Hospira UK Ltd v Genentech Inc

In this action the Claimant (“Hospira”) seeks revocation of the Defendant’s (“Genentech’s”) European Patent (UK) No. 1 037 926 (“the Patent”). The Patent relates to the use of trastuzumab in combination with a taxane for the treatment of HER2-positive breast cancer. HER2 (also referred to as ErbB2, among other names) is a gene the overexpression of which is associated with a particularly aggressive form of breast cancer. Trastuzumab, which is marketed by Genentech under the trade mark Herceptin, is a humanised anti-HER2 monoclonal antibody. The taxanes (also referred to as “taxoids”) are a class of chemotherapeutic agents which include paclitaxel (marketed by Bristol Myers-Squibb under the trade mark Taxol) and docetaxel (marketed by Sanofi-Aventis under the trade mark Taxotere).

There is no challenge to the claimed priority date of the Patent of 12 December 1997. The only grounds of invalidity relied on by Hospira are that the claims lack novelty, alternatively an inventive step, in the light of a single item of prior art, namely Baselga et al, “HER2 Overexpression and Paclitaxel Sensitivity in Breast Cancer: Therapeutic Implications”, Oncology, 11, Supp. 2, 43-48 (March 1997) (“Baselga 97”). Baselga 97 describes, among other things, a Phase III trial of trastuzumab in combinations with paclitaxel and other agents, but does not disclose any results from that trial.

The Patent contains a summary of the results of the trial, which show that trastuzumab in combination with paclitaxel yields a substantial increase in time to disease progression and tumour response rates in HER2-positive metastatic breast cancer patients compared to paclitaxel alone. It also shows that the combination of trastuzumab and paclitaxel achieves those clinical benefits without a significant increase in severe adverse events, and in particular without the cardiac side effects that are observed when trastuzumab is combined with anthracyclines.

The results contained in the Patent were first publicly presented at the American Society for Clinical Oncology (“ASCO”) meeting in Los Angeles in May 1998, where they generated considerable excitement. They led to the approval of Herceptin as a first line treatment for HER2-positive breast cancer in combination with paclitaxel by the United States Food and Drug Administration on 25 September 1998. This was followed by approval in Switzerland on 29 July 1999 and in the European Union on 28 August 2000. Herceptin is now the standard of care worldwide for the majority of patients with HER2-positive breast cancer, and is usually given in combination with a taxane. It has transformed the treatment of HER2-positive breast cancer and has been a hugely successful product.

Hospira has not challenged the validity of the basic patent for the amino acid sequence of Herceptin (European Patent No. 0 590 058) or its associated Supplementary Protection Certificate (SPC/GB04/015). The SPC expired on 29 July 2014. Now that Genentech’s basic monopoly has expired, Hospira wishes to market biosimilar trastuzumab. Hospira has therefore brought a series of actions to clear the way by revoking a number of other patents owned by Genentech relating to trastuzumab.

The first action related to three patents for various inventions, one of which Genentech surrendered before trial. The other two were held to be invalid by Birss J following a trial in March 2014 ([2014] EWHC 1094 (Pat)). Genentech appealed the decision in respect of one of those patents. The appeal was heard by the Court of Appeal in January 2015 and dismissed ([2015] EWCA Civ 57).

The second action related to two patents for lyophilised formulations of trastuzumab, both of which were held to be invalid by Birss J following a trial in October 2014 ([2014] EWHC 3857 (Pat)). Genentech has appealed that decision, and the appeal is currently pending.

The Examining Division of the European Patent Office refused to grant the Patent, holding that it would lack novelty over Baselga 97, but that decision was reversed by the Technical Board of Appeal. As a result, the Patent was not granted until 15 January 2014. The Patent has been opposed at the EPO, but the opposition proceedings are at an early stage.

Hospira’s expert was Professor Hilary Calvert, who is Emeritus Professor of Cancer Therapeutics at the University College London (“UCL”) Cancer Institute. He obtained a degree in Medical Sciences and Mathematics from the University of Cambridge in 1969 and completed his clinical studies at UCL in 1972. Having held a number of clinical posts, he was Research Fellow at the Royal Marsden Hospital from 1975 to 1977, where he conducted clinical research into the chemotherapeutic treatment of cancers. From 1977 to 1989 he was successively Lecturer, Senior Lecturer and Reader in Clinical Pharmacology at the Institute for Cancer Research and Honorary Senior Registrar and then Honorary Consultant at the Royal Marsden. In 1981 he obtained an MD for research into antifolates and their application in cancer chemotherapy. From 1989 to 2009 he was Professor of Medical Oncology and Clinical Director of the Northern Institute for Cancer Research at the University of Newcastle upon Tyne and Honorary Consultant at the Northern Centre for Cancer Care. From 2009 until 2014 he was the Director of Cancer Drug Discovery and Development at UCL. He was also a Visiting Professor in the Department of Mathematics and Statistics at the University of Newcastle upon Tyne from 2009 to 2012.

Although Prof Calvert has specialised in ovarian cancer, he has maintained a clinical and research interest in breast cancer throughout his career. He was personally responsible for the diagnosis and treatment of breast cancer patients in 1991-1992. He has also led clinical trials in breast cancer (including at least one trial involving trastuzumab). He has 15 publications in the area of breast cancer to his credit, out of some 230. He was made a Fellow of the Royal College of Physicians in 1988 and has received a number of awards, including the British Oncological Association Lifetime Achievement Award in 2009 and the European Society of Medical Oncology Lifetime Achievement Award in 2010. He has served on numerous advisory and editorial boards and committees.

Counsel for Genentech accepted that Prof Calvert was an eminent scientist who had done his best to assist the court in his evidence. He submitted, however, that Prof Calvert’s expertise was not as relevant to this case as that of Genentech’s expert for three reasons. First, because he was not a breast cancer specialist. Secondly, because his involvement with trastuzumab was limited. Thirdly, because his research interests were focussed on the early stages of drug discovery and development.

In my judgment Prof Calvert was appropriately qualified to give expert evidence in this case. In particular, so far as the first two points are concerned, I am satisfied that Prof Calvert did have sufficient expertise in breast cancer and trastuzumab to assist the court with regard to the knowledge and perceptions of the person skilled in the art. So far as the third point is concerned, I do not accept that Prof Calvert’s research interests meant he did not have relevant expertise; but I do accept that they affected the way in which Prof Calvert saw matters, and that this is something which must be taken into account when assessing his evidence.

Genentech’s expert was Professor Peter Barrett-Lee, who is Professor of Oncology in the School of Medicine at Cardiff University and Medical Director and Consultant Clinical Oncologist at Velindre NHS Trust. He obtained a BSc in the History of Medicine from UCL in 1979 and an MBBS from Westminster Hospital Medical School in 1982. From 1982 to 1985 he was a Medical Registrar at Mayday Hospital, Croydon. From 1986 to 1989 he was a Research Fellow at St George’s Hospital, London. In 1990 he was awarded an MD for research into growth factor transcripts in breast cancer. He then trained for five years in both Radiotherapy and Medical Oncology at the Royal Marsden. Having obtained the Fellowship of the Royal College of Radiologists in 1991, he practised at the Meyerstein Institute of Clinical Oncology at UCL from 1991 to 1994 gaining further clinical experience, particularly in breast cancer. He was appointed as a Consultant at Velindre in 1994, and became Medical Director in 2000. Having been Honorary Professor since 2008, he was appointed as Professor in 2012. He was made a Fellow of the Royal College of Physicians in 1998. He has served on a number of advisory boards.

Prof Barrett-Lee has specialised in the fields of breast and skin cancer since his appointment at Velindre. His publications include two chapters on breast cancer in course books published in 2008 and 2014 as well as some 95 papers. His role at Velindre includes advising patients on all aspects of non-surgical treatment of breast cancer. He has also been involved in a number of clinical trials and research programmes, including ones involving trastuzumab, and he currently has the lead role for breast cancer clinical research and trials at the Velindre Cancer Centre and for the South East Wales Breast Research Network.

It is important to note that, in one small but significant respect, Prof Barrett-Lee was a witness of fact as well as an expert witness. This is because he was a principal investigator in the Phase III trial described in Baselga 97 and reported in the Patent. Before deciding to participate in the trial, he was sent Genentech’s Investigator’s Brochure which contained information equivalent to that in Baselga 97. Having considered that information, he decided to participate in the trial and to enrol patients in it. I shall return to this point below.

Counsel for Hospira accepted that Prof Barrett-Lee was a well-qualified expert who had tried to assist the court, but nevertheless submitted that he had been inconsistent in some of his evidence. I do not consider that there was any significant inconsistency in Prof Barrett-Lee’s evidence, but I do think there was some tension between different aspects of his evidence in places. I have taken this into account in assessing his evidence.

