In a judgment dated 24 June 2015, Arnold J has delivered the latest blow in the ongoing saga surrounding trastuzumab (the monoclonal antibody in Herceptin) and Hospira's continued efforts to knock out Genentech's patents and clear the way for the launch of a generic version of the medicine.
This is not the first time the parties have clashed over the patents surrounding trastuzumab.
In the parties' first butting of heads (Hospira v Genentech (I)), Birss J saw fit, in April 2014, to invalidate two of Genentech's patents, one for a specific composition of trastuzumab (EP 1 308 455) and the other for a dosing regimen (EP 1 210 115) (see decision  EWHC 1094 (Pat)). Hospira appealed in relation to EP 1 308 455 but Birss J's decision was upheld by the Court of Appeal in February 2015 ( EWCA Civ 57).
The parties clashed again in a separate case decided in November 2014 ( EWHC 3857 (pat)). In that case Birss J revoked one of Genentech's patents relating to lyophilized mixtures containing trastuzumab (EP 2 275 119) and ordered another of its patents to be amended (EP 1 516 628). The appeal is currently pending.
In the meantime, Hospira's campaign to clear the way for generic trastuzumab has continued and a third action (Hospira v Genentech (III)) has now made its way before Arnold J. This time Hospira sought to invalidate EP 1 037 926 (the "Patent") which claimed a combination of trastuzumab and a taxane for the treatment of HER2-positive breast cancer. Arnold J's decision was handed down on 24 June 2015 ( EWHC 1796 (Pat).
The Patent contained two claims asserted to have independent validity, claims 1 and 10. Claim 1 was a Swiss form purpose-limited process claim. Arnold J broke the claim down to its integers as follows:
" Use of an anti-ErbB2 antibody in the preparation of a medicament,
 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,
 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,
 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,
 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 corresponded to claim 1, but was in the format of an EPC 2000 purpose-limited product claim. For the purposes of novelty and inventive step there was no relevant difference between claim 1 and claim 10, and so Arnold J focused his analysis on claim 1.
The construction of claim 1 was mostly not in dispute apart from three points:
- Does the clinical benefit required by integer  have to be shown by increased time to disease progression or could a different measure also suffice? Integers  and [5a] both explicitly require measurement of time to disease progression and so Arnold J found that clinical benefit would indeed require increased time to disease progression.
- Hospira argued that the requirement for reduced myocardial dysfunction in integer [b] was not a functional technical feature of claim 1, but neither Genentech nor Arnold J considered this as it was not relevant to novelty or obviousness.
- Precisely what was the relevant therapeutic purpose behind the claim? Hospira argued that the person administering the claimed combination must intend to treat breast cancer patients, but does not have to be certain that he would succeed in doing so. Genentech argued that the person administering the combination just has to intend to achieve the clinical benefit required by the claim, i.e. increased efficacy compared to taxane alone. Arnold J preferred Genentech's view on this.
However, none of these issues were particularly critical to novelty or inventive step. Arnold J also noted it was common ground (citing Warner-Lambert v Actavis  EWCA Civ 556) that the word "for" in claim 1 imports a mental element to claim 1, 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".
This construction would raise its head again, if only briefly, when discussing novelty of the claim.
The grounds of invalidity relied on by Hospira against the Patent were lack of novelty and lack of inventive step. Both of these were asserted over a single piece of prior art: 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 reported results from Phase II studies and activity in a mouse model. It reported that these results had led to the design of a Phase III study of trastuzumab in combinations with paclitaxel (a taxane) and other agents. The Phase III study was described as ongoing but no results were reported.
(The results from the Phase III trial subsequently demonstrated that the combination therapy had significant clinical benefits, as claimed by the Patent. The patent summarised the results of the trial).
Common general knowledge
The common general knowledge included the following:
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.
Arnold J's analysis of novelty focused on two key questions:
- What is required in order to anticipate a claim which includes a specified therapeutic effect?
- What is required in order to anticipate a purpose-limited claim?
As discussed above, Baselga 97 disclosed the existence of phase III trials concerning combinations of trastuzumab and paclitaxel, but did not disclose their results. In light of this, Arnold J reviewed existing European Patent Office (EPO) and UK case law and found that there was a well-established answer to the first question:
"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".
This view came principally from the case law of the EPO, but Arnold J found further support for it in Regeneron Pharmaceuticals Inc v Genentech Inc  EWHC 657 (Pat). In that case 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". The approach was also followed by Birss J in Hospira v Genentech (I).
