“Gestmin is not to be taken as laying down any general principle for the assessment of evidence. It is one of a line of distinguished judicial observations that emphasise the fallibility of human memory and the need to assess witness evidence in its proper place alongside contemporaneous documentary evidence and evidence upon which undoubted or probable reliance can be placed. … But a proper awareness of the fallibility of memory does not relieve judges of the task of making findings of fact based upon all the evidence. Heuristics or mental short cuts are no substitute for this essential judicial function. In particular, where a party’s sworn evidence is to be disbelieved, the court must say why that is; it cannot simply ignore the evidence.”
“On reading Heinrich, a ‘light bulb’ went on, and I immediately realised that it would be possible to close the open ends of the linear DNA single units of the Open-Ended Process to make them safer for transfection. … Moreover and beneficially, Heinrich also showed that TelN could be used to cleave the DNA at specific recognition sites, potentially eliminating or reducing the need for restriction enzymes. This was my ‘eureka’ moment. … I also realised at the same time that the single units of doggybone DNA (“dbDNA”) could be produced without any bacterial backbone and that as such, they would also be a perfect starting template for RCA… Knowing that there was now a solution to overcome the problem identified in Chen, I felt I could pick up my research where I left it, specifically trying to develop an RCA process using a thermophilic strand displacement, rolling circle DNA polymerase, followed by subsequent resolution of the concatemers produced into single units of covalently closed linear DNA (dbDNA) using a protelomerase. However, I realised that to obtain the full advantages of what I already expected would result from using a thermophilic DNA polymerase to produce optimised thermophilic RCA derived concatemers (i.e., reduced meshing issues), it would be sensible to continue the resolution of those concatemers into single dbDNA units using a thermophilic protelomerase…”
“Given Dr Porter’s role at this stage was to assess the value and viability of my ideas and to assist with obtaining patent protection over said ideas, I was aware that I needed to communicate my previous research, including my previous work with thermophiles and relating to the Open-Ended Process, and my most recent technical innovations (the Close-Ended Process and Thermophilic Close-Ended Process), in particular, as clearly and comprehensively as possible to Dr Porter in order to demonstrate to him that the innovations were worth investing in. I therefore provided Dr Porter with as much information as possible during the latter part of 2007.”
“1. The development of an expression cassette containing no bacterial vector sequences only the DNA required to express the required gene. … 2. A highly efficient in vitro process for amplifying the DNA cassette that does not require the use of living cells. This is an enzymic process employing a DNA amplification technique referred to as Rolling Circle Amplification (RCA) using a commercially available enzyme, E.coli phage 29 DNA polymerase.”
“Although there are aspects of Dr Hill's research results that could possibly be patented now, the real value would come from a small amount of directed research to create a stronger overall patent or patents. This would cover a new process that would overcome, in an innovative way, inefficiencies encountered at laboratory scale with the production of DNA cassettes. A strong process patent could generate significant future licensing revenue from its use in a range of applications. Discussions with Dr Hill have identified a number of areas of research that require refinement and could strengthen and add to the value of intellectual property. The prime objective would be to improve the performance of RCA to replicate expression cassettes (free from bacterial vector sequences) by reducing DNA mesh formation. Currently, DNA meshing reduces the efficiency of cassette formation by ~75%. Mesh formation is a result of long DNA strands binding back on itself and not with a complimentary strand, making the DNA unavailable for transcription. Key technical objectives would be as follows: • Reduce meshing through the introduction of single stranding binding proteins (Phi 29 DNA polymerase) • Investigate temperature profiling to control mesh formation ( using mesophilic Phi 29 polymerase) • Evaluate thermophilic enzyme homologues of Phi 29 over wider temperature range of reactions. Preliminary studies have aleady been undertaken. (PROKARIA ENZYME - COLLABORATION OPPORTUNITY?) • Isolate a single stranded binding protein from Thermus sp.and evaluate with the thermophilic enzyme. • Identify single primers for DNA amplification from a fixed point. Avoids the generation of “waste fragments” of DNA. • Make expression cassettes (+/- bacterial vectors) for utrophin (very large and unclonable by other methods), tetanus protein C (short), GFP (Green Fluorescent Protein) and -galactosidase. Measure efficiency of manufacture with new process. • Transfect cassettes into cell cultures and mice (muscle tissue) and compare expression levels and longevity of expression between pairs of cassettes (+/-) bacterial vectors • Measure levels of concatemerisation in vitro and in vivo • Evaluate single strand tailing to prevent concatemerisation of single cassettes”
“Here is a ref to N15 prophage that produces linear molecules with telomeric like ends-a patent search here would be appreciated ……… it’d be good if we could find a thermophilic equivalent for this to include in a thermophilic RCA process.”
“Upon infection of an Escherichia coli cell, the phage DNA circularises via cohensive [sic] ends. A phage-encoded enzyme, protelomerase, then cuts at another site, telRL, and forms hairpin ends (telomeres).”
“The method developed up to now, involves Phi29 DNA polymerase driven rolling circle amplification, to produce concatamers from a template of an open circle form of expression cassette. There are known to be certain problems involved with the present method in that religated template DNA results in 'meshing' of the concatamers that are produced. These concatamers are not cut with restriction enzymes to produce the required linear single units. The plan described here is one to investigate potential methodologies to overcome the meshing problem and to improve the actual process for the rapid production of high quality DNA material.”
“Addition of telomeric ends: whilst linear forms of expression cassette DNA is fine for cell factories etc, it is not adequate for DNA vaccines and gene therapy. Once inside the cell, linear DNA is known to concatamerise which will lead to greater expression due to increased gene dosage. This is unacceptable for both vaccines or gene therapy. An enzyme from phage N15 called protelomerase plus inclusion of a 56 base pair site within the expression cassette will allow the formation of linear DNA with closed ends that will not concatamerise. The revised full process for the production of linear closed DNA expression cassettes suitable for vector-free DNA vaccines and gene therapy is shown in Fig 2. (i) Insert the 56 bp site (see Fig 1) within the expression cassette containing an egfp reporter gene and check the formation of closed linear DNA In vitro using published methodologies. Optimise this process. (ii) Investigate the potential of obtaining a thermophilic version to produce a fully thermophilic process. (iii) Investigate the expression levels, longevity of expression and maintenance within tissue culture. (iv) Investigate the rate of cellular uptake of closed linear DNAs.” (i) Insert the 56 bp site (see Fig 1) within the expression cassette containing an egfp reporter gene and check the formation of closed linear DNA In vitro using published methodologies. Optimise this process. (ii) Investigate the potential of obtaining a thermophilic version to produce a fully thermophilic process. (iii) Investigate the expression levels, longevity of expression and maintenance within tissue culture. (iv) Investigate the rate of cellular uptake of closed linear DNAs.”
“Investigate the potential of obtaining a thermophilic version to produce a fully thermophilic process”
“As a result of extensive scientific discussion with Dr Hill, alternative designs for vaccines and gene therapy cassettes are proposed that offer improvements over the earlier described designs and processes which are subject to claims in published patent applications. A modified outline technical plan is as follows:”
“The output from this work will be a novel DNA expression cassette manufactured by an in vitro thermophilic process. Based on searches conducted to date, it should be possible to protect these ideas through patent applications. Critical to creating valuable IP will be the generation of data demonstrating the advantages of the new cassette design over existing methodologies.”
