CHANCERY DIVISION
PATENTS COURT
Strand, London, WC2A 2LL |
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B e f o r e :
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TEVA UK LIMITED |
Claimant |
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- and - |
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MERCK & CO., INC |
Defendant |
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Colin Birss QC and Tom Hinchliffe (instructed by Rouse Legal) for the Defendant
Hearing dates: 27th-29th October, 2nd November 2009
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Crown Copyright ©
Mr Justice Floyd :
Para | |
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 |
Technical Background
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 |
Trade name | Active ingredients |
GANDA | Guanethidine and epinephrine |
TIM-PILO | Timolol and pilocarpine |
E-PILO | Epinephrine and pilocarpine |
Witnesses
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.
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 glaucoma including 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.
The Patent
"there exist some patients with whom this treatment is not entirely satisfactory".
"do not take advantage of reducing the contribution to aqueous humour formation made by this carbonic anhydrase pathway".
"during an acute attack of alarmingly elevated IOP when no other agent is effective".
"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."
"[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 ß-adrenergic antagonist followed by administration of the other solution. The use of a single solution containing both active medicaments is preferred."
[0013] The combination disclosed herein is effectiveeitherby co-administration of the medicaments in one solutionor as a combined therapy achieved by prior administration of either the carbonic anhydrase inhibitor or the ß-adrenergic antagonist followed by administration of the other solution.The use of a single solution containing both active medicaments ispreferred.disclosed.
(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.
The claims
"1. Use of
(a) 0.05 to 5% (w/w) of dorzolamide, or an ophthalmologically acceptable salt thereof; and
(b) 0.01 to 1.0% (w/w) of timolol, or an ophthalmologically acceptable salt thereof;
for the manufacture of a medicament for the treatment of ocular hypertension or glaucoma in a patient who is insufficiently responsive to ß-adrenergic antagonists, wherein said medicament takes the form of a single solution adopted for topical administration.
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 claim1917, 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 to5.05.5-6.0 by the addition of a suitable reagent."
10. An ophthalmic formulation for the treatment of ocular hypertension or glaucoma in a patient population the members of which are insufficiently responsive to ß-adrenergic antagonists, which comprises:
(a) 0.05 to 5% (w/w) of dorzolamide, or an ophthalmologically acceptable salt thereof;
(b) 0.01 to 1.0% (w/w) of timolol, or an ophthalmologically acceptable salt thereof; and
(c) an ophthalmologically acceptable carrier.
Construction
Unamended claim 1
The use claim
"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."
Amendment and added matter
Amendment to claim 1
"(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."
Amendment to claim 18
"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."
"(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."
The cited prior art.
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 | PLACEBO 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.
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.
Lack of novelty – law
(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
Obviousness - law
"(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?"
"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."
"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)
"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."
"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".
"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."
Obviousness of amended claims in the light of Nardin
The person skilled in the art
Common General Knowledge - law
Common general knowledge about co-formulation
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.
"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."
The inventive concept
Difference between Nardin and the inventive concept
Teva's obviousness case
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.
"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."
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.
Would the project be abandoned before it is begun?
Would the pH problem cause the project to be abandoned?
"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)"
"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."
Does the evidence establish that the project would be successful thereafter?
"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."
Insufficiency
Conclusions
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.