Teva UK Ltd v Merck & Co, Inc [2009] EWHC 2952 (Pat)

[2009] EWHC 2952 (Pat)Case No HC08C002364
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Venue Royal Courts of Justice, Strand, London, WC2A 2LLDate 20/11/2009
Before
THE HON MR JUSTICE FLOYD
Between
TEVA UK LIMITEDClaimantMERCK & CO., INCDefendant
Simon Thorley QC and Tom Mitcheson (instructed by Bird & Bird) for ClaimantColin Birss QC and Tom Hinchliffe (instructed by Rouse Legal) for DefendantHearing Hearing dates: 27 th-29 th October, 2 nd November 2009
JudgmentMr Justice Floyd :
[1]Teva UK Limited (“Teva”) applies by this action for revocation of European Patent (UK) No 0 509 752 (“the Patent”). The Patent is in the name of Merck & Co. Inc (“Merck”). This judgment is divided into the following sections: Paragraph numbers Introduction 1-3 Technical Background 4-23 Witnesses 24-28 The Patent 29-44 The claims 45-47 Construction 48-59 Unamended claim 1 48-52 The use claim 53-59 Amendment and added matter 60-76 Amendment to claim 1 61-67 Amendment to claim 18 68-76 The cited prior art 77-80 Lack of novelty - law 81 Lack of novelty/obviousness of unamended claims 82-86 Obviousness - law 87-99 Obviousness of amended claims in the light of Nardin 100-118 The person skilled in the art 100 Common general knowledge – law 101-103 Common general knowledge about co-formulation 104-114 The inventive concept 115 Differences between Nardin and the inventive concept 116-118 Teva's obviousness case 119-161 Would the project be abandoned before it is begun? 131-135 Would the pH problem cause the project to be abandoned? 136-148 Does the evidence establish that the project would be successful thereafter? 149-161 Insufficiency 162-163 Conclusions 164[2]Teva claims that the Patent is invalid for obviousness in the light of a single item of prior art and common general knowledge. Teva also raises objections of added matter and insufficiency. Merck has, in response, applied unconditionally to amend the Patent. Teva says that the amendment does not save the Patent, and that the amendments are not allowable anyway. Merck says that although it wants the amendments if they are allowable, if the amendments are not allowable, the unamended Patent is not invalid.[3]The claimed invention relates to an ophthalmic formulation for the treatment of the eye disease glaucoma. The Patent claims protection, by means of various types of claim, for an eye drop containing two drugs, timolol and dorzolamide, for the treatment of glaucoma. Timolol is a beta-blocker. Dorzolamide is the name now given to the second drug, known at the priority date as MK 507, a carbonic anhydrase inhibitor. Before descending into more detail about the Patent, it would be useful to set out some common ground about what was known about glaucoma, and ways of treating it at the priority date in 1991.

Technical Background

[4]Glaucoma refers to the group of diseases which share common features including loss of visual function and atrophy of or damage to the optic nerve. Damage to the optic nerve is caused by an increase in intra-ocular pressure (“IOP”). The most common type of glaucoma 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.[5]Treatments of glaucoma rely either on reducing the rate at which aqueous humour enters the eye, or increasing the rate at which it leaves.[6]The process by which aqueous humour is created is dependent on the enzyme carbonic anhydrase. Inhibition of this enzyme reduces the production of aqueous humour.[7]In April 1991 the main classes of drugs used to treat chronic simple glaucoma were the following: Class Alternative name Examples cholinergic agonists miotics pilocarpine adrenergic agonists sympathomimetics adrenaline, epinephrine (US name for adrenaline), dipivalyladrenaline adrenergic potentiators guanethedine beta adrenergic receptor anatagonists beta blockers timolol, betaxolol, carteolol, levobunolol. carbonic anhydrase inhibitors CAIs acetazolamide[8]At the priority date, the beta blocker timolol was the most widely prescribed of these medications. 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 was known to cause constriction of the pupil or “brown out”, as well as stinging on application and headache. The adrenergic agonists led to reddening of the eye, stinging or burning and vaso-constriction leading to discomfort or disfigurement.[9]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.[10]Because it was recognised that a topical CAI would be likely to reduce side effects, 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 to be the best of the three.[11]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 require 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 point in time, he or she would be advised to wait 5 to 10 minutes between the instillations of the different drugs.[12]Both Professor Rennie and Professor Serle (Teva’s and Merck’s respective clinical experts) emphasised that the treatment options for glaucoma in 1991 were limited. Professor Rennie said that in 1991 he would, at one time or another, have had most patients on most different combinations.[13]Adjunctive therapy is a term I shall use 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) I shall use the term concomitant administration.[14]Adjunctive therapy is to be distinguished from a product where two active ingredients are formulated together in the same eye drop solution. I will refer to this as co-formulation.[15]At the priority date a number of co-formulated drugs had been marketed, but none with any great success: Trade name Active ingredients GANDA Guanethidine and epinephrine TIM-PILO Timolol and pilocarpine E-PILO Epinephrine and pilocarpine[16]There is a dispute, which I deal with below, as to whether these products were part of the common general knowledge.[17]Other methods of treating glaucoma included surgery (trabeculectomy) and laser surgery (trabeculoplasty).[18]An extremely important problem associated with glaucoma treatment in 1991 was the lack of patient compliance. This was for at least three reasons. Firstly, ocular hypertension is asymptomatic, so the patient is unaware of the IOP lowering effects of the drugs. Secondly, many of the drugs, as indicated above, 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.[19]Professor Serle (Merck’s clinical expert) pointed to the fact that there were other reasons for non-compliance as well, but she did not dissent from the existence of those mentioned above.[20]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.[21]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.[22]It was well known that the degree of corneal penetration of a drug depended on its degree of ionisation: un-ionised drug being better at penetrating the cornea. In consequence the degree of penetration was known to be dependent on pH.[23]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.

Witnesses

[24]Both sides called a clinical ophthalmologist and an ocular pharmacologist. Teva called the following two: i) Professor Ian Rennie who is currently Professor of Ophthalmology at the University of Sheffield and an Honorary Consultant Ophthalmic Surgeon at the Royal Hallamshire Hospital. His principal research has been in the field of genotypic and phenotypic properties of ocular melanomas. In the early 1980s he undertook some work on the use of beta blockers in the treatment of glaucoma. In the early 1990s he worked on the development of CAIs. In addition, as part of his general ophthalmology practice, he has treated patients with glaucoma. ii) Dr William Wilson who was, until he retired in 2005, a lecturer in Pharmacology at Glasgow University. His primary research interest has been in ocular pharmacology and in particular the investigation of drug mechanisms at the molecular level, specifically the way in which drugs can alter the progress of glaucoma by altering aqueous humour dynamics. He has studied beta blockers, CAIs, and adrenergic agonists amongst other drugs.[25]Merck called: i) Professor Janet Serle who is Professor of Ophthalmology at Mount Sinai School of Medicine. She has specialised in the treatment of glaucoma since 1985 and has been a principal investigator on pre-clinical and clinical studies for agents used to treat glaucomaincluding studies relating to timolol and dorzolamide. ii) Dr Michael Sugrue who is a pharmacologist who worked in industry from 1970 until he retired in 2000. From 1981 to his retirement he worked for Merck and was involved in ocular pharmacology. He worked on dorzolamide whilst at Merck.[26]Mr Thorley drew attention to the fact that Professor Serle was intimately involved with Merck’s topical CAI project. He says that she drew too heavily on her contemporaneous thinking, rather than placing herself in the position of an ordinarily skilled clinician reading the prior art document with interest. I do not think this is a valid criticism of her as a witness. It is true that the court is attempting to place itself in the position of a notional clinician, but it is entirely appropriate for a witness to rely on his or her contemporaneous thinking. If a witness read a prior art document, but was not led to think of the alleged invention at the time, that is material evidence which the court is entitled to take into account, together with the other evidence against which it must be weighed.[27]Mr Thorley launched a more pointed attack on Dr Sugrue, principally on his written evidence. He cited as an example the fact that Dr Sugrue said in his written report that the skilled person would not necessarily know what MK 507 was (the Merck name used for dorzolamide in the prior art) and would have to find out about it. I do not think that that Dr Sugrue did anything wrong here. His evidence was relevant to answering the attack of lack of novelty. He never asserted that Merck was trying to keep the identity of MK 507 a secret. It plainly was not.[28]Mr Thorley also criticised Dr Sugrue for his evidence concerning the amount of reduction in corneal penetration that would occur if the pH of the solution had to be reduced. I shall come to the evidence on this topic in due course. I was, however, rather surprised when Dr Sugrue declined to express an independent view at all on the correctness of Dr Wilson’s theoretical approach to the likely amount of pH reduction based on the distance away from the pKa value. I have to say that I would have thought that this was a topic on which a pharmacologist should be able to engage. I can well understand that he might not support the theoretical approach, but his reluctance to confirm the accuracy of the underlying science did not reflect well on his approach as a witness, which at times lacked balance. It seemed to me that he was reluctant to engage on the topic because he thought, rightly or wrongly, that his answers might be adverse to Merck. I have approached Dr Sugrue’s evidence with a degree of caution as a result.

