Uitspraken

Technische achtergrond

de (werking van de) blaas

overactieve blaas

“Urgency, with or without urge incontinence, usually with frequency and nocturia, can be described as the overactive bladder syndrome, urge syndrome or urgency-frequency syndrome.”

EP 427

(R)2(aminothiazool4yl)4'‑[2[(2hydroxy2fenylethyl)amino]ethyl]azijnzuuranilide

of een zout daarvan voor de behandeling van OAB. In het vervolg van dit vonnis zal genoemde stof worden aangeduid met zijn International Nonproprietary Name1“mirabegron”. De structuurformule van mirabegron ziet er als volgt uit:

“1. A remedy for use in the treatment of overactive bladder comprising

(R)-2(aminothiazole-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide or a salt thereof as an active ingredient.

2. A remedy for use according to claim 1 comprising a free substance of (R)2(aminothiazole-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide as an active ingredient.

3. A remedy for use according to claim 1 or claim 2, wherein it is a remedy for use in the treatment of overactive bladder as a result of benign prostatic hyperplasia.

4. A remedy for use according to claim 1 or claim 2, wherein it is a remedy for use in the treatment of urinary urgency.

5. A remedy for use according to claim 1 or claim 2, wherein it is a remedy for use in the treatment of urinary incontinence.

6. A remedy for use according to claim 1 or claim 2, wherein it is a remedy for use in the treatment of pollakiuria.”

De navolgende Nederlandse vertaling van de conclusies is op 18 april 2011 in het

Nederlandse octrooiregister geregistreerd:

“1. Geneesmiddel voor gebruik bij de behandeling van overactieve blaas dat (R)-2(aminothiazool-4-yl)-4'-[2-[(2-hydroxy-2-fenylethyl)amino]ethyl]azijnzuuranilide of een zout daarvan als werkzaam bestanddeel bevat.

2. Geneesmiddel voor gebruik volgens conclusie 1, dat de vrije stof van (R)-2(aminothiazool-4-yl)-4'-[2-[(2-hydroxy-2-fenylethyl)amino]ethyl]azijnzuuranilide als werkzaam bestanddeel bevat.

3. Geneesmiddel voor gebruik volgens conclusie 1 of conclusie 2, welk geneesmiddel een geneesmiddel voor gebruik bij de behandeling van overactieve blaas als gevolg van goedaardige prostaathyperplasie is.

4. Geneesmiddel voor gebruik volgens conclusie 1 of conclusie 2, welk geneesmiddel een geneesmiddel voor gebruik bij de behandeling van urinedrang is.

5. Geneesmiddel voor gebruik volgens conclusie 1 of conclusie 2, welk geneesmiddel een geneesmiddel voor gebruik bij de behandeling van urine-incontinentie is.

6. Geneesmiddel voor gebruik volgens conclusie 1 of conclusie 2, welk geneesmiddel een geneesmiddel voor gebruik bij de behandeling van pollakisurie is.”

“Technical Field

[0001] This invention relates to a remedy for use in the treatment of overactive bladder comprising (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl) amino] ethyl] acetic acid anilide or a salt thereof as an active ingredient.

Background Art

[0002] Bladder of mammals is under a dual control of autonomic nerve and detrusor relaxes via an adrenaline β receptor by stimulation of sympathetic nerve upon urination while, upon excretion of urine, it contracts via a muscarine receptor by stimulation of parasympathetic nerve. As a remedy for overactive bladder resulted when the dual control as such is unbalanced, anticholinergic agents such as propiverine hydrochloride and oxybutynin hydrochloride have been mostly used at present. However, there are intractable cases showing resistance to such compounds and there are side effects caused by anticholinergic agents such as urinary dysfunction and dry mouth and, therefore, it is the current status that satisfactory clinical results are not always achieved.

(…)

[0004] The present inventors reported in Example 41 of a pamphlet of International Laid-Open WO 99/20607 that (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]-ethyl]acetic acid anilide dihydrochloride has both promotion action for insulin secretion and enhancing action for insulin sensitivity and further has anti-obese and anti-hyperlipemic actions whereby it is a useful compound for the treatment of diabetes mellitus but there is neither suggestion nor disclosure for the therapeutic use for overactive bladder (refer to Patent Document 1).