The specification sets out the background to the invention at [0002]-[0012]. The HER2 gene (referred to by its alternative name of ErbB2), the protein it encodes (p185^HER2) and its role in breast cancer are introduced at [0002]-[0003]. At [0004]-[0010] the specification describes various anti-HER2 antibodies which have been produced, and the results obtained with such antibodies in in vitro and in vivo studies, including the murine 4D5 antibody. At [0011] the specification introduces Herceptin, which is a humanised version of the 4D5 antibody, and says that it has been clinically active in patients with HER2-positive breast cancer that had received extensive prior anti-cancer therapy (citing Baselga et al, “Phase II Study of Weekly Intravenous Recombinant Humanized Anti-p185^HER2 Monoclonal Antibody in Patients With HER2/neu-Overexpressing Metastatic Breast Cancer”, J. Clin. Oncol., 14, 737-744 (1996) (“Baselga 96”)).

At [0012] the specification notes that HER2 overexpression is commonly regarded as a predictor of a poor prognosis. It goes on to say that the odds of HER2-positive patients responding clinically to treatment with taxanes are three times those of HER2-negative patients (citing Baselga 97) and that Herceptin has been shown to enhance the activity of paclitaxel and doxorubicin against xenografts in mice injected with HER2-overexpressing human breast carcinoma cells (citing an abstract by Baselga et al from ASCO 1994, “Baselga 94”).

The specification summarises the invention at [00013]-[0018]. This section begins at [0013]:

“The present invention concerns the treatment of disorders characterised by overexpression of ErbB2, and is based on the recognition that while treatment with anti-ErbB2 antibodies markedly enhances the clinical benefit of the use of chemotherapeutic agents in general, a syndrome of myocardial dysfunction that has been observed as a side-effect of anthracycline derivatives is increased by the administration of anti-ErbB2 antibodies.”

After describing the figures at [0019], the specification sets out a series of definitions at [0020]-[0060]. None of these matter for present purposes, but it should be noted that the Patent uses the terms “HER2” and “ErbB2” and the terms “taxane” and “taxoid” interchangeably.

The specification goes on to describe the production of anti-HER2 antibodies at [0061]-[0115], pharmaceutical formulations at [0116]-[0120], treatment with the anti-HER2 antibodies at [0121]-[0126], articles of manufacture at [0127] and the deposit of materials at [0128]. Again, none of these details matter for present purposes, but it should be noted that it is made clear at [0122] that the treatment involves the combined administration of an anti-HER2 antibody and a taxane in the absence of an anthracycline.

The specification then describes an Example at [0130]-[0150]. This section begins by describing the production of Herceptin and some previous results obtained using it at [0130]-[0131]. The clinical trial protocol is then described at [0132]-[0147]. The patient eligibility and exclusion criteria are set out in [0132]-[0135]. The specification reports at [0136] that 469 patients were enrolled and randomised into two groups of equal size – those that were to receive Herceptin and chemotherapy and those that were to receive only chemotherapy. The dosage regimen used for Herceptin is set out in [0137], and the chemotherapy regimen is described at [0138]-[0141]. If patients had not received prior anthracycline therapy in the adjuvant setting (i.e. post-surgery), they were given cyclophosphamide and an anthracycline (doxorubicin or epirubicin). If they had received anthracycline in the adjuvant setting, they were given paclitaxel. Details of the dosage regimens are then provided. The specification goes on at [0142]-[0147] to explain the criteria for assessing response to therapy, including response rates (RR) and time to progression (TTP) (as to which, see below).

The results from the clinical trial are reported and commented on at [0148]-[0151]. The specification states at [0148] that assessment of TTP and response rates (RR) showed a “significant augmentation of the chemotherapeutic effect by Herceptin, without increase in overall severe adverse effects (AE)”. It then sets out the following results:

These results show that:

The specification also states at [0149] that a syndrome of myocardial dysfunction was observed much more commonly in the AC + Herceptin arm (18% Grade 3/4) as opposed to the other arms (between 0 and 3%). It is common ground that the skilled reader would regard the incidence of this adverse event in the AC + Herceptin arm as unacceptable, but the incidence in the paclitaxel + Herceptin arm would be regarded as acceptable.

The specification concludes at [0150]:

“These data indicate that the combination of anti-ErbB2 antibody treatment with chemotherapy markedly increases the clinical benefit, as assessed by response rates and the evaluation of disease progression. However, due to the increased cardiac side-effects of doxorubicin or epirubicin, the combined use of anthracyclines with anti-ErbB2 antibody therapy is contraindicated. The results, taking into account risk and benefit, favor the combined treatment with HERCEPTIN® and paclitaxel (TAXOL®).”

The claims are in two groups, those in Swiss (purpose-limited process) form and those in EPC 2000 (purpose-limited product) form. Claim 1 is as follows (broken down into integers for convenience):

“[1] Use of an anti-ErbB2 antibody in the preparation of a medicament

[2] for treatment to provide clinical benefit as measured by increased time to disease progression of malignant breast cancer characterised by overexpression of ErbB2 in a human patient,

[3] wherein said antibody binds to epitope 4D5 within the ErbB2 extracellular domain sequence as determined by a cross-blocking assay using said antibody and antibody 4D5 obtainable from deposit ATCC CRL 10463,

[4] and wherein the method comprises combined administration of the antibody with a chemotherapeutic agent which is a taxoid and not in combination with an anthracycline derivative,

[5] wherein the combined administration has:

[a] clinical efficacy as measured by determining time to disease progression and

[b] reduced myocardial dysfunction compared with combined administration of the antibody and anthracycline derivatives.”

Claim 10 is the corresponding EPC 2000 claim. Claims 2-9 and 11-18 are matching sets of dependent claims. It is unnecessary to consider these, since Genentech did not argue that any of the dependent claims were independently valid over claims 1 and 10 in closing submissions for the purposes of obviousness (it contended that claims 9 and 18 were independently valid for novelty purposes, but for reasons that will appear this question does not arise). Nor did either side argue that there was any distinction which was relevant to the issues in this case between claim 1 and claim 10. Accordingly, I shall focus on claim 1.

A patent specification is addressed to those likely to have a practical interest in the subject matter of the invention, and such persons are those with practical knowledge and experience of the kind of work in which the invention is intended to be used. The addressee comes to a reading of the specification with the common general knowledge of persons skilled in the relevant art, and he (or she) reads it knowing that its purpose is to describe and demarcate an invention. He is unimaginative and has no inventive capacity. In some cases, such as the present one, the patent may be addressed to a team of persons having different skills.

In the present case it is common ground that the Patent is addressed to a skilled person who is a clinical or medical oncologist specialising in breast cancer and who has a research interest. It is also common ground that he would need to be able to assess preclinical studies, both in vitro in cell cultures and in vivo in animal models, and data from Phase I and Phase II clinical trials. It is also common ground that, when it came to implementing the invention described in the Patent, the oncologist would need to obtain the assistance of others to select, humanise, purify and formulate an anti-HER2 antibody.

There is a minor difference between the parties and their respective experts as to the precise nature of the oncologist’s research interest. Hospira contend that the oncologist would have expertise in drug discovery and development, whereas Genentech contend that this need not be the case. I agree with Genentech on this point, but I agree with Hospira that this makes little difference to the assessment of obviousness.

I reviewed the law as to common general knowledge in KCI Licensing Inc v Smith & Nephew plc [2010] EWHC 1487 (Pat), [2010] FSR 31 at [105]-[115]. That statement of the law was approved by the Court of Appeal [2010] EWCA Civ 1260, [2011] FSR 8 at [6].

There is much common ground between the parties with regard to the skilled person’s common general knowledge, and in particular with regard to what facts were common general knowledge. There are nevertheless various differences of emphasis and nuance between the parties, particularly with regard to the perceptions of the skilled person. Only in relation to one topic, namely xenografts, is there real disagreement. In these circumstances, I do not intend to set out the parties’ rival contentions with regard to the other topics, or the evidence upon which they relied, but simply my findings as to the matters which were common general knowledge.

The taxanes, and in particular paclitaxel and docetaxel, were known to be effective chemotherapeutic agents for the treatment of breast cancer. Paclitaxel and docetaxel were both widely used for this purpose. Like other kinds of chemotherapeutic drugs, taxanes were known to have side effects, the most important being neutropenia. The taxanes were considered to be less cardiotoxic than doxorubicin and epirubicin, however. It was known that combined therapies involving paclitaxel and docetaxel were under investigation.

It was known that various antibodies were in clinical trials for the treatment of cancer, but few had been approved. Previously there had been concern as to the ability of antibodies to penetrate solid tumours, but this was starting to dissipate.