The Patent

[29]The Patent explains the background to the treatment of glaucoma. It explains at [0005] that many of the drugs used in the past to treat glaucoma, e.g. pilocarpine, did not prove to be entirely satisfactory. As to beta blockers, it explains again that: “there exist some patients with whom this treatment is not entirely satisfactory”.[30]The Patent points out at [0007] that neither pilocarpine nor beta blockers operate by inhibiting carbonic anhydrase, and thus: “do not take advantage of reducing the contribution to aqueous humour formation made by this carbonic anhydrase pathway”.[31]The specification acknowledges at [0008] that whilst CAIs are used to treat glaucoma by the systemic route, this has the disadvantage that the entire system is treated and can only be justified: “during an acute attack of alarmingly elevated IOP when no other agent is effective”.[32]Nevertheless it is acknowledged at [0009] that topically effective CAIs are disclosed in a number of US Patents and a PCT publication, but none are yet available for clinical use.[33]At [0010] the specification says:
“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.”
[34]At [0011] the specification explains the activity of CAIs currently under development wanes 6 to 9 hours after dosing, requiring tid dosing. The combination of the invention is said to maintain lowering of IOP for a full twelve hours, allowing bid dosing. As a result, patient compliance is anticipated to be greater.[35][0014] is the first paragraph to which an amendment is sought. Prior to the proposed amendment it reads:
“[0013] The combination disclosed herein is effective either by 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 β-adrenergic antagonist followed by administration of the other solution. The use of a single solution containing both active medicaments is preferred.”
[36]The proposed amended paragraph reads as follows: [0013] The combination disclosed herein is effective either by 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 β-adrenergic antagonist followed by administration of the other solution. The use of a single solution containing both active medicaments is preferred.disclosed.[37]Similar amendments are proposed elsewhere to the description and claims to make it clear that a co-formulation is now required, rather than merely preferred.[38][0014] contains a reference to US Patent No. 4 863 922 which suggests the “combination of this invention”, but points out that a precise formulation of the relative combination of medicaments to give effective reduction of IOP is not taught. This is a rather odd statement, given the extremely wide range of the relative amounts of the two drugs which follows in the description and claims.[39]The detailed description starts by stating that the invention relates to the use of (a) 0.05% to 5% w/w of dorzolamide (a CAI) and 0.01 to 1.0% timolol (a beta-adrenergic antagonist; to an ophthalmic formulation containing the same combination of active ingredients; and to a method of making an ophthalmic formulation.[40][0022] spells out ranges of concentration for the formulations of the invention:(a) 0.05-5%, usually about 0.5-3% of dorzolamide and(b) 0.01 to 1%, preferably about 0.1 to 0.5% of timolol.[41]Example 1 gives three example co-formulations at ratios of approximately 3:1, 9:1 and 1:6 of dorzolamide to timolol, with the pH adjusted to 6.0.[42]Example 2 gives three further example co-formulations at ratios of 4:1 and 1:2.5. The composition is adjusted to a pH range of 5.5 to 6.[43]Example 3 is a study of the concomitant administration (not co-formulation) of timolol 0.5% bid and dorzolamide 2.0% in patients. It is a notable feature of this case that the study is in all material respects identical to the single item of prior art relied on, the Nardin extract, which I have set out in full later in this judgment. It shows that timolol plus dorzolamide gave a 13 to 21% improvement over timolol alone. The improvement is described as clinically and statistically significant.[44]There is no example of a similar study in relation to the co-formulation.

The claims

[45]The claims in issue after amendment are the following. I have used the names dorzolamide and timolol in place of their full chemical names. For the amendments, I have shown additions by underlining and deletions by strikethrough : “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 β-adrenergic antagonists, wherein said medicament takes the form of a single solution adopted for topical administration. 6. Use as claimed in any one of claims 1 to 5 wherein the concentration of dorzolamide is 0.7 to 2.0% and the concentration of timolol is 0.5%. 2018. 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.” (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; (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;[46]For completeness I should add that claim 17 merely recites the addition of the two drugs in the same range of amounts as claim 18 to a carrier.[47]The other claims which I need to consider are unamended claims 1, 6 and 18 which can be seen from the above, and unamended claim 13 which is to a formulation as claimed in any of claims 10 to 12 wherein the concentration of dorzolamide is 0.5 to 3%. Unamended claim 10 reads: 10. An ophthalmic formulation for the treatment of ocular hypertension or glaucoma in a patient population the members of which are insufficiently responsive to β-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. Construction Unamended claim 1

Construction

[48]One issue of construction arises in relation to unamended claim 1. The question is whether the claim is already limited to the use of a single, co-formulated medicament, or whether it extends to the use of the two drugs by adjunctive therapy.[49]The correct approach to construction has been set out in a number of cases, and there was no dispute about it here. The task for the court is to determine what the skilled person would think that the patentee was using the language of the claim to mean. A legitimate canon of construction is that, normally, one would expect the claims to extend to all the ways of performing the invention described in the specification, not merely those which are said to be preferred.[50]Mr Simon Thorley QC, who appeared on behalf of Teva with Mr Thomas Mitcheson, submitted that the skilled reader would note from [0022] that the patentee considered that the combinations disclosed were effective either by co-administration in one solution (co-formulation), or by the prior administration of one or the other as a combined therapy. The skilled person would therefore fully expect that the patentee would wish to claim both types of use in the use claim, claim 1. He says this appreciation is rammed home when the one looks at the examples. Example 3 is an example of concomitant administration. Furthermore he submits that it is only claim 1 and claims dependent thereon which can possibly cover the adjunctive therapy. Unamended claims 10 and 19 are clearly limited to, respectively, a co-formulation and a process for making one.[51]Mr Colin Birss QC who appeared for Merck with Mr Thomas Hinchliffe laid stress on the singular form “medicament” in claim 1. In his oral submissions Mr Birss pointed out that Teva had not attacked unamended claim 8 for lack of novelty. Unamended claim 8 is a use claim where the “said medicament takes the form of a solution etc”. If “medicament” is broad enough to cover separately administered drugs, why had Teva not attacked this claim as well?[52]In my judgment claim 1 is plainly wide enough to cover co-administration as well as co-formulation for the reasons Mr Thorley gives. There is nothing in either of Mr Birss’ points. As to the first point, I see no reason why, in the context, making a “medicament” cannot describe making both drugs for separate administration. As to the second point, I consider Teva’s pleading to be an inadequate basis for reaching another conclusion. Mr Thorley’s response to the point, which Mr Birss had not articulated at any earlier stage, was to explain that claim 8 had been omitted from the list of claims said to lack novelty by an oversight. That submission is persuasive, as claim 9, which is a use claim where the medicament also “takes the form of a solution”, was attacked by Teva from the outset.

