength of the phosphor. Under cross examination, however, he accepted that a skilled person setting out to develop an SPT assay system in August 1997 would have needed to consider both halves of the equation, that is to say the reagent and the detector. He was then asked to consider a scenario in which the skilled person was particularly interested in carrying out an SPT assay in which drug uptake into cells was measured using a scintillating plate, a layer of cells on top and a solution with a radiolabelled drug; and that he was interested in making a single well plate and a series of multiwell plates with, for example, 96, 354 and 1536 wells. He gave the following answers (Day 5, at pp. 671-673): Q. I suggest to you that by August 1997 it follows from everything I have been putting to you that a CCD camera would be an obvious choice of detector? A. If you are going to 1536 it would be, otherwise I would not use it. Anything below 1536, I would stick with standard scintillation counter. Q. You might think that it was not necessary for lower densities but it would still be an entirely natural choice? A. No, I do not believe it would be, because in 1997, the 104. scintillation counters were still quite a bit faster and Q. Can I put the question this way: On my hypothesis, the 106. person or team is addressing this issue in 1997 -- and 107. concentrating for the moment on the 96 or the 354 -- it would 108. not require invention to decide to use a CCD camera, would it? 109. A. If all they wanted to do was to read a plate in 96 or 384 are we talking SPA or -- I guess it would not matter, any type of 110. light -- no, I do not think it would. Q. One of the problems that this person or team is going to be112. concerned about, for the reasons we discussed already, is colour113. quench. They may regard that as a big or small issue depending114. on the different perspectives that you already described, but115. they would certainly appreciate that it was an issue?116. A. Sure.117. Q. Since they are studying cells, it might be quite a big issue for118. them?119. A. It could be.120. Q. They would appreciate that one step they could take to eliminate121. or reduce colour quench would be to use a scintillant that122. emitted in the green or preferably in the red? A. They would understand that that would not get you around the 124. problem of colour quench, because everybody doing research in 125. this area, doing screening knew their libraries looked like a 126. rainbow, so if you remove quench in one you gain it in the other. 127. So no matter what you do, you are going to have to put in colour 128. quench correction curves or some other mathematics; you cannot get around colour quench completely. Q. If you are studying cells you would have lots of red brown and yellow around and they will appreciate that using a scintillant that emits in the green or the red will reduce colour quench for those cells? A. Yes, for those, but still 10-15% of your compounds are going to quench, so you have removed a little bit or some of your colour quench problem, but they would also be very concerned about the other colours, so I -- they would know instinctively they cannot get around colour quench.”[103]In that passage, Dr Oldenburg accepted that, at least for plates with a greater density of wells, it was obvious to the skilled person to use a CCD camera. He also accepted that one of the problems the skilled person would be concerned about was colour quench and that if the assay was for the study of cells, that might be quite a big issue. His answer as to whether or not it would be obvious in those circumstances to red shift the phosphor was not that the skilled person would not know of the possibility of using a red shifted phosphor but rather he would appreciate that it would not solve the problem of colour quenching altogether. Indeed, he accepted that the skilled person would appreciate that using a scintillant that emitted light in the green or the red regions of the spectrum would reduce colour quench for those cells which were coloured red, brown and yellow. As I have already explained, the Patent does not solve the problem to which Dr Oldenburg referred either. It only provides a solution to the problem of colour quenching in relation to samples which are coloured red, yellow and brown. This much, Dr Oldenburg accepted, would have been obvious. Not surprisingly, Dr Oldenburg also accepted that it would be expected that red, orange and yellow compounds would absorb less if one used green or red light than if one used blue light and therefore the results of Example 2 of the patent were entirely expected.[104]Dr Oldenburg was also asked to consider the scenario in which the skilled person was developing his own test and had his own choice of scintillant. In those circumstances, he accepted that if such a person had gone to a camera manufacturer who told him that cooled CCDs would be suitable, then he would appreciate that he should use a scintillant that emitted green or red light. In this regard, a chapter entitled “Assay Miniaturization” written by Dr Oldenburg in 1999 for the Handbook on Drug Screening is revealing. He said in relation to SPA miniaturisation:
“The scintillants used in the standard SPA beads have been optimized for use in photomultiplier-based detectors. Consequently, the scintillant was designed to emit light with an emission maximum at approximately 450 nm – the region of maximum sensitivity for this type of photomultiplier. CCD cameras, however, are maximally sensitive in the 600 - 700 nm region and thus required the development of an appropriate scintillating particle.”
Dr Oldenburg accepted that if the starting point was a cooled CCD camera that was maximally sensitive in the 600–700 nm region, then it would have required the skilled person to develop an appropriate scintillating particle to match it, that is to say, to have an emission maximum within that same range.[105]I am conscious that one must be very wary of applying hindsight in considering evidence of this kind. I also have very much in mind that it was not a matter of common general knowledge that an SPT could be imaged using a CCD camera. Further, I have no doubt that some workers in the field would have preferred an intensified camera to a cooled camera, but, in the light of all the evidence, it seems to me that they were both obvious alternatives. I also accept that there was evidence from both experts to the effect that if the skilled person started from the existing blue emitting assay then one would tend to ask the camera manufacturer to match the instrument to the assay and not vice versa. That was certainly an obvious way to go. But it was not the only one. It was also obvious to develop both parts of the system together. Overall, and after careful consideration, I have reached the conclusion that the weight of the expert evidence is that it was obvious, as of the priority date, to use a CCD camera for SPTs in conjunction with a red shifted phosphor.[106]There are a number of further matters which point to the same conclusion. First, and as I elaborate below, Packard arrived at the inventive concept independently. Packard first looked at CCD cameras as an alternative to scintillation counters in 1991. Packard approached Astromed, a UK company that developed cooled CCD cameras for low level light biomedical applications and Hamamatsu, a Japanese company that specialised in the production of PMTs and CCD image sensors. Packard learned that the scintillants would need to be red shifted in order to be efficiently detected by cooled CCDs. In the same year Packard attended a conference at which it learned about a CCD camera developed by Image Research, the predecessor to CIL. In 1993 Packard began collaborating with CIL in connection with the Optical Imager project for the purpose of detecting SPTs and other assays using an intensified CCD camera. The use of CCD cameras for the purpose of SPTs was promoted by the presentation of the Hooper paper at the first SBS conference in Philadelphia in November 1995 and a year later through the presentation of the Englert paper at the second SBS conference in Basel in October 1996.[107]Cooled CCDs were being offered by other suppliers for use in detecting SPTs by the mid 1990s. In particular, Noveltech (later Molecular Devices) was in contact with Amersham in connection with its FLIPR cooled CCD camera by November 1994. Imaging Research Inc. (“IRI”) was in contact with Amersham in connection with its Tundra cooled CCD camera in 1995. Further, IRI approached Affymax with its Tundra camera in 1994 and Dr Oldenburg’s group at DuPont once again made contact with IRI in connection with the Tundra camera at the end of 1996 or beginning of 1997. As Dr Oldenburg explained, they were very interested in seeing all the different things they could do with the camera. They quickly looked at fluorescence and, within six months, SPTs. This work was done with a standard Amersham kit. After this rapid initial development work, his team proceeded to look at fluorescence, chemiluminescence and then SPTs in turn. They only began to look at SPTs in detail in 1999. At about that time, Dr Oldenburg wrote the chapter “Assay Miniaturisation” to which I have already referred. Consistently with this, the use of a CCD camera for low level light detection was also suggested in Fluorescent and Luminescent Probes for Biological Activity by Mason (1993). Professor Tanke and Dr Oldenburg agreed the skilled person would likely have this book or at least something similar.[108]Against these matters I also have to take into account the fact that there was no suggestion to red shift FlashPlates, either for use with PMTs or the Optical Imager. As for FlashPlates with PMTs, these were designed for use alongside Amersham SPA beads with the standard TopCount and MicroBeta instruments and customers were well used to making standard colour quench corrections using those instruments or a colour correction curve. As for the Optical Imager project, I deal with this in addressing the entitlement dispute. As I explain, the Packard/CIL collaboration did, in my judgment, arrive at the inventive concept independently of Amersham. It is fair to say, however, that the project ultimately failed. But this must be seen in context. The aim of the project was to try and make a device which would cope both with the low light SPTs and bright fluorescent light. It was concluded that the highly sensitive CCD camera would be damaged when exposed to the higher light levels found in fluorescence.[109]In all these circumstances I have reached the conclusion that the invention was obvious in the light of the common general knowledge at the priority date. It was, in my judgment, obvious to use a CCD camera for SPTs. Further, it was technically obvious to address the problem of colour quenching, in particular in relation to biological samples coloured yellow or brown, by red shifting the phosphor. I also consider it was obvious to use a cooled CCD and that in connection with such a camera it was obvious to match the wavelength of light emitted by the phosphor to the spectral response of the detector. Cooled CCD cameras had their best spectral response in the green and red parts of the spectrum, and it was obvious to use a phosphor which emitted light of these colours.[110]I should say that I have reached this conclusion having also taken into account the various contentions raised in relation to the particular citations relied upon in support of the obviousness allegation. Further, my conclusion clearly has a significant bearing on the allegation that the invention is also obvious over those citations. I will address each citation in turn and indicate the extent to which my reasoning depends upon my conclusion that the invention is obvious in the light of the common general knowledge.