HER2 overexpression was known to be a marker for poor prognosis in breast cancer patients, particularly if the cancer was metastatic, and there was increasing evidence that HER2 was involved in the pathogenesis and clinical aggressiveness of overexpressing tumours. New and effective treatments for such patients were badly wanted. No HER2-specific therapy had been approved at the priority date, but HER2 was thought to be suitable for treatment with an antibody, because:

The evaluation and use of combination therapy, i.e. administering combinations of different drugs, was common. The idea behind combination therapy is to kill the cancer cells to the greatest extent possible in a single course of treatment by using different agents with differing methods of action and minimal overlap in toxicity profiles. In some instances combination therapy turned out not to provide any additional benefit, but these examples did not detract from the general understanding that a logical combination of two drugs which were individually effective, which were directed at different targets and which did not have significantly overlapping toxicity would be expected to have greater efficacy than either drug individually. It was standard practice to start to experiment with combinations even before a licence was obtained for monotherapy with a new agent.

Mouse xenograft studies involve athymic (i.e. immunocompromised) mice which have been injected with cells from human cancer lines. As a result of the disablement of the mice’s immune systems, these cells are able to grow in the mice and form “human” tumours. By administering an experimental agent to the mice, the effect of the agent on the growth of the tumours can be investigated.

There is disagreement between the parties as to how reliable positive results in mouse xenograft studies were perceived to be as predictors of efficacy in humans. Genentech contend that mouse xenograft data were recognised to be unreliable, whereas Hospira contend that they were universally used to judge whether to progress a drug to clinical trials and were a good model for testing drug interactions. In my judgment the evidence demonstrates that both parties are correct.

As Prof Barrett-Lee explained, mouse xenograft models had a number of well-recognised shortcomings, in particular the fact that the rest of the biological system was murine and that the mice did not have functioning immune systems. As a result, as he put it, “it was well-known that mouse xenografts were not always reliable predictors of clinical efficacy in humans [my emphasis]”. Accordingly, he said, “evidence of activity [in mouse xenografts] provided little assurance that the agent would ultimately demonstrate clinical efficacy in humans [my emphasis]”. Prof Calvert agreed that mouse xenograft models did not always predict efficacy accurately. He insisted, however, that they were universally used to decide to whether to take drugs forward. Prof Calvert also said that they were a good model for testing drug interactions. I did not understand Prof Barrett-Lee to dispute these points, subject to his overriding point that mouse xenograft models were not considered to be reliable predictors of clinical efficacy in humans.

The standard pattern for the development of a new drug, or combination of drugs, is that, if it shows promise in preclinical studies, it will pass sequentially through the various phases of clinical trials in turn. In general, therefore, the normal process would be to test the drug or combination in Phase II before proceeding to Phase III, to reduce the chance of failure.

The purpose of Phase I trials is principally for testing safety and dose ranging. They involve very small numbers of patients with (in oncology) refractory metastatic disease.

Phase II trials are typically single arm studies looking for initial indications of therapeutic activity, as well as to further define safety and in some cases to refine the dosing or administration schedule. In oncology, they also involve patients with refractory metastatic disease. A Phase II study would typically involve about 50 patients, although it can involve more. Because of the small patient numbers, the confidence intervals are wide. A single result can skew the data, and one has to be careful about over-interpreting observations in single patients.

In Phase II trials the usual endpoint was response rate rather than time-to-event outcomes (as to which, see below). It was generally accepted that spontaneous remissions of cancers in these patient groups was very rare, so that even in single armed trials an observed effect could be presumed to be related to the action of the therapy.

The results of Phase II trials provide an incentive or disincentive to enter into Phase III. Drugs which show higher response rates in Phase II trials are more likely to be taken forwards into Phase III (and would be perceived to be less likely to fail for efficacy reasons).

Phase III trials involve hundreds, if not thousands, of patients. They are randomised controlled studies with at least two arms comparing the efficacy of the agent or combination with that of existing therapies.

There were four clinical endpoints, one of which would have been selected as the primary outcome to be observed in clinical trials at the priority date. Prof Calvert described them in the following way at paragraph 4.31 of his first report (as subsequently corrected):

“(a)

Overall survival (OS) – the percentage of patients alive at a defined time after initiation of the treatment, often reported as a five year survival rate;

(b)

Progression free survival (PFS) – the proportion of patients who continue to live with a disease that is not getting worse;

(c)

Time to disease progression (TTP) – time from diagnosis or start of treatment until tumour progression, not including death; and

(d)

Response rate (RR) – measures tumour size to give an indication of whether the tumour is responding to a treatment, which includes:

(i)

Complete response (CR) – disappearance of all clinical evidence of disease;

(ii)

Partial response (PR) – at least a 50% reduction in two perpendicular dimensions of the size of all measurable tumours;

(iii)

Stable disease (SD) – tumour size remains the same or which increases/shrinks by less than 20-25% to take into account measurement errors and/or insignificant changes; and

(iv)

Progressive disease (PD) – proportion of patients with a greater than 25% increase in tumour size relative to the smallest measured size of the tumour.”

Whilst overall survival was (and is) the “gold standard”, difficulties in measuring it (especially given the timescale) led to reliance upon the other endpoints as measures of efficacy. The skilled person would be aware that TTP and response rates represent different aspects of the disease process which are not necessarily directly correlated.

The skilled person would be aware that, strictly speaking, it is not possible to compare response rates in different trials. Nevertheless, the skilled person would have considered that a positive response rate for Phase II in metastatic breast cancer patients was in the region of 20 – 40%. The skilled person would expect lower response rate in patients who had already been treated with chemotherapeutic agents than in patients who had not.

It was well known that, for a variety of reasons, there was quite a high failure rate of drugs in clinical trials. It was also well known that they failed at each stage: drugs which seemed promising in preclinical studies were sometimes found to be too toxic in Phase I trials, drugs which passed Phase I sometimes did not give evidence of activity in Phase II and drugs which appeared efficacious in Phase II sometimes failed Phase III e.g. because they were no better than existing treatments. This was despite the fact that there would always be a rationale for the trial of the drug. The skilled person would not have known of any precise statistics for the failure rates at each stage. In general, the further advanced the drug was in development, the greater would be the expectation that the drug would ultimately prove safe and efficacious, but it was appreciated that (for example) there was no guarantee of a successful result in a Phase III trial.

Unusually, there is relatively little dispute as to the construction of claim 1. There are nevertheless three important points to note.

First, it is common ground that the requirement for “clinical benefit” in integer [2] (and “clinical efficacy” in integer [5][a]) of claim 1 is a functional technical feature of the claim, i.e. the actual attaining of the clinical benefit is a technical feature of the claimed invention: see G2/88 Mobil Oil Corp/Friction reducing additives [1990] EPOR 73 at [9], T609/02 Salk Institute for Biological Studies/AP-1 complex (unreported, 27 October 2004) at [9] and Regeneron Pharmaceuticals Inc v Genentech Inc [2013] EWCA Civ 93, [2013] RPC 28 at [56] (Kitchin LJ).

There is a dispute, however, as to the effect of the words “as measured by increased time to disease progression” in integer [2] (and “as measured by determining time to disease progression” in integer [5][a]). Genentech contends that this means that the clinical benefit must be manifested in increased TTP compared to that arising from administration of the taxane alone. Genentech argues that this is made clear by the summary of the invention in [0013] and by the results in the Example.

Hospira accepts that the claim requires that the combination of antibody and taxane be more effective than the taxane alone, but it disputes that the claim requires an increase in TTP. Hospira argues that TTP provides a measure of clinical efficacy, but the skilled reader would appreciate that TTP was not the only measure of clinical efficacy, it just happened to be the one used in the Example. Thus the skilled reader would not consider it essential that there be an increase in TTP provided that there was an increase in clinical efficacy (say as measured by overall survival).

The difference between these two positions is narrower than might appear to be the case, because Genentech accepts that it may not be necessary to have an actual measurement of TTP in order to establish that this feature of the claim is satisfied if in the circumstances the skilled person could properly infer an increase in TTP from another measurement. Furthermore, it is common ground that the claim does not require any specific level of increase.

In my judgment Genentech’s construction is the correct one. Integer [2] explicitly requires clinical benefit “as measured by increased time to progression”. Similarly integer [5][a] explicitly requires clinical efficacy “as measured by determining time to disease progression”. This wording is clear. Furthermore, the skilled reader would notice that, in the Example, an improvement is reported both in TTP and in response rate, yet the claim only refers to the former. As noted above, the skilled reader would be aware that TTP and response rates represent different aspects of the disease process which are not necessarily directly correlated. Thus the skilled reader would understand that the patentee had chosen TTP as the applicable criterion for the purpose of the claim.

Secondly, Hospira contends that the requirement for reduced myocardial dysfunction compared to the combination of the antibody and anthracyclines in integer [5][b] is not a functional technical feature of the claim, but a negative feature of disclaimed subject matter. Counsel for Genentech did not take issue with this contention, perhaps because it does not appear to matter to the issues on novelty and obviousness.

