ON APPEAL FROM Chancery Division, Patents Court
Mr Justice Floyd
Strand, London, WC2A 2LL
B e f o r e :
LORD JUSTICE RICHARDS
LORD JUSTICE PATTEN
| MERCK SHARP & DOHME CORP (formerly known as MERCK & CO INC) (a company incorporated under the laws of the state of New Jersey, United States)
|- and -
|TEVA UK Ltd
Simon Thorley QC & Thomas Mitcheson (instructed by Bird and Bird) for the Respondent
Hearing date: 15 March 2011
Crown Copyright ©
"The topical carbonic anhydrase inhibitor MK-507 at 2% has demonstrated IOP lowering in patients treated three times daily. This was a 4 center, double-masked, randomised, placebo-controlled parallel study of the degree of additional IOP-lowering activity of 2% MK-507 q12hr given to patients with elevated IOP receiving 0.5% timolol q12hr. Entry criteria included bilateral primary open angle glaucoma or ocular hypertension with IOP > 22 mmHg after a 2-3 wk run-in on 0.5% timolol (8am – 8pm). After a 12 hr diurnal IOP curve on timolol alone, patients began dosing with 2% MK-507 (n=15) or Placebo (n=15) at 8:10 pm – 8:10 am (10 min post timolol dose) for 8 days. IOP was measured 8am & 9am on Day 2 with a 12 hr diurnal curve on day 8. MK-507 q12 hr demonstrated a clinically and statistically significant additive effect, ranging from 13%-21% based on a worse eye analysis."
The paper then set out the preliminary IOP data.
(1) The trial was designed to test for an additive effect on IOP lowering of 2% MK 507 given twice a day on patients receiving 0.5% timolol twice a day.
(2) The tests were performed on humans.
(3) The patients were given their MK 507 dose ten minutes after their timolol dose for 8 days.
(4) The results were statistically significant, meaning that they were very unlikely indeed to be due to chance; and clinically significant which meant that the improvements in IOP translated into real benefit for the patients.
(5) The two drugs were being concomitantly administered, despite the fact that this meant that MK 507 was being administered at less than the three times a day dosing that is referred to in the first sentence.
"Thus, when a carbonic anhydrase inhibitor is combined with a beta adrenergic antagonist, there is experienced an effect that reduces the intraocular pressure below that obtained by either medicament individually."
The specification as sought to be amended then continues in :
"The combination disclosed herein is effective
eitherby co-administration of the medicaments in one solution or as a combined therapy achieved by prior administration of either the carbonic anhydrase inhibitor or the ß-adrenergic antagonist followed by administration of the other solution.The use of a single solution containing both active medicaments is preferred.disclosed."
The specification continues with an explanation of various concentrations of timolol and dorzolamide and includes three examples, the third of which is identical to Nardin.
"1. Use of
(a) 0.05 to 5% (w/w) of dorzolamide, or an ophthalmologically acceptable salt thereof; and
(b) 0.01 to 1.0% (w/w) of timolol, or an ophthalmologically acceptable salt thereof;
for the manufacture of a medicament for the treatment of ocular hypertension or glaucoma in a patient who is insufficiently responsive to ß-adrenergic antagonists, wherein said medicament takes the form of a single solution adopted for topical administration."
"An ophthalmic formulation for the treatment of ocular hypertension or glaucoma in a patient population the members of which are insufficiently responsive to ß-adrenergic antagonists, which comprises:
(a) 0.05 to 5% (w/w) of dorzolamide, or an ophthalmologically acceptable salt thereof;
(b) 0.01 to 1.0% (w/w) of timolol, or an ophthalmologically acceptable salt thereof; and
(c) an ophthalmologically acceptable carrier."
Unamended claims 11 to 18 were dependent on claim 10.
"18. A process as claimed in claim
1917, for obtaining an ophthalmic formulation in the form of a solution, which comprises:
(1) suspending or dissolving in water:
(a) 0.05 to 5% (w/w) of dorzolamide or an ophthalmologically acceptable salt thereof; and
(b) 0.01 to 1.0% (w/w) of timolol, or an ophthalmologically acceptable salt thereof;
together with non-toxic auxiliary substances which may go with an ophthalmologically acceptable carrier; and
(2) adjusting the pH of the composition obtained to
5.05.5-6.0 by the addition of a suitable reagent."
In its unamended form it was dependent on claim 19 paragraph (2) being the additional integer. Thus the argument in this case has centred on amended claim 18 and the alteration of the lower end of the range of the pH of the composition from 5.0 to 5.5. Floyd J held that unamended claim 20 and amended claim 18 were both invalid for added matter but went on to consider both novelty and obviousness. For reasons I have explained in paragraph 3 above I am not concerned with the added matter objection.
"The question I must ask is whether it would be obvious to the skilled team on reading Nardin to use a co-formulation of the two drugs within claim 6 for treating glaucoma in patients for whom timolol is not good enough."