Hooper

[111]As I have explained, the difference between the disclosure of Hooper and the invention is that Hooper does not disclose the use of a phosphor with an emission maximum of 480 to 900 nm. It does, however, disclose the use of an intensified CCD camera for SPT, at least in a model system. Professor Tanke explained in his report that, in his opinion, it was obvious to go from Hooper to the invention for two reasons. First, Hooper discloses the use of a CCD camera in conjunction with a phosphor having a wavelength in the range 500-700 nm for a chemiluminescent assay. It would have been obvious that such a technique could be readily adapted to SPT. Secondly, it was obvious to the skilled person that a cooled CCD was an obvious alternative to an intensified CCD and, in that event, it would have been obvious to use a longer wavelength scintillant, as cooled CCD cameras have a greater efficiency in the green–red region of the spectrum. Under cross examination, he accepted that if the skilled person read this document and was interested in taking it further, one of the things he would do would be to set up a real live SPA and use an intensified CCD with contact imaging. For that purpose, one would get some blue emitting SPA test beads or microplates. Depending upon the results of the experiment, there might or might not be a reason to alter the wavelength of the emitted light. If the experiment worked satisfactorily then the skilled person would be pleased. This evidence does not seem to me to cast doubt on the proposition that it was technically obvious that colour quenching could be addressed, at least in part, by choosing a red shifted phosphor. Further, it does not cast doubt on the evidence that it was also technically obvious to use a cooled CCD camera with a phosphor which emitted a light of a wavelength which matched the spectral response of the camera.[112]Dr Oldenburg expressed the opinion in his report that the skilled person would be likely to try a real SPA assay with a CCD camera with contact imaging and image intensification. If he were to find that he could not get a sufficient signal with such a system, he would simply revert to using scintillation counters. There was no teaching in Hooper to indicate to the skilled person how he could move forward. In cross examination, he accepted that the skilled person interested in cytometry would appreciate that the technique described would be suitable for use for that application and that the authors had successfully demonstrated the successful imaging of an SPT, at least in a model system. They had also demonstrated the application of the technique to chemiluminescent and fluorescent assays. In particular, the authors had demonstrated successful fluorescent detection using Attophos, with an emission maximum of 560 nm. Importantly, he accepted that it was implicit in what Hooper had described that a phosphor of similar emission characteristics to Attophos could be used in an SPT with the CCD detector described.[113]Hooper teaches the skilled person that an intensified CCD camera can be used to image an SPT. It is also implicit in Hooper that a phosphor with an emission maximum of about 560nm can be used in connection with an SPT and detected using an intensified CCD camera. In both these respects the case of obviousness over Hooper is stronger than that over the common general knowledge. In the light of all the evidence, I conclude that it was technically obvious in the light of Hooper to use a red shifted phosphor within the claimed range to address the issue of colour quenching. It was also obvious to use a cooled CCD camera and a red shifted phosphor to match the emission maximum of the phosphor to the peak sensitivity of the camera. The invention of the Patent is therefore obvious over Hooper.

Rushbrooke

[114]In considering obviousness over Rushbrooke, it must be assumed that Rushbrooke does not disclose the use of the method and apparatus which it describes to image an SPT, and does not disclose the use for that purpose of a phosphor with an emission maximum of 480 – 900 nm.[115]Professor Tanke explained in his report that he considered it would have been obvious to go from Rushbrooke to the invention of the Patent for the following reasons. First, it would have been apparent to the skilled person in the light of Rushbrooke that a CCD camera could be used to image an SPT. If not expressly disclosed, it would nevertheless have been obvious that Rushbrooke had shown that CCD cameras could be used in fields where radioisotopes are used as labels, including, most importantly, radioimmunoassays. The skilled person would have known that SPTs may be radioimmunoassays. Secondly, Rushbrooke discloses the use of his system in relation to organic lanthanide chelates. The first lanthanides that would have come to mind would have been europium and terbium. In any event it discloses the use of P20, a commonly used phosphor, which has an emission maximum of 560 nm. Thirdly, it would therefore have been perfectly obvious in the light of Rushbrooke to use an intensified CCD camera to image SPTs using a phosphor with an emission maximum in the range 500 – 700 nm. It would also have been obvious to use a cooled CCD camera in the same way.[116]Under cross examination, Professor Tanke accepted that part of the teaching of Rushbrooke is to use short decay time phosphors, and that europium, for example, has a decay time an order of magnitude greater than the phosphors described. This may be so, but it does not alter the fact that one of the phosphors which is specifically described as suitable for use in the system is P20, which, as I have indicated, emits light in the green region of the spectrum. Further, he maintained that Rushbrooke does describe the use of the CCD camera in a situation which is very similar to that described in Cook and implemented in the Cytostar T Plates. In the circumstances, he maintained, it would have been obvious to apply the teaching of Rushbrooke to SPTs.[117]Dr Oldenburg considered that the focus of Rushbrooke is autoradiography which is materially different to SPT technology, that there is no teaching that a CCD camera would yield any advantages over traditional scintillation counting in connection with SPT, the reader is taught nothing about the optimal wavelength at which a CCD camera detects light and contains no reference to SPT beads or red shifted phosphors. He was cross examined generally as to the disclosure of Rushbrooke and then, in particular, as to the disclosure in Rushbrooke that the method and apparatus may be used to measure drug uptake by cellular monolayers. Dr Oldenburg accepted that that was indeed disclosed. He also accepted that, in principle, there was no difference between growing a cellular monolayer on a plastic sheet containing a rare earth chelate, as described in Rushbrooke, and using a scintillating microplate such as a Cytostar T or FlashPlate where the plastic, for example polystyrene, contains a scintillant. In re-examination, Dr Oldenburg explained that the reader would understand that Rushbrooke’s teaching in this regard involved growing a monolayer of cells on a petri dish, washing away the media containing growth materials, adding a drug and incubating, washing away the surplus to remove radioactivity, fixing the cells and then bringing the sample into contact with the phosphor screen. This, of course, is not a description of an SPT.[118]As I have indicated, I accept that Rushbrooke does not expressly disclose the use of his apparatus and method in connection with an SPT. Nevertheless, it seems to me that it would have been perfectly obvious to a skilled person at the priority date that the CCD system that Rushbrooke does describe could be used in connection with a scintillating microplate such as the Cytostar T Plate or FlashPlate. Although Rushbrooke does not expressly describe the use of the CCD system for SPT it does describe its use for detecting radioisotope labelled materials, including labelled immunoassays and cellular monolayers. It also discloses the use of a green emitting phosphor, P20. In both these respects the case of obviousness over Rushbrooke is stronger than that over the common general knowledge alone. Of course SPTs do not require a separation step but it seems to me that in the light of the disclosure it was obvious that the Rushbrooke system could also be applied to SPTs. In this regard I prefer the evidence of Professor Tanke to that of Dr Oldenburg. It is also clear the system is suitable for use with a green emitting phosphor such as P20. This would have been a technically obvious phosphor to use to address colour quenching by yellow or brown coloured samples. I conclude that the invention of the Patent was obvious over Rushbrooke.

Bosworth

[119]This is a paper by Amersham scientists published in Nature in 1989. It explains that Amersham has introduced a new product, namely an SPA.[120]The authors describe the production of a better SPA bead than those previously used. The previous beads used fluoromicrospheres based on organic phosphors. The authors describe a new bead based on yttrium silicate and doped with rare earth elements. In particular, in the second column on page 167, Bosworth discloses:
“Yttrium silicate… doped selectively with rare earth elements to facilitate the production of light with the optimum emission characteristics for the photomultipliers and electronic circuitry used in commercially available scintillation counters.”
In this passage, the authors are explaining that they have chosen an appropriate rare earth element for use in connection with a scintillation counter. No other details are, however, given.[121]The authors conclude:
“There are important concurrent developments in related research areas: antibody and receptor solid-surface coupling methods are being improved, cloned receptors (especially human) are becoming increasingly available, and inorganic phosphors are being developed with higher photon yields. The inevitable availability of more sophisticated scintillation counters will allow the simultaneous counting of many samples.”
[122]In the circumstances, it is apparent that the differences between Bosworth and the inventive concept of the Patent are that there is no disclosure of phosphors emitting light at the claimed wavelengths and no disclosure of the use of a CCD camera.[123]Professor Tanke explained in his report that anyone putting Bosworth into effect in 1997 would very likely end up with an SPT emitting light in the range of 500 to 700 nm because europium and terbium would have sprung to mind as suitable phosphors. Further, by 1997, CCD cameras were well known and would have been obvious candidates to choose for detection of SPT emissions. Dr Oldenburg, on the other hand, considered it was not obvious to go from Bosworth to the inventive concept. He would not have been encouraged to try using a CCD camera with SPA, and even if he did try a CCD camera, he would try first the conventional SPA bead to see if he could get a sufficient signal. Under cross examination, Professor Tanke maintained that a skilled person would very likely have thought of lanthanides like europium and terbium, but it was not self evident that a cooled or intensified CCD camera would produce the same results as a PMT. For his part, Dr Oldenburg would not accept that the skilled person would make the connection between the europium based phosphors used in DELPHIA and SPA. Further, he maintained that all the skilled person would understand from the reference to more sophisticated scintillation counters in the final paragraph of Bosworth was PMTs capable of detecting more wells at a time.[124]Overall, I have reached the conclusion that Bosworth does not materially advance the case of obviousness based on the common general knowledge. The Patent is obvious over Bosworth but only because it is obvious over the common general knowledge.