To answer the second question, Arnold J turned to the decision of the House of Lords in Synthon BV v SmithKline Beecham plc  UKHL 59. In that case the House of Lords ruled that anticipation requires prior disclosure of subject-matter which, when performed, must necessarily infringe the patented invention.
As part of his analysis Arnold J had to consider whether Genentech's invention would inevitably be performed by a skilled man performing the subject-matter of Baselga 97. Here the mental element construed into claim 1 came in to play. Arnold J found that the invention would not be inevitably performed because the word "for" had imported a requirement of knowledge or reasonable foreseeability that the invention would be achieved. The invention required that the combination would produce a clinical benefit and, 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 reader of Baselga 97 would not have known that a clinical benefit would be obtained. As such, Hospira's arguments on novelty failed and Arnold J went on to consider inventive step.
The key issue with inventive step was whether, based on Baselga 97, it would have been obvious for the person skilled in the art to try to perform Genentech's invention.
Arnold J referred to the Court of Appeal's judgment in MedImmune v Novartis  EWCA Civ 1234 and its comments on the 'obvious to try' doctrine.
Genentech argued that, based on Conor Medsystems Inc v Angiotech Pharmaceuticals Inc  UKHL 49, the correct question was whether it was obvious that the claimed technical effect would be achieved by the skilled person, not merely that he might achieve it.
However, Arnold J thought that Genentech's reliance on Conor was misplaced. According to Arnold J, Conor was really saying that what matters is whether the person skilled in the art would have had an expectation of success sufficient to induce him to perform the invention. As Arnold J summarised:
"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."
Arnold J summarised the dispute on inventive step as follows:
"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."
A fair expectation of success in all the circumstances
Following this reasoning the Patent would be obvious if, based on Baselga 97, the person skilled in the art would have had a fair expectation that he could achieve increased efficacy by the combination of trastuzumab and a taxane (i.e. paclitaxel) over that of the taxane alone.
In his assessment of the circumstances in the present case, Arnold J considered the following:
- How motivated would the skilled man have been to try to find such a treatment?
- Would the trial be a routine one?
- Would that trial be burdensome?
- Would the trial present a risk to patients?
- What alternative options were there?
- What was the scientific context in which Baselga 97 would be read?
- Where there any "lions in the path" that would deter the skilled man from performing the invention?
- Failure rates in Phase III trails: The skilled man would know that trials of the nature required (Phase III trials) would not necessarily succeed.
- How would the skilled person view the results reported in Baselga 97?
Genentech's expert accepted that the Phase II trial demonstrated clinical activity in humans and was enough to take the drug further into clinical trials.
Arnold J found on the facts that the skilled person would have been highly motivated to discover the invention, would carry out a routine phase III trial that was not overly burdensome, would expect a low risk to patients, would see only a limited number of alternatives from Baselga 97, would know that combinations of this type are a well-established way to treat cancer, would not perceive any serious reasons why he should not proceed, and would view Baselga 97 as the result of over a decade of study by distinguished scientists in the field.
Following this, although the results included in Baselga 97 were more disappointing than the skilled reader might have hoped, taking all of the circumstances in to account he would have had a sufficient expectation of success to justify carrying out further trials regarding whether a combination of trastuzumab and paclitaxel would generate a clinical benefit.
In the process of carrying out such trials the skilled reader would therefore discover Genentech's invention and, accordingly, the Patent was invalid for lack of inventive step.
It is the clear intention of legislatures around the world that the patent system incentivises investment in research, including into innovative medical uses of known drugs. However, medical research is heavily regulated. By necessity it involves patients, doctors, hospitals and academic institutions. The patent system has not been designed to accommodate this.
Patents are jurisdiction-specific but filing may be coordinated and streamlined to some degree. A portfolio of patents is needed for effective 'global' coverage. There are different requirements for sufficiency/plausibility in different jurisdictions. In the course of collaborative, multi-centre medical research, information on the existence of clinical trials will often reach the public domain before data demonstrating efficacy has been obtained and/or published.
So when do you file? Do you wait until you have sufficient data to demonstrate sufficiency/plausibility, risking the emergence of information on a trial which demonstrates activity and renders the invention 'obvious'? Or do you file earlier, with the risk that the patent/application is invalid for insufficiency?
Arnold J's decision in this case (Hospira v Genentech (III)) serves as a stark reminder of the difficult choice currently faced by the innovative pharmaceutical industry. The decision may well be appealed and higher court guidance would be welcomed. Such guidance would preferably follow consideration of the balance between the patent law requirements for sufficiency and inventive step, and the regulatory requirements for safety and efficacy testing and the ethical conduct of clinical trials, not just in the context of the UK, but reflecting the global environment in which medical research is conducted.