He concluded in paragraph 161 that that claim was obvious and thereby invalidated the patent as a whole. He did so by reference to a product called Ganda, an earlier patent granted to Merck and common general knowledge at the time. In its notice of appeal Merck sought permission to appeal from that conclusion on grounds 7 to 13 to the effect that the judge had wrongly found that at the priority date the co-formulation of timolol and dorzolamide in the amounts specified in claim 6 was obvious either as part of the common general knowledge or by reference to Ganda.
(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) Ask whether, when 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?"
"114. ...the skilled person would know as part of the common general knowledge that co-formulation was a valuable and appropriate measure where the circumstances justified it. It would always bring with it the advantage of patient compliance. It would be particularly suitable where the two drugs can be administered concomitantly at the same dosage interval.
The inventive concept
115. There is no sense in fudging the issue of the inventive concept of claim 1. It is using a co-formulated solution of dorzolamide and timolol for treating glaucoma in patients for whom timolol is not good enough. For that purpose I will consider the narrowest use claim advanced, claim 6. If that is obvious, the patent does not survive – all the other claims relied on are of equivalent width or broader, or are not contended to be independently valid."
"...whether it would be obvious to the skilled team on reading Nardin to use a co-formulation of the two drugs within claim 6 for treating glaucoma in patients for whom timolol is not good enough."
"(i) Additive therapy was commonplace;
(ii) Timolol was the first line, gold standard treatment. When it was not good enough, a variety of unsatisfactory drugs were prescribed as adjunctive therapy. There was no satisfactory adjunctive compound;
(iii) Co-formulations were well known in ocular treatment in general. Clinical approval had been obtained for some co-formulations;
(iv) The desirability of one-drop medication for compliance reasons was well known;
(v) Workers in the field wanted a topical CAI to gain the advantage of the reduction of aqueous humour formation which was known to be achieved when administered orally;
(vi) It would accordingly be natural to investigate whether any potentially useful CAI had an additive effect when co-administered with timolol, particularly when administered twice daily as timolol was habitually administered;
(vii) The skilled reader would readily understand, therefore that this is what Nardin was doing with MK 507, the best bet at the time for a topical CAI;
(viii) The results shown in Nardin, namely an additive effect when administered twice daily (not three times daily) would have been credible and interesting;
(ix) The skilled reader would understand that the fact that there was an additive effect rendered moot any debate about whether the CAI mechanism of action could add anything to an optimum timolol dose;
(x) The importance of twice daily administration would not be lost on the reader: to spell it out the patient would have to apply two drops (as with all adjunctive therapy) but in this case would be able to apply them on the same two occasions and no others; and
(xi) The results in Nardin would therefore naturally and non-inventively suggest a co-formulation."
"In my judgment the idea of co-formulating MK 507 and timolol would occur to the notional skilled team if they read Nardin with interest. There is no doubt that the Nardin disclosure would have been seen as an important and exciting one. I do not think, as Merck submits, that it would only become a natural consideration once the dorzolamide mono-therapy had been more extensively worked on, or once co-administration had, as [counsel for Merck] puts it, been "bottomed out". Once the essential facts are appreciated as they would be, namely (a) additivity to timolol's best dosage regime and (b) concomitant administration at the same dosage times and intervals, a co-formulation would be a startlingly obvious thing to consider. The skilled team would plainly have seen, without any hindsight prompting, the bonus that a co-formulation would offer."
"(i) Armed with the results from Nardin the skilled team would know that a development programme would be necessary which could be time consuming and expensive. A question therefore arises as to whether the team would abandon it at that stage.
(ii) Nothing in Nardin would lead the skilled team to abandon the project before it began.
(iii) On starting the project, the team would discover that one cannot dissolve enough dorzolamide in a 0.5% solution of timolol at the pH at which timolol is formulated, pH 6.8. This would rapidly lead to the knowledge that a pH of around 6.0 was required.
(iv) The skilled team would recognise that lowering the pH at which timolol was formulated could lead to a decrease in the bioavailability of timolol.
(v) This knowledge would not cause the skilled team to abandon the project. The skilled team would still want to obtain animal data or, if it paused to consider theory, would appreciate that the reduction in bioavailability is not likely to be great.
(vi) Thereafter the project is a normal drug development program."
"The real questions are whether the skilled team would embark on the project at all, whether, after starting the project, the pH/bioavailability problem would lead to abandonment, and whether, if not, the team would eventually arrive at an effective formulation for use."
He then proceeded to answer each of those questions. For the reasons given in paragraphs 131 to 135 he considered that the project would not be abandoned before it was begun. He referred to the evidence of the parties' respective professors in ophthalmology and concluded that:
"…the skilled team would be highly motivated to produce the co-formulated product, given the quantitative results in Nardin and the patient compliance benefits of a co-formulation. The quantitative results obtained at bid would lead the team to expect success. Of course the skilled team would realise that something might go wrong on the way, but nothing concrete was suggested which would have affected the skilled team's prognosis at the outset."