Beverloo

[125]Beverloo is a paper written by a group at Leiden University, including Professor Tanke, and published in 1992. It describes a TRF system. Bound phosphors are excited with UV light, and the emission detected. The introduction refers to the problem of autofluorescence, and that this may be addressed by the use of TRF, in which there is a delay between excitation and detection during which the autofluorescence decays but the fluorescence of interest does not. A particular focus of the paper is the preparation of small phosphor particles and their coupling to antibodies to produce phosphor conjugates or immunophosphors. It explains that by using a variety of different phosphors, several different cell surface antigens can be labelled during the course of a single assay.[126]Table 1 on page 562 of the paper discloses the emission maxima of a number of the inorganic phosphors tested. It includes yttrium oxysulphide (Y 2O 2S) doped with Eu3+ with emission maxima of 616, 626 and 704 nm, yttrium oxysulphide doped with Tb3+ with emission maxima of 490, 546 and 588 nm and yttrium oxide (Y 2O 2) doped with Eu3+ with emission maxima of 612 and 630 nm.[127]These phosphors are generally described in the introduction as follows:
“We recently described a new type of label for this purpose, consisting of ground luminescent inorganic crystals (phosphors), widely used in cathode-ray tubes, television screens and luminescent lamps. The luminescence of these phosphors is strong and practically non-fading and not significantly influenced by pH or temperature.”
[128]Beverloo describes the use of a time resolved microscope to view the assay. However, it also discloses the use of a solid state camera to detect luminescence and CCD cameras belong to the family of solid state cameras. Further, figure 1 shows that a cooled CCD camera was used to detect TRF.[129]It is apparent from this summary of the disclosure that Beverloo does disclose the use of phosphors with emission maxima within the claimed ranges and of a CCD device for detecting radiation emitted by those phosphors. It does not, however, disclose an SPT. On the contrary, it is a fluorescence assay.[130]Professor Tanke explained in his report that he considered it was obvious to apply the teaching of Beverloo to SPT assays. He also explained that his laboratory did not take that step because although they had some familiarity with SPTs and an interest in that area, it was off the path of their research focus. Under cross examination, he accepted that the amount of light available in a fluorescence assay is much larger than in an SPT, and there was nothing in the paper to suggest that the described phosphors could be excited by the short path length radioactive particles used in an SPT.[131]Dr Oldenburg explained in his report that in his opinion there was nothing in Beverloo to attract the attention of a skilled person concerned with SPTs. Further, there was nothing in the paper to guide the skilled person as to which phosphor to use in connection with an SPT. Under cross examination, he accepted that Beverloo discloses phosphors which have strong luminescence, and this would be seen as advantageous for SPTs because it deals with a concern about the low light levels which an SPT produces. However, I consider he was not prepared to agree that the skilled person, as he identified him, would understand that the phosphors could be stimulated by beta particles and accordingly used for SPTs.[132]In the light of all this evidence, I have reached the conclusion that Beverloo is consistent with but does not materially advance the case that it was obvious in the light of the common general knowledge to use a CCD camera for SPTs as of August 1997. Beverloo does, however, expressly disclose the advantages of the use of terbium and europium in connection with TRF, namely strong emissions, an ability to couple them to macromolecules and grindability to a small size. Indeed, this is expressly acknowledged in paragraph [0018] of the Patent. It also discloses that, when excited by UV light, such phosphors are suitable for use with a CCD camera. To this extent therefore the disclosure supports the case of obviousness based upon the common general knowledge. The Patent is obvious over Beverloo because it was obvious in the light of the common general knowledge to use a CCD camera for SPTs and to adopt a red shifted scintillant to address the issue of colour quench or to match the emission maximum of the phosphor to the peak sensitivity of the camera. In my judgment Beverloo then clearly points to suitable red shifted phosphors to use.

Tafti

[133]Tafti is a paper which was written by a number of authors from Lumigen Inc. and published in 1994. The paper reports two findings. First, the design and construction of a CCD camera and its use to detect light from chemiluminescent reagents. Secondly, the development of two new luminescent reagents, Lumi-Phos Plus for the detection of alkaline phosphatase and Lumigen PS for the detection of horseradish peroxidase.[134]Tafti explains that imaging systems based on CCD technology are commercially available and can potentially image all types of samples with acceptable sensitivity, dynamic range and speed. Further, since the entire two-dimensional area of the test sample is imaged simultaneously, and measurement can be repeated quickly, a large amount of information can be obtained. Quantitative data can be readily measured, stored and processed on a personal computer. All of this, says Professor Tanke, illustrates the versatility of CCD cameras.[135]The particular CCD camera which the Tafti team developed was a cooled camera, and they describe it in the following terms:
“The CCD detector has a maximum quantum efficiency of approximately 70% in the red region of the visible spectrum. Quantum efficiency ranges between 30% and 60% in the blue-green region of the spectrum where most chemiluminescent reagents emit.”
[136]The authors explain that the new chemiluminescent reagent, Lumi-Phos Plus emits light at 470 nm in the blue part of the visible spectrum, whereas an earlier molecule Lumi-Phos 530 emits light at 530 nm in the green part of the visible spectrum. Nevertheless, the authors point out that Lumi-Phos Plus suffers less background noise and consequently has a better signal to background ratio and a faster detection on membranes in spite of the lower sensitivity of the camera in the blue spectral region. The authors found that the use of the new molecule produced greatly increased light emission from the membrane. They recognised however:
“The red-shifted emission from the dioxetane in Lumi-Phos 530 is especially suited for detection with the CCD camera which has maximum sensitivity in the red region of the spectrum.”
Once again, it is apparent that Tafti discloses use of a phosphor within the ranges claimed in the Patent, and of a CCD device for detecting light emitted by the phosphor. It does not, however, disclose their use in an SPT assay.[137]Professor Tanke considered that it would have been obvious in the light of Tafti to use such a camera for SPTs, particularly in the light of the described benefits of such cameras. Further, it would have been obvious to match the emission wavelength of the phosphor to the spectral characteristics of the cooled CCD. In cross examination he accepts there was nothing in the article to suggest the authors had looked at anything apart from chemiluminescence and further, matching the sensitivity of the camera and the wavelength of the phosphor does not necessarily translate into an advantage for the detection system. Dr Oldenburg explained that a key difference between an SPT and chemiluminescence is that the light intensity generated by a chemiluminescent reaction is around 100-1000 times greater than light generated by an SPT. Further, the chemiluminescent agents could not be incorporated into an SPT bead. There is no teaching about suitable phosphors to use in connection with SPTs. And, moreover, Tafti demonstrates the effect of moving to a red-shifted reagent does not necessarily improve the overall performance of a test.[138]Having considered the evidence of the experts, I have reached the conclusion that Tafti is once again consistent with but does not materially advance the case that it was obvious in the light of the common general knowledge to use a CCD camera for SPTs as of August 1997. It does, however, provide confirmation of the use of CCDs in relation to chemiluminescence assays and the general benefit of matching the wavelength of the phosphor to the peak response of a camera, and that the cooled CCD camera used had its greatest sensitivity in the red region of the spectrum. For these reasons the Patent is obvious over Tafti in the light of the common general knowledge.

Cook

[139]Cook is a patent application by Amersham published on 25 November 1994. It describes the Cytostar T Plate. This is a vessel having a base which comprises a scintillant substance and which is adapted for the attachment or growth of cells. This permits the examination of cellular processes by an SPT using a reagent labelled with a radioisotope.[140]In referring to the prior art, Cook explains that this reveals the scintillant can be a cerium-loaded glass or may be based on rare earths such as yttrium silicate with or without activators such as Tb3+, Eu3+, Li+. Dr Oldenburg accepted that the skilled person would understand from this that he could use an SPT scintillant consisting of yttrium silicate with one of these activators. In the description of the invention on page 11, Cook explains that the base plate can be composed of any transparent material containing scintillant, such as a scintillant glass based on lanthanide metal compounds. Dr Oldenburg accepted that the reader would understand that Tb3+ or Eu3+ would be among the lanthanides he could use. Further, Cook teaches that the base plate may preferably be made out of polystyrene into which one of these lanthanides has been incorporated.[141]On page 11, Cook also explains that a wavelength shifter may be included:
“to absorb the light emitted by the scintillant substance and re-emit longer wavelength light which is a better match to the photo-sensitive detectors used in scintillation counters.”
This plainly teaches that it is a good idea to match the light emitted by the scintillant to the spectral response of the detector. It is right to note that in this section of the publication Cook explains that other scintillant substances and polymer bodies containing them are described in EPA 556005 (the Bell application referred to in paragraph [0020] of the Patent). Cook explains, however, that the nature of the scintillant substance is not material to the invention. Bell discloses rare earth organic chelates including chelates of terbium and europium and Dr Oldenburg accepted that the skilled person would understand that these would be useful in SPTs.[142]Overall, Cook therefore discloses use in connection with SPTs of phosphors with emission maxima within the ranges claimed in the Patent. However, it does not disclose a CCD device for detecting the light emitted by such phosphors. The experts, not surprisingly, took opposite positions on this issue. Professor Tanke accepted that Cook did not contain any guidance as to the wavelength of the phosphor that should be used in the plate, and agreed there was no technical teaching of any improvement in detection systems. Dr Oldenburg considered that a skilled person carrying out Cook would use a standard scintillation counter, and Cook’s preferred scintillant which emitted light in the blue region of the spectrum. But he accepted that if a skilled person wanted to use a particular CCD camera described by Princeton Instruments as having the highest quantum efficiency in the green of any imaging in CCD camera available, he would appreciate that the terbium and europium chelates were suitable for use with that camera and, other things being equal, would expect success with them.[143]In the light of the evidence of the experts, I consider that Cook does not advance the case that it was obvious to use a CCD camera in connection with SPT over the common general knowledge. In my judgment, there can be no doubt, however, that if it was obvious to use a CCD in connection with SPT in the light of the common general knowledge then, in the light of Cook, it was also obvious to match the light emitted by the scintillant to the spectral response of the detector, and if the detector was most sensitive to light in the green or red regions of the spectrum, then europium and terbium chelates or inorganic host materials doped with such lanthanides would be suitable phosphors to use. These were also obvious phosphors to use to deal with colour quenching. Conclusion on

Obviousness

[144]For all the reasons I have given, I have reached the conclusion that each of the claims in issue is invalid for obviousness.