(…)

[0012] WO02/0062 [bedoeld is WO02/0662, toevoeging rechtbank] discloses β3 adrenergic receptor agonists for the treatment of overactive bladder, pollakiuria and urinary incontinence.

(…)

Disclosure of the Invention

[0013] The present inventors have carried out intensive studies for finding new pharmacological effects of (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]-ethyl]acetic acid anilide or a salt thereof (hereinafter, referred to as "the active ingredient of the present invention") which is useful as a remedy for diabetes mellitus and, as a result, they have found that the active ingredient of the present invention is useful as a remedy particularly for use in the treatment of overactive bladder. In the present invention as defined by the claims, overactive bladder is defined as a disease by which urinary urgency is frequently resulted. Although benign prostatic hyperplasia is exemplified as one of the causes for overactive bladder, there are many cases where the cause is ambiguous and they are called idiopathic overactive bladder. Although overactive bladder is sometimes accompanied by urinary frequency and urinary incontinence, it is not limited to the disease which is always accompanied by urinary frequency and urinary incontinence. Thus, in the case of mild overactive bladder, a patient is sensitive to the sense of wishing to urinate and frequently has a sense of wishing to urinate but, actually, he/she is able to hold his/her urine for a while. However, even in the case of a mild overactive bladder, its improvement has been strongly demanded in view of QOL (quality of life) of a patient. On the other hand, a severe overactive bladder is sometimes accompanied by urinary frequency and urinary incontinence. Urinary frequency is a state where number of times of urination is more than the normal one and is said to be not less than about two times at night and not less than about 8 times during 24 hours. In urinary incontinence, there is an involuntary leakage of urine and that is defined as a state where there is a problem socially or hygienically and is classified into stress urinary incontinence which occurs when abdominal pressure is applied such as cough and sneeze, urinary urge incontinence where a desire to urinate suddenly occurs and urine leaks before arriving at the toilet and urinary incontinence of a mixed type where both stress urinary incontinence and urinary urge incontinence are present.

[0014] The characteristic feature of the present invention is that the active ingredient of the present invention mitigates especially the frequent occurrence of urinary urgency of a patient and number of times of urination and state of urination are made into a more normal state. It goes without saying that overactive bladder in the present invention includes not only that as a result of benign prostatic hyperplasia but also that accompanied with urinary urgency, urinary incontinence and pollakiuria.

[0015] In Patent Document 1 [WO 99/20607, toevoeging rechtbank], the active ingredient of the present invention is useful, in addition to treatment of diabetes, as an agent for prevention and treatment of other diseases where an improvement in symptom is able to be achieved by reducing the symptom of obesity and hyperlipemia such as arteriosclerosis, ischemic cardiac disease such as cardiac infarction and angina pectoris, brain artery sclerosis such as cerebral infarction, aneurysm, etc. However, there is neither description nor suggestion at all to the effect that the active ingredient of the present invention is useful as a remedy for overactive bladder.

[0016] In Patent Document 2 [WO 98/07445, toevoeging rechtbank], use for overactive bladder is not mentioned as well. In Patent Document 2, there is a description that only CGP-12,177A has a relaxation action to bladder as a compound having a selective stimulating action to a β3-adrenaline receptor. However, as compared with CGP-12,177A, the active ingredient of the present invention has far stronger relaxation action for bladder. In addition, in Patent Document 2, there is no description for in vivo tests showing the usefulness for the treatment of overactive bladder such as "rat rhythmic bladder contraction measurement test" and "urination function measurement test on cyclophosphamide-induced overactive bladder model rat".