“The main focus of this report has been the interrogation of the technical proposals from the Stage 1 Report with respect to the potential for generating commercially valuable intellectual property. The discovery of published patent applications relevant to Project 1 led to a refocus of the project objectives to get around potential issues. The aim now is to develop linear expression cassettes for vaccine or gene therapy use that are not capable of concatarmerising when introduced into a target cell. A method of achieving this has been identified and no published documents/patent applications have yet been discovered that use the methodology in therapeutic DNA cassettes. Also, and building on past experience, an in vitro thermophilic process will be developed for manufacture of the DNA cassette in a way that could generate intellectual property.”
“Acting on a telomere resolution site telRL, the protelomerase converts circular plasmid DNA into linear covalently closed dumbbell-shaped molecules (“doggybones”) in a single-step enzyme reaction.”
“Check for patents last night on the ‘doggybones’ vector (I love that name!!!). They have filed a patent but not on the construct and use of the construct- only on nucleic acid expressing IL 12 and its therapeutic use. I think we should focus on developing a thermophilic process for in vitro amplification of the doggybones cassette using proprietary reagents that we need to discover. The fall back position is that these can be sold or licensed and therefore have value.”
“Production of doggybone vector-free cassette to produce linear molecules with closed hairpin end using N15 protelomerase (ProTL):- • Insert into the vector-free cassette (constructed previously) the 56 base pair protelomeric recognition site. • Clone in a) egfp and b) lacz reporter genes into the cassette with the ProTL recognition site. • Investigate ways to clone and express the protelomerase gene within E.coli and purify the ProTL protein for use within doggybone vector production experiments. • Optimize production of doggybone cassettes in vitro.”
“No reports of a thermophilic equivalent of this enzyme has been reported and my recent BLAST searches using both ProTel protein and DNA sequence data yielded no matches within the NCBI data base. Screening for an equivalent thermophilic phage carrying this gene could take some time especially in the light of lack of extensive hot water samples although initially screening can take place using thermophilic bacteria gene libraries in hand. Prokaria may be able to help here using their extensive stocks of thermophilic phage. Perhaps it would be sensible to come rto some arrangement for them to screen their libraries for us. In the meantime we could progress with the mesophilic version and clone this gene. The sequence is fully available and there is now a cloning vector developed by Lucigen that carries the gene within the vector. We can order a sample of this vector and PCR up the full gene and the necessary telomeric binding domain.”
“Screening for Thermophilic phage that may carry a temperature stable protelomerase (TProTel). I am now confident after a brief literature search that there are a number of possible candidate phages that may well carry a version of this gene.”
“High temperature enzymic process for producing therapeutic DNA products”, it stated that: “a number of opportunities have been identified to improve this process efficiency and generate intellectual property as follows: • Develop a high temperature process for faster process reactions with benefits such as reduced risk of biological contamination • Screen, isolate and test new high temperature enzymes and proteins to improve process efficiency • Screen, isolate and test new high temperature enzymes to create improved vector constructs for gene delivery and expression • Develop a scalable process for in vitro DNA vaccine/gene therapy production”
“Our client is in the early stages of planning a research project directed to developing a new process for the production of DNA vaccines. This will be a cell-free process carried out at high temperature using enzymes isolated from thermophilic organisms. The process will be used to produce DNA vaccines that are free from bacterial sequences ie are not in plasmid form.”
“would be used to insert telomeric ends into the linear DNA vaccine product, forming a closed “doggybone” shaped linear structure. In this structure, there are no exposed DNA ends. This is an advantageous feature for a DNA vaccine as it prevents a non-specific immune response being generated against free DNA ends in vivo. Also, it prevents integration of a linear DNA vaccine into host DNA, improving safety. Furthermore, the structure prevents concatemerisation of vaccine molecules in the host cell (which leads to over-expression of the encoded antigen).”
“An in vitro high temperature cell-free process for production of a DNA vaccine comprising: a) contacting a DNA template with one or more primers and a thermophilic DNA polymerase; b) incubating the DNA template under conditions promoting DNA replication by displacement of replicated strands through strand displacement replication of another strand, wherein the DNA template comprises a sequence of interest but is devoid of bacterial plasmid replication sequences and/or CpG motifs.”
“The process of claim 1 or 2 further comprising: c) incubating the DNA vaccine product of b) with a thermophilic protelomerase to insert telomeric ends into the DNA.”
“That concept was never conveyed to us at any meeting with Dr Hill or in any of the project materials that I use for drafting.”
“I remember drawing out the 2-step process for him on a piece of paper and showing him how the restriction enzyme site that is used in the Open-Ended Process is replaced with a protelomerase site in the Close-Ended Process and how the action of the protelomerase on the concatemers results from the amplification step cuts the concatemers and closes the ends of the single units to form a closed “doggybone” shaped linear structure.”
“Finally, we have a question for Vanessa before our meeting. In the DNA vaccine process technology project, there is mention of use of protelomerase. This is used to convert linear DNA vaccine molecules into closed structures which will not concatamerise/provoke a non-specific immune response. Would the protelomerase enzyme be present during the step of DNA replication or alternatively, would it be added in a final step to convert all vaccine molecules into closed structures?”
“It is most likely that we will add a thermophilic version of protelomerase as a final step. We need to let the replication stage go unhindered first, then treat with the protelomerase. We may be able to include both the DNA polymerase and the ProTL together in the reaction if the required reaction temperatures allow us to do one step followed bya second step using a different temperature of incubation.”
“a) Number of essential method steps; order in which they can be performed. b) Reaction components - enzymes/other proteins; all publicly available? If not, how can be obtained e.g thermophilic protelomerase. Reaction conditions – basic protocol/requirements for each element to work c) Structure of template; basic elements of expression construct. d) Structure of initial RCA product; downstream processing to give final product.”
“Close ends of these linear DNA molecules”
“either shows the concatemers being cut by a restriction enzyme and then the open ends closed using protelomerase (which would require two protelomerase target sites in the template) or it shows that the protelomerase first cuts the concatemers before going on to close the open ends of the single units to create the doggybone vectors (which would require one protelomerase target site).”
“As outlined above, strand displacement reactions, in particular those using rolling circle amplification, produce a continuous series of tandem units of the amplified DNA (a concatamer). In many embodiments, the amplified DNA will be required for use as a single unit, and so such concatamers require processing to release single units of the amplified DNA. Accordingly, where the amplified DNA comprises concatamers comprising tandem units of DNA sequences amplified from the DNA template, the process may further comprises the additional step of c) cutting the concatamers to produce single units of amplified DNA sequence. Resolution of concatamers will typically be carried out by cutting with one or more restriction endonucleases. Typically, a restriction endonuclease will be selected to cut at a single site in the amplified DNA. Where the DNA template houses a gene or other DNA sequence of interest, the DNA template may be selected to contain one or more rare-cutting restriction endonuclease sites in the region outside the gene or other DNA sequence of interest. Rare-cutting restriction endonucleases are enzymes whose recognition sites are found in low frequency in genomic DNA. Examples include [Examples of rare cutters]. Use of rare cutting restriction endonucleases is selected to avoid excision in the resolution step of a portion of the amplified DNA e.g. an expression cassette or gene which is required to be retained in the final product. In some embodiments, the cutting step will also be carried out at a thermophilic temperature for optimum efficiency. In such embodiments, restriction endonucleases which are functional at thermophilic temperatures will be used. Examples of such restriction enzymes include [Insert thermophilic restriction enzymes]. Alternatively, the product mixture may be cooled to a lower temperature to allow use of other types of restriction endonuclease. Following resolution into linearised single units, there may be a step of religation of the linearised DNA so as to form a closed circular DNA (ccDNA). Preferably, a DNA ligase enzyme may be used in this step. The ccDNA may then be subjected to supercoiling by incubation with a topoisomerase enzyme.”