Thirdly, it is common ground that the word “for” in integer [2] imports a mental element, namely that it is known to, or reasonably foreseeable by, the manufacturer of the medicament that the antibody will be intentionally administered in combination with a taxane for the relevant therapeutic purpose: see Warner-Lambert Co LLC v Actavis Group PTC EHF [2015] EWCA Civ 556 at [118]-[129] (Floyd LJ).

There is a dispute, however, as to precisely what the relevant therapeutic purpose is. Hospira accepts that the person administering the combination must intend to treat patients with HER2-positive breast cancer, but contends that he does not have to be certain of success because the combination is not 100% effective. Genentech contends that the person administering the combination must intend to achieve the clinical benefit required by the claim, i.e. increased efficacy compared to the taxane alone. In my judgment Genentech is correct about this.

Baselga 97 is a review article published by four authors, two of whom were well-known figures in the field based at the Memorial Sloan-Kettering Cancer Center (“MSK”) in New York, nine months before the priority date of the Patent. Since the disclosure of Baselga 97 is central to the issues in the case, I must describe it in some detail. I shall do under the same headings and sub-headings as Baselga 97. Before doing so, it is convenient to note two points, neither of which is in dispute. The first is that the skilled reader would appreciate that much of the work described in Baselga 97 related to Genentech’s development of trastuzumab. The second is that the skilled reader who was interested in Baselga 97 would be likely to follow up a few of the key references, and in particular Baselga 96.

The introductory section discusses the taxanes, and in particular paclitaxel, noting that “paclitaxel has been shown to have a high degree of antitumor activity in women with metastatic breast cancer” (page 43 left-hand column). This section concludes (at page 43 left-hand to middle columns):

“An area of increasing interest in clinical research on taxanes is the possible role of oncogenes, such as HER2, in determining clinical response to paclitaxel. Studies have examined whether strategies can be designed to increase the agent’s efficacy (or curb resistance to it) in breast cancers that overexpress HER2. Available data that will be presented in this review suggest that HER2 overexpression may influence the response to paclitaxel in patients with metastatic breast cancer and that anti-HER2 monoclonal antibodies significantly increase the antitumour activity of paclitaxel in vitro and in vivo.”

This section of the paper starts by explaining the role of HER2 in breast cancer.

Role of Monoclonal antibodies. This sub-section begins by saying that “Several lines of evidence support a direct role for HER2 in the pathogenesis and clinical aggressiveness of overexpressing tumors”. After summarising five such lines, the paper introduces the murine antibody 4D5, which is said to be “a potent inhibitor of in vitro growth and, in xenograft models, of human breast cancer cells overexpressing HER2”. It then introduces its humanised version rhuMoAb HER2 (i.e. trastuzumab), which it says “was found to be safe and to have dose-dependent pharmacokinetics in two prior phase I clinical trials” (all quotations page 44 left-hand column).

HER2 Overexpression as a Predictor of Response to Taxanes. This sub-section notes attempts to ascertain whether HER2 overexpression is a predictor for response to systemic therapy.

Dose-Response Effects to Anthracyclines. This sub-section discusses the relationship between HER2 overexpression and anthracyclines. It concludes (at page 44 middle to right-hand columns):

“ … findings from the CALGB study suggest that there is a significant dose-response effect of adjuvant therapy with an anthracycline-containing regimen in patients with HER2 overexpression but not in patients with no or minimal HER2 expression. The group’s final conclusion was that HER2 overexpression may be a useful marker for identifying patients who are most likely to benefit from high doses of adjuvant doxorubicin-based chemotherapy.”

HER2 Overexpression and Taxane Sensitivity. This sub-section reports a study by MSK analysing the relationship between HER2 overexpression and responses to taxanes in patients with metastatic breast cancer. The study was a retrospective one which involved immunohistochemical analysis of archived tumour sections. Most of the patients had received paclitaxel, but some had received docetaxel. It was found that “[r]emarkably, 65.2% of patients with HER2-positive tumors responded vs. 35.5% of patients with HER2-negative tumors”. The conclusion drawn by the authors from this study, after adjusting the odds ratios for various factors, is as follows (at page 45 left-hand column):

“Thus, despite a positive correlation of HER2 expression and poor prognostic features, the odds of HER2-positive patients responding clinically to taxanes were greater than three times those of HER2-negative patients.”

Tentative Results With Polyclonal Antibody. This sub-section discusses results from a study with a polyclonal antibody.

Paclitaxel and the Signal Transduction Pathway. This sub-section begins (at page 45 left-hand to middle columns):

“The possible mechanisms underlying the interaction between HER2 overexpression and taxane sensitivity are unknown. Paclitaxel stabilizes microtubules, prevents tubulin depolymerization, and promotes tubulin bundling. In addition to this well-documented mechanism of action, some evidence suggests that paclitaxel activates key elements of the HER2 signal transduction pathway….”

After discussion of the evidence, the authors conclude (at page 45 middle to right-hand columns):

“The activation of the HER2 signal transduction pathway by paclitaxel could also result in activation of paclitaxel-induced apoptosis. [31] Thus, HER2 overexpression would provide an increased opportunity to enhance the cytotoxic effects of paclitaxel.”

This section begins (at page 45 right-hand column):

“As already mentioned, p185^HER2 represents a potential target for tumors that overexpress HER2. A novel approach that is currently being explored is the combined use of therapies directed at p185^HER2, such as MoAbs given alone or in combination with conventional chemotherapeutic agents, including paclitaxel.”

The authors go on to say (at page 45 right-hand column):

“In extensive studies conducted at Genentech, Inc, a clear relationship between the level of HER2 proto-oncogene expression and sensitivity to the growth-inhibitory effects of the antibodies was observed. [20,21,34]”

They then refer to studies in cell-lines which showed that the most potent growth inhibitory monoclonal antibody was 4D5, and to studies of 4D5 and its humanised version in the nude mouse xenograft model which found inhibition of tumour growth and eradication of well-established tumours.

A “Humanized” Antibody. This subsection describes a recent Phase II trial of trastuzumab as a single agent in 46 patients with metastatic breast carcinomas overexpressing HER2, most of whom had received extensive prior anticancer therapy. The results are reported as follows (at page 46 middle column):

“Toxicity was minimal, and no antibodies against rhuMoAb HER2 were detected in any patient. Objective responses were seen in 5 of the 43 evaluable patients: 1 complete remission and 4 partial remissions (overall response rate, 11.6%; 95% CI, 4.36% to 25.9%) Responses were observed in liver, mediastinum, lymph nodes, and chest wall lesions. Minor responses, seen in 2 patients, and stable disease, occurring in 14 patients, lasted for a median of 5.1 months. One patient is still in pathologically confirmed complete remission 72 months after starting therapy.

Thus, rhuMoAb HER2 is clinically active in patients who have metastatic breast cancers that overexpress HER2 and have received extensive prior therapy. A confirmatory study that will include 200 patients with less heavily pretreated metastatic disease is currently underway.”

The reference given for this work, reference [39], is Baselga 96. The reader who pursued the reference would find that it supported the summary given in Baselga 97.

Anti-HER MoAb Combined With Chemotherapy. This sub-section discusses some studies combining anti-HER2 antibodies and cisplatin. The authors report (at page 46 right-hand column):

“Slamon, in studies using MoAb 4D5, has demonstrated that 4D5 enhances sensitivity to cisplatin in cisplatin-resistant ovarian carcinoma cell lines. A possible mechanism is 4D5’s interference with the repair of cisplatin-induced DNA damage, thus promoting cisplatin cytotoxicity.[36]”

Paclitaxel/Doxorubicin/rhuMoAb HER2 Regimen. Although the heading and first sentence refer to rhuMoAb HER2, this sub-section describes studies using paclitaxel or doxorubicin in combination with 4D5 in cell culture and in nude mice xenografts. The authors report the results of the in vivo work as follows (at page 46 right-hand column):

“Therapy with MoAb 4D5 alone produced a 35% growth inhibition, and paclitaxel alone resulted in a 35% growth inhibition when compared with animals treated with a control MoAb. The treatment with paclitaxel plus 4D5 resulted in major antitumor activity, with 93% inhibition of growth. This result was markedly better than an equipotent dose of doxorubicin (10 mg/kg IP) and 4D5 (70% inhibition). In addition, paclitaxel combined with 4D5 resulted in the disappearance of well-established xenografts.[37]”

Reference 37 is an abstract by Baselga et al which appears to be equivalent to Baselga 94.

Cisplatin/rhuMoAb HER2 Therapy. This sub-section describes a Phase II study combining trastuzumab in combination with cisplatin in patients with breast carcinomas that overexpress p185^HER2 and a history of proven refractoriness to chemotherapy. The authors summarise the results as follows (at page 46 left-hand column):

“In this group of patients with expected cisplatin resistance, the observed response rate to the combined therapy was 25%, suggesting that the synergy observed in the laboratory was reproducible in the clinic. In addition, the combined therapy was no more toxic than cisplatin alone.”

