Negative decision for anti-HIV therapy patent: Merck Sharpe & Dohme v Shionogi Co Limited
Last week saw another Michaelmas decision from Mr Justice Arnold in the Patents Court in the form of Merck Sharpe and Dohme Limited v Shionogi & Co Limited [2016] EWHC 2989 (Pat). Alongside the usual analysis of validity and infringement, the case has the attraction of providing guidance on how experts should be cross examined [and more importantly, how they should not be cross-examined, says Merpel]. This follows on from previous guidance on the instruction of experts in Medimmune v Novartis.
Background
The dispute concerned Shionogi's European Patent (UK) No 1 422 218. Shionogi counterclaimed infringement of the patent by Merck's product raltegravir, which is marketed under the trade mark Isentress. Raltegravir is an anti-HIV therapy, which treats HIV-1 (the most common type). It is a 'first in class' drug, being the first antiretroviral integrase inhibitor approved by the US FDA in 2007. Integrase is an enzyme found in retroviruses. It is essential for integration of the viral DNA into the host cell DNA. Integrase inhibitors target the viral integrase and interfere with integration of HIV DNA into the DNA of the infected cell.
The patent was opposed by Merck at the EPO, but maintained in an amended form. That decision is under appeal, and the central amendment has therefore been suspended. In the meantime, Shionogi made an unconditional application to amend the UK designation of the patent in accordance with the claims maintained at the EPO. It also made two conditional applications to the Patents Court to amend. There are parallel proceedings in Germany and the Netherlands which are ongoing.
Skilled team
It was common ground that the skilled team would consist of persons with expertise in three areas: medicinal chemistry, biochemistry, and virology. There was however, a disagreement as to whether the skilled team would have experience in the field of integrase inhibition. Arnold J concluded that at the priority date (Aug 2002), real research teams in the field to which the patent is directed would have acquired experience with integrase inhibition.
Cross-examination of expert witnesses in patent cases
At paras 88 - 93 of the judgment, Arnold J took the opportunity to extend his previous guidance concerning the instruction of experts in Medimmune v Novartis [2011] EWHC 1169 (Pat) (see para 99-114) into the realm of cross-examination.
"In my experience too much time is spent by cross-examiners in patent cases on ad hominem attacks [i.e. attacks directed at the person rather than the position they are maintaining] that are unfair to the witness, unhelpful to the court and waste expensive time. It is, of course, both legitimate and helpful to explore such matters as the witness' qualifications and experience, and hence the extent to which the witness has relevant expertise and/or is representative of the skilled person; the basis upon which the witness considers that information was or was not common general knowledge (which may include whether the witness has correctly understood the concept); the witness' approach to issues such as obviousness (which may include whether the witness has fully appreciated the need to avoid hindsight and whether he or she has actually avoided hindsight); and so on. But cross-examiners must refrain from using the fact that the expert has not mentioned something in their report as a stick to beat the witness with unless the cross-examiner has real grounds for suggesting that this reflects on the witness' impartiality, competence or approach to the issues rather than upon the instructions they have been given. (If the witness has been wrongly instructed, that is, of course, a highly relevant matter, but it is a point for submissions rather than criticism of the witness.)
A particular difficulty which often arises in multiple expert cases is the distribution of responsibilities between the experts".... "This difficulty is exacerbated where there is an overlap between the expertises of the experts, as in the present case."... "In such cases it may well be legitimate and helpful for the cross-examiner to explore the division of responsibility between the experts and the extent to which, collectively, they have approached matters in a manner which reflects the approach of the notional skilled team. What will rarely be legitimate or helpful is to criticise a witness for failing to deal with a point which he or she could have dealt with when it has been addressed by another expert, because this is unlikely to have been a decision made by the witnesses."
Counsel on both sides were criticised for 'unfair' cross-examine of the expert witnesses.
Obviousness and insufficiency
The specification explained that the invention related to "an antiviral agent, especially, a compound having an a-hydroxy-a, ß unsaturated ketone as a partial structure and a pharmaceutical composition as an integrase inhibitor containing the same". Claim 1 contained a Markush formula, and the subsidiary claims related to six-sub-classes of compounds. The permissible substituents RA, RC, RD, Y and Z were defined in claim 1 (see pargaraphs 57-59 of the judgment for the full - and lengthy - details). Merck's apparently unchallenged expert evidence was that there was a staggeringly vast number of compounds covered by the Markush formula in claim 1 of the Patent - some 1039 compounds. Perhaps as a consequence of that, and unusually for a patent case of this nature, disclosure on the validity issues appears to have been voluminous. Both parties had given disclosure in the usual two year window falling either side of the priority date. Data from a total of 104 compounds from Shionogi and 139 from Merck were disclosed. Unsurprisingly, there was a sufficiency/obviousness squeeze.
The Court concluded that at best, a tiny fraction of the class of claimed compounds were plausible (in addition to the small number of compounds for whom data is reported in the patent specification), but this plausibility derived from the skilled team's common general knowledge and not from the patent. The scope of the monopoly claimed was not justified by the contribution to the art, and accordingly lacked an inventive step.
On insufficiency, later evidence suggested that formula 1 covered large groups of compounds that were unlikely to possess integrase inhibitory activity and be suitable for treating a viral disease. In addition, the disclosure process had revealed that a significant proportion of the compounds for which there were experimental data either did not possess antiviral activity, or possessed antiviral activity but were unduly toxic. The final nail in the coffin was the fact that the patent presented the skilled team with a vast research project with a high degree of failure, but "claims the results if they happen to succeed, even if (as in the case of raltegravir) such success has nothing to do with the teaching in the patent." Accordingly, it was not possible to perform the invention across the scope of the claim.