“Accordingly, the invention provides for excision of the expression cassette from DNA amplified by the above process. Typically, this requires the presence of restriction endonuclease sites flanking the expression cassette on either side. As above, such sites may be recognised by rare-cutter restriction endonucleases to minimise the possibility of cutting within the expression cassette. … In a related embodiment directed to production of DNA molecules of improved safety, there is a step of incubation of single units obtained according to the above process with a protelomerase (ProT) enzyme, optionally bacteriophage N15 ProT. In one embodiment, the linearised single units obtained following resolution of the concatamers produced in the amplification step of the process are religated to form ccDNA but are then converted into closed linear DNA molecules by the action of ProT. In other embodiments a minimal expression cassette excised from the single unit may be incubated with ProT. ProT is able to introduce telomeric ends into DNA. Molecules generated by ProT have a dumb-bell structure shaped with left and right hairpin ends flanking a central double-stranded core. Thus, such molecules are not circular, but are "closed linear "in structure. The term "closed linear" describes a structure where the base-paired double stranded region is covalently linked at either end by the hairpin loop. This may be contrasted with an "open linear" structure where the two strands in the double stranded DNA are only bonded together by base pairing interactions. Formation of the closed linear structure typically requires the presence of a telRL target site for ProT in the single unit. In particular, the closed linear molecule may have hairpin ends comprising telL and telR sites flanking a central double-stranded region. The hairpin ends may comprise regions of DNA where conventional Watson-Crick base pairing is not present. [More detail needed here about mechanism of action of ProT; definition of telL sites, other types of ProT]. The incubation step with ProT, and the production of closed linear DNA molecules, is selected to prevent the presence of exposed DNA ends where a linear DNA molecule is required for the therapeutic application of interest. [Why are linear molecules preferred over circular molecules?] Absence of exposed DNA ends increases the stability of the DNA molecule and prevents generation of a non-specific immune response against the exposed termini. Also, the chances of integration of the linear DNA into the host chromosome are greatly reduced. Furthermore, the structure prevents concatamerisation of the DNA molecules in the host cell. Concatamerisation in cells leads to increased gene dosage and consequently greater expression, so its prevention allows for better control of expression level.”
“Could you please carefully review the attached patent application and Jimmy’s [Dr Nicholls’] comments and questions so that we can discuss week ahead of Friday’s meeting.”
“Substrate for ProT needs to be covalently closed i.e. circular, Vanessa to confirm this”
“Please can you also confirm whether it is appropriate for claim 9 to be dependent on claim 3, or if in practice ProT only works on religated circular templates (claim 5).”
“Neil telephoned to discuss the “improved expression cassette” concept. He indicated that following his review of the mechanism of action of protelomerase (ProT), Touchlight would want to cover an additional aspect in the proposed application. ProT has a combined endonuclease and ligase activity, such that it can cleave and rejoin double stranded DNA molecules without the need for separate use of restriction enzymes and DNA ligases. Thus, we should add a claim to a process for making the expression cassette molecule which involves the direct generation of the expression cassettes from material amplified by DNA polymerase. In particular, where the DNA application is rolling circle, the concatamers that are generated can be directly resolved into the expression cassette molecules using protelomerase and no other resolving enzymes.”
“After our conversation Wednesday, I realised that we had gone a bit off track with the RCA patent. I suspect this is due to such a long break since we last saw Jamie [sic] and being so thinly spread with so much other stuff to do at this time. I think what he has done, is concentrated on the RCA papers I wrote and has not looked at the technical plan we gave him. The papers really relate mostly, to how to clone something into our linear cassette and the technical plan relates to the actual vaccine production process. The original technical plan (attached) from Dec '07 clearly relates that the Protelomerase is used to cut and ligate the ends directly after the RCA amplification step and hence we did not propose to use restriction enzymes or a ligase. In the light of this and the new idea of splitting this patent into 2, I think we need to sit down together with the 3 separate areas of work (the 3rd being the cassette design) and work out how best to organise these 1/2 patents. Once we have sorted this one then we can move to the TLVector system. Hope this all makes sense!”
“We can discuss these patent options when we meet on Monday. I agree that it is complicated but things are coming together. I also agree with you that we should discuss and agree the patenting strategy ie number of patents etc.”
“In regards to the second patent application (improved expression cassette; our ref: N.106698), he indicated that Touchlight were particularly excited about this project. The process Touchlight have in mind is using a closed linear DNA molecule as a starting template, which would then be denatured and amplified, preferably by RCA. The denaturation step converts the closed linear molecule into a circular molecule, and so RCA can be used to amplify these circle forming long concatamers. The key point is that ProT can be used to resolve such concatamers directly without need for additional enzymes, as discussed in our5 November 2008 phone call. [xxxxxxxxx xxxxxxxxxx xxxxxxxxxxx xxxxxxxxx xxxxxxxxx xxxxxxxxxxxxx xxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx xxxxxxxxxxxxx xxxxxxxxxxxxx xxxxxxxxxxx xxxxxxxxxxxx xxxxxxxxxxx xxxxxxxxxxxx xxxxxxxxxx xxxxxxxxxx xxxxxxxxxx xxxxxxxxx xxxxxxxxxx xxxxxxxxxx xxxxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxxx xxxxxxxxx xxxxxxxx xxxxxxx xxxxxxxx xxxxxxxxx xxxxxxxx xxxxxxxxx xxxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxxx xxxxxxxxx xxxxxxxxxxxxxxx]”
“Cut and close ends of these linear DNA molecules with a thermophilic protelomerase”
“I had a chat with Neil regarding inventorship as we previously discussed yesterday. I think the first thing to say is that Neil is a grown up lad, is aware of the sensitivities around the subject, and completely recognises that Touchlight is a result of your lifetimes work. In me asking him the question ‘what bits of the patent do you think you invented', he responded with 'do you (vanessa) think that we would have got the initial ideas into a patentable form without Neils contribution'. If the answer to that is 'yes', then he will totally accept it. I think he thinks that it would be 'nice' to acknowledge his contribution. … So please just have a little think about this. Clearly it is your work, and I will go with whatever you think. And am sure Neil will too. I just want to get the whole patent area tidied up.”
“I TOTALLY understand and the inventorship and ideas behind it came from you. Frankly, it’s a lot easier that way too. Neil will be fine- and if he’s not that’s his problem not ours. I will get the form prepared for you.”
“I thought that patent and grant preparation was why we were employing him (at a wage greater than his top consultancy fee rate) so I don't understand this need for 'special appreciation' at having done the job. Yes he worked hard and did a thorough job but that does not warrent falsifying inventorship rights. I guess I am somewhat surprised at this, as he knew what crap I suffered at the RHUL, with this type of issue and I'd have thought he would realise its not a good idea repeating such nonsense as I won't put up with it. He does lose the plot at times!! Oh well time to forget and move on.”
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“[xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxxx xxxxxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxxxx xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxxxx xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxxxx xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxx xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxx]”
“So the question we have to ask ourselves is if/when do we break it to Vanessa. As you rightly ask will she take it out on Neil or the company? My guess would be both (if she is still involved with the company then and if we have to disclose it to her).”