The use claim

[53]Claim 1 requires the use of the co-formulated drugs “for the manufacture of a medicament for the treatment of ocular hypertension or glaucoma in a patient who is insufficiently responsive to β-adrenergic antagonists”. Claim 8 (as amended) calls for a formulation “for the treatment of ocular hypertension or glaucoma in a patient population the members of which are insufficiently responsive to β-adrenergic antagonists.” Process claim 18 contains no such limitation.[54]Mr Birss submitted that the claim means that the medicament is effective to treat the disease in question. He relied on what Laddie J said in the Viagra case: Pfizer’s Patent [2001] FSR 201 at [40] to [42]. In that case Pfizer submitted that the claim in second medical use form required that the use of the compound be both for trying to treat the illness in question and be in fact suitable for treating it. The party applying for revocation argued that it was enough if the use of the compound was for the purpose of trying to treat the illness.

The Judge favoured Pfizer’s construction:

“A second medical use claim only survives because the compound is effective to achieve a new treatment. If it is not effective, or not discernibly so, it is not suitable for that treatment.”
[55]Thus he submitted that if the medicament is not effective, the claim is insufficient. Equally the target for the obviousness attack is an effective treatment for the disease in question.[56]Mr Thorley submitted in paragraph 48 of his opening skeleton that the phrase meant no more than the medicament is useful for trying to treat patients.[57]I have no difficulty in accepting Mr Birss’ submissions. The formulation must produce some discernible effect in the relevant patient class. The claim does not specify any particular degree of effectiveness, beyond the fact that the effect must be shown in a patient who is insufficiently responsive to beta blockers, presumably timolol alone.[58]I think the same must apply to the formulation claims, which also contain the requirement that the formulation is “for the treatment of ocular hypertension in a patient population the members of which are insufficiently responsive to beta-adrenergic antagonists”. The skilled reader would understand that the ophthalmic formulations must be effective for the treatment of the patient class concerned.[59]Some idea of what is called for can be seen from the Examples. Example 3, as I have said, discloses a 13-21% improvement over timolol alone when 2% dorzolamide and 0.5% timolol are co-administered. Example 2, formulations I and II, show that for a roughly 2% w/w solution of dorzolamide one may include 0.7% or 0.13% timolol and still obtain a formulation illustrative of the invention.

Amendment and added matter

[60]Teva oppose the amendments, principally on the grounds that they add matter. There was no serious dispute about the law on added matter. It has most recently been set out by the Court of Appeal in Napp v Sandoz[2009] RPC 18 at §§69-71, where the relevant authorities are considered.

Amendment to claim 1

[61]The amendment sought to claim 1 is to make it clear that claim 1 is limited to the use of a topical co-formulation. Teva’s statement of objection raises two objections to this amendment:
“(1) The Patent as proposed to be amended discloses that the feature sought to be introduced into claim 1 (wherein the medicament takes the form of a single solution) has technical significance. There is no disclosure of this technical significance in the application as filed and its selection amounts to an impermissible intermediate generalisation. (2) Further or alternatively, the only disclosure in the application as filed of the administration of a medicament to a patient is in example 33 (equivalent to example 3 of the Patent as granted). This discloses the administration of separate solutions of timolol and dorzolamide, and is the equivalent of the Nardin prior art relied upon. To the extent that it is contended that claim 1 is inventive over Nardin, the Claimant will say that claim 1 contains added matter because the application as filed discloses no more than Nardin.”
[62]The first question is whether any subject matter has been added. In my judgment it is plain that it has not. The specification before amendment clearly disclosed both concomitant administration and co-formulation in a single solution: see the paragraph bridging pages 5 and 6 of the application as filed. Thus the feature sought to be added by amendment is clearly and unambiguously disclosed in the application as filed.[63]The first paragraph of Teva’s objection recognises this fact, but contends, firstly, that the technical significance of the feature is not disclosed in the application as filed and, secondly, that this amounts to added matter, by intermediate generalisation. I have no hesitation in rejecting both limbs of that submission.[64]As to the first limb, once co-formulation is in fact disclosed, and stated to be preferred, its technical significance would at once be appreciated by the skilled person. The skilled person would appreciate that the two drugs can be co-formulated. The skilled person would understand that co-formulation brings with it advantages of patient compliance. All these are technical matters which would be appreciated from the application as filed. It is not therefore necessary for me to express a view on whether matter could ever be regarded as added for the purposes of this objection if all that is alleged is that technical significance is attached to a feature which was disclosed in the application as filed.[65]As to the second limb, it is correct that matter can be added by intermediate generalisation. Thus to take a feature which is disclosed only in one context and to combine it with other features disclosed in another context may be impermissible. But, in my judgment, nothing of that nature is effected by the amendment to a single solution. Merck is limiting its use claim to the preferred use, which was separately described in the application as filed.[66]The second paragraph of Teva’s objection also fails. It is founded on the proposition that the application as filed (like Nardin) only discloses adjunctive therapy, not use of a co-formulation. But this is only correct if one confines one’s attention to Example 33 of the application. Other examples in the application as filed disclose co-formulated ophthalmic formulations, including examples equivalent to Examples I and II in the granted Patent. When the application says at page 6 that “the use of a single solution is preferred” it is disclosing, inter alia, the use of those co-formulations. So the factual basis of the objection is not made out.[67]No matter is added by the addition of the words sought to be added to claim 1 to make it clear that only a co-formulation is claimed.