Phase III Study of rhuMoAB HER2 Combined With Chemo. This sub-section begins (at page 47 left-hand column):

“Results from the phase II studies and the activity of rhuMoAb HER2 against xenografts when given in combination with doxorubicin and paclitaxel have been encouraging. These positive results have led to the design of a phase III multinational study of chemotherapy in combination with rhuMoAb HER2 in patients with HER2-overexpressing breast tumors who have not received prior chemotherapy for metastatic disease (Figure 2).”

This study, which is described as “ongoing”, is the study reported in the Patent. The majority of the features of the study reported in the Patent are described in the paper (treatment arms, patient characteristics, study end points etc). The paper explains that the “main goal” of the study is “to determine whether the addition of trastuzumab increases the time to disease progression compared with” the control group (page 47 left-hand column). This passage mistakenly describes the control group as “patients treated with antibody alone”, but the remainder of the text and Figure 2 makes clear that the control group is being given chemotherapy alone.

This section identifies some other possible new agents, and the authors state that once the activity of these agents has been defined “a logical next step would be to combine them with paclitaxel in vitro and in vivo” (page 47 middle column). The authors continue (at page 47 middle to right-hand columns):

“It is likely that these agents may be able to increase the antitumour activity of paclitaxel in a similar fashion to that observed with anti-HER2 antibodies.”

The paper concludes (at page 47 right-hand column to page 48 left-hand column):

“The predictive value of HER2 overexpression for paclitaxel response requires independent confirmation in advanced disease and early breast cancer. This question could be addressed in ongoing studies of paclitaxel-based adjuvant therapy in breast cancer. In preclinical models, the combined therapy of breast cancer cells that overexpress HER2 with agents that interfere with HER2 function and paclitaxel results in a marked antitumor effect. One such strategy, the combination of anti-HER2 MoAb with paclitaxel, is currently being evaluated. If the results of these studies are positive, we might be faced with a novel paradox, in which expression of a receptor that confers a worse prognosis provides us with an opportunity for increased response to taxanes.”

In order for a claim in a patent to be valid, the claimed process or product must be novel. The leading English case on the law of novelty is the decision of the House of Lords in Synthon BV v SmithKline Beecham plc [2005] UKHL 59, [2006] RPC 10. As Lord Hoffmann, with whom the other members of the House agreed, made clear, there are two requirements for a claim to be deprived of novelty by the prior art, namely disclosure and enablement. For the purposes of the present case, it is only necessary to consider the first of these.

The arguments in this case require consideration of two questions in the law concerning disclosure. The first is what is required in order to anticipate a claim which includes a specified therapeutic effect. The second is what is required in order to anticipate a purpose-limited claim.

So far as the first question is concerned, it is now well established in the case law of the Boards of Appeal of the EPO that a prior disclosure of the existence of a clinical trial does not anticipate a claim which includes a specified therapeutic effect revealed by the (undisclosed) results of that clinical trial unless the therapeutic effect can be derived directly and unambiguously from the prior disclosure.

The first in this line of cases was T 158/96 Pfizer/Obsessive-compulsive disorder [1999] EPOR 285, where the claim was a Swiss form claim for the use of sertraline to treat OCD. The Board started by noting (at [3.1]) that the claim was to be construed as including the functional technical feature that sertraline achieved the claimed therapeutic effect. Accordingly, the Board went on to assess whether the prior art disclosed that therapeutic effect itself or a pharmacological effect directly and unambiguously underlying that therapeutic effect. The prior art disclosed that sertraline was undergoing Phase II trials for OCD (see [3.2]), but no results of those trials were reported (see [3.4]) and the skilled person could not conclude that the trials would be successful (see [3.4.1]). The skilled person would know that sertraline must have passed pre-clinical and Phase I trials in order to progress to Phase II. If one could conclude from this that sertraline must have demonstrated a clinical effect on OCD, or a pharmacological effect which directly and unambiguously underlay such a clinical effect, then the claim would lack novelty (see [3.5]). But on the facts of that case this could not be deduced, either from the fact that it had passed Phase I trials (see [3.5.1] – [3.5.2]) or from the fact that it had passed pre-clinical studies (see [3.6] – [3.6.2]).

This approach has been followed in T 715/03 Pfizer/Use of ziprasidone for treating Tourette’s syndrome (unreported, 16 January 2006) at [2.2] – [2.3], in T 385/07 Pharma Mar/Aplidine (unreported, 5 October 2007) at [3]-[9] and in T 734/12 Genentech/Arthritis patients with an inadequate response to a TNF-alpha inhibitor (unreported, 17 May 2013) at [23]. It has also been followed by the Board in its decision concerning the Patent, T 1859/08 Genentech/Anti-ErbB2 (unreported, 5 June 2012), which I will consider below.

T 158/96, T715/03, T 385/07 and T 1859/08 are all cited in the 7^th edition of the Case Law of the Boards of Appeal of the EPO at pages 105-106. Thus there can be no doubt that this line of cases represents the settled approach of the EPO. It follows that this Court should adopt the same approach unless convinced it is wrong: see e.g. Actavis UK Ltd v Merck & Co Inc [2008] EWCA Civ 444, [2008] RPC 26 at [45]-[48].

Furthermore, this approach has been followed in this jurisdiction. In Regeneron Pharmaceuticals Inc v Genentech Inc [2012] EWHC 657 (Pat) at [109]-[110] Floyd J (as he then was) accepted the submission that, to deprive a claim of this type of novelty, the prior disclosure must contain material from which one could directly and unambiguously deduce the claimed therapeutic effect. And in Hospira UK Ltd v Genentech Inc [2014] EWHC 1094 (Pat) Birss J said at [59] that:

“… such claims are generally regarded as novel over a mere proposal to administer the drug to patients in the manner claimed. That is because the mere proposal does not disclose that the treatment is indeed efficacious.”

Turning to the second question identified in paragraph 82 above, in Synthon Lord Hoffmann quoted earlier statements of the law by Lord Westbury LC in Hills v Evans (1862) 31 LJ Ch (NS) 457 at 463 and Sachs LJ in General Tire and Rubber Co v Firestone Tyre and Rubber Co Ltd [1972] RPC 457 at 485-486. He then said:

“22.

If I may summarise the effects of those two well-known statements, the matter relied upon as prior art must disclose subject-matter which, if performed, would necessarily result in an infringement of the patent. That may be because the prior art discloses the same invention. In that case, there will be no question that performance of the earlier invention would infringe and usually it will be apparent to someone who is aware of both the prior art and the patent that it will do so. But patent infringement does not require that one should be aware that one is infringing: ‘whether or not a person is working [an]… invention is an objective fact independent of what he knows or thinks about what he is doing’: Merrell Dow Pharmaceuticals Inc v H N Norton & Co Ltd [1996] RPC 76, 90. It follows that, whether or not it would be apparent to anyone at the time, whenever subject-matter described in the prior disclosure is capable of being performed and is such that, if performed, it must result in the patent being infringed, the disclosure condition is satisfied. ...

23.

Thus, in Merrell Dow, the ingestion of terfenadine by hay-fever sufferers, which was the subject of prior disclosure, necessarily entailed the making of the patented acid metabolite in their livers. It was therefore an anticipation of the acid metabolite, even though no one was aware that it was being made or even that it existed. But the infringement must be not merely a possible or even likely consequence of performing the invention disclosed by the prior disclosure. It must be necessarily entailed. …

24.

Although it is sometimes said that there are two forms of anticipatory disclosure: a disclosure of the patented invention itself and a disclosure of an invention which, if performed, would necessarily infringe the patented invention (see, for example, Laddie J. in Inhale Therapeutic Systems Inc v Quadrant Healthcare Plc [2002] R.P.C. 21 at [43]) they are both aspects of a single principle, namely that anticipation requires prior disclosure of subject-matter which, when performed, must necessarily infringe the patented invention.”

It should be noted that Synthon concerned an ordinary product claim, by which I mean a claim to a product which is not purpose-limited.

Lord Hoffmann also gave the leading speech, with which the other members of the House of Lords agreed, in Merrell Dow Pharmaceuticals Inc v H N Norton & Co Ltd [1996] RPC 76. In his speech in Merrell Dow, Lord Hoffman observed (at 86):

“… a gap has opened between the tests for infringement and anticipation. Acts done secretly or without knowledge of the relevant facts, which would amount to infringements after the grant of the patent, will not count as anticipations before.”

Immediately after the statement which he later quoted in Synthon, Lord Hoffmann added (at 90-91):

“(The position may be different when the invention is a use for a product; in such a case, a person may only be working the invention when he is using it for the patented purpose: see the discussion of the MOBIL/Friction reducing additive case in the next section.)”