“Subsequent to September 2008, difficulties were encountered on the research side in isolating suitable thermophilic enzymes for use in the planned process. This prompted a re-evaluation both of patent strategy and of the nature of the process to be commercialised by Touchlight. Further to a review meeting on27 October 2008 together with Dr Hill and J A Kemp, it was decided to pursue a separate patent application in relation to an in vitro process of DNA manufacture carried out at high temperature, to allow for more time for successful exemplification of use of thermophilic enzymes. As regards protection around the planned closed linear DNA product, a more detailed re-evaluation was needed as regards the possible scope for patent claims. Likely difficulties for patentability of product per se claims to closed linear DNA expression cassettes lacking bacterial vector sequences were discussed at the review meeting. This led us to instead consider protection of a process for production of closed linear DNA. In the period subsequent to the review meeting on27 October 2008 , an idea was developed of commercialising a wholly enzymatic in vitro process for production of closed linear DNA. This process would combine use of a DNA polymerase and a protelomerase enzyme in an in vitro, cell-free environment, allowing for amplified DNA to be directly converted to closed linear DNA without need for bacterial propagation of DNA. The process could also be carried out with known enzymes, without use of high temperature, allowing us to exemplify the process more rapidly. It also appeared that such a process had not been described previously in the prior art and could thus provide a basis for patentable process claims, avoiding difficulties around claiming closed linear DNA products per se. I do not specifically recollect the exact date on which the above concept of an in vitro, cell-free process for production of closed linear DNA was first discussed at Touchlight Genetics, but I believe it clearly arose subsequent to the review meeting of27 October 2008 , further to which a significant re-evaluation was needed in relation to patent strategy for protection of our planned closed linear DNA technology. I also recall discussions with Dr James Nicholls of J A Kemp during November 2008 of a particular plan to combine use of the Rolling Circle Amplification (RCA) DNA polymerase phi29 together with a protelomerase in an in vitro cell-free process in which protelomerase would resolve concatamers of amplified DNA created by RCA into single closed linear DNA units.”
“[Dr Hill] acknowledges that [TGL] is the sole owner of any and all Intellectual Property Rights and insofar as any of the Intellectual Property Rights are not vested in [TGL] and in consideration of the salary payable to [Dr Hill] under the terms of this Agreement, [Dr Hill] assigns to [TGL] with full title guarantee, the entire copyright (including future copyright) and all other rights and interests of whatsoever nature in and to the Intellectual Property Rights and any products of the Employment together with the right to take proceedings and recover damages and obtain all other remedies for past infringements in respect thereof throughout the world for the full period of copyright (and of any analogous rights) and all revivals renewals extensions and novations thereof and thereafter (so far as possible) in perpetuity, together with the rights to the same in any manner and through any media as [TGL] shall in its absolute discretion decide.”
“[Dr Hill] acknowledges that she is in a position of special responsibility and under a special obligation to further the interests of [TGL]. Accordingly any discovery, invention, secret process or improvement in procedure discovered, invented, developed or devised by [Dr Hill] during the Employment (and whether or not in conjunction with a third party) and in the course of [Dr Hill’s] duties affecting or relating to the Projects or (subject to Clause 11.7) otherwise relating to the business of [TGL] or any other Group Company or capable of being used or adapted for use in it, shall immediately be disclosed by [Dr Hill] to [TGL] and subject to such rights as [Dr Hill] may have under the Patents Acts 1977 and 2000 will belong to and be the absolute property of [TGL] and shall not be disclosed to any other person, firm or company without the prior written consent of [TGL].”
“It is accepted that [Dr Hill] will continue to be involved (outside the course of the Employment) in academic research in relation to matters other than the Projects and it is agreed that any intellectual property rights arising in relation to such research will belong to [Dr Hill].”
“Touchlight is seeking funding of£1.8 million over the course of the next three years to develop the company’s existing knowledge, to secure that knowledge in the form of patented intellectual property and to exploit its significant commercial value. The two specific projects relate to:- (1) Novel gene based treatments for bacterial infection. (2) Novel processes for the rapid production of superior DNA vaccines. It is anticipated that up to£900,000 will be raised at this stage and a further£900,000 in approximately 18 months time once the patent application process is well advanced.”
“Touchlight has identified two projects with significant need and market opportunity to generate valuable IP. The projects share unique technology based on the use of thermophilic bacteria, hitherto an unexplored branch of genetic science. The technology is described in further detail in Appendices 8 and 9.” “Thermophilic bacteria” is defined in the Glossary as “any bacterial species capable of growth above 45°C up to 300°C.”
“Project 1: Novel gene based treatments for bacterial infection This will be the lead project and will commence as soon as laboratory facilities have been established. The plan indicates a provisional start date in April 2008. The company has coined the term ‘ThermoLethal Vectors’ (TLV) to describe the technology (Appendix 9). Two “warhead designs” have been identified and will be genetically designed, constructed and evaluated in parallel. One or both of the warheads will then be further developed and optimised to improve the bacterial lethality properties of the TLV. Project 2: Novel processes for the rapid production of superior DNA vaccines This project will begin three months after Project 1 to allow the research to be firmly established and give time for personnel recruitment. The project will screen for 2 new proteins that will form part of a novel and rapid process for manufacturing DNA vaccines and gene therapy treatments.”
“A licence agreement will need to be put in place between Dr Hill and TGL giving TGL the right to develop, trial and ultimately bring to market the products derived from the lines of research on which Dr Hill has been working.”
“xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxxxx xxxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxxxx xxxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxx xxxxxx xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxx”
“(4) Temperatures - Only thermophilic step is amplification step b) - Ensure other steps can be non-thermophilic or thermophilic - NB doesn’t matter if temp is cooled after amplification as SSBPs prevent snap back of unmeshed concatamers – allude to this?”
“3. Non-thermophilic steps As explained in our meeting, claim 1 only requires a thermophilic amplification step. All other process steps can be carried out at any temperature. Also, the claim does not exclude the possibility of initial non-thermophilic and/or PCR-type steps. I will ensure that the description provides a disclosure that all steps other than amplification step b) may be thermophilic or non-thermophilic, and a list of appropriate temperatures.”
“Vanessa has pointed out that, at present, our claims appear to cover only the use of a single DNA polymerase. …”
“As suggested, the application is now focussed on a process for production of closed linear DNA that involves use of DNA polymerase and protelomerase in combination. … The proposed claims are broadly directed to amplification based on any DNA template comprising a protelomerase target sequence, using any DNA polymerase, and a subsequent processing step for the amplified DNA using any protelomerase. Please let me have your comments on this proposed claim scope. …”
“As we now have nearly 2 patents completed I think we should rest from doing any more here (apart from getting the final draft of 1b [i.e. that relating to production of closed linear DNA]) and clear this backlog of tasks ASAP.”
“Neil and I have been through the patent this morning and apart from getting the word telomere resolvase into it somewhere all seems fine-very thorough I think-James has done a very good job here.”
“A serious problem is my contract of employment. I explicitly agreed to come on board this venture only if certain criteria were fulfilled. The most important of those was the separation of any rights to my work concerning a new ground breaking theory I am developing with a quantum physicist and any spin-off technologies that may come from them or, indeed, any other ideas that are unrelated to the Touchlight projects. I now find I have a contract which, although prepared by our company lawyer, who was explicitly told by myself my requirements, is actually one that threatens my full IP ownership rights and requires me to take the company to court to prove these ideas do not belong to TLG! I had to resign on the basis of this very fact alone, as I cannot accept the situation at all.”
“(4) She had agreed to transfer her ground breaking ideas in return for a 49% stake in the Company. (12) She was concerned that her ideas for “Natures Code” had been included in the transfer to the Company and that ideas outside of the specifics referred to in the “Information Memorandum” had also been transferred and that she would have to sue the Company to prove her rights.”
