Merck Sharp & Dohme Corp v Teva UK Ltd

Glaucoma is the name given to a group of disorders of the eye characterised by the intraocular pressure (“IOP”) being so high as to damage the nerve fibres in the retina and optic nerve as it leaves the eye. On 11th April 1991 the Association for Research in Vision and Ophthalmology (“ARVO”) published as part of its Abstract Program Book for its annual meeting to be held between 28th April and 3rd May 1991 in Sarasota, Florida a paper submitted by George Nardin and others (including 3 representatives of the appellant, Merck Sharp & Dohme Corp (“Merck”)). The paper (“Nardin”) related to the additive effect in reducing IOP of administering an eye-drop including 2% of a drug then known as MK 507 some ten minutes after the administration of an eye-drop containing 0.5% of a drug called timolol. The paper suggested, on the basis of experimental tests carried out on humans over a period of 8 days, that such consecutive administration improved reduction of IOP by about 17%. On 14th April 1992 Merck filed its application for a patent in respect of “ophthalmic compositions comprising combinations of [MK 507] and [timolol]” for the treatment of glaucoma. The priority date for the patent EP 0 509 752 B1 granted later (“the Patent”) was 17th April 1991, namely some six days after the publication of Nardin.

On 19th August 2008 the respondent, Teva UK Ltd (“Teva”), instituted proceedings in the Patents Court seeking a declaration that the Patent is and has at all material times been invalid and an order that it be revoked. The grounds of invalidity relied on were want of novelty, lack of an inventive step, insufficiency and added matter. Merck sought to meet these objections by applying on 11th May 2009 for an order under s.75 Patents Act 1977 permitting the amendment of the Patent. The action was tried by Floyd J on four days between 27th October and 2nd November 2009. For the reasons given in his judgment handed down on 20th November 2009 Floyd J concluded that the Patent both as originally granted and as proposed to be amended was invalid for lack of an inventive step. In addition he made certain alternative findings in the event that he was wrong on his principal conclusion. On 11th December 2009 Merck applied again for an order permitting amendment of the Patent under s.75 in certain additional respects. By his order made on 16th December 2009 Floyd J dismissed both applications to amend the Patent, ordered that it be revoked and refused permission to appeal.

On 18th January 2010 Merck issued an appellant’s notice. It sought permission to appeal and for an order reversing that of Floyd J on 14 grounds. The application came before Jacob and Lloyd LJJ on 11th May 2010. They gave Merck permission to appeal on grounds 1 to 6 (both inclusive) and 14 only. Those grounds relate only to claim 18 of the Patent as proposed to be amended and take issue with the judge’s conclusion on obviousness (ground 14) and added matter (grounds 2 to 6). Thus the issues before us were limited to those two objections to that claim. The parties agreed that if we upheld the judge’s conclusion on obviousness then the issue on added matter would not arise. Having heard full argument from both sides on obviousness we concluded that the judge was right and that argument on added matter was unnecessary. Accordingly we did not hear argument on that issue. My judgment is, therefore, limited to the issue of obviousness in relation to amended claim 18. Before I deal with that issue it is necessary to describe in a good deal more detail the common general knowledge and prior art at the priority date, the specification and claims in the Patent and the judgment of Floyd J.

The technical background is set out with conspicuous clarity by Floyd J in paragraphs 4 to 23 of his judgment. The description which follows is taken from those paragraphs. Glaucoma, which I have already described in paragraph 1 above, is caused by an increase in IOP. The most common type results from impedance to the flow of aqueous humour through the exit routes from the eye, causing the IOP to rise. It results in progressive loss of field of vision. Treatments of glaucoma rely either on reducing the rate at which aqueous humour enters the eye, or increasing the rate at which it leaves.

The process by which aqueous humour is created is dependent on the enzyme carbonic anhydrase. Inhibition of this enzyme, by means of a carbonic anhydrase inhibitor (“CAI”) reduces the production of aqueous humour. At the priority date, chronic simple glaucoma was treated with four main classes of drug, namely, miotics, sympathomimetics, beta blockers and CAIs. Of these the beta blocker timolol was the most widely prescribed. It was the “first line” treatment and regarded as the gold standard. It had no major side effects in the majority of patients. Apart from timolol all the other drugs had some unpleasant side effects. Pilocarpine, a miotic, was known to cause constriction of the pupil or “brown out”, as well as stinging on application and headache. The beta blockers led to reddening of the eye, stinging or burning and vaso-constriction leading to discomfort or disfigurement.