Entitlement

[145]PerkinElmer contended that if the invention claimed in the Patent is novel and not obvious then they are entitled to it as successors in title to Packard and/or CIL, since Packard and/or CIL devised the invention and disclosed it to Amersham in confidence on a number of occasions. In the light of my finding on validity, the issue of entitlement does not arise. Nevertheless, in case this case should go further, it is right that I set out my conclusions.[146]It is now well established that the necessary enquiry in a case such as this is as follows. First, it is necessary to identify the inventive concept in the patent, and then to identify who came up with that concept. He or they are the inventors. A person is not an inventor merely because he contributes to a claim; his contribution must be to the formulation of the inventive concept: University of Southampton’s Application [2004] EWHC 2107 (Pat); [2005] RPC 11 at [35]-[39]. For this purpose, the precise form of the claims is immaterial. As Jacob LJ explained, in giving the judgment of the court in Markem Corp v Zipher Ltd [2005] EWCA Civ 267; [2005] RPC 31: “101. Accordingly we think one is driven to the conclusion that s.8 is referring essentially to information in the specification rather than the form of the claims. It would be handy if one could go by the claims, but one cannot. s. 8 calls for identification of information and the rights in it. Who contributed what and what rights if any they had in it lies at the heart of the inquiry, not what monopolies were actually claimed.102. It is not possible to be very specific about how this is to be done. But as a general rule one will start with the specific disclosure of the patent and ask whether that involves the use of information which is really that of the applicant, wholly or in part or as joint owner. Here the specific disclosure of the Zipher patents is clearly Mr McNestry's basic idea – his particular "clever way." Without that the disclosure would be near valueless. True the patent would have claims covering bi-directional or dual purpose printers, but without any practical way of achieving them. What one is normally looking for is "the heart" of the invention. There may be more than one "heart" but each claim is not to be considered as a separate "heart" on its own. That is consistent with the view of Laddie J in University of Southampton's Appn. [2005] RPC 11.103. Likewise we think that Christopher Floyd QC, sitting as a Deputy Judge was right when he said in Stanelco Fibre Optics v. Bioprogress (unrep. 1st October [2004] EWHC 2187 Ch): "15. It is clear that a mechanistic, element by element approach to inventorship will not produce a fair result. If A discloses a new idea to B whose only suggestion is to paint it pink, B would not be a joint inventor of a patent for A's product painted pink. That is because the additional feature does not really create a new inventive concept at all. The feature is merely a claim limitation, adequate to overcome a bare novelty objection, but having no substantial bearing on the inventive concept. Patent agents will frequently suggest claim limitations, but doing so does not make them joint inventors. Some stripping of a claim of its verbiage, may be necessary to determine the inventive concept, and consequently the inventor. But one must keep in mind that it is the inventive concept or concepts as put forward in the patent with which one is concerned, not their inventiveness in relation of the state of the art."104. We would qualify his last comment slightly – for the reasons we have indicated novelty and obviousness are relevant where they are inherent or implicitly accepted in the case advanced to establish entitlement.” "15. It is clear that a mechanistic, element by element approach to inventorship will not produce a fair result. If A discloses a new idea to B whose only suggestion is to paint it pink, B would not be a joint inventor of a patent for A's product painted pink. That is because the additional feature does not really create a new inventive concept at all. The feature is merely a claim limitation, adequate to overcome a bare novelty objection, but having no substantial bearing on the inventive concept. Patent agents will frequently suggest claim limitations, but doing so does not make them joint inventors. Some stripping of a claim of its verbiage, may be necessary to determine the inventive concept, and consequently the inventor. But one must keep in mind that it is the inventive concept or concepts as put forward in the patent with which one is concerned, not their inventiveness in relation of the state of the art."[147]Secondly, it must be shown that the claimant is entitled to the patent. He must be able to invoke some rule of law to establish that he has title to the patent and that the defendant has contravened some legal right of the claimant by filing the patent application, such as by acting in breach of confidence or breach of contract. As the court held in Markem:
“77. We begin by observing that it is conceded that if A is to be entitled to a patent or part of a patent applied for by B, then there must be some sort of link between the two. If A makes an invention but does not apply for a patent, and B independently comes up with the same idea and applies first, A cannot either complain or claim any part of B's patent. Like nearly all countries (save for the USA) we operate on a first to file system. 78. It follows that it is not enough for A to assert that the invention or concept (we use the expression loosely at this stage) was known to its employees and that that itself gave A an entitlement to make an application under s.7 What has to be shown is that A is entitled to B's application or part of it. In the usual run of case, such an entitlement will arise by reason of the operation of some independent rule of law, such as contract, breach of confidence or the like. So, for example, if an employee in breach of confidence takes a trade secret consisting of an invention and applies for a patent in his own name, the employer can properly say the employee was not entitled (i.e. had no right) to apply for the patent by reason of the fact that the invention (i.e. the right to deal with and use the relevant information) belonged to the employer. Or, where two people co-operate in making an invention, there will be some agreement express or implied about who is to own any corresponding patent. Probably there will be joint ownership. There may be an inquiry as to who actually contributed relevantly to the concept, but that inquiry will not alone determine the matter. In the end the question is always "who was to own the invention and the corresponding patent?" The question is about "title" and that involves a question of legal rights. 79. We think it follows that, whether or not A is entitled to apply for a patent pursuant to s.7 is, as such, irrelevant to whether or not he can claim an entitlement to an application by B. For the latter he must be able to show that in some way B was not entitled to apply for the patent, either at all or alone. It follows that A must invoke some other rule of law to establish his entitlement – that which gives him title, wholly or in part, to B's application.”
And a little later:
“83. Moreover, submitted Mr Watson, it can hardly be the case that Parliament intended to confer on the Comptroller a jurisdiction to consider breach of confidence – he was just given a simple jurisdiction over entitlement. We think that a thoroughly bad point. The word "entitlement" clearly imports notions of "title" – of legal rights between the parties. To decide an entitlement question one is bound to have to go not only into who was responsible for devising what but also into the legal rights of the rival claimants with respect to each other. Doubtless that will sometimes involve complicated questions of fact or law (whether in breach of confidence), contract or in some other way. And doubtless that is why the Comptroller is empowered under s.8(7). s.12(2) and s.37(8) to decline to decide the question of entitlement if it would more properly be decided by a court. As happened here.”
[148]In the present case, the parties were agreed that, for the purpose of considering entitlement, the invention described in the specification is the idea of using in an SPT a phosphor with an emission maximum in the green-red part of the visible spectrum and a CCD detector.[149]In opening the case, PerkinElmer submitted that there were four strands to the entitlement case: i) Packard and CIL suggested repeatedly and over a long period of time to Amersham the use of red shifted scintillants in SPT, in particular to reduce colour quench; ii) Packard and CIL repeatedly suggested over a long period of time the use of CCD detectors for SPT; iii) On several occasions, Packard and CIL combined those two suggestions and suggested the use of red shifted scintillants for use in SPT, detected by a CCD imager; iv) In parallel with the discussions about SPT, Packard and CIL also discussed with Amersham the use of CCD detectors for other assays with red shifted scintillants, such as fluorescence assays and, in particular, HTRF. PerkinElmer accepted that the entitlement case could only succeed if strand iii) is established, but submitted that the other strands provide a useful background against which the disclosures relied upon to support strand iii) should be considered. It is also to be noted that there is no case that PerkinElmer is jointly entitled to the Patent. The allegation is that the invention was conceived by Packard/CIL, disclosed to Amersham in confidence and that Amersham applied for the Patent in breach of confidence. There is no dispute that such disclosures that were made by Packard/CIL to Amersham were made in confidence. Accordingly, the real issues between the parties are(a) whether Packard/CIL disclosed the inventive concept to Amersham and(b) whether the named inventor, Dr Robert Jessop, arrived at the inventive concept himself and independently of any such disclosure.[150]It is convenient at this point to identify the witnesses who gave evidence on this aspect of the claim. On behalf of PerkinElmer, I heard evidence from the following persons: a) Mr Gustaaf (“Staf”) Van Cauter. He was employed by Packard from 1975 to 2001. From 1992 to 1998 he was Vice President of Marketing and responsible for, inter alia, identifying emerging technologies, evaluating and initiating technology and defining and planning new product development. He is named as an inventor on a number of Packard applications and is alleged by PerkinElmer to be one of the devisers of the inventive concept of the Patent. He is currently employed by Bioscan Inc. b) Mr Philip Harrison. At all relevant times he was employed by Packard in the Business Development Department headed by Mr Van Cauter. He is also alleged by PerkinElmer to be one of the devisers of the inventive concept of the Patent. He is now Product Manager at Cronus Technologies Ltd. c) Dr Claire Hooper. She worked for and was a director of CIL throughout the relevant period and is also alleged to be one of the devisers of the inventive concept of the Patent. She is now a Research Director of PerkinElmer Ltd in the UK.[151]On behalf of Amersham, I heard evidence from the following witnesses: a) Dr Robert (“Bob”) Jessop. He was initially employed by Amersham as a Research Scientist in the Tritium Section of the Research and Development Group where he was involved in developing methods of radio-labelling compounds. He worked with tritium for two years and then moved to the Carbon-14 Group until 1989. He then moved to the Assay Group as a Senior Development Scientist, and has remained there ever since. b) Dr Nigel Bosworth. He was employed by Amersham until his retirement in May 2003. From 1987 to 1983 he was involved in the development of SPA technology in the Assay Group. In 1993 he was moved to the Light Emitting Polymer (“LEP”) Group. He is named by PerkinElmer as a recipient of confidential information. c) Dr John Sutton. He was Manager of the Assay Group at Amersham from 1988 to November 1993. He remains employed by the business and is currently involved in product acquisition and licensing operations. He is named by PerkinElmer as a recipient of confidential information. d) Dr David (“Dougal”) Burns. He worked for Amersham at all material times and retired in November 2003. From 1991 until about 2001 he was engaged in the field of fluorescence technology. He had a particular responsibility for evaluating non-radioactive technologies and reported to Dr Neil Cook in the Cell Biology department.[152]Each side advanced criticisms of the witnesses of the other. Amersham’s criticisms were mainly levelled at Mr Van Cauter. It was submitted that he was prone to exaggeration and “spin”, that he was keen to give evidence that was helpful to PerkinElmer’s case but less keen to answer questions put to him. I have carefully considered these criticisms and consider that the accusations of spin and exaggeration are not made out. They carry with them the suggestion that Mr Van Cauter deliberately shaded his evidence and I reject that suggestion. Nevertheless, I did form the view that Mr Van Cauter’s recollection of events, whilst apparently clear, was not always accurate or complete. For example, he gave evidence that the change of supplier in connection with the Optical Imager project was to do with wavelength shifting when in fact the original supplier was experiencing manufacturing problems. He also recalled that Amersham acquired a dye company which advertised its dyes as having less autofluorescence and colour quench. Under cross examination, however, he explained that he assumed that they had made oral recommendations to customers. Further, and more importantly, he gave evidence about the purpose of Mr Don Osten’s visit to Cardiff in August 1994. This was a visit to which I refer later in this judgment in dealing with the issue of disclosure. Mr Van Cauter gave evidence that the purpose of the meeting was to get Amersham to change to red shifted beads. But this was not a meeting which Mr Van Cauter actually attended and his recollection was not supported by the evidence of Mr Harrison or by the report of the trip made by Mr Osten. Mr Van Cauter also suggested in his statement that at some time before the autumn of 1995 he told Amersham on a number of occasions that, in the context of imaging, it would be advantageous to red shift the scintillant in the SPA beads. This was important. It was evidence of disclosure of the inventive concept. However, under cross examination, Mr Van Cauter said it related to TopCount and went back to 1994.[153]Amersham made no substantial criticisms of Dr Hooper and Mr Harrison. In my judgment they gave their evidence carefully and fairly. I believe that they were doing their best to assist the court throughout.[154]Turning to the Amersham witnesses, PerkinElmer suggested that they made no effort to consider the context in which meetings and discussions took place, confined themselves to specific meetings and were frequently unable to recall the conversations that had taken place. I reject these criticisms. The allegations of disclosure were extensive and ranged over a considerable period of time. They took place some 10 years ago. Investigation of them in evidence took a good deal of court time. I formed the view that the Amersham witnesses endeavoured to deal with the issues in a focused but fair way.[155]Specifically, it was suggested that Dr Jessop was evasive in answering questions about a number of matters relating to the inventive concept of the Patent. For example, it was suggested that he was evasive in dealing with the problem of colour quench. I did not find him so. He accepted that colour quench was a problem but it was one which was addressed in SPA by correction. Dr Sutton was said to be an unsatisfactory witness because he gave contradictory answers, was unreliable on dates and products and had an axe to grind against Packard. I do not accept these criticisms. Dr Sutton endeavoured to answer the questions put to him and made concessions where appropriate. He was a fair and honest witness. Dr Bosworth was said to have given evidence which was confused and which did not make sense. To the contrary, I found Dr Bosworth direct and clear. Finally, the criticism of Dr Burns was that he failed to refer to certain relevant matters in his witness statements. It is certainly true that he did not expand upon certain matters to which PerkinElmer attached considerable importance. Given the extensive nature of the allegations made this is not entirely surprising. Further, I consider that he gave his evidence in an honest and straightforward manner.