“(4) It was agreed that she had transferred her ideas but that this was in connection with the “Projects” as defined in her contract and contained in the Information Memorandum. (12) The question of Natures Code research had been addressed as it was not within the “Projects” and therefore remained her property.”
“Contract alterations re Nature’s code and any other ideas/technologies that are not directly related to the technology I have brought to TLG. Removal of clauses that say I have to present these other ideas for TLGs consideration first-this should remain at my discretion alone.”
“As I am a Director and the major share holder of [TGL], it is obviously in my interests that the company does well. It is also obvious that I should want to that see that my original, lifetimes work is being furthered in the best manner possible for this company’s interests.”
“As the patent lawyers have advised, [xxxxxx xxxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxx]”
“Paul and I require further clarification of the present status of the company's two patents (referring to them as patent 1 (part 1 of process) and patent 2 (part 2 of process)) that were filed in January 2009. We need this information before we can come to a decision regarding the purchasing of further shares. Please answer these points as fully as possible. 1. How many of the individual claims have been fully supported by actual hard data both in patents 1 and 2? 2. Has the data been generated to fully support the high temperature aspects of these patents both in patents 1 and 2? 3. Have the patents been withdrawn or are they continuing to international status and therefore will be published in 18 months (approx) time? 4.Why have I, the original inventor, not been requested to sign the inventorship forms? 5. Who has been declared as inventor/s upon patents 1 and 2?” 5. Who has been declared as inventor/s upon patents 1 and 2?”
“A PCT application for patent 2 entitled "Production of closed linear DNA" has been filed. We believe that all the claims in this patent have been substantiated by scientific data developed between May and December 2009. The patent application covers widest range of physical conditions for carrying out the process including temperature. Our patent attorneys inform us that Dr Vanessa Hill has been declared as the only inventor on the PCT application. The application will be published in six months time (six months from the31st January 2010 ).”
“In conclusion, 1 presume 1 am correct in saying, that supporting data was only obtained for patent 2 and yet only the mesophilic range of temperature of operation within that patent; Targets were not reached for patent 1 and no data at all obtained for the TLV system. So effectively, supporting data for only 1 third of the proposed patents were obtained and only the lower temperature part supported here. This falls well short (by aprox 80%) of our initial plan. Am I correct in this?”
“The second technology also, has been drastically compromised as most of the required, crucial research targets were not realised. As a consequence, one of the patents (GB0901592.6) has been withdrawn and re-submitted (thus losing prior art date) and the second patent (GB0901593.4) has also been seriously compromised by the lack of supporting data. This has meant that Touchlight has not acquired the all important proprietory enzymes and DNA products/methodologies that would have given Touchlight's technology the leading edge over our main competitors. In fact, submission of patent (GB0901593.4) has actually advertised to our competitors a way of obtaining an advantage over our company as it is now published and in the public domain. I also have concerns that with the publication of the patent WO/2007/087478 and other academic publications by these authors, that many of the claims in our own will be lost due to the lack of high temperature counterparts. This situation is drastic and has now greatly reduced the potential efficacy and value of the intellectual property held by Touchlight.”
“I have now had the opportunity to take advice on our ongoing matters. As you are aware I have already sent documents and emails that appear to raise questions regarding whether the invention in the Touchlight patent application was first conceived prior to me joining Touchlight Genetics Limited. This appears to bring into question the ownership of the invention and the right of Touchlight Genetics Limited to apply for patents for that invention. It would be good to resolve this matter. As you are aware, all I want from you is the standard assignment from you to me of the Thermolethal Vector Technology (TLV), which has already been provided to you. In return, I’m happy to retrospectively assign any and all rights I own in the invention disclosed in the International Patent Application No PCT/GB2010/000165, subject to the condition below. It is quite clear that there are questions in relation to ownership of the invention disclosed in that patent application that should be addressed. Consequently, I regard it as only fair and proper that some payment should be made to me to clear these matters up and to move forward. To that end, I suggest a sum of£200,000 given the value of the markets in which you wish to exploit this patent and how this invention is likely to be of outstanding benefit to Touchlight Genetics Limited.”
“As you will be aware, the definition of “Intellectual Property Rights,” as laid out in the Service Agreement, is specifically focused on IPR “created by the Director in the course of the Employment together with all such rights, applications, copyright, know-how and confidential information relating to the Projects (my emphasis) owned or created by or in the knowledge of the Director prior to the commencement of the Employment.”
“Relying on the understanding and assurance that Dr Hill was satisfied with everything as I have just described, the board permitted [TGL] to finalise and make the Priority Application (as well as the subsequent PCT Application, which resulted in granted patents) and to expend significant time and money developing the business into what it is today.”
“she doesn’t really understand the patent process (…remember she didn’t even read Kemp’s drafting before submission).”
“(5) On any such reference [i.e. one under s.37(1)] no order shall be made under this section transferring the patent to which the reference relates on the ground that the patent was granted to a person not so entitled…if the reference was made after the second anniversary of the date of the grant, unless it is shown that any person registered as a proprietor of the patent knew at the time of the grant or, as the case may be, of the transfer of the patent to him that he was not entitled to the patent. (9) The court shall not in the exercise of any such declaratory jurisdiction [see s.37(8)] determine a question whether a patent was granted to a person not entitled to be granted the patent if the proceedings in which the jurisdiction is invoked were commenced after the second anniversary of the date of the grant of the patent, unless it is shown that any person registered as a proprietor of the patent knew at the time of the grant or, as the case may be, of the transfer of the patent to him that he was not entitled to the patent.”
“1. If a Community patent has been granted to a person who is not entitled to it under Article 60(1) European Patent Convention, the person entitled to it under that provision may, without prejudice to any other remedy which may be open to him, claim to have the patent transferred to him. 2. Where a person is entitled to only part of the Community patent, that person may, in accordance with paragraph 1, claim to be made a joint proprietor. 3. Legal proceedings in respect of the rights specified in paragraphs 1 and 2 may be instituted only within a period of not more than two years after the date on which the European Patent Bulletin mentions the grant of the European patent. This provision shall not apply if the proprietor of the patent knew, at the time when the patent was granted or transferred to him, that he was not entitled to the patent.”
“…the Claimants’ claim in restitution, if it exists at all, is right at the fringes of a developing part of the law and I do not think it would be right or useful to make a decision about the boundaries of such a claim on the basis of the somewhat incomplete argument I have received, in circumstances where I have already dismissed the Claimants’ claim on conventional grounds.”