Amendment to claim 18

[68]The proposed amendment to claim 18 is to limit the range in the pH adjustment step to 5.5 to 6.0 from the previous range of 5.0 to 6.0. This arises in connection with an objection of added matter which was made to the granted Patent. It is convenient to decide that issue here. The pleaded objection reads:
“The disclosure of the Patent extends to a pH range for the co-formulation of timolol, dorzolamide and various excipients of pH 5.0 to pH 6.0. The application as filed for the Patent, as exemplified in Example 10 on page 13, does not disclose a pH range for the co- formulation of timolol, dorzolamide and various excipients between pH 5.0 and pH 5.5 and therefore does not extend to this subject matter.”
[69]In the examples in the application, sometimes pH is adjusted to 5.0 to 6.0 (e.g. Example 11 which is not a dorzolamide example) whereas others (like Example 10, which became Example 2 in the granted Patent and Example 1, which became Example 1 in the granted Patent) adjust to pH 5.5 to 6.0 or pH 6.0. There is no general discussion of pH elsewhere in the document.[70]I think that there is added matter in the granted, but unamended Patent. Once the claim is limited to the specific co-formulation of dorzolamide and timolol, there is no basis for the disclosure of a process for making a co-formulation by adjusting to a pH other than 5.5 to 6.0.[71]Merck seek to excise the added matter by the amendment to claim only the pH range 5.5 to 6.0. Is that amendment allowable? The objection is the following:
“(1) The Patent as proposed to be amended discloses that the feature sought to be introduced into claim 18 (adjusting the pH of the coformulation of dorzolamide and timolol to 5.5-6.0) has technical significance. There is no disclosure of this technical significance in the application as filed and its selection amounts to an impermissible intermediate generalisation. (2) In example 1 of the application as filed (example 1 of the Patent), the pH of the solution composition is adjusted to 6.0. In example 10 of the application as filed (example 2 of the Patent), the pH of the solution composition is adjusted to 5.5-6.0. The specification of the Patent does not otherwise refer to the pH of the coformulation.”
[72]Mr Thorley advanced the point in rather a more specific way in his reply speech. He said that pH 5.5 to 6.0 was only disclosed in relation to a formulation of dorzolamide in combination with gellan gum, a particular form of viscosifier (Example 10 in the application as filed). Example 1 used HEC as a viscosifier at a pH of 6.0. The upshot of the submission was that, given the paucity of the disclosure about pH generally, the only disclosure that the skilled person would take out of the application as filed for combinations of dorzolamide and timolol would be gellan gum at pH 5.5 to 6.0 and HEC at pH 6. To claim a range of pH 5.5 to 6.0 for dorzolamide irrespective of viscosifier amounts to an impermissible intermediate generalisation.[73]Dr Sugrue was asked some questions on this general topic in cross examination. He was taken through the pH shown in Examples 1 and 2 of the granted patent (Examples 1 and 10 of the application as filed). He volunteered that a key difference between the Examples was that Example 2 used gellan gum as viscosifier. He said it was “certainly different” from Example 1 and that gellan gum was a better viscosifying agent than HEC. Later he said that, for dorzolamide, gellan gum had no beneficial effect as compared with HEC. Dr Sugrue did not however explain in what respects gellan gum was “better” than HEC. It was not put to him that he would infer from the Examples that the lower pH was only accessible if gellan gum was used. Given the stage at which it was raised, and the rather inconclusive evidence, I prefer not to place any weight on the point about gellan gum.[74]Nevertheless, the skilled person reading the application would see that for a range (3:1 to 1:6) of relative concentrations of dorzolamide and timolol, Example 1 teaches a step of adjusting the pH to 6.0. Further, the skilled person would see that for a narrower range of relative concentrations in Example 10 (4:1 to 1:2.5), a choice of final pH in the range of 5.5 to 6 is given. Finally he would see that there were numerous differences between the details of the formulation in Example 10 from that in Example 1.[75]The added matter is said to reside in claim 18 as proposed to be amended. It is always important to distinguish between what a claim covers and what it discloses. One of the processes which claim 18 as proposed to be amended does disclose is the addition of the minimum amount of dorzolamide (0.05%) to the maximum amount of timolol (1.0%), followed by a pH adjustment step to pH 5.5. These are values which are expressly mentioned, and therefore disclosed in the claim. This represents a ratio of dorzolamide to timolol of 1:20. Similarly there is disclosed a process in which the maximum amount of dorzolamide (5%) is added to the minimum amount of timolol (0.01%) and again adjusted to pH 5.5. That represents a ratio of 500: 1 dorzolamide to timolol. Even taking the two minimum amounts disclosed one arrives at a ratio of 5:1 dorzolamide to timolol. All these ratios are outside the range of ratios disclosed in Example 10 of the application as filed.[76]On this basis I consider that the amendment to claim 18 adds matter. I therefore cannot allow the amendment. The unamended claim is invalid. The cited prior art.[77]Teva rely on a single prior published document. As I have said, its disclosure is the same as that of Example 3 of the Patent. It is so short that I can set out the whole of it here. The authors include scientists from Merck as well as other highly respected investigators. ACTIVITY OF THE TOPICAL CAI MK-507 BID WHEN ADDED TO TIMOLOL BID George Nardin*, Richard Lewis+, Erik A Lippa#, Edwin Keates@, Anne Coleman^, Coleen Clineschmidt#, Deborah Panebianco#, Harry Quigley^, Thom Zimmerman* (*Univ Kentucky, Louisville, KY, +Univ California, Davis Sacramento, CA, #Merck Sharpe & Dohme Res Lab, Westpoint, PA, @Scheie Eye Inst, Philadelphia, PA, ^Wilmer Eye Inst, Baltimore, MD) 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. Preliminary IOP data follows: MEAN IOP DATA PRESTUDY AND PERCENT CHANGE IN IOP ON DAY 8 FROM PRESTUDY MK-507 PLUS TIMOLOL GROUP PLACEBO PLUS TIMOLOL GROUP TIME TIMOLOL BASELINE TIMOLOL PLUS MK-507 TIMOLOL BASELINE TIMOLOL PLUS PLACEBO 8 am* 27.4 -16.8 % 26.9 - 3.4 % 9 am 27.1 -21.0 % 24.2 - 4.5 % 10 am 25.4 -18.9 % 23.3 - 1.7% Noon 25.6 - 17.3 % 23.2 + 0.2% 2 pm 24.5 -18.6 % 21.6 + 0.1% 4 pm 25.2 -17.0 % 22.7 - 0.1% 6 pm 25.7 -18.2 % 23.1 - 3.7% 8 pm 24.4 -13.2 % 21.9 + 6.6% *immediately before timolol dose.[78]Nardin was published in 1991. It was published in the 1991 Annual Abstract Issue of the Association of Research in Vision and Opthalmology known as ARVO, one of the most prestigious conferences in the field. A copy was delivered to the British Library some 6 days before the priority date and in advance of the meeting due to occur in Florida some weeks later.[79]There are a number of things to note from the disclosure of Nardin: i) the expression “BID” in the title means twice a day (bis in die); ii) the abstract begins by referring to other work in which it has been demonstrated that MK 507 at 2% is effective in lowering IOP in patients treated three times a day (ter in die); iii) the present 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; iv) the tests are performed in humans; v) the patients were given their MK 507 dose ten minutes after their timolol dose for 8 days; vi) the study included a group of patients who were given timolol plus placebo; vii) the study showed a 13-21% additive effect over the timolol baseline for those patient who were given both drugs; viii) patients given timolol plus placebo showed results ranging from a 4.5% improvement to a 6.6% deterioration; ix) 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; x) Nardin does not disclose the chemical identity of MK 507.[80]A striking feature of the disclosure of Nardin was that 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.

Lack of novelty – law

[81]The law of novelty is concisely stated by Lord Hoffmann in Smithkline Beecham plc’s (Paroxetine Methanesulfonate) Patent [2005] UKHL 59, [2006] RPC 10. In summary, and for present purposes:(1) There are two requirements for anticipation which it is important to keep separate, (a) disclosure and (b) enablement;(2) So far as disclosure is concerned, the prior art must disclose subject-matter which, if performed, would necessarily result in an infringement of the patent.

Lack of novelty/obviousness of unamended claims

[82]Lack of novelty is alleged against unamended claims 1-6, 8 and 9. Two distinctions are maintained: the absence of a teaching of co-formulation in Nardin and the absence of any teaching of the identity of MK 507.[83]I have already decided that as a matter of construction claim 1 is not limited to a co-formulation and extends to making both drugs for concomitant administration as shown in Example 3. It follows that claim 1 is not distinguishable from Nardin on this basis.[84]Nardin does not identify what MK 507 is. MK 507 is the name which Merck gave to the drug which became dorzolamide. The evidence established that the skilled person would without undue burden be able to discover the identity of MK 507. Although Merck made rather more of a meal of this point in their written evidence, by the end of the trial it became clear that there were a variety of ways in which a reader of Nardin would have been able to equate MK 507 and dorzolamide, not least telephoning Merck and asking their scientists. If the skilled reader were too bashful to do this, then he or she could have done a straightforward search through recent literature, as a result of which a number of articles connecting the two would have been found.[85]One could have a fruitless debate about whether, on this evidence, the claim lacked novelty or was merely obvious. It is plainly the latter. As I shall show later, on the evidence, the skilled person would be highly motivated to discover the identity of the compound. No invention can possibly lie in the mere verification of the identity of the compound by taking routine steps. Claim 1 cannot survive the publication of Nardin.[86]In my judgment, none of the remaining use claims is limited to a co-formulation, as none specify a single solution. Accordingly unamended claims 1-6 and 8-9 are all invalid.

