Hospira UK Ltd v Genentech, Inc.
| Jurisdiction | England & Wales |
| Judge | Lord Justice Floyd,Lord Justice Kitchin,Lord Justice Longmore |
| Judgment Date | 30 November 2016 |
| Neutral Citation | [2016] EWCA Civ 1185 |
| Docket Number | Case No: A3 2015 3238 |
| Court | Court of Appeal (Civil Division) |
| Date | 30 November 2016 |
[2016] EWCA Civ 1185
IN THE COURT OF APPEAL (DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
THE HON MR JUSTICE ARNOLD
Royal Courts of Justice
Strand, London, WC2A 2LL
Lord Justice Longmore
Lord Justice Kitchin
and
Lord Justice Floyd
Case No: A3 2015 3238
Michael Tappin QC with Mark Chacksfield (instructed by Marks & Clerk Solicitors LLP) for the Appellant
Richard Meade QC, Thomas MitchesonQC andJeremy Heald (instructed by Taylor Wessing LLP) for the Respondent
Hearing dates: 8 November 2016
The appellant, Genentech, Inc ("Genentech"), is the proprietor of European Patent (UK) No. 1037926 ("the patent"). The respondent, Hospira UK Ltd ("Hospira") obtained an order for revocation of the patent before Arnold J, who, in his judgment dated 24 June 2015, found the claims of the patent to be novel but lacking in inventive step. Genentech appeals with permission granted by the judge himself.
The patent relates to the use of the antibody trastuzumab in combination with a chemotherapeutic agent, a taxane, for the treatment of HER2-positive breast cancer. At the priority date of the patent, 12 December 1997, a phase III clinical trial of trastuzumab in combination with a taxane (paclitaxel) was under way. The trial had already been described by Baselga et al in an article entitled " HER2 Overexpression and Paclitaxel Sensitivity in Breast Cancer: Therapeutic Implications", Oncology, 11, Supp.2 43–48 ("Baselga 97"). Baselga 97 did not, however, disclose any results from the trial.
The patent summarises the results of the trial of trastuzumab in combination with paclitaxel described in Baselga 97. The results show that the combination treatment results in a substantial increase in time to disease progression ("TTP") and tumour response rates in HER2-positive metastatic breast cancer patients compared to paclitaxel alone.
The results reported in the patent led to the approval of trastuzumab as a first line treatment for HER2 positive breast cancer, first in the US in 1998 and subsequently elsewhere. Trastuzumab, under its trade name Herceptin, has now become the standard of care worldwide for the majority of women with such cancers, usually given in combination with a taxane. It is a very successful drug.
Before coming to the issues on the appeal, it is necessary to say a little more about the patent itself and also about Baselga 97.
The patent
At [0011], the patent explains that Herceptin " has been clinically active in patients with ErbB2-overexpressing metastatic breast cancers that had received extensive prior anti-cancer therapy." ErbB2 and HER2 are alternative names for the same gene. At [0012] the specification notes that ErbB2 overexpression is commonly regarded as a predictor of a poor prognosis for the patient. It continues by explaining, perhaps somewhat paradoxically, that ErbB2 overexpression is associated with a greater clinical response to taxanes:
"However, despite the association of ErbB2 overexpression with poor prognosis, the odds of a HER2-positive patients responding clinically to treatment with taxanes were greater than three times those of HER2-negative patients… [Trastuzumab] was shown to enhance the activity of paclitaxel… against breast cancer xenografts in nude mice… which express high levels of HER-2."
Later, the specification sets out, by way of example, the clinical trial of the combined treatment. The patient population enrolled for the trial was split into two groups. One group was to receive trastuzumab and chemotherapy whilst the other was to receive only chemotherapeutic agents. For reasons explained, the chemotherapy administered was either paclitaxel or an anthracycline/cyclophosphamide treatment. The results of the clinical trial are then set out in the table which appears at [148]:
CRx: chemotherapy
AC: anthracydine/cyclophosphamide treatment
H: HERCEPTIN®
T: TAXOL®
| Enrolled | TTP(months) | RR(%) | AE(%) | |
| CRx | 234 | 5.5 | 36.2 | 66 |
| CRx+H | 235 | 8.6 * | 62.00 ** | 69 |
| AC | 145 | 6.5 | 42.1 | 71 |
| AC+H | 146 | 9.0 | 64.9 | 68 |
| T | 89 | 4.2 | 25.0 | 59 |
| T+H | 89 | 7.1 | 57.3 | 70 |
The specification says that the assessments of TTP and response rates showed a significant augmentation of the chemotherapeutic effect of paclitaxel, without an increase in overall severe adverse events.
The tabulated results show that, taking the two chemotherapy groups together, the addition of trastuzumab extended time to progression by 3.1 months and the response rate by 25.8%. Looking at each of the chemotherapy groups separately, there are increases in both time to progression and response rates as a result of the addition of trastuzumab. In the paclitaxel group, TTP was increased by 70% and response rate by 130%.
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."
The claims
It is common ground that only claim one needs to be considered. This is in so-called Swiss form. The claim uses the term "taxoid", but that is the same thing as a taxane. I adopt the judge's breakdown of the claim into integers, which is as follows:
"[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."
Baselga 97
Baselga 97 is a review article. The authors were Jose Baselga, a member of the Oncology Service at the Hospital General Universitari, Val d'Hebron, Barcelona, Andrew Seidman and Larry Norton, of the Breast Medicine Service in the Department of Medicine at the Memorial Sloan-Kettering Cancer Center, New York, and Peter Rosen of the Department of Pathology at the same institution. The abstract reads as follows:
"Overexpression by the HER2 gene plays a significant role in breast cancer pathogenesis, and the phenomenon is commonly regarded as a predictor of a poor prognosis. HER2 overexpression has been linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluorouracil) and anthracyclines. Studies of patients with advanced disease demonstrate that, despite the association of HER2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to taxanes were greater than three times those of HER2-negative patients. Further studies in preclinical models used combination therapy for breast cancer cells that overexpress HER2, and the use of agents that interfere with HER2 function plus paclitaxel (Taxol) resulted in significant antitumor effects."
The introductory section of Baselga 97 explains that the taxanes are an important new class of anti-cancer agents with a unique mechanism of action. Paclitaxel was selected for clinical development based on impressive anti-tumour activity in xenograft tests. It goes on to explain that paclitaxel has been shown to have a high degree of anti-tumour activity in women with metastatic breast cancer. The introductory section concludes:
"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 antitumor activity of paclitaxel in vitro and in vivo."
The suggestion that an anti-HER2 antibody (such as trastuzumab) may enhance the anti-tumour activity of the taxane paclitaxel in vivo is close to a teaching that the two should be administered in combination.
Under the heading "Role of Monoclonal Antibodies", Baselga 97 explains that the murine monoclonal antibody 4D5 directed against the extracellular domain of p185 HER2 had been found to be a potent inhibitor of human breast cancer cells overexpressing HER2 in mouse xenograft studies. These studies, it is reported, led to the development of a humanised anti-p185 HER2 antibody, namely trastuzumab. Trastuzumab was:
"found to be safe and to have dose-dependent pharmacokinetics in two prior phase I clinical trials."
Another section of Baselga 97 is headed "HER2 overexpression and taxane sensitivity". This section reports work at the Memorial Sloan-Kettering Cancer Center investigating the possible relationship between HER2 overexpression and response to taxanes in patients with metastatic breast cancer. The authors report that:
"In 37.7% of patients, tumors were positive by immunohistochemistry with the 4D5 antibody. The overall response to taxanes for all patients in this...
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