Entitlement – the disclosures

[156]Shortly before the trial, PerkinElmer served draft Re-Re-Amended Grounds of Invalidity, setting out in considerable detail particulars of all the meetings and communications upon which it relied in support of its entitlement case. At the commencement of the trial, I gave PerkinElmer leave to make the amendments requested. In this judgment I will address the issue of disclosure by reference to the allegations made in that pleading.

Discussions and collaboration in the period 1989 – 1996 in connection with SPA

[157]There is no dispute between the parties that from 1988 Amersham and Packard collaborated on the development of the TopCount detector for SPA. Packard wished to ensure that TopCount would be compatible with the SPA system marketed by Amersham. At the same time, Amersham was collaborating with Wallac in relation to the latter’s MicroBeta detector, and there was something of a three-way relationship. During the course of this early collaboration, Dr Jessop visited Packard’s Downer’s Grove site for at least a week, in the course of which Packard disclosed to him its know how regarding two phosphors, butyl-PBD and DPA. These emitted light in the blue part of the spectrum, but were considered to be superior to the particular phosphor called PPO which Amersham was using at that time in connection with its PVT beads. The advantage of the phosphors identified by Packard was that they had a longer decay time.

Discussions about colour quenching in 1991 – 1994

[158]PerkinElmer contended that in the period 1991 to 1994, there were a number of meetings between Packard and Amersham to discuss colour quench correction in SPA assays, and a number of people at Packard, including Mr Van Cauter, Don Osten, John Tomisek and possibly Ken Neumann were responsible for finding solutions. Despite the implementation of colour quench correction, Amersham and Packard continued to receive complaints, and Packard therefore encouraged Amersham to consider the use of red shifted scintillants, since most of the assay samples were yellow and brown, and therefore absorbed blue light. PerkinElmer contended that this issue was discussed at a number of meetings and over the telephone and, moreover, that the issue of red shifted scintillants was also raised by a number of Amersham’s and Packard’s customers, such as Glaxo and Zeneca.[159]There was a substantial dispute between the parties on this issue. PerkinElmer essentially relied upon the evidence of Mr Van Cauter. He said, in his witness statement, that conversations about colour quench with Amersham started in about 1991 and that by about 1994, he, Don Osten, and possibly Ken Neumann and Phil Harrison, had told Amersham a number of times that it would be advantageous to use scintillants with longer wavelengths in their SPA assay to reduce the effects of colour quench. In cross examination he maintained this had happened, although he was unable to identify a particular conversation at which such a suggestion was made except at a strategy meeting in late 1993, which forms the next allegation of disclosure. The Amersham witnesses had no recollection of the conversations to which Mr Van Cauter referred. Nevertheless, Dr Bosworth did recall discussing red shifting scintillants with Mr Harrison from 1989 onwards. Initially, Mr Harrison was employed by Wallac, and he joined Packard in 1992. Dr Bosworth also explained that the use of a red shifted scintillant was something that Amersham knew it was theoretically possible to use: all that was necessary was to take a scintillant which emitted light which was not absorbed by the sample.[160]It is also relevant to consider the background against which these alleged conversations took place. I have no doubt on the evidence that Packard and Amersham were well aware of the problem of colour quenching. So too were their customers, who certainly passed comments, if not complaints, back to Packard and Amersham. These users were aware that the problem was that the red, brown and yellow compounds in their libraries absorbed the blue light emitted by the beads, and that colour quench was a particular problem with SPA for two reasons: first, because SPAs produce a low level of light and secondly, because the homogenous nature of the assay meant that the colour was not removed before the measurements were taken. I also have no doubt that despite the colour quench correction methods which were employed, colour quenching remained a serious issue right through to April 1996. I think it also relevant that, as Dr Sutton explained, Amersham was reluctant to change its SPA beads. It wanted to make sure, however, that those beads would be compatible with the 384 well TopCount system that was contemplated in late 1993. As he also explained, its existing kits had taken a significant amount of development work, and it had no wish or desire to change its kits or beads simply to accommodate a new instrument. Both these matters are consistent with the suggestion that discussions took place about using a red shifted scintillant for SPA.[161]In light of all the evidence, I have reached the conclusion that it is more likely than not that some discussions took place between Amersham and Packard in the period from 1991 to 1994 concerning the possible use of a red-shifted scintillant in connection with SPA. I am satisfied, however, that this was something of which Dr Bosworth was already aware, quite independently of any discussion with employees of Packard. Further, any such discussions that did take place in connection with the use of a red shifted scintillant were in the context of TopCount and MicroBeta. They did not involve the disclosure of the inventive concept.

Strategy meeting in late 1993

[162]PerkinElmer contended that in about late 1993 there was a strategy meeting which took place at Amersham’s offices. At that meeting there was a discussion of where Packard and Amersham wanted to go with SPA. Packard wanted to know if Amersham was intending to develop the technology further to deal with the effects of colour quench, and Amersham expressed an interest in doing so and in using other scintillants to improve performance and miniaturise assays.[163]This contention was supported by the evidence of Mr Van Cauter who said that he recalled that Dr Sutton told him that Amersham was interested in developing the technology of SPA further. He also recalled that Amersham expressed an interest in the possibility of using other scintillants, the major reasons being to further improve the performance of SPA with colour quenched samples and to further miniaturise assays. Under cross examination, Mr Van Cauter explained that the reason for discussing colour quench was because of complaints from customers. Packard could not do any more to improve the instrumentation, and it wanted to know whether Amersham was prepared to change the composition of the SPA beads to address the colour quench issue. Dr Sutton could not recall this particular meeting, but accepted that it was likely that there was some meeting at this time and that the conversation would have been about the development of TopCount 384. He did recall a general discussion of colour quench, but not any discussion about the possibility of using other scintillants. His recollection was that Packard wanted to make sure that the performance of the assays with the 384 well TopCount would be at least equivalent to their performance with the 96 well TopCount. Further, customer feedback was that customers wanted an instrument that was compatible with the products that had already been developed.[164]Again, I have reached the conclusion that it is likely that a discussion took place at about this time between Mr Van Cauter and Dr Sutton at which the issue of colour quench was discussed and further, that it is likely that the use of other scintillants in connection with SPA was also raised. Nevertheless, it does not, in my judgment, advance the case of PerkinElmer because any such discussion was in the context of TopCount and it did not involve the disclosure of the inventive concept.

Meeting on 3 December 1993

[165]PerkinElmer contended that there was a meeting at Amersham’s premises on 3 December 1993 attended by Mr Van Cauter, Al Kolb and Mr Harrison of Packard, and Mr Nicholls, Dr Sutton and possibly Neil Cook of Amersham. At this meeting, Packard gave Amersham an overview of the HTRF assay using a red Eu3+ cryptate as the phosphor and its project for the CCD-based Optical Imager. Packard suggested the Optical Imager as an alternative instrument for detecting SPA assays, and particularly for the miniaturisation of SPA assays in 384 and higher densities for high throughput applications.[166]There was no dispute between the parties that a meeting took place on this date. There was also no dispute that, at about this time, Packard disclosed to Amersham the work that it was doing on TRF, and in particular, homogenous TRF assays, including the use in connection with such assays of a red Eu3+ cryptate. I am not satisfied, however, that there was any disclosure at this time of anything to do with the Optical Imager project. The development and licensing agreement between CIL and Packard had been signed in March 1993, but the first meeting of the Optical Imager Engineering Group did not take place until 13 May 1994, and it seems that CIL was not requested to do any work on SPA or HTRF until the summer of 1995. Dr Sutton had no recollection of the Optical Imager being referred to, and Mr Van Cauter’s belief was that Dr Sutton would have become aware of the Optical Imager project in 1994, following a meeting on 23 June 1994, at which a confidentiality agreement was signed.[167]It is convenient to mention at this point further work that CIL conducted from late 1993 through to 1995. Dr Hooper explained that in about late 1993 and early 1994, CIL recommended to Packard that to optimise the readout from ultra-low light radioisotopic assays, it would be advantageous to move away from detecting light at the blue end of the visible spectrum to the green part of the visible spectrum. Nevertheless, CIL understood that most commercially available radioisotopic assays used scintillants that emitted in the blue region of the spectrum and the Optical Imager would therefore need to have an ability to detect such assays. This imposed a technical constraint. Although CIL could develop an imager that would detect both blue and green assays, it did not anticipate it was possible for such an imager to have sufficient sensitivity in the red part of the spectrum. Thereafter CIL established a programme with a company called Levy Hill and requested numerous phosphor sheets that emitted light at different wavelengths from the blue to the green parts of the spectrum, and which CIL tested on Optical Imager prototypes.