Obviousness - law

[87]It is convenient to address the question of obviousness by using the structured approach explained by the Court of Appeal in Pozzoli v BDMO [2007] EWCA Civ 588; [2007] FSR 37. This involves the following steps:
“(1) (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?”
[88]In Conor v Angiotech [2007] UKHL 49; [2008] RPC 28 at [42] Lord Hoffmann approved the following statement by Kitchin J in Generics (UK) Ltd v H Lundbeck A/S [2007] RPC 32 at [72]:
“The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.”
[89]Mr Birss drew my attention to the closing words of that extract. He submitted correctly that expectation of success can be a relevant consideration, the weight to be attached to it depending on the facts of the case. He then reminded me of the words of Jacob LJ in St Gobain v Fusion Provida [2005] EWCA Civ 177 where he explained the role of “obvious to try” in the assessment of inventive step: “Mere possible inclusion of something within a research programme on the basis you will find out more and something might turn up is not enough. If it were otherwise there would be few inventions which were patentable. The only research which would be worthwhile (because of the prospect of protection) would be in areas totally devoid of prospect. The “obvious to try” test really only works where it is more-or-less self evident that what is being tested ought to work” (his emphasis)[90]This passage was the subject of approval and explanation by Lord Hoffmann in Conor v Angiotech (supra) at [42]:
“In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns−Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case.”
[91]Lord Justice Jacob’s phrase “more-or-less self-evident that what is being tested ought to work” is explained by Lord Hoffmann as a “fair expectation of success”, with the degree of expectation depending on the facts of the case.[92]Conor v Angiotech also explains therole played by the data presented by the patentee in the patent specification. A lucid explanation of the issues in that case is to be found in the judgment of Warren J in Actavis v Novartis [2009] EWHC 41 (Ch) at 149 to 163. I agree with Warren J when he says at [161] that the principle of general application which is to be derived from Conor is that the patentee is entitled to have his invention tested for obviousness by reference to the claim and not by reference to a paraphrase based on the extent of the disclosure in the description: see Lord Hoffmann at [3], [17] and [19].[93]I think that the judgments in Conor of the trial judge (Pumfrey J) and the Court of Appeal on the one hand and the House of Lords on the other also reveal an important point about the approach to obviousness. The invention in Conor was a taxol coated stent for preventing restenosis. The invention was clearly a product claim, which would be infringed by anyone making a taxol coated stent effective for this purpose. Pumfrey J held that it was enough to establish obviousness if the evidence established that the skilled person would coat a stent with taxol for the purpose of testing to see if it was effective for this purpose. What is important to note is that he did not do so because, in the course of testing, the skilled person would inevitably make something falling within the claims. He relied, instead, on a comparison between what the skilled man would have done by taking steps which were obvious and the extent of disclosure in the claims. It was here that the House of Lords held he fell into error.[94]It is implicit in Pumfrey J’s judgment that if the specification had gone further, and demonstrated that a taxol coated stent would work, his decision would have been that the patent was valid: see Lord Hoffmann at [40] and [41]. And this would have been despite the fact that a skilled person would have included a taxol coated stent (which would in fact work) in a trial to find out if it worked. So a claim to a product which does a particular job may be valid, despite the fact that it may be obvious to make exactly such a product to find out if it does the job.[95]This analysis might appear to run counter to a basic proposition of patent law, that the objection of obviousness exists to prevent a patentee from monopolising products or activities which the skilled person should feel free to make or perform without worrying about the existence of a patent. As Aldous J said in Hallen v Brabantia [1989] RPC 307 at 327: “The law on obviousness goes back many hundreds of years. The basis of the law is that the public are entitled to manufacture that which has been published …. with obvious modifications. By ‘obvious modifications’ are meant that which technically or practically would be obvious to the unimaginative skilled addressee in the art. Such a skilled man should be assured that his actions will not be covered by any monopoly granted to another if he does that which is part of the state of the art with modifications which are workshop modifications or otherwise technically or practically obvious alterations”.[96]As Conor shows, the courts have not rigidly applied this doctrine where claims specify a product with a technical effect. The correct approach is encapsulated in [17] of Conor:
“It is the claimed invention which has to involve an inventive step. The invention means prima facie that specified in the claim: see section 125(1) of the 1977 Act. In the present case, the invention specified in claim 12 was a stent coated with taxol. There was no dispute that this was a new product. The question should therefore simply have been whether it involved an inventive step. As in the case of many product claims, there was nothing inventive in discovering how to make the product. The alleged inventiveness lay in the claim that the product would have a particular property, namely, to prevent or treat restenosis. (Compare Pharmacia Corp v Merck & Co Inc [2002] RPC 775). So the question of obviousness was whether it was obvious to use a taxol−coated stent for this purpose.”
[97]So a claim to a product which is obvious to make may properly be deemed inventive if it is not obvious to use it for a particular purpose so as to achieve a technical effect (prevention of restenosis). Such a result is consistent with cases decided by the European Patent Office’s Technical Board of Appeals, such as AgrEvo /Triazole herbicides T 0939/92, [1996] EPOR 171. Products, themselves uninventive, could be inventive provided that they plausibly displayed the asserted technical effect when used.[98]I think that Mr Birss is right that one must proceed with caution when faced with an obviousness attack based on a suggestion that the skilled person would embark on a research program in the course of which he would discover that a product or compound was effective. This is particularly so where the technical effect is one which is newly discovered, or impossible or very hard to predict. That is because the expectation of success may be zero, or inadequate to drive the research forward. In the end it will all depend on weighing the various factors as they appear from the evidence in the case. That is what I have endeavoured to do in the present case.[99]Mr Birss also submits that all the above applies a fortiori in the case of a use claim of the type under consideration in claim 1. I agree. Such claims are traditionally drafted because the compound in question is itself old, and may even have been previously used for a medicinal purpose. The claims acquire novelty, not because the compounds have not previously been used for the manufacture of medicines, but because they have not previously been used for the manufacture of medicines for the new medicinal purpose. If the new medicinal purpose is a sufficient distinction to provide for novelty, it must equally be a relevant distinction for the purpose of assessing inventive step. Obviousness of amended claims in the light of Nardin The person skilled in the art

Obviousness of amended claims in the light of Nardin

[100]I have identified the person skilled in the art as the team of a clinical opthamologist and an ocular pharmacologist. The team would possess, together, the knowledge I have identified above in the section headed “Technical Background” subject to the exception I have noted.

Common General Knowledge - law

[101]A question arises as to whether it is sufficient to establish that a particular fact was known in the United Kingdom, or whether it is necessary to establish, where the art is an international one, that it was known more widely.[102]Mr Thorley maintained that the relevant common general knowledge was that in this country. Mr Birss was content to accept that proposition, whilst pointing out that where the art was an international one, it is relevant on the facts to take account of evidence that individuals abroad had not heard of it. Neither side showed any enthusiasm for arguing that common general knowledge had to be more extensive than the United Kingdom.[103]I am content to proceed on this legal basis, as I did not hear detailed argument on the point. It would seem to me to be an odd result if a patent for the UK could survive if it was obvious in the light of the common general knowledge in this country. A more difficult question may arise if a fact is only common general knowledge abroad. But that does not arise here.