[0017] Further, use for overactive bladder is not mentioned in Patent Documents 3 to 5 as well. Compounds mentioned in Patent Documents 3 to 5 and the active ingredient of the present invention are different in their fundamental structures in such respects that the compounds mentioned in the documents always have a phenol ring but have no thiazole ring and also have no amide bond. In addition, in Patent Documents 3 to 5, there is no description for in vivo tests showing the usefulness for the treatment of overactive bladder such as "rat rhythmic bladder contraction measurement test" and "urination function measurement test on cyclophosphamide-induced overactive bladder model rat".

(…)

Best Mode for Carrying Out the Invention

[0027] The present invention will now be specifically illustrated by way of the following Examples.

Example 1 (Isolated rat bladder smooth muscle relaxation test) Test Method

[0028] The test was conducted by referring to The Journal of Urology, 1999, volume 161, page 680.

[0029] Male rats of Wistar strain of 10 to 11 weeks age were sacrificed by depletion, whole bladder was isolated by laparotomy and bladder sections each being in a size of about 3 X 10 mm were prepared in a nutrient solution which was well oxygenated with 95% O2 and 5% CO2 (Krebs-Henseleit solution (118.4 mM NaCl, 4.7 mM KCl, 1.2 mM KH2PO4;

mM MgSO4, 2.5 mM CaCl2, 25.0 mM NaHCO3 and 11.1 mM glucose)). The section was hung in a Magnus tube in which a nutrient solution (Krebs-Henseleit solution) of 37°C into which 95% O2 and 5% CO2 were aerated, stabilized for 30 to 60 minutes with a load of 1 g and 10-6 M carbachol (CCh) or 40 mM potassium chloride (KCl) was repeatedly

applied thereto whereupon it was confirmed that reactivity to CCh or KCl became almost constant. After contraction by 10-6 M CCh or 40 mM KCl was induced and the generated tension was stabilized, a test drug (compound A or CGP-12,177A) was cumulatively administered in 10-fold ratio with intervals of about 10 minutes and the relaxation reaction was observed. After completion of observation of relaxation reaction at maximum concentration of the test drug, 10-4 M papaverine was added to induce the maximum relaxation and a relaxation rate was calculated where the relaxation reaction was defined as 100%.

Results

[0030] As a result of the above test, the compound A which is the active ingredient of the present invention showed a strong relaxation action in antagonism test to contraction by carbachol and antagonism test to contraction by potassium chloride in an isolated rat bladder smooth muscle relaxation test. In addition, the compound A showed a significantly

strong relaxation action as compared with CGP-12,177A (control compound).

Table 1 EC50 and maximum relaxation rate of the test drug in the antagonism test to contraction by carbachol

Table 2 Concentration comparison of the compound A expressing the maximum relaxation rate of CGP-12,177A in antagonism test to contraction by carbachol

Table 3 EC50 and maximum relaxation rate of the test drug in the antagonism test to contraction by potassium chloride

Table 4 Concentration comparison of the compound A expressing the maximum relaxation rate of CGP-12,177A in antagonism test to contraction by potassium chloride

Example 2 (Rat rhythmic bladder contraction measurement test) Test Method

(…)

Example 3 (Test for measurement of urination function of model rat suffering from overactive bladder induced by cyclophosphamide)

(…)

Example 4 (Formulation example)

(…).”

Op basis van EP 427 heeft Astellas op 20 juni 2013 bij Octrooicentrum

Nederland een aanvrage voor een aanvullend beschermingscertificaat (hierna: ABC)

ingediend. Dit ABC is op 3 januari 2017 onder nummer ABC 300599 (hierna: ABC 599) afgegeven en heeft de titel “Mirabegron and salts thereof”.

Het prioriteitsdocument

“[claim 1] An agent for treating or preventing pollakiuria or urinary incontinence comprising (R)-2(aminothiazole-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide or a salt thereof as an active ingredient.

[claim 2] An agent for treating or preventing pollakiuria or urinary incontinence comprising (R)-2(aminothiazole-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide as an active ingredient.”