"…the problem might cause the skilled team to appreciate that there might be a problem en route to their ultimate goal which they had not appreciated at the outset. But I do not think it is realistic to suggest that it would have caused the team to abandon the project. The motivation to obtain a co-formulation would remain unaltered, making abandoning it in favour of pursuing co-administration alone an unattractive proposition. Other drug combinations had not been suggested in Nardin. Moreover the pH problem did not mean that the co-formulation would not work. Nardin predicted a 13 to 21% increase in efficacy. The actual reduction in bioavailability might be very small indeed, or non-existent, given the distance from the pKa value. There would also be a question as to whether any reduction in timolol availability would matter clinically. The clinician on the team would know that the 0.5% timolol dose was at the top of the dose response curve, and that there was not much evidence of any difference in effect as compared to 0.25% so the reduction in bioavailability might well not matter. The possible effect would not cause the skilled team to abandon the project."
"I need, at the end to take a step back. [Counsel for Merck] reminded me that I must be careful not to allow hindsight to colour my judgment when considering the fourth step [in Pozzoli], particularly when an "obvious to try" case is being run. Many cases have stressed this. Nevertheless, I am driven to the conclusion that the use of the co-formulation to treat glaucoma as claimed in claim 6 does not involve an inventive step. The skilled team would have been highly motivated to achieve such a use. They would have entertained throughout a fair expectation of success and would have arrived at their goal without any invention. None of the other claims can survive these findings."
"Further the learned judge failed to deal adequately or at all with [Merck]'s case that the step by step project proposed by [Teva] as the obvious way forward would not arrive at a formulation with the features called for by the independently valid claims, even if it was not abandoned outright. In particular the learned judge addressed the possibility that the skilled person would abandon the project but he failed to consider the impact on the later steps in [Teva]'s step by step approach of the outcomes of the tests [Teva] contended would be performed at earlier steps. [Teva] needed to establish that the outcome of its step by step approach would be a formulation formulated at a pH range of 5.5-6.0 required by proposed amended claim 18 and (or) with the amounts of the two drugs such that the concentrations fell within the scope of the claims, and in particular claim 6. [Teva] failed to do so. Although the judge expressed the conclusion that the use of a formulation within claim 6 does not involve an inventive step his reasoning does not adequately support that conclusion. The correct conclusion is that the claims are not obvious on this basis."
(1) As Nardin said nothing about how to suspend or dissolve both timolol and dorzolamide in water so as to constitute a co-formulation the skilled team would have to find that out in the six days which elapsed between the publication of Nardin and the priority date.
(2) Notwithstanding his correct self-direction on the law the judge wrongly applied hindsight in concluding that the skilled team starting with Nardin would end up with a co-formulation within amended claim 18.
"The state of the art in the case of an invention shall be taken to comprise all matter (whether a product, a process, information about either, or anything else) which has at any time before the priority date of that invention been made available to the public (whether in the United Kingdom or elsewhere) by written or oral description, by use or in any other way."
By s.2(1) an invention is to be taken to be new if it does not form part of the state of the art. The only element of time is that the relevant state of the art is that which exists on the priority date.
"An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2(2) above…"
There is no additional time requirement in that case either. If by reference to the relevant state of the art the invention is obvious then it matters not that it may take time to perform the necessary routine tests. It is a matter of simple comparison between the relevant art and the claimed invention.
"…superficially one might think this conclusion is a bit odd given that the invention was once obvious – one might assume that when an invention becomes obvious it must remain so thereafter. But such an assumption would be wrong: obviousness must be determined as of a particular date. There is at least one other well-known example showing how an invention which might be held obvious on one date, would not be so held at a later date. That is where there has been commercial success following a long-felt want. Time can indeed change one's perspective. The perspective the court must bring to bear is that of the skilled man at the priority date and not any earlier time."
If an earlier date is excluded then so must be a later date. The only relevant date is the priority date. In addition, problems or time taken to obtain regulatory approval are not relevant to the question of obviousness. This is clear from the statement of Aldous LJ in Richardson Vick's Patent  RPC 888, 896 and of Lewison J in Ivax Pharmaceuticals UK Ltd v Akzo Nobel BV  EWHC 1089 (Ch)  RPC 3 paras 41 to 43.
"It is worth reviewing at this stage the factors which should be borne in mind in any assessment of obviousness. So far as motivation is concerned, I consider that the skilled team would be highly motivated to produce the co-formulated product, given the quantitative results in Nardin and the patient compliance benefits of a co-formulation. The quantitative results obtained at bid [twice daily administration] would lead the team to expect success. Of course the skilled team would realise that something might go wrong on the way, but nothing concrete was suggested which would have affected the skilled team's prognosis at the outset."
I see nothing in this section to suggest that impermissible hindsight had crept in. Nor do I accept the submission of counsel for Merck that if a step is obvious it will not be taken because no patent protection will arise at the end. The true test is whether the improvement involves an inventive step, not a commercially attractive one.
"...it is realistic to suggest that it would have caused the team to abandon the project. The motivation to obtain a co-formulation would remain unaltered, making abandoning it in favour of pursuing co-administration alone an unattractive proposition."
Lord Justice Richards
Lord Justice Patten