Common general knowledge about co-formulation

[104]I have mentioned the three commercial co-formulations above. Of the three, only Ganda is a candidate for being common general knowledge here. The pilocarpine combination products were known to Professor Serle, but not known to Professor Rennie before this action. Dr Sugrue had heard of tim-pilo, not e-pilo. Dr Wilson had not heard of tim-pilo. It was not in general clinical use.[105]Ganda sales in the UK in 1991 totalled £291,700 made up of 55,800 units. In comparison sales of timolol were £17,285,000 made up of more than 3 million units. The 1989 edition of the leading textbook Becker-Shaffer refers to combinations of guanethidine and epinephrine, including, if one studies the footnotes, one drop combinations. But it does not refer to Ganda by name.[106]Ganda, on the other hand, was not known to either of Merck’s witnesses. This is despite the fact that the art is very internationally based. Professor Serle trained with Dr Stephen Podos, considered the foremost ocular pharmacologist in the world, yet Ganda was never mentioned to her by him. Further, Dr Sugrue was working in France in the early 1980s and had not heard of Ganda then.[107]It is perhaps surprising that Professor Serle and Dr Sugrue had not heard of the product, but its relatively minor scale of use may account for the fact that it was not discussed at international conferences. In my judgment, a competent clinical ophthalmologist practising in the United Kingdom in 1991 would know of Ganda. There were relatively few commercial IOP lowering agents available. Ganda was one of the agents that a competent clinician would be aware of.[108]It must nevertheless be borne in mind that Ganda was not a combination of two freestanding IOP lowering agents. Guanethidine was of little use as an IOP lowering agent on its own: its role was to potentiate the action of epinephrine. Mr Birss submitted that the skilled team would therefore view it as a formulation of epinephrine.[109]In my judgment the skilled team would regard Ganda as a formulation where two drugs are co-administered in the same drop. Although the role of guanethidine is as a potentiator, it is nevetheless a drug, and is described in Becker-Schaffer as such.[110]However, the skilled person’s experience and consciousness of co-formulation would not be limited to Ganda. When two drugs can be conveniently administered in a co-formulation, such as steroids and antibiotics in post-operative situations, they were. The skilled team would have been conscious of this fact, although it would have been unaware of any specific cases where two free-standing and effective ocular hypotensive agents had been used in combination in a single drop.[111]Mr Birss sought to cast doubt on this conclusion, or at least to lower the level of consciousness of the idea of co-formulation, by referring to a number of articles where the possibility of a co-formulation was not mentioned. These were: i) A paper by Longstaff in which Professor Rennie is named as co-author. The paper examines the concomitant administration of two ocular hypotensive agents (carteolol, a beta-blocker and dipiverfrin, an adrenaline like drug) to see if they were additive. The study is in two parts, one designed to see whether there was an additive effect and the other to see whether it is maintained long term. Professor Rennie was asked to confirm that the article did not mention co-formulation, which he did. ii) A patent filed by Professor Blackburn arising out of some work on topical CAIs in the early 1990s which he did with Professor Rennie. Professor Rennie accepted that there was nothing in the document about co-formulating these compounds with beta blockers. The same was true in relation to a paper by Jayaweera relating to topical CAIs and coming from Professor Blackburn’s group. iii) A comment made by Dr Robert Allen, a well respected scientist in the field, at the end of a paper by Lippa in the March 1991 issue of Opthalmology. The paper is entitled MK 507 versus sezolamide, also known as MK 417. The passage is worth setting out, because I think it fairly represents the attitude of the art to topical CAIs in 1991:
“Just as the synthesis of methazolamide several decades ago represented a specifically synthesized molecule that enabled lower dosing decreased side-effects with oral treatment, the two compounds under discussion also represent the culmination of a long line of topical "designer drugs" that seem to have pharmacologic characteristics that allow maximal penetration into the eye, advantageously high affinity for the carbonic anhydrase II isoenzyme in human ciliary body, and some binding to pigment that may affect their activity. Both of the study agents would appear to be reasonable candidates for a commercially viable and clinically useful topical drug. The question remains whether they would be effective in the initial treatment of glaucoma either as twice daily or three times daily agents, but this discussant continues to hope this will be possible. It would also seem appropriate to consider them both as candidates for adjunctive treatment with other antiglaucoma drugs either in a twice daily application of the MK 507 or three times daily application of the slightly less potent MK 417. It is my hope that fellow Academy members share my excitement at this first Annual Meeting presentation where a truly viable compound of this class has been shown to be not only safe but very effective in lowering IOP in glaucoma patients. ... Obviously more studies will be required to show a long term efficacy and more importantly the safety of this "new class" of drugs since the studies today have been confined to short-term treatment. Hopefully, the topical carbonic anhydrase inhibitors will be a clinical reality in the very near future. Dr Lippa and co-authors are to be thanked and congratulated for their contribution to this cause.”
Mr Birss draws attention to the fact that Dr Allen asks only whether CAIs (MK MK 417 and MK 507) would be effective on their own or as candidates for adjunctive therapy. Professor Rennie said that he would have interpreted this as being a reference to concomitant therapy rather than co-formulation. iv) Finally a lengthy review written by Dr Sugrue in 1989 has nothing about co-formulations in it at all.[112]Mr Birss asks why it is that, if co-formulation is such an obvious next step in this art, these papers all fail to mention it? Of course, one answer to that may be that it is not always necessary to state the obvious. Another answer is that against this selection one can place the earlier Merck patent, US 4,863,922, which is referred to in the Patent. The earlier Merck patent relates to novel CAIs and suggests, amongst other means of administration that they would be suitable for topical administration so as to avoid the systemic side effects of oral CAIs. At column 12 line 58 its says:
“The medicament in the novel topical ocular formulation comprises one of the novel compounds of this invention either alone or in combination with a beta-adrenergic blocking agent such as timolol maleate or a para-sympathomimetic agent such as pilocarpine. In such combinations the two active agents are present in approximately equal amounts.”
[113]Dr Sugrue appeared to read this as relating to co-administration. I do not think this is right, given the last sentence which says that the agents are present in the combination in equal amounts. It was clear from Dr Sugrue’s answer that in this instance he was relying on internal Merck knowledge, rather than reacting to the passage as a skilled person would. The passage provides some support for the suggestion that the skilled team would be conscious of the possibility of co-formulations. Whether they would pursue one in any given situation is of course another matter.[114]I conclude that 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.

Difference between Nardin and the inventive concept

[116]There are only two differences between Nardin and the inventive concept. The first is the identification of MK 507. I have dealt with that above when dealing with the validity of the unamended claims. The skilled person would readily and rapidly discover what MK 507 was. It was not suggested that the skilled person would be unable to make it or obtain it.[117]The remaining difference between Nardin and the inventive concept is that Nardin does not teach using a co-formulation of the two drugs for treating patients for whom timolol is not good enough. One must keep in mind the concentrations in claim 6, but if the Nardin concentrations are used in the co-formulation, then they will fall within this claim.[118]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.

Teva’s obviousness case

[119]Mr Thorley summarised his obviousness case in the following way. Firstly he says that the results in Nardin would naturally and without invention suggest a co-formulation of the two drugs. This is principally because the skilled person would approach Nardin with the following background: 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 bid 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 bid (not tid) 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 bid 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.[120]It is convenient to consider the first stage of the argument before proceeding to the second, whilst recognising that it is only a first step without which the second stage will not occur.[121]I accept the propositions numbered (i), (iv), (v), (vi), (vii), (viii), (xi) and (x) as being well established by the evidence.[122]I also accept proposition (ii), but I bear in mind that oral CAIs used as adjunctive therapy were unsatisfactory in that they produced side effects as well.[123]Proposition (iii) is very broadly stated. It was certainly not the case that every adjunctive therapy would be thought suitable for a co-formulation. For example a combination of timolol (which is bid) and pilocarpine (which is dosed four times a day) would not be a natural choice for a co-formulation (even though this was the basis of Tim-pilo). But it is correct to say that co-formulations of drugs (such as co-formulations antibiotics and steroids used post-operatively in opthalmic surgery) were well established in the clinician’s consciousness, and there was certainly no prejudice against them. I have dealt with all this under the heading of the common general knowledge and do not repeat it here.[124]Professor Rennie said in his written evidence that if he had been asked by Merck to consider the implications of the results in Nardin, he would have advised them that the natural next step would have been to investigate the efficacy of MK 507 administered in a single solution with timolol. The reason he gave was that the results showed that the administration of two drugs in two drops ten minutes apart gave an additive effect. He says he would have assumed that the co-formulation of the two products was the ultimate objective of the Nardin trial. His written evidence is absolutely clear that he would have assumed that this was what Merck were intending to do. He explained in cross examination that if the authors had been looking to support the idea of co-administration rather than co-formulation he would have expected to see the MK507 used at the higher dosage, tid, rather than bid.[125]In cross-examination Professor Rennie explained that he also considered pursuing concomitant therapy a natural thing to do in the light of Nardin, and that it would be reasonable to take both forward at the same time. He did not think that any of this needed to wait for regulatory approval to be given to the single drug. He also explained that he would have been strongly driven by his knowledge of the efficacy of orally administered CAIs. “Q. What is driving the project forward without hindsight in 1991 is the Nardin abstract? A. The Nardin abstract and my knowledge of beta blockers and carbonic anhydrase inhibitors. I think we should be clear at this point one of the reasons I would be so keen to pursue a co-formulation is that I have been, as an ophthalmologist, using at that time systemic carbonic anhydrase inhibitors for my entire career. I was aware of their efficacy and I was aware that if they could be put into a topical solution, if that same efficacy could be achieved it would be an extremely potent agent. To put the two together in a bottle with another extremely potent agent would give you the magic bullet. Yesterday you mentioned the prostaglandin analogues and my knowledge of them at the time. One of the reasons I would be less interested in them is that there were no previous prostaglandin analogues on the market. I would have no experience of using them as clinician. I had experience of using carbonic anhydrase inhibitors as a clinician then and today and I know their potency, so I would have been strongly driven by the knowledge that a topical carbonic anhydrase inhibitor existed and to me, the formulation with another potent drug would have been something I would have pursued extremely aggressively.”[126]Professor Serle agreed that the idea of adding a topical CAI to beta blockers, which was the gold standard therapy, was an exciting idea at the time. The essence of Professor Serle’s evidence was that there was no reason why the Nardin abstract would have suggested co-formulation. She relied heavily on the fact that she and her colleagues were more focussed at the time on obtaining another drug. The idea of obtaining a co-formulation was not a priority at the time, it was regarded as a bonus – an added benefit but not a requisite one.[127]In the end, I think that Dr Sugrue accepted that, proceeding from Nardin, one would consider a co-formulation, although, based upon his experience at Merck, he would not have considered it a number one priority.[128]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 Mr Birss 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.[129]The second stage of Mr Thorley’s argument is as follows: 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.[130]Propositions (iii) and (iv) are well established by the evidence. 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.