None of the proposed claim amendments overcame the obstacles on validity. The patent was found invalid on the basis of obviousness and insufficiency (but not added matter), though it would have been infringed had it been valid.
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| The IPKat pondering expert XX |
The dispute concerned Shionogi's European Patent (UK) No 1 422 218. Shionogi counterclaimed infringement of the patent by Merck's product raltegravir, which is marketed under the trade mark Isentress. Raltegravir is an anti-HIV therapy, which treats HIV-1 (the most common type). It is a 'first in class' drug, being the first antiretroviral integrase inhibitor approved by the US FDA in 2007. Integrase is an enzyme found in retroviruses. It is essential for integration of the viral DNA into the host cell DNA. Integrase inhibitors target the viral integrase and interfere with integration of HIV DNA into the DNA of the infected cell.
The patent was opposed by Merck at the EPO, but maintained in an amended form. That decision is under appeal, and the central amendment has therefore been suspended. In the meantime, Shionogi made an unconditional application to amend the UK designation of the patent in accordance with the claims maintained at the EPO. It also made two conditional applications to the Patents Court to amend. There are parallel proceedings in Germany and the Netherlands which are ongoing.
Skilled team
It was common ground that the skilled team would consist of persons with expertise in three areas: medicinal chemistry, biochemistry, and virology. There was however, a disagreement as to whether the skilled team would have experience in the field of integrase inhibition. Arnold J concluded that at the priority date (Aug 2002), real research teams in the field to which the patent is directed would have acquired experience with integrase inhibition.
Cross-examination of expert witnesses in patent cases
At paras 88 - 93 of the judgment, Arnold J took the opportunity to extend his previous guidance concerning the instruction of experts in Medimmune v Novartis [2011] EWHC 1169 (Pat) (see para 99-114) into the realm of cross-examination.
"In my experience too much time is spent by cross-examiners in patent cases on ad hominem attacks [i.e. attacks directed at the person rather than the position they are maintaining] that are unfair to the witness, unhelpful to the court and waste expensive time. It is, of course, both legitimate and helpful to explore such matters as the witness' qualifications and experience, and hence the extent to which the witness has relevant expertise and/or is representative of the skilled person; the basis upon which the witness considers that information was or was not common general knowledge (which may include whether the witness has correctly understood the concept); the witness' approach to issues such as obviousness (which may include whether the witness has fully appreciated the need to avoid hindsight and whether he or she has actually avoided hindsight); and so on. But cross-examiners must refrain from using the fact that the expert has not mentioned something in their report as a stick to beat the witness with unless the cross-examiner has real grounds for suggesting that this reflects on the witness' impartiality, competence or approach to the issues rather than upon the instructions they have been given. (If the witness has been wrongly instructed, that is, of course, a highly relevant matter, but it is a point for submissions rather than criticism of the witness.)
A particular difficulty which often arises in multiple expert cases is the distribution of responsibilities between the experts".... "This difficulty is exacerbated where there is an overlap between the expertises of the experts, as in the present case."... "In such cases it may well be legitimate and helpful for the cross-examiner to explore the division of responsibility between the experts and the extent to which, collectively, they have approached matters in a manner which reflects the approach of the notional skilled team. What will rarely be legitimate or helpful is to criticise a witness for failing to deal with a point which he or she could have dealt with when it has been addressed by another expert, because this is unlikely to have been a decision made by the witnesses."
Counsel on both sides were criticised for 'unfair' cross-examine of the expert witnesses.
 |
| Markush formula in claim 1 |
The specification explained that the invention related to "an antiviral agent, especially, a compound having an a-hydroxy-a, ß unsaturated ketone as a partial structure and a pharmaceutical composition as an integrase inhibitor containing the same". Claim 1 contained a Markush formula, and the subsidiary claims related to six-sub-classes of compounds. The permissible substituents RA, RC, RD, Y and Z were defined in claim 1 (see pargaraphs 57-59 of the judgment for the full - and lengthy - details). Merck's apparently unchallenged expert evidence was that there was a staggeringly vast number of compounds covered by the Markush formula in claim 1 of the Patent - some 1039 compounds. Perhaps as a consequence of that, and unusually for a patent case of this nature, disclosure on the validity issues appears to have been voluminous. Both parties had given disclosure in the usual two year window falling either side of the priority date. Data from a total of 104 compounds from Shionogi and 139 from Merck were disclosed. Unsurprisingly, there was a sufficiency/obviousness squeeze.
The Court concluded that at best, a tiny fraction of the class of claimed compounds were plausible (in addition to the small number of compounds for whom data is reported in the patent specification), but this plausibility derived from the skilled team's common general knowledge and not from the patent. The scope of the monopoly claimed was not justified by the contribution to the art, and accordingly lacked an inventive step.
On insufficiency, later evidence suggested that formula 1 covered large groups of compounds that were unlikely to possess integrase inhibitory activity and be suitable for treating a viral disease. In addition, the disclosure process had revealed that a significant proportion of the compounds for which there were experimental data either did not possess antiviral activity, or possessed antiviral activity but were unduly toxic. The final nail in the coffin was the fact that the patent presented the skilled team with a vast research project with a high degree of failure, but "claims the results if they happen to succeed, even if (as in the case of raltegravir) such success has nothing to do with the teaching in the patent." Accordingly, it was not possible to perform the invention across the scope of the claim.
None of the proposed claim amendments overcame the obstacles on validity. The patent was found invalid on the basis of obviousness and insufficiency (but not added matter), though it would have been infringed had it been valid.