Later in his speech, Lord Hoffman discussed the MOBIL/Friction reducing additive case, and said this (at 92-93):

“The Enlarged Board said …:

‘… under Article 54(2) EPC the question to be decided is what has been “made available” to the public: the question is not what may have been “inherent” in what was made available (by a prior written description, or in what has previously been used (prior use), for example). Under the EPC, a hidden or secret use, because it has not been made available to the public, is not a ground of objection to [the] validity of a European patent.’

My Lords, I do not think that this principle is in issue in this appeal. I have accepted it fully in the discussion of anticipation by use ... It was applied by the Technical Board of Appeal to the facts of MOBIL/Friction reducing additive when that case went back to the Technical Board of Appeal after the decision in principle by the Enlarged Board: see [1990] E.P.O.R. 514. The Technical Board decided that so far as friction reduction had been an inevitable concomitant of the use of the additive for other purposes, it was a case of uninformative use like Bristol-Myers Co. (Johnson's) Application. Or to put the same thing in another way, a description of the product by its chemical composition or as ‘something in the lubricating oil which inhibits rust formation’ or any other of the descriptions under which it was previously known would not enable anyone to use it for the purpose of reducing friction, even though this would be the inevitable consequence of doing so. It did not therefore prevent the invention in the form sanctioned by the Enlarged Board from being novel.”

Lord Hoffmann’s reasoning in the passages from Merrell Dow cited above has recently been applied by Floyd LJ when considering the mental element of Swiss form claims in Warner-Lambert v Actavis:

“121.

Thus the skilled person would understand that the technical subject matter of the claim was concerned with the ultimate end use of the medicament, from which it derived its novelty. The therapeutic treatment is of course new because, and only because, it is carried out with the intention of producing the new therapeutic effect. The prior use of the compound may have in fact produced the effect ... This demonstrates, to my mind, that it is the intention for which the compound is administered which is at the heart of the invention.

…

124.

… If a product is ‘for’ a particular therapeutic indication if it is reasonably foreseeable that it will be used intentionally for the treatment of pain, then it will not be rendered lacking in novelty by showing that products in the prior art had been manufactured in circumstances when it was not possible to foresee such a result.

125.

Mr Speck [argued] that no-one should be prevented by the grant of a patent from doing that which they did, or could have done, before. He called this the ‘golden thread’ of English patent law. That principle is not, however, an entirely reliable one. It was relied on in Merrell Dow (supra) to suggest that the patent was invalid because it would have the effect of restraining the continuance of the prior use. The principle was ineffective there because the old use itself was ‘uninformative’. At pages 86-87 Lord Hoffmann recognised that a gap had opened up under the 1977 Act between anticipation and infringement. The present case is another situation in which one cannot rely on the principle, because the subject matter of the invention is concerned with the purpose of acts which are in themselves no different from those which were done before. In any case it is not correct that the patent can prevent that which was done before. It was not possible before the patent was granted to foresee that the product would intentionally be used for treating pain.”

Hospira puts its case in both of the ways mentioned by Lord Hoffman in Synthon at [24]. It contends that Baselga 97 discloses the invention of claim 1, alternatively that Baselga 97 discloses subject-matter which, if performed, would necessarily infringe claim 1.

So far as the first way of putting its case is concerned, Hospira of course accepts that Baselga 97 does not disclose the results of the Phase III trial. Nevertheless, it contends that Baselga 97 contains other information from which the clinical benefit can be directly and unambiguously derived. In this regard, Hospira relies upon the whole disclosure of Baselga 97, but in particular upon three passages:

In my judgment these passages do not enable the clinical benefit claimed in the Patent to be directly and unambiguously derived. They do not disclose that the combination of trastuzumab and paclitaxel has increased efficacy in human beings compared to paclitaxel, and certainly not increased efficacy as measured by TTP. The xenograft results might give the skilled person some expectation that the Phase III trials would be successful (a question which I shall consider below), but they do not show that those trials will be successful.

Turning to the second way in which Hospira puts its case, Hospira points out that Baselga 97 fully and accurately discloses the design of the Phase III trial. All that is missing is the results. The Patent shows what the results of the trial were. Accordingly, Hospira contends that the inevitable result of following the directions in Baselga 97 is the carrying out of the claimed process.

In my view this way of putting the case is more persuasive than the first way. Nevertheless I am unable to accept it. The reason I am unable to accept it is because of the mental element in the claim. As counsel for Genentech submitted, one cannot intend to administer the combination of trastuzumab and a taxane to achieve increased efficacy in the treatment of breast cancer compared to the taxane alone unless one knows that that clinical benefit will be obtained.

The Examining Division had refused to grant the Patent on the ground that it lacked novelty over Baselga 97 (known in the EPO proceedings as D1). The Board started by saying (at [7]):

“…the intended medical use is the provision of a clinical benefit as measured by increased time to disease progression of malignant breast cancer characterised by overexpression of ErbB2 in a human patient, and wherein the method comprises combined administration of an anti-ErbB2 antibody with a taxoid to a human patient.

For the purpose of assessing novelty, it thus has to be examined whether or not the same therapeutic effect is directly and unambiguously derivable from a prior art document, upon using the same combination therapy in a human patient.”

The Examining Division had relied on the passage in Baselga 97 which disclosed the results of Herceptin and paclitaxel in the mouse xenograft model (see paragraph 75 above). But, as the Board said, these were not studies in humans (see [9]-[11]). The Examining Division had also relied on the passage in Baselga 97 which says that “a novel approach which is currently being explored is the combined use of therapies directed at [HER2], such as MoAbs given alone or in combination with conventional chemotherapeutic agents, including paclitaxel” (see paragraph 70 above). As to that, the Board said (at [13]-[14]):

“However, a mere statement that a combination therapy is being explored does not amount to a novelty-destroying disclosure of what is claimed in claim 1, because claim 1 is a medical use claim which includes, as a technical feature of the claim, the achievement of a clinical benefit in breast cancer patients as measured by an increased time to disease progression.

The present ‘currently being explored’ situation, where no clinical benefit is disclosed, falls within the rationale of decisions T 158/96 and T 715/03. According to those decisions, if a prior art document discloses clinical investigations such as phase I, II or III studies (or states that these investigations are ongoing), but the document fails to disclose the final result of these studies, this document is not novelty-destroying.

The examining division argued that by applying the combined therapy of D1, one would inherently come to the claimed effect, which could not render a known therapy novel.

However, decision G/88 … point 10.1 states: ‘Under Article 54(2) the question to be decided is what has been “made available” to the public: the question is not what may have been “inherent” in what was made available’. Therefore, while it may be true that the claimed effect is inherent once applying the claimed therapy, the decisive question to be answered by the board remains whether or not this effect was a ‘hidden’ one or was accessible to the skilled person before the priority date.”

The Board went on to deal with a further passage relied upon by the Examining Division, namely that describing the ongoing Phase III trial (see paragraphs 77-78 above). It first addressed a misunderstanding on the part of the Examining Division, which had wrongly believed that “results from the phase II studies” referred to in that passage had involved the combination of Herceptin and paclitaxel (see [16]-[20]). It then said (at [21]):

“As for the planned or ongoing phase III clinical trial, it cannot be derived directly and unambiguously from these trials … that a therapeutic effect is obtained, let alone one translating into an increased time to disease progression.

Moreover, since document D1 fails to disclose any encouraging phase II trial using an anti-ErbB2 antibody in combination with a taxoid, the rationale of decisions T 158/96 and T 715/03 applies also to the planned phase III clinical trial … which is not novelty-destroying for claims 1 and 10.”

Counsel for Hospira criticised this reasoning on three grounds. First, he submitted that the Board had been wrong to construe the claim as requiring increased TTP. I disagree with this for the reasons given above.

Secondly, he submitted that the Board had failed to take into account the three passages relied on by Hospira as discussed above. It is true that the Board did not consider whether these passages in combination disclosed the claimed clinical benefit, although it did consider the third passage. But I have concluded that they do not.

Thirdly, he submitted that the Board was wrong to reject the argument that the inevitable result of carrying out the Phase III trial would infringe the claim. I disagree with this for the reasons given above.

In order for a claim in a patent to be valid, the claimed process or product must not be obvious. The structured approach to the assessment of allegations of obviousness first articulated by the Court of Appeal in Windsurfing International Inc v Tabur Marine (Great Britain) Ltd [1985] RPC 59 was re-stated by Jacob LJ in Pozzoli v BDMO SA [2007] EWCA Civ 588, [2007] FSR 37 at [23] as follows:

“(1)(a) Identify the notional ‘person skilled in the art’;

(b)

Identify the relevant common general knowledge of that person;

(2)

Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;

(3)

Identify what, if any, differences exist between the matter cited as forming part of the ‘state of the art’ and the inventive concept of the claim or the claim as construed;

(4)

Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?”