Would the project be abandoned before it is begun?

[131]Mr Thorley submitted that the evidence showed that the project would not be abandoned before at least some testing had been done. He submitted that this more or less followed from having the idea in the first place. The skilled person would not see any a priori reason why a co-formulation would not display the same sort of advantages as co-administration for a beta-blocker and a topical CAI. He relied, obviously, on Professor Rennie’s evidence about the aggressiveness with which he would pursue the goal.[132]Mr Birss’ principal attack on this evidence was based on the evidence of Professor Serle. Her position was that it was premature to be considering a co-formulation project. The first question, for her, was to determine whether the topical CAI would actually be effective in the long term, and at what dose and dosing schedule.[133]I have no doubt that Professor Serle’s opinion was genuinely held on this point. But it seemed to me that the view she expressed did not take account of the full import of the Nardin disclosure. Nardin shows that Merck were already thinking in terms of the potential for MK 507 to work as a concomitant therapy with timolol, as Dr Lippa had suggested. The art was no longer waiting for MK 507 to produce long term results, or precise dosing schedules. Merck were producing multiple publications on it, some of which were the abstracts in the same volume of ARVO abstracts as Nardin. Work was moving on to the next stage. In the light of these considerations the skilled team would not consider a co-formulation to be premature, any more than investigation of co-administration was premature.[134]I think, on this, that Professor Rennie’s assessment is the more realistic. A skilled team would no doubt wish to investigate concomitant administration as well, a fact which Mr Birss urges me, correctly, to keep in mind at the next stage. But that the co-formulation would be considered well worth investigating seems inescapable.[135]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 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.

Would the pH problem cause the project to be abandoned?

[136]Once a clinician had decided on the basis of Nardin that a co-formulation should be tested, he or she would approach an ocular pharmacologist and ask for a co-formulation. The first step would be to attempt to dissolve the dorzolamide in the existing timolol 0.5% preparation. Timolol is formulated at pH 6.8. The pharmacologist would discover that at pH 6.8 it was not possible, due to the insolubility of dorzolamide, to dissolve the amount of dorzolamide into the timolol solution necessary to achieve the 2% concentration used in Nardin.[137]Although there might be other ways of overcoming the solubility problem, the evidence establishes that the most straightforward would be to lower the pH of the solution. The pharmacologist would rapidly discover that the Nardin concentrations could be achieved by lowering the pH to pH 6.0, a reduction of 0.8 pH points. The skilled person would appreciate that the consequence of this reduction in pH would be a reduction in the ocular penetration of the timolol. Mr Birss had a criticism of Dr Wilson in that he had excluded other options from his report at the insistence of the lawyers, but his evidence was nevertheless clear that the pH route to achieving the necessary solubility was the most obvious one.[138]Dr Wilson’s view was that, although he would have been aware of the possible effect of the lowering of pH on the corneal penetration of the drug, he does not think he would have paused to consider it as such, but would have proceeded with a trial of the co-formulation on animals. Had he paused to consider it, he would have known that timolol, being a weak base, would have had a pKa well above 7. He would have known that at pH 6.8 the timolol would have been already very largely ionised. Thus shifting the pH further away from the pKa, from 6.8 to 6.0 would be unlikely to have had a significant effect on its absorption and therefore its activity.[139]Dr Wilson’s views accord with Merck’s contemporaneous documents. For example the project report for July, August and September 1990 reports on co-formulations at pH 5.9-6.0 which contained 0.5% hydroxyethyl cellulose, a viscosity agent. The report says:
“Ocular bioavailabilty data previously obtained in the albino rabbit have shown that the addition of 0.5% HEC largely compensates a possible negative effect due to a slightly lower pH than in Timoptic (6.0 instead of 6.8)”
[140]The report for October, November and December reviews bioavailabilty of timolol in studies in albino rabbits. These showed that timolol was more available in the case of the co-formulation. The authors explain that “the higher [results obtained for the co-formulations] are due to the increase in viscosity by the presence of HEC [hydroxyethyl cellulose viscosity modifier] in the vehicle of the combination. The slight decrease in ocular bioavailability that would have been predicted by the decreasing pH, viz 6.8 for Timoptol and 6.0 for the combination, was not observed because the effect due to viscosity was larger.”[141]The data accompanying the report shows that ocular bioavailability of timolol reduced from 61 to 50.6 when placed in MK 507 at the lower pH without HEC, but shot up to 120.7 when HEC was added.[142]The inference I draw from these documents is that Merck’s prediction was that any drop in bioavailability due to the lowering of pH would be slight. I appreciate that these statements are made after bioavailability tests had been done, but they are consistent with a theoretical prediction of a small drop, and inconsistent with a prediction of a large one.[143]In his written evidence, Dr Sugrue opined that, although it would not be possible to predict the magnitude of any reduction in bioavailability, the skilled person would nevertheless think it would be substantial. He placed some reliance on two articles which he considered that the skilled person would have consulted on the point: one by Ashton et al (which was not published until after the priority date) and another by Kyyronen and Urtti published in 1990. The latter paper did show a drop of about 50% in penetration between pH 7.5 and pH 6.2, a drop which is not much smaller between pH 6.9 and 6.2.[144]It was not established that the quantitative figures in either Ashton or Kyyronen formed part of the common general knowledge. Indeed, had they been, one would not have expected Merck’s scientists to make the statements which they did. In my judgment the skilled person would be aware of the possible effect, but would not have any view as to how significant it might be.[145]Merck also rely at this stage on a concern about increased lacrimation and stinging caused by the more acid pH. I do not think this would have deterred the skilled team. Products were on the market in the range pH 5.5 to 6.0. Professor Rennie’s evidence was that the acceptable pH range was 5 to 8. There was no evidence that a change in pH from 6.8 to 6.0 would in fact cause a significant increase in lacrimation. A paper by Conrad, on which Dr Sugrue had originally relied, did not show that there would be an appreciable change over such a small pH change.[146]Mr Birss submitted that these new uncertainties would be sufficient to divert the skilled team in other directions. He pointed out that there were other combinations of drugs which might not suffer from this solubility/pH/bioavailability problem. Alternatively the skilled team might be diverted into concentrating solely on co-administration.[147]Mr Birss is correct that 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.[148]I am fortified to some degree in this view by Merck’s contemporaneous documents, to which I have referred above. The use of expressions such as, “The slight decrease in ocular bioavailability that would have been predicted…” is not evocative of a serious concern such as would lead to project abandonment.