Meetings on 25 March 1994 and 1 June 1994

[168]Further meetings took place on 25 March 1994 and 1 June 1994. No witness had any recollection of what was discussed at these meetings.[169]Meantime, as I have indicated, Packard was liaising with Levy Hill to obtain phosphors for CIL to test on the Optical Imager. The first such phosphors were obtained in the period May to July 1994, but they proved to be too fragile. As a result, Mr Harrison and Don Osten were given the task of trying to obtain further scintillant materials.

Meetings in June 1994

[170]PerkinElmer contended that on 23 June 1994 there was a meeting between at least Mr Van Cauter of Packard and Dr Sutton, Mr Chambers and Dr Cook of Amersham. At the meeting Mr Van Cauter on behalf of Packard, and Mr Chambers on behalf of Amersham signed a confidentiality agreement. After this, it is said, Packard disclosed to Amersham its plans for CCD imaging, including various applications.[171]It is clear that a confidentiality agreement was signed on that occasion by Mr Chambers and Mr Van Cauter. After the agreement had been signed, Amersham disclosed information relating to its Cytostar T plates and Packard disclosed its plans to use CCD imaging. I conclude in the light of the evidence that it is likely that at this meeting the application of imaging to SPA was discussed.[172]It seems likely that on the same occasion, but, in any event in the same month, Mr Harrison met Dr Bosworth. This meeting forms the basis of an important allegation upon which particular reliance is placed by PerkinElmer. PerkinElmer contended that Dr Bosworth showed Mr Harrison some of the emergency signs that he was developing in the course of his work in the light emitting polymer (“LEP”) group to which he had moved in 1992. These signs had a green emitting terbium polymer scintillant. It was further contended that Mr Harrison suggested to Dr Bosworth that the terbium scintillant could be used for SPA. Mr Harrison requested samples of the terbium polymer and explained that he was interested in the samples for imaging radioactivity using the Optical Imager.[173]This contention was supported by the evidence of Mr Harrison. He specifically recalled suggesting to Dr Bosworth that the terbium polymer could be used for SPA. He was conscious that the terbium scintillant was excited by tritium and this was one of the most important isotopes used in SPA assays. He recalled Dr Bosworth responding that he was no longer involved in SPA and that it was his impression that Dr Bosworth did not want to discuss the matter further. In addition, Mr Harrison was interested in sourcing phosphors for CIL to detect the presence of radioactivity in tissue sections by whole-body autoradiography. Accordingly, he asked Dr Bosworth for samples of the terbium polymer and explained that he was interested in the samples for imaging radioactivity using the Optical Imager.[174]Mr Harrison maintained this position in cross examination. However, it is also apparent from that cross examination that insofar as Mr Harrison considered that the terbium polymer might be suitable for SPA, what he had in mind was the detection of the light emitted by TopCount.[175]Dr Bosworth did not recall any suggestion being made by Mr Harrison about the use of terbium in SPA, and indeed said that if it had been suggested to him it would have been insulting because it would have been obvious to both of them that he, Dr Bosworth, knew that it was an efficient scintillator. Further, he had been instructed not to discuss scientific matters with Mr Harrison.[176]I have reached the conclusion that it is more likely than not that Mr Harrison’s recollection is essentially correct and that he did make some observation to Dr Bosworth to the effect that the terbium polymer could be used for SPA. I also accept, however, that Dr Bosworth was very reluctant to engage in any scientific discussion because of his instructions, and would have attached little or no importance to the observation which Mr Harrison made to him because, as he put it, the suggestion was already obvious to him.[177]I am also satisfied that Dr Bosworth understood that Mr Harrison wanted samples of the terbium for the purposes of detecting radioactivity in tissue sections using the CCD system. This was not, however, SPA but rather an autoradiography application.[178]Moreover, Dr Bosworth was at this time within the LEP group and was conscious that he should not be discussing anything of a technical nature with Mr Harrison. It seems to me therefore most unlikely that anything Dr Bosworth was told by Mr Harrison as to the possible use of terbium in connection with SPA would have gone any further. In Mr Harrison’s words, Dr Bosworth was “very straight” and “scrupulously honest”.[179]Further, there was no disclosure of the whole of the inventive concept in any event. Mr Harrison did not suggest the use of terbium in an SPA detected by a CCD camera.

Contact on 1 August 1994

[180]It seems there may have been further contact between Mr Harrison and Amersham on the subject of alternative phosphors early in August 1994. In particular there may have been a discussion between Dr Bosworth and Mr Harrison, but it is not suggested that this takes the matter any further. 22 August 1994[181]PerkinElmer contended that during a meeting on 22 August 1994 between Mr Harrison and Mr Osten of Packard, and at least Dr Bosworth of Amersham, Mr Harrison and Mr Osten discussed the terbium polymer samples further. The purpose of the discussion, so it was said, was to find a scintillant that would deal with the problem of colour quenching in SPA, as well as one that could be used to image radiolabelled rat brain sections on the Optical Imager. It was further contended that Mr Osten met Dr Jessop and Dr Sutton and that Dr Sutton told Mr Osten that Amersham had no interest in using other scintillants for their SPA beads.[182]These contentions were based upon the evidence of Mr Van Cauter and his recollection of the purpose of the discussion, and what was reported to him by Mr Osten. Mr Van Cauter did not attend the meetings. He maintained in cross examination that there was a dual purpose for Mr Osten’s visit. Mr Osten wanted to find out whether Amersham was considering using terbium for SPA beads, and Mr Harrison wanted samples of the terbium sheet for use in other applications. Packard was keen to know Amersham’s intention so that the TopCount 384 could be developed to be compatible with the Amersham product.[183]Amersham vigorously disputed Mr Van Cauter’s contention and maintained that the subject under discussion at the meeting was the use of terbium samples for CIL’s autoradiography experiments, and there was no discussion of the use of terbium in SPA. Amersham’s position is supported by a number of matters. First, although Don Osten did not give evidence, he supplied PerkinElmer’s solicitors with some documents from his computer during the course of the trial. One of these was a report of his visit to Europe during the week commencing August 22 1994, which includes a report on his visit to Amersham with Mr Harrison. This report contains no reference to any discussion about red shifting of the scintillators used in SPA beads. Secondly, Mr Harrison gave evidence that the purpose of the meeting was to source phosphors for CIL’s autoradiography work, and in this connection to discuss the terbium polymer samples. It was his evidence that the topic of red shifting scintillants for use in SPA was probably not discussed. He recalled his original discussion with Dr Bosworth, from which he had gained the impression that Dr Bosworth did not want to discuss SPA at all. Thirdly, as to the suggestion that Dr Jessop and/or Dr Sutton were present at the meeting, it is notable that Don Osten’s report makes no mention of them, and Dr Bosworth was clear that they would not have been present. He was also clear that although he might have discussed some details of the terbium phosphor with Messrs Harrison and Osten, he would not have discussed with them what the uses of that phosphor were to be.[184]I have no doubt that the position taken by Amersham as to what was discussed at this meeting is to be preferred. It has not been established that there was any discussion of red-shifted scintillants in connection with SPA on 22 August 1994.[185]I should also deal with a further suggestion by Mr Van Cauter that when Mr Osten reported back to him that there was no interest from Amersham in changing their beads to the terbium scintillator, he rang Dr Sutton to find out why the decision had been made not to use alternative scintillators, and Dr Sutton’s response was that there were no plans to make a change. Dr Sutton’s evidence was that he did not recall meeting Don Osten on 22 August 1994, did not talk to him about red shifting the SPA scintillant in order to reduce the effects of colour quenching, and there was no telephone call from Mr Van Cauter asking why Amersham would not contemplate changing the scintillant used in the SPA beads. I am not satisfied that any such phone call took place. For all the reasons I have given in connection with the meeting, I consider it more likely than not that there was no discussion at the meeting of red shifting the SPA scintillant, and I accept Dr Sutton’s evidence that there was no phone call. 31 August 1994 meeting[186]Mr Harrison attended a meeting with Amersham in Cardiff on this date, but there is no evidence as to what was discussed.

Delivery of terbium polymer samples in September 1994

[187]It is accepted that a number of terbium samples were supplied to Packard or CIL by Amersham in September 1994. Some five different formulations were provided. The samples included samples of ALP-1. 8 November 1994[188]Another meeting took place on this date, but there was no evidence as to what was discussed.

Discussions in 1995 – 1996

[189]It was contended by PerkinElmer that on a number of occasions in 1995 and 1996, Mr Van Cauter told Amersham that, in the context of imaging, it would be advantageous to red shift the scintillant in the SPA beads, both for the purposes of colour quench correction and for HTS and miniaturisation.[190]Mr Van Cauter gave some evidence to this effect in his first witness statement. However, during the course of cross examination, it was not maintained. Instead he referred back to events which had occurred in 1994.