The correct approach to the fourth step in a case such as the present was summarised by Kitchin LJ, with whom Lewison and Moore-Bick LJJ agreed, in MedImmune Ltd v Novartis Pharmaceuticals Ltd [2012] EWCA Civ 1234, [2012] RPC 27 as follows:

“90.

One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.

91.

For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way. Lord Hoffmann summarised the position in this way in Conor at [42]:

‘In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case.’

92.

Moreover, whether a route is obvious to try is only one of many considerations which it may be appropriate for the court to take into account. In Generics (UK) Ltd v H Lundbeck, [2008] EWCA Civ 311, [2008] RPC 19, at [24] and in Conor [2008] UKHL 49, [2008] RPC 28 at [42], Lord Hoffmann approved this statement of principle which I made at first instance in Lundbeck:

‘The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.’

93.

Ultimately the court has to evaluate all the relevant circumstances in order to answer a single and relatively simple question of fact: was it obvious to the skilled but unimaginative addressee to make a product or carry out a process falling within the claim….”

This approach has been followed and applied in a number of subsequent Court of Appeal and first instance decisions: see in particular Regeneron v Genentech in the Court of Appeal at [86] (Kitchin LJ).

Counsel for Genentech submitted that, in a case such as the present, the question was whether it was obvious that the product or process would achieve the claimed technical effect not whether it might. In support of this submission, he relied upon a number of passages in the opinion of Lord Hoffmann in Conor Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] UKHL 49, [2008] RPC 28. Before turning to those passages, it is necessary to put them in context. The issue in that case was as to the validity of claim 12 of the patent in suit. Claim 12 was to a stent coated with Taxol “for treating or preventing recurrent stenosis”. Lord Hoffmann construed this as meaning a Taxol-coated stent which was effective to prevent or treat restenosis (see [17], [20]-[22], [27], [36] and [39]). The key point which Lord Hoffmann made in his opinion was that the issue of obviousness was to be determined by reference to this claim (see [17]-[19]). As he explained, there was no allegation of insufficiency. Accordingly, there was no dispute that the skilled reader of the Patent could make a Taxol-coated stent which would in fact be effective to prevent or treat restenosis (see [13] and [23]-[25]).

Counsel for Genentech relied upon the following passages from Lord Hoffmann’s opinion (emphasis in the original):

“17.

… The alleged inventiveness lay in the claim that the product would have a particular property, namely, to prevent or treat restenosis. … So the question of obviousness was whether it was obvious to use a taxol-coated stent for this purpose. …

27.

… the teaching of the specification, so far as it supported claim 12, was that a taxol-coated stent would prevent or treat restenosis. …

28.

The question was whether that was obvious and not whether it was obvious that taxol (among many other products) might have this effect. …

40.

… the correct question [was] whether it was obvious to use a taxol-coated stent to prevent restenosis.”

I agree that, at first blush, these passages appear to support counsel’s submission. But there are other passages in the opinion which in my view demonstrate that this was not what Lord Hoffman meant. First, immediately after the sentence in [28] relied on by counsel for Genentech, Lord Hoffmann went on (my emphasis):

“It is hard to see how the notion that something is worth trying or might have some effect can be described as an invention in respect of which anyone would be entitled to a monopoly. It is therefore perhaps not surprising that the test for obviousness which Pumfrey J. devised for such an ‘invention’ was whether it was obvious to try it without any expectation of success. This oxymoronic concept has, so far as I know, no precedent in the law of patents.”

Secondly, the sentence in [40] relied on by counsel for Genentech needs to be read in context:

“40.

In the event, therefore, neither the judge nor the Court of Appeal answered what I consider to have been the correct question, namely, whether it was obvious to use a taxol-coated stent to prevent restenosis. One can however, deduce the answer which Pumfrey J. would have given to this question from the way in which he formulated the issue which he had to decide. It was, at the end of the passage I have quoted:

‘is the patent vulnerable only if it can be shown that the skilled person would have an expectation of success sufficient to induce him to incorporate taxol in a drug-eluting stent, or is it sufficient that without any expectation of success he would test or screen taxol?’

41.

The judge answered this question in the second sense, from which I think it can be inferred that he would have rejected the attack on the patent if he had answered it in the first and in my opinion correct sense. …”

Thirdly, Lord Hoffmann went on:

“42.

In the Court of Appeal, Jacob L.J. dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock L.J. in Johns-Manville Corporation's Patent [1967] R.P.C. 479, by saying that the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case. As Kitchin J. said in Generics (UK) Ltd v H Lundbeck A/S [2007] R.P.C. 32 para.72:

‘The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.’

43.

But Jacob L.J. rejected this approach (at para.48) on the grounds that ‘this is not an “obvious to try” case of the Johns-Manville type’ because ‘the patent has not in any way demonstrated that taxol actually works to prevent restenosis.’ I agree with the Dutch court that patent law does not require such a demonstration. It was not a sufficient reason for not applying the ordinary principles of obviousness to the claimed invention. …”

Thus what Lord Hoffmann was saying was that, in order to demonstrate that claim 12 was obvious, it was not enough to show that a skilled person would include a Taxol-coated stent in a screening programme without any expectation of success. Rather, what had to be shown was that the skilled person had a “fair expectation of success”, that is to say, “an expectation of success sufficient to induce him to incorporate taxol in a drug-eluting stent”. On the facts of that case, the skilled person would not have had a fair expectation of success.

Further light is shed on the distinction Lord Hoffmann was making by the concurring opinion of Lord Walker of Gestingthorpe, with whom Lord Neuberger of Abbotsbury agreed. Lord Walker quoted (at [48]) from an article by Sir Hugh Laddie which made the point that the problem with the concept of “obvious to try” if it is not applied with care is that, if the potential rewards are large enough and the researcher has the necessary resources, then it is rational to investigate every option even if the prospects of any one of them succeeding are low. In such circumstances, it would be rational systematically to test a large number of products to see if they had the desired property (in that case, preventing or treating restenosis when coated on a stent) even if one had no expectation that any one of those products would be successful. But that would not mean that it was obvious to try the particular one that turned out to work. Lord Walker went on (at [50]):

“This background helps to explain the question which the judge asked himself (at the end of para.61 of his judgment), including the reference to testing a product ‘without any expectation of success’ (which Lord Hoffmann refers to as an ‘oxymoronic concept’). The judge sought to answer the question (para.62) by assessing the contribution to the art made by the specification, and decided (para.64) that the only real contribution was a proposal for testing (and no more). In this way arguments that would normally be regarded as relevant to insufficiency crept into a challenge on the ground of obviousness.”

Accordingly, I consider that the correct test is whether the skilled person would have a “fair expectation of success” if he were to try the claimed product or process. As the Court of Appeal has held in MedImmune and other cases, what amounts to a “fair expectation of success” depends on all the circumstances.

Baselga 97 contains a summary of the work done to date on, in particular, (i) HER2 overexpression and taxane sensitivity, (ii) trastuzumab as a single agent and (iii) combination therapy using trastuzumab and taxanes. It also describes an ongoing Phase III trial of the combination. I do not understand it to be in dispute that it would not be obvious to the skilled person from reading Baselga 97 that the combination would result in increased efficacy as measured by TTP compared to taxane alone. It is also not in dispute that the skilled person would concur with the organisers of the Phase III trial that such a trial was worth undertaking at least because of the hope that it would succeed and the benefit that would be obtained if it did. The issue is whether the skilled person would have a fair expectation of success, meaning a fair expectation of increased efficacy as measured by TTP of the combination compared to taxane alone, if he were to undertake such a trial.

In resolving this issue, the key question is how the skilled person would interpret Baselga 97. There is no real dispute as to what Baselga discloses. The dispute is as to how the skilled person would view that disclosure, and in particular as to how encouraging the skilled reader would consider the results from previous studies reported in Baselga 97 to be. Putting it simplistically, would the skilled person think that the glass was half full (or more than half full, as Hospira contend) or half empty (or more than half empty, as Genentech contend)? Before turning to that question, it is convenient first to consider the other relevant circumstances.

Motivation? It was common general knowledge that new and effective treatments for HER2-positive breast cancer were badly needed. Thus the skilled person would be strongly motivated to find such a treatment. Furthermore, the skilled person would appreciate that the whole point of developing trastuzumab was to try to improve these patients’ situation.

Would the trial be a routine one? It is common ground that Phase III trials were regarded as routine in the sense that they were well known and frequently undertaken. This is particularly so here given that the design of the trial had already been established, and therefore all that the skilled person would have to do would be carry it out.