Does the evidence establish that the project would be successful thereafter?

[149]On Mr Thorley’s case, the next stage in the project would have been tests on animals. This gave rise to a dispute between the experts as to what studies would have been done and whether they would have produced results encouraging enough to lead the team to use the co-formulation for the treatment of glaucoma.[150]Mr Thorley submitted that Merck were at this stage caught on the horns of a classic patent law dilemma. The development work which the skilled team now faced was not different from the problem faced by the skilled team in possession of the Patent. The Patent contains no animal tests showing that the co-formulation reduces IOP in rabbits. If it is postulated that the notional skilled team working from Nardin would hit an insuperable obstacle at this stage, then so also would the notional team carrying out the teaching of the Patent. He submits that if the Patent is to be held non-obvious solely because the skilled team would, on the evidence, not be able to demonstrate an IOP lowering effect in animals, then the Patent must be insufficient on this ground.[151]Mr Birss reminded me that great care needs to be taken with short-cut arguments of this kind. Firstly, the starting points are different. Whereas Nardin discloses only concomitant administration, leaving the skilled team to make its own co-formulation, the Patent discloses actual co-formulations containing a viscosity modifying agent. Secondly, and in consequence, the skilled team carrying out the Patent would be testing something different from that which Dr Wilson suggested the notional skilled team carrying out Nardin would test. Dr Wilson’s formulation was potentially compromised by reduced bio-availability as compared with a 0.25% timolol/2% dorzolamide co-formulation with a viscosity modifier. Mr Birss submits that one does not know what would happen with Dr Wilson’s formulation, whereas there can be no real doubt that the formulations disclosed in the Patent will work. Thirdly, the Patent, as Mr Birss emphasises, makes a promise that the co-formulations can be used to treat glaucoma whereas the team starting with Nardin would have no such promise in mind.[152]Mr Birss fortifies his position by reference to evidence about the difficulty of demonstrating an effect on IOP lowering in rabbits, which are the animals of choice for testing of this kind. The evidence established that these experiments had to be carried out with extreme care in order to show differences in activity.[153]Mr Thorley’s riposte is that, if it is being said that it is impossible to demonstrate the effect with Dr Wilson’s formulation, then the patent is insufficient.[154]Dr Sugrue was cross examined about the steps which were necessarily to be taken in carrying out the teaching of the patent, starting with Example 3:
“Q. Starting at line 50, if you read that through I think you may see it is pretty similar to the Nardin paper. A. I think we have all concurred that that is the same. Q. All I am putting to you, those are the only clinical data in the patent? A. Yes. Q. The other two examples, example 1 and example 2, give you a number of potential formulations of varying concentrations and ratios of dorzolamide and timolol; are you aware of that? A. Yes. Q. There is a wide variety of possible combinations that you could adopt; but again, if I am talking to the wrong person tell me, there is nothing in the patent which helps you choose which of those you should select? A. There is nothing that helps you choose, I think some of the claims narrow it down to which would be the preferred concentrations. Q. That is, I think, claim 6, if you look on page 7, the concentration of dorzolamide is 0.7 to 2% and the concentration of timolol is 0.5%. A. Yes. Q. So it is still a fairly broad range to have a go at with dorzolamide? A. I guess it just clarifies what I mentioned before, that we still were not sure what the concentration of dorzolamide would be. Subsequent studies looked at it at 0.7%, 1.4% and 2%. Q. If you were putting the patent into effect you would have to choose what concentrations you were going to use and then put those concentrations into a co-formulation, put them through preclinical trials, clinical trials, stability tests and so on to see whether any of problems that you thought might arise did arise? A. You would have to do all the studies, yes. Q. It would be exactly the same, if on reading Nardin you decided to implement Nardin as a co-formulation, except that Nardin does tell you what concentrations to use? A. Nardin tells you what concentrations they used in their study. It does [not] necessarily say those are the ones you have to use, but yes. Q. But the process would then be exactly the same? A. Exactly the same as? Q. To make the formulation, preclinical trials, clinical trials, stability testing and so on? A. The evaluation to determine what product would eventually go to market, yes.”
Q. But the process would then be exactly the same? A. Exactly the same as?

Q. To make the formulation, preclinical trials, clinical trials, stability testing and so on?

[155]In the light of this evidence, I think it is right to say that the patent assumes that the skilled team would be able to take the co-formulation through the necessary steps to the point where it could be used to treat glaucoma. One essential step in that process would be to demonstrate the effect pre-clinically, otherwise the practical route forward to actual use would be blocked. I therefore approach with some scepticism the suggestion that the skilled team, proceeding from Nardin, would not be able to demonstrate a sufficient effect to justify clinical use.[156]I reject Mr Birss’ submission that the skilled team starting from Nardin would not be able to carry the project through to actual use.[157]As to Mr Birss’ specific points, firstly, I do not think that much weight can be attached to the teaching of a viscosity modifying agent in the Patent, when this is a well known expedient and the skilled team would know in both scenarios that a viscosity modifier could be used to counteract any pH effect. Whilst it is true that this is a difference in actual disclosure, viscosity modifiers do not represent any addition to that which the skilled team would know.[158]Secondly, I do not consider that it is likely that that Dr Wilson’s first formulation would fail to demonstrate IOP lowering in properly conducted animal tests. It is true that it would be compromised to a degree by the pH effect, but it is, on the evidence, unlikely in the extreme that it would be reduced to a level where an effect could no longer be shown. I accept Dr Wilson’s evidence that it was understood at the time that the rabbit model was a reliable one for the pre-clinical testing of timolol provided that the tests were properly set up and run. In 1984 Bar-Ilan demonstrated the effects of separate and combined topical application of timolol and trifluoromethazolamide in normotensive rabbits, showing that the combined effect was greater than that with timolol alone. Dr Sugrue pointed out that meaningful and consistent results had been obtained with some studies and not others. I do not see this as effectively contradicting Dr Wilson’s evidence.[159]Furthermore, I do not think that the promise of a successful result in the Patent provides a distinction.[160]I therefore reject Merck’s contention that the necessary tests to demonstrate pre-clinical efficacy of a co-formulation based on Nardin are beyond the capacity of the skilled team, or would lead to abandonment of the project.[161]I need, at the end to take a step back. Mr Birss reminded me that I must be careful not to allow hindsight to colour my judgment when considering the fourth step, 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.

Insufficiency

[162]Teva alleges that, to the extent that the claims are not anticipated and/or obvious, the specification of the Patent does not disclose the invention clearly or completely enough for it to be performed by a person skilled in the art. In support, Teva alleges that the disclosure of the Patent no more enables the invention claimed than does the disclosure of Nardin and the common general knowledge.[163]I have come to the conclusion that the Patent is invalid for obviousness, and so Teva’s objection of insufficiency does not arise. However, if I had come to the conclusion that the skilled team armed with Nardin would not have been able to demonstrate the necessary pre-clinical effect as Merck alleged, I would have held that at least the use claims of the Patent were invalid on this ground. The reasons for this view should appear adequately from my judgment on obviousness, and I will not repeat them here.

Conclusions

[164]My conclusions are i) the Patent as proposed to be amended is invalid for lack of inventive step; ii) had the Patent as proposed to be amended not been invalid, I would have allowed the amendment to claim 1, but not the amendment to claim 18 (which adds matter); iii) unamended claims 1 to 6 and 8 to 9 lacked inventive step; iv) unamended claim 20 added matter.

Cited in 7 later judgments