Discussions in August – December 1995

[191]PerkinElmer alleged that during the period August to December 1995, Mr Harrison had a number of discussions with Dr Jessop concerning miniaturisation of SPA assays on the Optical Imager, and that one of the subjects of discussion was colour quench.[192]I am satisfied in the light of the evidence that over this period Mr Harrison spoke to Dr Sutton and Dr Jessop about miniaturisation of SPA assays from the 96 well format to the 384 well format and about colour quenching. Dr Sutton asked how colour quench could be tackled and, in particular, whether it could be tackled in an analogous way to that adopted for the TopCount and MicroBeta systems, and whether or not that was possible with the CCD imager. There is no suggestion, however, that red shifting of SPA scintillants was discussed in this context.

Meeting in late August or September 1995

[193]This is another allegation of considerable importance. PerkinElmer contended that in or about late August or September 1995, in a meeting between Mr Harrison of Packard and Dr Sutton of Amersham, Mr Harrison told Dr Sutton that if Amersham really wanted to miniaturise SPA assays, it should use a cooled CCD camera and red emitting SPA beads. Mr Harrison also told Dr Sutton during the same conversation that Amersham could try using Eu3+ cryptate as the red emitting fluor. Dr Sutton made no comment about the suggestion, and Mr Harrison came away from the meeting feeling that it had not gone very well.[194]In his witness statement, Mr Harrison explained that he met Mr Sutton in late August or September 1995 because he was concerned about the level of signal that could be obtained from miniaturised assays. At the time, imaging of SPA in 384 well plates with the Optical Imager looked to be possible, but he was under the impression that imaging SPA in 864 and 1536 well plates would not be possible due to the low light levels emitted from each well. He recalled discussing various options with Dr Sutton, but believed they had “hit the wall”. He wanted to keep Amersham’s interest in further discussions with Packard and, for that reason, towards the end of the meeting said to Dr Sutton that if Amersham really wanted to miniaturise SPA assays, they should use a cooled CCD camera and red emitting SPA beads. He told Dr Sutton that Amersham could try using europium cryptate as the red emitting fluor, but that it was prohibitively expensive.[195]There are a number of curious features about Mr Harrison’s recollection. First, under cross examination he described the route that he had taken to Dr Sutton’s office. However, Dr Sutton gave evidence that the office that Mr Harrison described would not have been his office at any time after mid 1994. Secondly, Mr Harrison explained that his reason for telling Dr Sutton about the use of red shifted scintillants and a cooled CCD for SPA was to keep Amersham’s interest in Packard alive. Yet Packard and CIL were collaborating on an intensified, as opposed to a cooled, CCD camera at the time. Towards the latter part of 1995, Packard had begun to investigate cooled CCD cameras, but such investigations were at an early stage. Thirdly, it is rather strange that Mr Harrison suggested europium cryptate. This was, in Mr Harrison’s words, prohibitively expensive, and Mr Harrison apparently thought that terbium would be a good scintillant for SPA. Further, this was a scintillant which Mr Harrison knew that Amersham already had access to.[196]It is also highly significant that, under cross examination, Mr Harrison appeared to have considerable difficulty placing a date on the meeting. As I have indicated, in his witness statement he thought it likely the meeting took place in late August or early September 1995. Under cross examination, however, he thought the meeting took place after the SBS meeting in November 1995, and could have been February 1996. Despite considerable agonising, he simply could not work out when it had taken place.[197]Dr Sutton, on the other hand, was adamant that Mr Harrison had made no such suggestion. He did not believe that europium cryptate was a suitable scintillant for SPA, and did not recollect anybody from Packard disclosing to him that a red shifted scintillant would be the way to miniaturise. His view was that the existing beads should be used. From his perspective, customers wanted the beads and kits that they were used to, but a faster detector. The Optical Imager potentially gave a route to that, and he could not see any context in which Mr Harrison would have been talking about red shifted scintillants.[198]Having considered this evidence carefully, I have reached the conclusion that it is likely that Mr Harrison did make a suggestion to Dr Sutton to use red shifted scintillants with a cooled CCD camera. But I am far from satisfied that the suggestion was made at the end of August or beginning of September 1995. In the light of Mr Harrison’s evidence I think it more likely that it took place much later in 1995, after the SBS conference, or even in early 1996. Moreover, it fell on deaf ears. It was not something that Dr Sutton was interested in because, for the reasons he explained, he thought his customers would like to stick with their existing product. These points are significant because, as I explain later in this judgment, by this time Dr Jessop had already made the inventive concept embodied in the Patent.

The SBS conference in November 1995

[199]At the November 1995 meeting of the SBS, the Hooper paper was presented. The presentation included work that CIL had been conducting on imaging SPA assays in 384 well plates, and there was significant interest from the pharmaceutical companies in miniaturisation and 1536 well plates. Although the Hooper paper does not mention cooled CCD cameras, Dr Hooper explained that during the panel session following the presentation, there was an open discussion with Kirk Schröeder of Noveltech regarding the pros and cons of cooled and intensified CCD cameras. Mr Schröeder argued that cooled CCD cameras were appropriate detectors for miniaturised assays.[200]It also seems clear on the evidence that at this conference a discussion took place between Dr Hooper and Dr Rushbrooke of CIL and Dr Sutton about the miniaturisation of assays. They explained to Dr Sutton that miniaturisation had the potential to boost SPA sales and by using imaging with a sensitive detector, such as the Optical Imager, with a high resolution, miniaturisation would be achieved and this would extend the commercial lifetime of SPAs.[201]I am satisfied that the discussions to which I have referred took place at the SBS conference but they did not involve the disclosure of the inventive concept.

The Optical Imager Consortium

[202]The Optical Imager Consortium was made up of six pharmaceutical companies including Glaxo, Zeneca, Merck, Amgen and Bristol Myers Squibb. Mr Van Cauter explained that these companies were interested in having first access to the Optical Imager for detecting SPA and HTRF. Packard envisaged Amersham’s commitment to be the delivery to the Consortium members of SPA assays that would be compatible with the Optical Imager. Glaxo especially was concerned about the colour quench issue with SPA and wondered how Packard and Amersham were going to deal with it. Eventually, according to Mr Van Cauter, Amersham was not willing to confirm that it would provide Consortium members with access to the next generation of SPAs, and so Packard had to implement traditional methods of colour quench on the Optical Imager.[203]On the evidence I am satisfied that Amersham had very little to do with the Consortium. Dr Sutton was aware of the idea of the Consortium, but was vague about whether it was actually set up. He did, however, agree that one of the concerns of Glaxo at that point in time was colour quench. Eventually, the Consortium collapsed because it was not possible to develop a multi modal imager. In particular, it was found that the ultra sensitive camera required for SPA would be damaged when exposed to the higher light levels found in conventional fluorescence.[204]I am satisfied there was no disclosure of the inventive concept in the context of the Optical Imager Consortium.

Meeting in about late 1995 or early 1996

[205]Mr Van Cauter recalls a meeting in late 1995 or early 1996 with Dr Cook and Dr Sutton, at which assay miniaturisation and cooled and intensified CCDs were discussed. I accept that such a meeting took place at or shortly after the SBS conference, but there is no suggestion that the inventive concept was disclosed.

Communications between Amersham, Packard and CIL in January – March 1996

[206]Evidently, a number of telephone conversations took place between CIL and Amersham in the first quarter of 1996. These were leading towards a top level meeting arranged by Mr Van Cauter which was to take place between Amersham, Packard and CIL on 22 March 1996.[207]During the course of this time it is apparent that Amersham approached CIL directly to see whether there was any possibility of working with them independently of Packard. Amersham was interested in discussing the Optical Imager with pharmaceutical companies, and wanted to see if there was any scope for a collaboration with CIL. I am satisfied in the light of this evidence that, during the course of these discussions, issues such as the advantages of miniaturisation, the efficiency of detection of light emissions from assays, the wavelength at which assays emitted light and the types of detectors that could be used to miniaturise assays, together with fluorescence imaging, were all discussed, at least in broad outline. Nevertheless, I am also satisfied that there was no disclosure of the inventive concept as such.

Cancellation of 22 March 1996 meeting

[208]In the event, the meeting scheduled 22 March 1996 was cancelled, because of Amersham’s interest in purchasing Noveltech. That came to nothing and so in late May or early June 1996, a telephone conversation took place between Mr Van Cauter and Mr Trevor Nicholls in the course of which the meeting originally arranged for 22 March 1996 was rearranged for 27 June. Mr Van Cauter told Mr Nicholls of Packard’s collaboration with a company called Aurora to develop an imaging instrument to detect Aurora’s red shifted fluorescence cell based assays using green fluorescent protein.