Would the trial be burdensome? It is common ground that Phase III trials were regarded as logistically complicated, time-consuming and expensive. But that does not mean that the Phase III trial described in Baselga 97 would be regarded as technically burdensome. Counsel for Genentech submitted that the trial would be burdensome because of the need for anyone other than Genentech to make, purify and formulate an anti-HER2 antibody and conduct pre-clinical and clinical trials on it before starting the Phase III trial. (Rightly, he did not rely upon the fact that no one else could use trastuzumab itself because of Genentech’s basic patent.) As counsel for Hospira pointed out, however, this is no more than the skilled person would have to do in order to implement the Patent. If the skilled person could not do these things without undue burden, the Patent would be insufficient. Although the Patent contains instructions on how to do these things, it is not suggested that those assisting the skilled person would not know how to do them without such instructions, nor is it suggested that the instructions would reduce the amount of work required. Thus the work would take time and money, but it would not be technically burdensome.

Would the trial present a risk to patients? The skilled person would appreciate that trastuzumab, as a humanised antibody, was designed to present a low risk of side effects. Furthermore, Baselga 97 presents evidence that this is indeed the case. Furthermore, all the patients in the trial would receive standard chemotherapy, so they would not miss out on a treatment they would otherwise receive.

What alternative options were there? The only alternative options which Genentech suggested would occur to the skilled reader of Baselga 97 were (i) taking trastuzumab further as a monotherapy before attempting to combine it, (ii) carrying out a Phase II trial of the combination before carrying out the Phase III trial and (iii) the anthracycline (doxorubicin) arm of the Phase III study. These are very limited alternatives, and none of them detracts from the obviousness of carrying out the Phase III trial of trastuzumab and taxane.

The scientific context. As counsel for Hospira submitted, the skilled person would view the Phase III trial proposed by Baselga 97 in the context provided by (a) the general rationale for combined therapies and (b) the prior work on trastuzumab and combinations thereof. So far as (a) is concerned, the skilled person would know that combined therapy was a well-established approach to the treatment of cancer and that the combination of trastuzumab and a taxane fitted the rationale for combining agents. So far as (b) is concerned, the skilled reader of Baselga 97 would appreciate that it summarised over a decade’s worth of systematic scientific development, first of trastuzumab and secondly of trastuzumab in combination therapy, in particular with taxanes.

No lions in the path. This is not a case in which it has been suggested that the skilled person would perceive that there were any “lions in the path” deterring him from proceeding as proposed by Baselga 97. The nearest Genentech came to this was to point out that taxanes were among the leading chemotherapeutic agents available at the priority date and that it was therefore “a big ask” to try and obtain increased efficacy with the combination. I accept this, but it does not detract from the message conveyed by Baselga 97 discussed below.

Failure rates in Phase III trials. The skilled person would know that it was not at all uncommon for Phase III trials to fail for one reason or another. Thus he would appreciate that the fact that a Phase III trial was being undertaken did not necessarily mean it would be successful.

How would the skilled person view the results reported in Baselga 97? The starting point here is the way in which Baselga 97 itself presents those results, bearing in mind that Baselga 97 was a review article by distinguished scientists in the field. So far as this is concerned, it is worth repeating what Baselga 97 says (at page 47 left-hand column, emphasis added):

“Results from the phase II studies and the activity of rhuMoAb HER2 against xenografts when given in combination with doxorubicin and paclitaxel have been encouraging. These positive results have led to the design of a phase III multinational study …

In this ongoing study …”

Thus Baselga 97 says that the results of the Phase II trials and the xenograft studies have been “positive” and “encouraging”. Moreover, it says that these results have “led to” the design of the Phase III trial, which is “ongoing”.

The parties disagree as to whether the results of the Phase II trials and the xenograft studies of trastuzumab in combination with doxorubicin and paclitaxel would give the skilled reader an expectation that the Phase III trial would succeed in demonstrating increased efficacy of the combination of trastuzumab and a taxane compared to the taxane alone.

So far as the Phase II trial of trastuzumab monotherapy is concerned, the dispute centres on the reported response rate of 11.6%. Prof Calvert’s view was that this would be seen as promising, because the patients had been more heavily pre-treated than those who participated in early trials of doxorubicin and paclitaxel and because trastuzumab was a novel agent with a novel mechanism, yet it was producing results in a patient group which it was difficult to get responses from. Prof Barrett-Lee’s view was that the results were “disappointing”, but he accepted that the Phase II trial demonstrated clinical activity in humans and was enough to take the drug further into clinical trials. In my view the skilled person would regard the results as disappointing, since the response rate was lower than the range of 20-40% he would have had in mind as a benchmark, but nevertheless the skilled person would agree with the authors of Baselga 97 and Prof Barrett-Lee that in the circumstances it was sufficiently encouraging to justify progression to further clinical trials.

As for the Phase II trial of trastuzumab with cisplatin, the dispute again centres on the response rate of 25%. Prof Calvert’s view was that this was promising, since the expected response rate from pre-treated cisplatin patients would have been 10%. Prof Barrett-Lee did not agree that the result was promising, but he accepted that it was worth pursuing further. It is common ground that the skilled person would regard this result as less relevant to the present question since it concerned a different combination. Nevertheless, I consider that the skilled person would regard it as a small additional cause for optimism.

So far as the xenograft studies are concerned, the dispute centres on how predictive the skilled reader would consider these to be of efficacy in humans. I have considered the common general knowledge on this question above. So far as the results reported in Baselga 97 are concerned, Prof Calvert’s view was that the results for the combination of trastuzumab and paclitaxel were striking, because they showed 93% inhibition of growth compared to 35% for either agent and the disappearance of well-established xenografts. Counsel for Genentech criticised Prof Calvert for stating in cross-examination that this was evidence of potentiation of one agent by the other. I do not accept this criticism. In the first place Prof Calvert was making essentially the same point as he had made in paragraph 6.11 of his first report. In the second place Prof Barrett-Lee agreed that this was evidence of potentiation. Prof Barrett-Lee also agreed that the xenograft data was “very striking”, but maintained that the skilled person would not draw any conclusions from it regarding humans. As counsel for Hospira submitted, this evidence does not sit easily with his evidence that it was the animal data that reassured him that it was worth proceeding with the Phase III trial. In my view the skilled person would be aware that the xenograft results were not reliably predictive of what would happen in humans, but would nevertheless regard them as promising.

Overall, I consider that the skilled person would agree with the assessment of the authors of Baselga 97, namely that results of the previous studies were “positive” and “encouraging” and justified the decision to move forward to a Phase III trial even though there had been no Phase II trial of the combination of trastuzumab and a taxane.

Secondary evidence. Hospira strongly relied on Prof Barrett-Lee’s own reaction when he read the Investigator’s Brochure for the Phase III trial. As noted above, this contained information equivalent to that contained in Baselga 97. Having read the Brochure and discussed with the company contracted by Genentech to organise the Phase III trial, Prof Barrett-Lee decided to participate in the trial and to enrol his patients in it. (So did his fellow investigators.) Prof Barrett-Lee’s evidence was that he considered that the results of the Phase II monotherapy trial were disappointing, but that the mouse xenograft results, the impressiveness of the science regarding the development of trastuzumab and the rationale supporting the combination made up for this. He did not express concern at the ability of the antibody to penetrate solid tumours or over safety. Hospira contends that this shows that Prof Barrett-Lee, who was representative of the skilled person and read the equivalent of Baselga 97, had a sufficient expectation of success to induce him to proceed with the Phase III trial. I agree with this.

Genentech relied on the contrast between the reception accorded to the results of the Phase II monotherapy trial, which were first reported by Baselga et al at ASCO 1995 and subsequently in Baselga 96, and that accorded to the results of the Phase III trial. Although Prof Calvert saw the former as a “paradigm shift”, they do not appear to have generated much attention, let alone excitement, at the time. By contrast, as noted above, the latter generated considerable excitement at ASCO 1998. Genentech contends that this shows that it was the latter which represented the true paradigm shift. While I accept that Prof Calvert’s classification of the Phase II results reflects his perspective, which as stated above I have taken into account, I do not consider that the excitement generated by the presentation of the Phase III results at ASCO 1998 assists Genentech. The excitement was generated by the confirmation of a new and more efficacious therapy for HER2-positive breast cancer. That represented an important advance, but it does not show that the skilled reader of Baselga 97 would not have had a fair expectation of success. That is particularly true if, as is implicit in Genentech’s case, those who were excited at ASCO 1998 were not familiar with Baselga 96 (in which case they would unlikely to have been familiar with Baselga 94 either).

Conclusion. Prof Calvert’s overall view was that the skilled person would have had a reasonable expectation of success in the Phase III trial. Prof Barrett-Lee was not prepared to go that far, but he accepted that it was justified to proceed with the Phase III trial. In my judgment the conclusion to be drawn from the matters considered above is that the skilled person would have had a fair expectation of success in the sense defined above. Accordingly the claimed inventions were obvious.

For the reasons given above, I conclude that the claims of the Patent are novel over Baselga 97, but are obvious in the light of Baselga 97. It follows that the Patent is invalid.