“[0003]

In the meanwhile, in a pamphlet of International Laid-Open WO 98/07445, as an agent for prevention and treatment of urinary frequency and urinary incontinence containing a drug having stimulating action to a β₃-adrenaline receptor as an active ingredient, there is described that CGP-12,177A represented by the following chemical structural formula has a relaxation action for bladder (refer to Patent Document 2). CGP-12, 177A has been known as a selective drug having stimulating action to a β₃-adrenaline receptor (refer to Non-Patent Documents 1and 2).

(…)

[0006] [Problems that the Invention is to Solve]

Bladder of mammals is under a dual control of autonomic nerve and detrusor relaxes via an adrenaline β receptor by stimulation of sympathetic nerve upon urination while, upon excretion of urine, it contracts via a muscarine receptor by stimulation of parasympathetic nerve. As a remedy for urinary frequency and urinary incontinence resulted when the dual control as such is unbalanced, anticholinergic agents such as flavoxate hydrochloride and

oxybutynin hydrochloride have been used at present.

However, there are intractable cases showing resistance to such compounds and there are side effects caused by anticholinergic agents such as urinary dysfunction and dry mouth and, therefore, it is the current status that satisfactory clinical results are not always achieved.

Further, as a result of increase in population of aged people in recent years, numbers of patients suffering from urinary frequency and urinary incontinence are increasing

year by year and, in view of QOL (quality of life) of patients, there has been a brisk demand for the development of new drugs.

[0007] [Means for Solving the Problems]

The present inventors have carried out intensive studies for finding new pharmacological effects of (R)-2-5 (2-aminothiazol-4-y1)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl] acetic acid anilide or a salt thereof (hereinafter, referred to as "the active ingredient of the present invention") which is useful as a remedy for diabetes mellitus and, as a result, they have found that the active ingredient of the present invention is useful as an agent for prevention and treatment of urinary frequency and urinary incontinence.

In Patent Document 1, there is a description that the active ingredient of the present invention is useful, in addition to treatment of diabetes mellitus, as an agent for prevention and treatment of other diseases where an improvement in symptom is able to be achieved by reducing the symptom of obesity and hyperlipemia, such as arteriosclerosis, ischemic cardiac disease such as cardiac infarction and angina pectoris, brain artery sclerosis such

as cerebral infarction, aneurysm, etc. However, there is neither description nor suggestion at all to the effect that the active ingredient of the present invention is useful as an agent for prevention and treatment of urinary frequency and urinary incontinence.

In Patent Document 2, there is a description that only CGP-12,177A has a strong relaxation action to bladder as a compound having a selective stimulating action to a β3-adrenaline receptor. However, as compared with CGP-12,177A, the active ingredient of the present invention has far stronger relaxation action for bladder.

Compounds mentioned in Patent Documents 3 to 5 and the active ingredient of the present invention are different in their structures in such respects that the compounds mentioned in the documents always have a phenol ring but have no thiazole ring and also have no amide bond.”

Stand van de techniek op de prioriteitsdatum

“192. Although there are important arguments in both directions, I have come to the conclusion that the obviousness attack over `288 fails. I will explain my reasons, without I hope unduly repeating what I have already said.

193. It is true that at the priority date the β3-AR agonism mechanism had “momentum” relevant to OAB arising from the recent advancements in understanding that I have identified in relation to the CGK, and hence β3-AR agonists had, in a general sense, potential as agents to treat OAB.

194. However, the Claimants’ case suffers from the two defects of overstating the confidence that that would give the skilled addressee, and of oversimplifying the situation, in particular to the effect that any β3-AR agonist would be likely to succeed as a treatment. One can see these two problems clearly in the formulation of the Claimants’ case that they put forward in their written opening and which I have quoted above.

195. As to overstating the skilled addressee’s confidence in β3-AR agonism for OAB, I bear in mind that the mechanism had not been used successfully in any drug for any condition, and it had failed for diabetes. While there were potential reasons for this that would leave open the possibility of success for OAB, this is not a good starting point for the Claimants.

196. As to the clinical prospects for OAB, the review papers, examples of which I have given above, certainly said that clinical trials were needed for β3-AR agonists for the condition, but my overall assessment of those, as I have touched on already, is that the authors were saying that clinical evidence was what was missing and should be looked for, not that it would necessarily fall into place. Doing those clinical trials would be an exercise in hoping to find something new and promising, not a routine matter with a strong or clear expectation of positive results.

