09 December 2010

Success of Phase 3 Trials 'Obvious' In View of Phase 1 and 2

Genentech, Inc [2010] APO 27 (15 November 2010)

None of my inventions came by accident. I see a worthwhile need to be met and I make trial after trial until it comes. What it boils down to is one per cent inspiration and ninety-nine per cent perspiration.
- Thomas Edison (1929 press conference)

While Edison's inventions were generally of a more macroscopic nature, his words are perhaps nowhere more apt than in the pharmaceutical industry.  Indeed, a mere 99% perspiration may be an understatement.  The path leading from a promising drug candidate, or an idea for a therapeutic treatment, to an actual successful product or therapy that can be used on humans is long, expensive, and uncertain.  Which is why patents provide an important economic incentive in this field, and also why this Patent Office decision, by Delegate Dr Steven Barker, is potentially of concern to researchers and companies active in this area.

Specifically, the decision seems to stand for a general proposition that a claim directed to a method of medical treatment of humans, supported by successful phase 3 trial results, will necessarily be considered obvious in view of any prior disclosure of promising phase 1 and 2 trials.


Not a great deal was in dispute in this case.  The claimed invention was 'a method for the treatment of a human patient diagnosed with a malignant progressing tumor or cancer' comprising administering an effective combination of a particular antibody and a chemotherapeutic agent (specifically a taxoid, such as TAXOL).  It was undisputed that the antibody (in a suitable 'humanised' form) was known, the chemotherapeutic agent was known, and the alleged invention therefore lay in the development of a combined therapy that was more effective that the use of the chemotherapeutic agent alone.

It was also not disputed by Genentech that the most pertinent prior art document was a paper in the journal Oncology, published shortly before the priority date of the application, describing phase 1 and 2 trials of the therapy conducted by Genentech.  As the Delegate kindly explains in paragraph 4 of the decision:

Phase 1 trials assess whether an experimental medication or treatment is safe, and gather information on how the active agents are absorbed, metabolised, etc..
Phase 2 trials are done to assess the short term therapeutic effect of the medication or treatment.
Phase 3 trials are done on a large number of patients over a prolonged period, to demonstrate advantages over other therapies.
In this case, the phase 2 trials involved tests 'conducted in monolayer cell culture soft agar as well as breast cancer human tumor xenografts in nude mice' (xenografts are cells transplanted from one species into another).  It was therefore also not in dispute that claims directed to a method of treatment of a human patient were novel.  The sole issue was whether the claims embodied an inventive step.


The current approach of the Patent Office to assessing inventive step has been discussed on this blog previously.  While the Delegate (quite rightly in our view) did not express the question in terms of 'obvious to try', he did cite (at [15] and [16]) the same tests upon which the guidance in the Examiner's Manual is based:

...whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.
Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art and the facts, directly be led as a matter of course to try the invention as claimed in the expectation that it might well produce a solution to the problem?


Genentech led evidence of an expert (Dr Sliwkowski), and argued to the effect that successful xenograft tests were insufficient to predict necessary success of a corresponding clinical treatment on human patients, and thus that the completion of phase 3 trials is an essential step in determining whether or not the claimed invention actually works.

The Delegate was not persuaded that this was sufficient to support an inventive step (at [31]):

Dr Sliwkowski's point seems to be that success in phase 3 is not guaranteed, which is clearly correct.  However, Dr Sliwkowski seems to equate matters of routine, reasonable expectations of success and guarantee of success.  ...  The proper question is whether there would have been an "expectation that it might well" be successful.  Consequently I have come to a different conclusion to Dr Sliwkowski, and I am satisfied that it would have been a matter of routine in the art to advance to phase 3 as indicated in D1.  It also follows that I believe there would have been a reasonable expectation of success (while accepting that success was not guaranteed).


We may be wrong about this, since it is outside our area of technical experience and expertise, however the logical inference here would seem to be that successful phase 2 trials would, under this test, always render obvious a subsequent claim to a corresponding method of treatment of human patients.

It is axiomatic that failure at phase 1 or phase 2 would prevent an advance to phase 3, and that successful phase 1 and 2 trials are a necessary (though perhaps not sufficient) precondition for a phase 3 trial to proceed.  If the phase 3 trial is successful then, with the benefit of hindsight, it will inevitably appear reasonable to have expected that success. 

For the Delegate to have overruled expert opinion on this point seems a little unreasonable.  As he points out (at [19]-[20]) the standard for assessment of inventive step is 'the balance of probabilities'.  However, the balance in this case seems to be between expert opinion, and the Delegate's own views on the matter.  Clearly Genentech was never going to lead evidence that was adverse to its interests, but Australia has a pre-grant opposition process precisely so that interested parties can bring forth prior art and additional evidence that might not be available to an examiner.

As a final point, Genentech appears to have created a problem for itself in this instance, by causing the results of its phase 1 and 2 trials to be published prior to the filing of the priority application.  However, the patent specification itself gives some indication of the duration of the phase 3 trial, in that results were assessed at a median follow-up time of 10.5 months, so it is clear that the human trial was well underway before publication of the phase 1 and 2 results.  In the US, Genentech could no doubt 'swear behind' its own prior publication, but this course of action is not available in a 'first-to-file' regime.  However, even in the absence of the publication in Oncology, we wonder whether phase 1 and 2 trials would, or could, be conducted in secret.

It is not yet all over for Genentech, however.  It will be interesting to see whether the Delegate's decision is appealed.  Alternatively, Genentech has also filed a further divisional application (this is already its third attempt to gain acceptance of its claims).


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