“23. Unless the public can see and understand a judge's reasons they cannot hold the courts to account. There is therefore a strong principle that all parts of a judgment should normally be publicly available. Nevertheless there are occasions on which judgments may be redacted. Redactions will require powerful reasons, supported by cogent evidence which addresses the details. Generalities will not do. Although redactions will be rare indeed when looking across the legal system in general, certain kinds of proceedings may regularly involve redactions due to the nature of the proceedings and the material involved. In any event however redactions must be kept to the bare minimum. 24. Factors which will be relevant include: i) the nature of the information itself: for example cases in which some redaction may more readily be accepted could include technical trade secrets and private information about family life. ii) the effect of the publication of the information. This will be a critical factor. If publication would be truly against the public interest then no doubt the information should be redacted. If publication would destroy the subject matter of the proceedings – such as a technical trade secret – then redaction may be justified. The effect on competition and competitiveness could be a factor but will need to examined critically. iii) the nature of the proceedings: for example privacy injunctions and competition law claims may require some redaction while an intellectual property damages claim may not. The point is not that different kinds of case demand a different approach, it is that the balance of factors will change in different cases (e.g. the need to encourage leniency applications in competition law). iv) the relationship between the information in issue and the judgment (as well as the proceedings as a whole). Obviously judges do not deliberately insert irrelevant information into judgments but not every word of a judgment is as important as every other word. It may be that some sensitive information can be redacted without seriously undermining the public's understanding of the reasons. v) the relationship between the person seeking to restrain publication of the information and the proceedings themselves (including the judgment). For example, a patentee seeking damages for patent infringement on a lost profit basis knows that they will have to disclose their profit margin in the proceedings and that those proceedings are public. A third party whose only relationship with the case is that they are a party to a contract disclosed by one of the parties to the litigation is in a different position.” i) the nature of the information itself: for example cases in which some redaction may more readily be accepted could include technical trade secrets and private information about family life. ii) the effect of the publication of the information. This will be a critical factor. If publication would be truly against the public interest then no doubt the information should be redacted. If publication would destroy the subject matter of the proceedings – such as a technical trade secret – then redaction may be justified. The effect on competition and competitiveness could be a factor but will need to examined critically. iii) the nature of the proceedings: for example privacy injunctions and competition law claims may require some redaction while an intellectual property damages claim may not. The point is not that different kinds of case demand a different approach, it is that the balance of factors will change in different cases (e.g. the need to encourage leniency applications in competition law). iv) the relationship between the information in issue and the judgment (as well as the proceedings as a whole). Obviously judges do not deliberately insert irrelevant information into judgments but not every word of a judgment is as important as every other word. It may be that some sensitive information can be redacted without seriously undermining the public's understanding of the reasons. v) the relationship between the person seeking to restrain publication of the information and the proceedings themselves (including the judgment). For example, a patentee seeking damages for patent infringement on a lost profit basis knows that they will have to disclose their profit margin in the proceedings and that those proceedings are public. A third party whose only relationship with the case is that they are a party to a contract disclosed by one of the parties to the litigation is in a different position.”
“An in vitro high temperature cell-free process for production of a DNA vaccine comprising: a) contacting a DNA template with one or more primers and a thermophilic DNA polymerase; b) incubating the DNA template under conditions promoting DNA replication by displacement of replicated strands through strand displacement replication of another strand, wherein the DNA template comprises a sequence of interest but is devoid of bacterial plasmid replication sequences and/or CpG motifs.”
“The process of claim 1 or 2 further comprising: (c) incubating the DNA vaccine product of b) with a thermophilic protelomerase to insert telomeric ends into the DNA.” 115. Dr Hill submitted that the product of step b) would be a concatemer, with which the protelomerase is incubated in step c) to produce dbDNA. Hence, Dr Hill submitted, the skeleton claims are to the Close-Ended Process. Again Touchlight responded by noting that the starting point of step c) is a DNA vaccine product, which it said was something capable of being a DNA vaccine rather than a concatemer. 116. Again, this all seemed to involve subjecting the skeleton claims to a level of analysis which was not justified. As Dr Nicholls explained, the purpose of preparing the skeleton claims was to use words that might end up being used in claims to enable the search agents to identify keywords and classification codes, and to draft them broadly to catch as much prior art as possible. Rejected. The submission that the skeleton claims in Document A were to the Close-Ended Process was a significant one and it is important for the public to be able to understand the basis for that submission and the reasons given for rejecting it. In my view it is not realistic to say that publication of the skeleton claims (which were compiled for the reasons explained at the end of paragraph 116) and the submissions based on them is likely to damage Touchlight. 117. Of course, Document A could only reflect the Close-Ended Process if that process had not only been conceived by May 2008 but also communicated to Kemps. Dr Hill said in her first statement that, at the first substantive meeting with Kemps, she explained that the process would be a two-step thermophilic one, involving a thermophilic polymerase for the amplification step and a thermophilic protelomerase for the step of insertion of the telomeric ends. However, Dr Nicholls said that he did not recall and did not believe that such a two-step process was discussed at the initial meeting, but instead developed as the patent applications were drafted (see further below). In his oral evidence he was clear about this. It was put to him that in her5 June 2008 email (see below) Dr Hill was saying that the protelomerase could be used directly on the concatemers. His response was: “That concept was never conveyed to us at any meeting with Dr Hill or in any of the project materials that I use for drafting.” 118. In her second statement Dr Hill said that she believed that “we settled on the skeleton claims…through a mixture of emails and meetings” and in her oral evidence she claimed to have been “heavily involved” in the creation of the skeleton claims, including in phone calls with Kemps. However, there was no record of any such calls, Dr Nicholls did not recall any discussion with TGL about how the skeleton claims should be drafted, and it is apparent from the documents that Kemps sent Document A to the search agents without reference to TGL. 119. In her first statement Dr Hill said that at the9 May 2008 meeting (or a subsequent meeting, though there is no further meeting that would fit into the chronology) she spoke to Dr Ali while Dr Porter was speaking to Mr Woods about something else (and Dr Nicholls was not present). She said, inter alia: “I remember drawing out the 2-step process for him on a piece of paper and showing him how the restriction enzyme site that is used in the Open-Ended Process is replaced with a protelomerase site in the Close-Ended Process and how the action of the protelomerase on the concatemers results from the amplification step cuts the concatemers and closes the ends of the single units to form a closed “doggybone” shaped linear structure.”
“Finally, we have a question for Vanessa before our meeting. In the DNA vaccine process technology project, there is mention of use of protelomerase. This is used to convert linear DNA vaccine molecules into closed structures which will not concatamerise/provoke a non-specific immune response. Would the protelomerase enzyme be present during the step of DNA replication or alternatively, would it be added in a final step to convert all vaccine molecules into closed structures?” 123. Dr Hill responded 90 minutes later, saying: “It is most likely that we will add a thermophilic version of protelomerase as a final step. We need to let the replication stage go unhindered first, then treat with the protelomerase. We may be able to include both the DNA polymerase and the ProTL together in the reaction if the required reaction temperatures allow us to do one step followed bya second step using a different temperature of incubation.” 124. Dr Hill’s submissions relied heavily on her reply to Mr Woods’ question. It was submitted that the language used to describe the first option, “let the replication stage go unhindered first, then treat with the protelomerase”, suggested that there was nothing between those two steps. Further, it was suggested that the language used to describe the second, one pot, option indicated that there were only two steps, because only two enzymes, steps and temperatures were mentioned. 125. The first point to make is that (contrary to what Dr Hill said), Dr Hill’s email does not show that she had the Close-Ended Process in mind. Her submission relies once again on parsing language which cannot have been chosen with the point now under debate in mind – the question she was asked was about a different issue (would the protelomerase be present from the outset or only at the end). Prof. Wittig said that, if he had not read other documents, he could see how reading what Dr Hill said about the first option might suggest direct action of protelomerase on the concatemers. But my task is not to consider this document on its own but to assess it together with the remainder of the evidence. 126. Prof. Wittig was scathing about the one pot suggestion – regardless of whether the two-step Close-Ended Process was envisaged or the Cut and Ligate Process. His view was that including the protelomerase in the reaction mixture during RCA would hinder amplification because it would bind to the template. Of course, my task is to assess what Dr Hill meant, not whether her proposal was technically sound, but Prof. Wittig’s evidence does suggest that her answer was not fully thought through. Rejected. The5 June 2008 emails were a major part of the case on the Timing Issue. I do not see how the public can begin to understand the argument, let alone my reasoning, without being able to see what the emails said. Further, the question and answer in the5 June 2008 emails (and the arguments based on them) relate to purely technical matters and the language used to convey them, rather than advice by Kemps. I do not see how it can realistically be said that publication of the material proposed to be redacted could damage Touchlight. Further meetings with Kemps 128. The results of the landscape searches, which were broadly positive, were discussed at a further meeting on13 June 2008 . There is a note of the meeting prepared by Kemps, but neither party said that its contents advanced their case on the Timing Issue. 129. A further meeting with Kemps was held on14 July 2008 . Kemps’ note of the meeting does not record who was present, and Dr Hill said that she did not recall it, but the documents show that it was rearranged specifically so that she could attend, so it is likely that she did. The note records a number of points under the heading “DNA vaccine process technology: Process patent” including: “a) Number of essential method steps; order in which they can be performed. b) Reaction components - enzymes/other proteins; all publicly available? If not, how can be obtained e.g thermophilic protelomerase. Reaction conditions – basic protocol / requirements for each element to work c) Structure of template; basic elements of expression construct. d) Structure of initial RCA product; downstream processing to give final product.”