197. I also think the appropriate caution as it would be seen by the skilled addressee is evidenced by the large number of possibilities in play to improve the existing treatments for OAB. Some companies were exploring β3-AR agonism (along with other mechanisms) but others were not.

198. So I thought that Dr [1] and Dr [2] gave a much fairer impression of the state of play in seeking to improve OAB treatments than did Dr [3] : it was possible that β3-AR agonists would work for OAB and it was possible that they would not. The same could be said for a number of the other mechanisms under consideration for OAB that I have touched on above.

199. As to oversimplification, the central problem facing the Claimants seemed to me to be the poor quality of the disclosure of `288 as it applied to mirabegron in particular and the Examples generally, with the very limited data given. It was because of that that the Claimants had to contend, effectively, that any selective β3-AR agonist would be seen as obvious to use for the treatment of OAB. My findings on the evidence as set out above are that that is not so and was not the perception of the skilled addressee. It could not be assumed that any β3-AR agonist would work and it could not be predicted that the results for one would necessarily apply to another. The Claimants put to Astellas’ witnesses, and argued, that no β3-AR agonist had ever failed to show activity in detrusor tissue, but I accept the answer given, that failures would not be published, and I have already said that Dr [2] gave evidence that at Pfizer some agonists found to be potent in cell assays did not work in detrusor muscle.

200. This does not mean that the skilled addressee would positively think that mirabegron or the other Examples in `288 would not work, but it does mean that there would be a substantial degree of uncertainty. Furthermore, `288 does not “show its working”; the choice of compounds and structures to explore and test is not explained. The reader would probably expect that the thinking was shaped by the application that the authors had in mind (diabetes), and I was not at all convinced by the Claimants’ response to that, which was that it did not matter what condition the authors were working on, provided that they came up with β3-AR agonists in the end.

201. The Claimants tried to bring some unity and reality to their arguments about β3-AR agonism on the one hand and `288 on the other by the contention that the mechanism had been seen as extremely attractive for some time by the priority date, but was held up by the lack of appropriate compounds. Then, it was said, `288 would provide a good way forward for the first time. I have rejected this on the facts in dealing with the CGK. At least some other suitable compounds were around, and the skilled addressee would not think that there was a limitation such that they would naturally decide to proceed with the ill-characterised compounds in `288. As I have said, the argument was also unconvincing because Dr [3] had not with any clarity spelled it out in his written evidence, and I accept Astellas’ contention that it only really surfaced in the Claimants’ opening oral submissions.

202. It is of some relevance that `288 does not mention OAB in the list of possible conditions to be treated, but I do not think that it is a critical point in isolation, mainly because of my view that there is force in the Claimants’ argument that the skilled addressee would think OAB’s omission might be explained by `288 having been written before the advances I have identified above. In the course of oral closing argument and in the context of this point, I asked Counsel for Astellas whether he would accept that if `288 disclosed mirabegron as an excellent, potent and specific β3-AR agonist, it would then be obvious to try it for OAB, despite the condition’s not being mentioned in the list. Initially he accepted that it “probably” would be (although he caveated this shortly afterwards) and Counsel for the Claimants understandably sought to leverage this so as to argue that all the Claimants had to show was that `288 in fact did disclose mirabegron as a good compound (in being selective). I certainly did not think that Counsel for Astellas was abandoning all its points about the general uncertainty around β3-AR agonism and OAB, and in my view the shortcomings of `288 and the art’s perception of β3-AR agonism have to be seen and assessed as a whole.

203. Finally, a point made by the Claimants was that the effort involved in making the six compounds exemplified in `288 would not be great. I accept that so far as it goes, and Dr [2] did accept that the effort in making 23 compounds in the context of a commercial research organisation would not be “unreasonable”, but it is a small part of the picture and one still has to inquire which 6 compounds (or 23) to make, for what purpose and with what confidence that they might succeed.”