June and July 1996

[209]It was contended that during the course of June and July 1996, a number of meetings took place between Mr Harrison and Dr Jessop, at which Mr Harrison identified and explained Packard’s interest in developing an SPA with an emission wavelength biased towards the red end of the spectrum in order to work more efficiently with CCD based imaging detectors. In the event, Mr Harrison’s evidence did not support this allegation. Mr Harrison did, however, contact Dr Jessop to arrange for the supply of an SPA assay for use by CIL. In my judgment, this does not add to the entitlement case. 27 June 1996 meeting[210]This meeting was apparently attended by Mr Van Cauter, Mr Harrison and Mr Englert of Packard, Dr Hooper and Dr Rushbrooke of CIL, and Dr Cook, Mr Nicholls, Dr Burns and two others on behalf of Amersham. Prior to the commencement of the meeting, a confidentiality agreement between Amersham and CIL was signed. Thereafter, it seems a number of different topics were discussed, including: Packard’s Discovery instrument, which was a scintillation counter based on red-sensitive PMTs that had been developed for use with CIS Bio’s HTRF assay; TopCount 384; Cytostar T plates and CIL’s work on the Optical Imager and its ability to detect signals from a range of different assays, including SPA. Particular reliance was placed by PerkinElmer upon the evidence of Dr Hooper and Mr Van Cauter.[211]Dr Hooper explained that Packard and CIL emphasised that the future for high throughput screening was using CCD based cameras. She also gave evidence about her presentation. This related to the work done on low light imaging and contact imaging in areas they thought might be of interest to Amersham. She spoke about the use of CCD based detectors, their spectral sensitivities, and the use of blue, green and red emitting assays for imaging on these detectors. She also presented results from imaging of luminescence, chemiluminescence, bioluminescence and radioisotopes, including SPA. She spoke about the work that CIL had done with SPA test beads, and described the results obtained. She explained that the Optical Imager had the potential to extend Amersham’s SPA market by allowing high throughput and miniaturisation. In the context of SPA imaging, she talked about colour quench, what caused colour quench and colour quench correction. She explained that they had developed a method of colour quench correction with imaging and showed data on this. She also explained the approach of imaging from either the top or the bottom of the well plate, and that the amount of colour quench would depend on the spectral absorbance of the coloured compounds in the sample and whether that overlapped with the emission of the scintillant being used. Dr Hooper’s evidence was not challenged on these issues and I accept it.[212]Mr Van Cauter gave evidence which, to my mind, was to much the same effect. He explained in his statement that they mentioned their concerns about colour quench in miniaturised samples and wondered if the next generation SPA assays would use brighter beads to enable miniaturisation and red shifted beads to address the colour quench problem. He reiterated that Packard wanted to develop an imaging product that could do as many assays as possible and that, for example, Zeneca had insisted that Packard agree to try to make the Optical Imager compatible with red emitting assays. He explained to Amersham that the reagents market was moving towards red emitting assays and instruments were being developed that would be compatible with this technology, such as the Discovery instrument. Amersham was apparently interested in developing this instrument for its own version of the HTRF assay. Packard suggested that Amersham should develop its next generation SPA technology to be compatible with the next generation of detector instruments. Overall, Packard tried to determine whether Amersham was planning to red shift the wavelength of its SPA assays. Finally, Mr Van Cauter explained that Packard told Amersham either at that meeting or at a subsequent point, that they either had or were funding the development of a red sensitive image intensifier for testing in the Optical Imager. The aim was to help determine whether Packard could pursue the development of the Optical Imager for red light emitting assays, or would need to focus on cooled CCD instrumentation instead.[213]I have considered this evidence and the cross examination very carefully. In my judgment it does, as a whole, amount to a disclosure of the inventive concept. In the course of the discussion Packard and CIL raised the issue of red shifting the SPA beads to address the colour quench problem and produce more light, they discussed the importance of matching the sensitivity of the detector to the assay being detected and vice versa and they discussed their work on the Optical Imager and its use for imaging fluorescence, chemiluminescence and SPA. It may be that the thrust of the presentation was that the Optical Imager could be used SPA in its conventional form, as Dr Burns explained. Nevertheless, I consider that those present for Amersham must have understood that one of the things being suggested was the use of red shifted phosphors in SPAs detected by CCDs.[214]A further meeting took place in November 1996 to discuss HTRF but I do not understand it to be suggested that this involved a disclosure of the inventive concept. Entitlement - Dr Jessop and the

Inventive concept

[215]In 1995, Amersham started to investigate imaging technology. As Dr Jessop explained, this came about because of the drive to increase the number of wells in multi-well plates, and because it was becoming apparent that scintillation counters could not keep up with the development. The sheer size of PMTs meant that they were limited in their ability to count lots of very closely spaced wells simultaneously. For this reason, Amersham began to look at alternative means of detection. Dr Cook of Amersham had come across the FLIPR – the Fluorometric Imaging Plate Reader – which was a cooled CCD camera being developed by Noveltech. Dr Cook realised that the FLIPR instrument would be quite useful for Cytostar T assays, and he assigned Dr Jessop to the project because of his interest in instrumentation.[216]On 11 May 1995, Dr Jessop made contact with Mr Schreder at Noveltech. Noveltech evidently had asked for some microplates to be sent to test the instrument. Dr Jessop sent to Noveltech the emission profile of the scintillant in the microplates, this being information Noveltech needed to make a comparison with the spectral response of the detector.[217]Dr Jessop sent to Dr Schröeder a fax on 3 July 1995 from which it is apparent that he had, by this time, despatched the test plates to Noveltech. Dr Jessop indicated that he hoped there was time for Noveltech to do the initial evaluation in advance of a visit which was planned for the end of the month.[218]Dr Jessop visited Noveltech on 27 July 1995 and wrote a note of his meeting which is dated 31 July 1995. Dr Jessop explained that during the meeting he was shown the FLIPR and given basic operating instructions. A discussion took place as to how matters were progressing and about the results of the tests carried out by Noveltech using the Amersham test plates. Those tests indicated that FLIPR had difficulties in detecting the very low light levels produced by SPA. Mr Schröeder emphasised to Dr Jessop the importance to FLIPR of the signal to noise ratio. Dr Jessop explained this was a new factor for him to consider, and was not an issue that he had previously had to deal with in scintillation counting.[219]At or shortly after the meeting, Dr Jessop thought that one option was to change the scintillant and incorporate a more efficient or brighter fluor. He was aware of various polymers developed by Amersham – the ALPs – and reference to a report by Martin James from the LEP group indicated that one of the most efficient fluors was ALP-1 which emitted approximately five times as many photons per disintegration as butyl-PBD/DPA. ALP-1 incorporated terbium with a maximum emission in the green region of the spectrum. The substance of this is recorded in a note of the meeting prepared by Dr Jessop on 31 July 1995.[220]Dr Jessop also explained that having chosen to investigate ALP-1, it occurred to him that the CCD cameras about which he had read were likely to be more sensitive to light of longer wavelength than the light emitted by conventional SPA beads. It also occurred to him that the use of ALP-1 might have some beneficial effect on the colour quench problem.[221]In cross examination it was put to Dr Jessop that it was Noveltech that had suggested the use of alternative fluors and this is the only explanation for an observation written in the note of the meeting that:
“The ALP-1 fluor, (or at least something with greater efficiency and longer emission wavelength than b-PBD/DPA) seems essential.”
Dr Jessop would not accept this in cross examination. Further, I do not consider that the evidence given by Dr Jessop is in any way inconsistent with the note of the meeting. I accept Dr Jessop’s evidence on this point. It was also suggested to Dr Jessop that he took advice on what fluors to use by consulting Dr Bosworth, and that Dr Bosworth gave him the Martin James report. Dr Jessop had no recollection of this, and Dr Bosworth was clear that he had not given Dr Jessop the report. Most importantly, I can find no evidential basis for a submission by PerkinElmer that Dr Jessop – or someone else at Amersham – recalled and told Dr Jessop that Amersham had supplied ALP-1 to Packard in August to September 1994 and that Packard had expressed interest in its brightness and suitability for use with an imager.[222]I have reached the conclusion in the light of all the evidence that Dr Jessop arrived at the inventive concept of the Patent at the end of July 1995 and further, that the concept was not derived from Packard.[223]During the autumn of 1995, Dr Jessop carried out experiments on ALP-1. He investigated its thermal stability, ways in which it could be incorporated into polystyrene discs, the various factors which might affect light output, and how to incorporate the polymer into plates. In December, he informed Noveltech that he had prepared some plates for them to test with FLIPR. Some plates contained blue fluors and others contained green fluors. A monthly report for February 1996 summarised the results that Noveltech achieved with the discs made by Dr Jessop. It was found that the ALP-1 fluor gave three to four times more light than butyl-PBD/DPA. It was considered a significant result.[224]On 11 March 1996, Dr Jessop wrote up a record of invention form in his notebook. He referred to the use of CCD cameras and that this meant that alternative fluors could be used with a view to maximising the light output from the system. One such fluor was ALP-1, but that related compounds such as ALP-3 and other lanthanides containing compounds described in the US equivalent to the Bell patent might also be considered. He pointed out that ALP-1 produced more light than butyl-PBD/DPA, emitted light at a wavelength of 550 nm, being a wavelength to which the CCD camera was more sensitive, and also noted that the longer wavelength might help to overcome colour quench problems. He also stated that ALP-1 might be incorporated into microspheres and used in the same manner as SPA beads.[225]During the course of the spring of 1996, Dr Jessop waited for Noveltech to complete the production and delivery of a FLIPR instrument. It was expected at the end of May but in the event was delayed and the instrument was not obtained until the end of the year. In the meantime, Dr Jessop contacted Dr Peter Ramm of IRI, expressing an interest in their CCD cameras for use in connection with SPA. This followed an approach by Dr Ramm himself to Amersham at the SBS conference in November 1995. In July, Dr Jessop requested a timescale as to when a CCD camera would be ready, and proposed terms for a non-disclosure agreement.[226]Finally, in the summer of 1996, Dr Jessop began to investigate the use of red fluors in connection with SPT. In particular, at a project review meeting of 13 July1996, a project was approved for the incorporation of lanthanide chelates such as ALP-1 and ALP-7 into microparticles for SPA applications. Further, in September 1996, a company called Porvair was asked to make europium based discs to fit into the bottom of a 96 well plate.[227]It was suggested that the impetus for Amersham to produce red scintillating beads for the purposes of imaging SPA came from the disclosures made by Packard at the 27 June 1996 meeting. I reject this submission. It was Dr Jessop’s evidence that ALP-7 had been thought of quite early on in the project when they started looking at alternative phosphors. They started to work on ALP-1 for the practical reason that this was available in the laboratory. At the same time, they knew of the other ALP phosphors that were available. They did not work on those immediately because they would have had to be synthesised. I have no reason to doubt this evidence and indeed accept it.

Infringement

[228]There is no real dispute between the parties on the issue of infringement. PerkinElmer have offered for sale and supply Image FlashPlates containing a scintillant which emits in the red region of the spectrum at about 600 nm for use in SPT assays, and a CCD camera called the ViewLux. PerkinElmer have promoted the products as being designed to be used together and, in the circumstances, have offered the claimed process for use in the United Kingdom and have supplied and offered to supply in the United Kingdom means relating to an essential element of the claimed invention, for putting the invention into effect. Subject to the issue of validity, PerkinElmer have infringed each of the claims in issue.

Conclusion

[229]The claims in issue were obvious. The Patent is invalid and must be revoked. If it had been valid it would have been infringed and the claim for entitlement would have failed.