All but the CAIs were administered topically (eyedrops). CAIs were given by mouth. Diamox was the trade name of a clinically approved oral CAI. This had the effect of inhibiting the enzyme in the whole body, with the consequence that the side effects were experienced systemically. It could cause tingling in the extremities, depression, loss of libido and other undesirable side effects. It was well recognised that a topical CAI would be likely to reduce and localise any side-effects. Accordingly, much research had been done by the priority date into identifying and obtaining approval for a CAI which could be administered topically. A number of compounds had been suggested in the literature, but none had yet obtained clinical approval. The front runners at the priority date were MK 507, sezolamide and a compound called MK 927. MK 507 was Merck’s name for the compound which became known as dorzolamide. A review of the literature would have shown MK 507 or dorzolamide.

Clinically, glaucoma would be treated first with a single drug. It was common practice, where a single drug was not proving effective, for a second drug to be prescribed. About 50% of glaucoma patients required a second drug. Some would be on more than two drugs. If a patient was required to take doses of both drugs at the same time, he or she would be advised to wait 5 to 10 minutes between the instillations of the different drugs. The parties’ clinical experts agreed that in 1991 the treatment options for glaucoma were limited.

Adjunctive therapy is the term used by Floyd J to describe the therapy in which the patient takes a number of medicaments for the same complaint. Where the patient takes doses of the two medicaments at effectively the same time (i.e. separated by the 5 minute interval) he used the term concomitant administration. Adjunctive therapy is to be distinguished from a product where two active ingredients are formulated together in the same eye drop solution. The judge referred to this as co-formulation. At the priority date a number of co-formulated drugs had been marketed, but none with any great success. Other methods of treating glaucoma included surgery (trabeculectomy) and laser surgery (trabeculoplasty).

An extremely important problem associated with glaucoma treatment in 1991 was the lack of patient compliance. This was for at least three reasons. First, ocular hypertension is asymptomatic, so the patient is unaware of the IOP lowering effects of the drugs. Secondly, many of the drugs have unpleasant side effects including stinging, irritation and discomfort upon instillation. Thirdly, the physical act of administering the drug is difficult, particularly in the elderly and those suffering from poor vision.

All or nearly all commercially available drugs in 1991 were designed so that only one drop needed to be administered at any one time. The reason is again that the act of placing the drop in the eye is difficult. The problem is exacerbated where the drug causes discomfort. The taking of concomitant medication at 5-10 minute intervals was also seen as a significant inconvenience for some patients.

At the priority date the commercial formulation of timolol that was on the market was available at concentrations of 0.25% and 0.5%. The dose was administered twice a day. It was recognised that 0.5% twice a day was at the top of the dose response curve. In other words no added benefit could be obtained by increasing the concentration or repeating the dose more frequently. It was formulated at a pH of 6.8. It was well known that the degree of corneal penetration of a drug depended on its degree of ionisation: un-ionised drugs being better at penetrating the cornea. In consequence the degree of penetration was known to be dependent on pH. However, the degree of penetration did not depend solely on pH. In particular it was well known that the degree of penetration could, if necessary, be increased by the inclusion of a viscosity modifying agent, so as to prolong the contact time of the drug with the eye and therefore give it more opportunity to penetrate.

The prior art on which Teva relied for its claim of want of novelty or inventive step was, in the context I have described, Nardin. That document was entitled “Activity of the topical CAI MK-507 bid [sc. bis in die or twice daily] when added to timolol bid.” After setting out the names of the contributors and the organisations to which they belonged it continued:

In relation to Nardin, Floyd J commented on a number of significant features. They included the following:

The Patent explains the medical context I have summarised in paragraphs 4 to 11 above. The specification notes that topically effective CAIs had been disclosed though none was available for clinical use and continues at [0010]:

Claim 1 as proposed to be amended and substituting their full chemical names with dorzolamide and timolol would read:

Claims 2 to 7 were dependent on unamended claim 1. The proposed amendment deleted claims 8 and 9. Unamended claim 10 is to:

Unamended claims 19 and 20 were to a process for a formulation as claimed in any of unamended claims 10 to 18. Unamended claim 20 would become amended claim 18 in the following form:

For the reasons given in paragraphs 81 to 86 the judge concluded that claims 1 to 6 and 8 and 9 were all invalid for want of novelty. Merck did not seek to appeal from that conclusion. The judge then considered the narrowest use claim in claim 6 on the basis, as expressed in paragraph 115, that all other claims relied on were of equivalent width or broader or were not claimed to be independently valid. In paragraph 118 he said:

As I have already indicated, permission to appeal on those grounds was refused. Accordingly, it is necessary to consider the rest of the judgment of Floyd J on obviousness by reference to amended claim 18 alone. In paragraphs 87 to 99 Floyd J directed himself as to the law on obviousness by reference to the well known passages in Hallen v Brabantia [1989] RPC 307; St Gobain v Fusion Provida [2005] EWCA Civ 177 and Conor v Angiotech [2007] UKHL 49. It is common ground that such direction was entirely correct. It is said that he did not properly apply it to the facts of the case. His approach was to follow the four steps suggested by the Court of Appeal in Pozzoli v BDMO [2007] EWCA Civ 588, namely:

In paragraphs 100 to 113 the judge considered the first question. In paragraphs 114 and 115 he concluded that:

The judge then considered the differences between Nardin and that inventive concept. He considered that there were only two, namely the identification of MK 507 and co-formulation. He considered that the skilled man would readily and rapidly discover what MK 507 was. The remaining question posed in paragraph 118 was:

The case for Teva in respect of that question, which he accepted, was in two parts. The first part set out in paragraph 119 was:

Floyd J accepted all these steps and concluded in paragraph 128:

The judge then recorded the second stage of the argument for Teva as follows:

He accepted propositions (iii) and (iv) as being well established by the evidence and continued in paragraph 130:

Floyd J then considered in paragraphs 136 to 148 whether the pH problem would cause the project to be abandoned. He concluded in paragraph 147 that:

Finally Floyd J considered whether the evidence established that the project would be successful. In paragraphs 149 to 159 he considered whether the skilled team starting from Nardin would be able to carry the project through to actual use. He concluded that it would. In paragraph 161 he concluded:

In the light of his conclusions on obviousness the judge did not have to deal with the objection based on insufficiency. He concluded that the patent as sought to be amended was invalid for want of an inventive step. In addition he considered that unamended claims 1 to 6, 8 and 9 also lacked an inventive step. Had the patent been otherwise valid he would not have allowed the amendment to unamended claim 20 (amended claim 18) anyway on the ground that it added matter.

The permissible grounds of appeal are grounds 1 and 14. The effective ground is ground 14. In view of some of the submissions made to this court I find it necessary to set out that ground in full. But the reader must bear in mind that when originally formulated it was in the context that co-formulation, as claimed in claim 6, was not obvious. Ground 14 is as follows:

The effect of the decision of this court in allowing permission to appeal on ground 14 but not grounds 7 to 13 is that the only permissible ground left to Merck is that expressed in the middle of ground 14, namely, whether Teva had established that the outcome of its step by step approach would be a formulation of timolol and dorzolamide in the proportions specified in claim 6 at a pH range of 5.5-6.0 as required by proposed amended claim 18. Counsel for Merck submits that the proper conclusion on that issue is in the negative. He relies on the following propositions:

In support of his first proposition counsel for Merck emphasised the regulatory environment involved in the introduction of new medicinal products. He pointed out, correctly, that all those steps could not possibly be completed in six days. Indeed he questioned whether the skilled team would even find out in that period that dorzolamide would not dissolve in water with timolol at the concentration for which claim 6 provided without making some adjustment to the pH. He accepted that discovering what that adjustment was is a matter of trial and error and does not involve any inventive step but suggested that the trials and errors would take a substantial period of time.

In relation to his second proposition counsel for Merck contended that the judge had wrongly employed hindsight in concluding that the skilled team would ever start out on a project for the co-formulation of timolol and dorzolamide. If, as the judge had decided, the development of such a co-formulation would not qualify for patent protection why spend the time and money necessary for its development. This part of his argument involved a challenge to the reasoning and conclusion of the judge on the first of the questions he posed for himself in paragraph 130 I have quoted in paragraph 25 above.