“Substrate for ProT needs to be covalently closed i.e. circular, Vanessa to confirm this”
“Please can you also confirm whether it is appropriate for claim 9 to be dependent on claim 3, or if in practice ProT only works on religated circular templates (claim 5).” 158. It therefore appears that at the meeting of 27 October a question arose as to whether protelomerase required a circular substrate, and that the outcome of the discussion was that it did, but Dr Hill would confirm. I agree with Touchlight that if Dr Hill had been aware that protelomerase also operated on linear DNA and so did not need a circular substrate, it is surprising that she did not mention that at the meeting when the question was posed. 161. However, even if Dr Hill had not read the draft patent application in advance of the meeting, it is hard to see why she would have been baffled and confused by the question of whether protelomerase needed a circular DNA substrate. That would have been an easy technical question for Dr Hill to answer (if she knew the answer) regardless of whether she had read the draft patent application and regardless of whether she knew the reason for the question being asked. Rejected. The question raised at the27 October 2008 meeting, and Dr Hill’s recorded response to it, were a key part of Touchlight’s case on the Timing Issue. Redaction of the question and the response would make it hard for the public to understand the argument and my reasoning. Further the material in question concerns technical fact rather than any advice given by Kemps. I cannot see how publication of the passages sought to be redacted could realistically be said to damage Touchlight. The5 November 2008 call and the7 November 2008 email 163. On4 November 2008 Dr Porter emailed Dr Nicholls to thank him for the meeting summary, saying that they would start to put together the additional information that he had requested. He also emailed Dr Hill to confirm that they were due to meet on 10 November to prepare a response to Kemps and to ask Dr Hill if she could “come up with some “doggybone” designs based on some of your thoughts at the Kemp meeting”. 164. On5 November 2008 Dr Porter called Dr Nicholls. Dr Nicholls’ file note of that conversation starts as follows: “Neil telephoned to discuss the “improved expression cassette” concept. He indicated that following his review of the mechanism of action of protelomerase (ProT), Touchlight would want to cover an additional aspect in the proposed application. ProT has a combined endonuclease and ligase activity, such that it can cleave and rejoin double stranded DNA molecules without the need for separate use of restriction enzymes and DNA ligases. Thus, we should add a claim to a process for making the expression cassette molecule which involves the direct generation of the expression cassettes from material amplified by DNA polymerase. In particular, where the DNA application is rolling circle, the concatamers that are generated can be directly resolved into the expression cassette molecules using protelomerase and no other resolving enzymes.” 165. As will be apparent, what Dr Nicholls records Dr Porter as having described on this call was the Close-Ended Process. Dr Nicholls’ evidence was that this was the first time that the concept of having the protelomerase act directly on the amplified material was raised, and that he recalled thinking that [xxxxxxx xxxxxx xxxxx xxxxx xxxxxx xxxxx xxxxxxx xxxxxx xxxxxx xxxxxxxxx]. His recollection of his reaction about[xxxxx xxxxx xxxxx xxxxx] is inherently plausible and is consistent with his recommendation, also recorded in his file note, to separate off protelomerase aspects to a separate application. 166. Dr Porter had no real recollection of the events surrounding this call. Dr Hill’s evidence fluctuated somewhat, but the thrust of it was that shortly before 5 November she and Dr Porter had sat down at the end of the lab to run through the draft patent application (she said that was the first time she had read it) and she was shocked to notice that the document contained material based on her draft RHUL papers and mistakenly referred to ligation of the single units before the protelomerase step. She said she told Dr Porter that needed to be corrected, and that they had a further conversation by telephone about it on 5 November, at which she reiterated the mistake and the need for correction. She said that Dr Porter was embarrassed, tense and angry but promised to call Kemps to explain the position. 167. On Friday7 November 2008 Dr Hill emailed Dr Porter as follows: “After our conversation Wednesday, I realised that we had gone a bit off track with the RCA patent. I suspect this is due to such a long break since we last saw Jamie [sic] and being so thinly spread with so much other stuff to do at this time. I think what he has done, is concentrated on the RCA papers I wrote and has not looked at the technical plan we gave him. The papers really relate mostly, to how to clone something into our linear cassette and the technical plan relates to the actual vaccine production process. The original technical plan (attached) from Dec '07 clearly relates that the Protelomerase is used to cut and ligate the ends directly after the RCA amplification step and hence we did not propose to use restriction enzymes or a ligase. In the light of this and the new idea of splitting this patent into 2, I think we need to sit down together with the 3 separate areas of work (the 3rd being the cassette design) and work out how best to organise these 1/2 patents. Once we have sorted this one then we can move to the TLVector system. Hope this all makes sense!” 172. Dr Hill submitted that it was critical to Touchlight’s case that it was Dr Porter that conceived of the Close-Ended Process in early November 2008. It was said that there were only two options – Dr Porter conceived the invention then and called Kemps (either before or after speaking to Dr Hill about it) or Dr Porter discussed matters with Dr Hill and called Kemps having appreciated that the draft patent application had failed to reflect the Close-Ended Process which had been conceived of by Dr Hill long before then. I do not agree that those are the only two options or that Touchlight’s case relies on the first option being true. Touchlight’s case is that the Close-Ended Process was conceived of by Dr Hill in early November 2008. That is not inconsistent with Dr Porter then calling Kemps to tell them about it following a discussion with Dr Hill. Rejected, save as indicated below in relation to paragraph 165. The5 November 2008 call and the7 November 2008 email were at the core of the case on the Timing Issue. Unless their contents are included in the judgment the public will not be able to understand my reasoning. Paragraph 163 does not contain any material the publication of which could damage Touchlight. As to paragraph 164, the5 November 2008 file note does not record any technical matter or communication between TGL and Kemps that is not apparent from the priority application. As to paragraph 165, Dr Nicholls’ evidence as what was mentioned on this call for the first time was important on the Timing Issue. I do not accept that the material about mechanics at the end of paragraph 165 could be damaging to Touchlight. However, I am prepared to redact the words after “thinking that” in the second sentence, and those between “reaction about” and “is inherently” in the third sentence of paragraph 165. I do not believe that doing so will materially hinder understanding of my judgment. As to paragraph 166, see my comments above relating to the September 2008 draft application. As to paragraph 167, the passages sought to be redacted compare the September 2008 draft application (as to which see above) to documents which are not said to be confidential and are addressed elsewhere in my judgment or relate to mechanics. I note that no privilege was claimed in the7 November 2008 email in any event. The decision on paragraph 172 flows from the above. The12 November 2008 call 173. On12 November 2008 Dr Porter called Dr Nicholls. Dr Nicholls’ manuscript notes of the conversation were disclosed, as was his file note. The file note records that Dr Porter had called to update him following a TGL meeting on 10 November and goes on to say: “In regards to the second patent application (improved expression cassette; our ref: N.106698), he indicated that Touchlight were particularly excited about this project. The process Touchlight have in mind is using a closed linear DNA molecule as a starting template, which would then be denatured and amplified, preferably by RCA. The denaturation step converts the closed linear molecule into a circular molecule, and so RCA can be used to amplify these circle forming long concatamers. The key point is that ProT can be used to resolve such concatamers directly without need for additional enzymes, as discussed in our5 November 2008 phone call. [xxx xxx xxx xxx xx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxxxx xxxxxxx xxxxx xxxxx xxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxxxx xxxxxxx xxxxx xxxxx xxxx xxx xxxx]” 174. The manuscript notes are consistent with the file note. They include “Linear DNA with telomeric ends as starting material … Heat -> converts doggybone -> circular molecule in cassette, have Pro T binding sites … [then do RCA via mech of 1st patent – long concatamers of original material] … Pro T resolves directly (no need for extra enzymes)”. 175. This is the first record of the idea of using doggybone DNA as a template for RCA and accordingly of the dbDNA Template Process. Dr Nicholls’ evidence was that this was, as far as he could recall, the first he had heard of this concept, and that is consistent with his contemporaneous notes. Rejected, save to the extent indicated below in relation to paragraph 173. The12 November 2008 call was also important to Touchlight’s case on the Timing Issue. Unless the public are able to see the key aspects of the notes and Dr Nicholls’ evidence they will not be able to understand my reasoning. Further, the technical matters referred to in the notes are to be found in the priority application. However, some of the quote in paragraph 173 consists of advice which it is not necessary to see in order to understand my reasoning. I will therefore redact the second paragraph of the quote after “phone call.”
“So the question we have to ask ourselves is if/when do we break it to Vanessa. As you rightly ask will she take it out on Neil or the company? My guess would be both (if she is still involved with the company then and if we have to disclose it to her).”
“(4) Temperatures - Only thermophilic step is amplification step b) - Ensure other steps can be non-thermophilic or thermophilic - NB doesn’t matter if temp is cooled after amplification as SSBPs prevent snap back of unmeshed concatamers – allude to this?”
“3. Non-thermophilic steps As explained in our meeting, claim 1 only requires a thermophilic amplification step. All other process steps can be carried out at any temperature. Also, the claim does not exclude the possibility of initial non-thermophilic and/or PCR-type steps. I will ensure that the description provides a disclosure that all steps other than amplification step b) may be thermophilic or non-thermophilic, and a list of appropriate temperatures.” 261. It is also relevant to note that at this stage claim 14 was a product claim, to closed linear DNA having hairpin ends comprising telL and telR sites flanking a central double-stranded region. The handwritten notes record Dr Nicholls advising that [xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxx xxxxxxx xxx xxx xxx xxx xx xxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxxxx xxxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxxx xxxxxx xxxxxx xxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxxxx xxxxxx xxxxx xxxxx xxxxxx xxxxxxx xxxxxx] (original emphasis). Similarly, the letter advised that “claim 14 does not limit preparation of the product to a particular process; it covers the product made by any process. [xxxxxx xxxxxx xxxxxxxx xxxxxx xxxx xxxxx xxxxxx xxxxx xxxxxx xxxxx xxxxxxxx xxxxxxxx xxxxxx xxxxxxx xxxxx]” 262. It is clear from the handwritten notes that Dr Nicholls explained at the meeting on 27 October that the draft patent application was not limited to processes carried out wholly under thermophilic conditions. As mentioned above, Dr Hill said that she had not read the draft application before the meeting (which I have rejected) and that she was baffled and confused by some of the questions raised. The notes of the meeting indicate that she was engaged (and it appears from Dr Porter’s email of4 November 2008 that she came up with cassette designs at the meeting – see paragraph 163 above). Further, Dr Nicholls’ explanation that the draft application was not limited to wholly thermophilic processes was not a question, let alone one which could have baffled and confused Dr Hill. She also suggested that she had been confused because Dr Porter had told her on the way to the meeting that there would be broad-ranging discussions and that nothing was set in stone, but at the meeting she found that everything had been set in stone. In fact, it is clear from the notes of the meeting that things were not set in stone. In any event, that does not grapple with the point, which is about whether she understood Dr Nicholls’ explanations. I find that Dr Hill must have understood Dr Nicholls’ explanations, but even if she did not, TGL was entitled to assume that she had. 263. In any event, Dr Hill was sent the letter of 3 November which reiterated those explanations. Dr Hill suggested that she had not read it, but it is inherently unlikely that she would not have read such a letter on a topic of great importance to TGL. Further, on 4 November Dr Porter emailed Dr Nicholls to thank him for the meeting summary, saying “I have spoken to Vanessa and Jonny and we agree with your recommendation to separate the product and process claims and submit two separate patent applications. We shall now start to put together the additional information you have requested. As you pointed out, we need to put some additional thought into inventive steps related to the products. We’ll work on this and get back to you for opinion.”
“Vanessa has pointed out that, at present, our claims appear to cover only the use of a single DNA polymerase. …” 266. On12 December 2008 Dr Nicholls emailed Dr Porter, Dr Hill and Mr Ohlson a finalised version of the same application and a covering letter asking for comments and for agreement to place it on hold pending completion of the second application. Again Dr Hill suggested that she would not have read these documents. This time there is no documentary indication that she did what would have been expected of her, but in any event TGL was entitled to assume that she had. 267. On18 December 2008 Dr Nicholls emailed Dr Porter, Dr Hill and Mr Ohlson to say that he had been reviewing material provided by Dr Porter (including cassette designs based on Dr Hill’s November 2008 slide deck) and suggesting that, to assist drafting and save costs, Dr Porter and Dr Hill might prepare some descriptive text for the second application. Following discussion with Dr Hill, Dr Porter sent a draft to Dr Nicholls on7 January 2009 . Dr Nicholls then sent a draft application entitled “Production of Closed Linear DNA” to Dr Porter, Dr Hill and Mr Ohlson on16 January 2009 , together with a covering letter. The letter explained (original emphasis): “As suggested, the application is now focussed on a process for production of closed linear DNA that involves use of DNA polymerase and protelomerase in combination. … The proposed claims are broadly directed to amplification based on any DNA template comprising a protelomerase target sequence, using any DNA polymerase, and a subsequent processing step for the amplified DNA using any protelomerase. Please let me have your comments on this proposed claim scope. …”
“As I am a Director and the major share holder of [TGL], it is obviously in my interests that the company does well. It is also obvious that I should want to that see that my original, lifetimes work is being furthered in the best manner possible for this company’s interests.”
“As the patent lawyers have advised, [xxxxx xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxxx xxxxxxx xxxxxx xxxxxx xxxxx]”
“A PCT application for patent 2 entitled "Production of closed linear DNA" has been filed. We believe that all the claims in this patent have been substantiated by scientific data developed between May and December 2009. The patent application covers widest range of physical conditions for carrying out the process including temperature. Our patent attorneys inform us that Dr Vanessa Hill has been declared as the only inventor on the PCT application. The application will be published in six months time (six months from the31st January 2010 ).”