Counsel for Merck then went on to suggest that even if the skilled team had set out on trying to provide a co-formulation of timolol and dorzolamide their subsequent realisation of the problems of solubility of dorzolamide at the pH at which timolol is formulated would lead them to abandon the project. This part of his case appears to me to involve a challenge to the reasoning and conclusion of the judge in respect of the second of the questions suggested in paragraph 130 of his judgment quoted in paragraph 25 above.

Both propositions were disputed by counsel for Teva. He contended, by reference to Patents Act 1977 ss.1(1), 2(1) and (2) and 3 that the test of obviousness does not involve any express or implied time limit. In relation to the second he contended that the characterisation of the judge’s approach as a classic step by step analogy, which is recognised as possibly involving hindsight to an impermissible degree, was not correct. Rather the judge reached essential conclusions of fact on the basis of the evidence before him.

I will deal with the two propositions in turn. The tests for novelty and obviousness both depend on the statutory definition of ‘state of the art’ in s.2(2) Patents Act 1977. That is in the following terms:

The test of obviousness is prescribed by s.3 in these terms:

That this is so is consistent with the decision of this court in Actavis UK Ltd v Merck & Co. Inc. [2008] EWCA Civ 444 [2008] RPC 26. In that case it was asserted that the invention had been obvious but had been rendered inventive because of some supervening publications. That submission was upheld by the judge and the Court of Appeal. In paragraph 119 Jacob LJ noted that:

But that is not the end to the objections to which this submission gave rise, namely that this point was not raised in the court below, nor, for that matter in the grounds of appeal. Had it been raised in the court below some evidence would have been necessary to indicate how long it would have taken for the skilled man to appreciate the necessity for and the extent of the adjustment of the pH of the formulation to ensure the solubility of the dorzolamide. There was none. Indeed I understood counsel for Merck to accept that it would have been obvious to the skilled man that some such adjustment would be required and it was a mere matter of trial and error to discover what it was. Accordingly I conclude that this point is not open to Merck, permission to raise it should not be given, and that it is in any event incorrect as a matter of law.

I turn then to the second proposition. Counsel for Merck submitted that the reasoning of the judge involved no fewer than 23 steps, 17 from the first stage and 6 from the second. He claimed that such a quantity was unparalleled and itself indicative of the use of hindsight. I would reject this submission. The first ten in the first stage are different elements in the relevant state of the art and the eleventh is the conclusion the judge drew from them. It seems to me that the first stage involves one step only, namely embarking on the project which Nardin suggested.

The judge considered this in detail in paragraphs 131 to 135. In paragraphs 133 and 134 he evaluated the evidence of Professors Serle and Rennie, the ophthalmological experts for Merck and Teva respectively, and preferred the latter as the more realistic. On this aspect he considered that the conclusion that co-formulation would be considered well worth while investigating was inescapable. He concluded in paragraph 135:

Similarly the six steps suggested to form the second stage appear to me to involve only one namely appreciating the need to adjust the pH of the formulation and then conducting the routine tests required to discover to what pH it needed to be adjusted. Indeed when pressed counsel for Merck accepted that there were only two steps in respect of which the judge used hindsight, namely embarking on the project in the first place, with which I have already dealt, and continuing it after appreciating the need to adjust the pH of the formulation. This was the issue with which the judge dealt in paragraphs 136 to 148.

On this issue the judge accepted (paragraph 137) the evidence of Dr Wilson, the expert pharmacologist for Teva, that “the pH route to achieving the necessary solubility was the most obvious one”. In addition it was supported by the contemporaneous documents produced by Merck to the effect that any drop in bioavailability due to the lowering of pH would be slight. He rejected the contrary submission of Merck on the ground that the works on which it relied were not part of the common general knowledge at the time. On this aspect of the case he did not consider that:

I detect no hint of impermissible hindsight being used here either. The judge’s conclusion was based firmly on his evaluation of the evidence, both oral and documentary, adduced before him. It is accepted that the judge correctly directed himself. Further he was conscious of the dangers of hindsight creeping in. He stood back and reconsidered his conclusions with the consequence recorded in paragraph 161 quoted in paragraph 27 above. Indeed given the facts that Nardin, Ganda and the need to adjust pH to ensure solubility were all part of the common general knowledge or relevant state of the art he could not sensibly have arrived at any other conclusion. I see no error on the part of the judge which could entitle this court to interfere with his conclusion. I would dismiss this appeal.