T 0099/14 - Pharmaceutical combination therapy

Key points

• The claimed invention is the combination of two compounds (timolol and bimatoprost) for treating ocular hypertension. Both active ingredients are known as monotherapy for ocular hypertension. Is combining them obvious? Combination therapy with timolol and latanoprost is also known. Starting from the known combination therapy, there is no technical effect.  "The technical problem has to be seen as the provision of an alternative fixed combination for the treatment of ocular hypertension." 
• " Bimatoprost has a molecular structure that is very similar to the structures of prostaglandins, especially to the structures of [...] latanoprost." 
• Still, the Board finds the replacement of latanoprost by bimatoprost inventive. This finding hinges essentially not on the cited prior art but on the fictional skilled person.
• " A skilled person would be, however, well aware that small differences in structure may lead to major differences in activity. This general knowledge is confirmed by the mechanistic considerations as set out in the following." 
• " [D7] discloses that bimatoprost has no affinity to prostaglandin receptors []). Consequently, it cannot act, like [] latanoprost, via binding to the prostaglandin receptor. [D7] thus provides evidence that at the effective date of the patent in suit, a skilled person would not have considered bimatoprost to be a functionally equivalent derivative of prostaglandins." 
• " The skilled person would thus have been well aware that mechanisms on a molecular basis were decisive when deciding on the combination of two hypotensive compounds." 
• " The provision of a fixed combination in the specific case of treating ocular hypertension is not per se trivial. The skilled person would be aware that careful considerations concerning the choice of the active agents have to be made to avoid effects that may be counterproductive in view of the condition to be treated. Consequently, the skilled person, in the specific case of the treating ocular hypertension, would not simply combine any active agent with any other active agent. When trying to provide an alternative fixed combination the skilled person would take particular care to replace one active only with another active known to act by exactly the same mechanism on a molecular basis." 
• "  Since there is evidence that [...] latanoprost act via different receptors than bimatoprost, the skilled person would not have replaced [...] latanoprost with bimatoprost when aiming at the provision of an alternative fixed combination." 
• Hence, the invention is according to the Board not obvious in view of the known combination therapy.
• As a comment, the Board takes care to emphasize " in the specific case of treating ocular hypertension" but the decision does not explain why ocular hypertension is special or different from other diseases. 
• There was a second attack starting from monotherapy with bimatoprost ."However, the closest prior art document discloses the use of bimatoprost essentially for mono-therapy and does not mention further specific hypotensive actives. Starting from such a disclosure involves an ex post facto analysis to rely on the teaching of documents referring to the second claimed active in combination with further actives, which are irrelevant in the context of the patent in suit.". This even despite "timolol [being] "the" hypotensive active used for reducing intraocular pressure and that timolol was well established in combination treatments", according to the opponents (and not refuted by patentee it seems).

EPO T 0099/14 - link

6. Inventive step (Article 100(a) and Article 56 EPC)

6.1 The patent in suit relates to the provision of a composition for treating ocular hypertension and providing enhanced benefits and/or having reduced side effects (paragraph [0001]). Compositions comprising timolol and bimatoprost allow for the same or better reduction of intraocular pressure while leading to a reduced number and/or reduced severity of side effects (paragraphs [0024] and [0026]).

6.2 Two separate lines of arguments have been put forward:

The first starting point for the assessment of inventive step relies on disclosures relating to fixed combinations of timolol and a prostaglandin derivative for the treatment of elevated intraocular pressure. Documents (4) and (24) have been identified as the closest prior art documents.

The second starting point is one of a series of documents that employ bimatoprost in essentially a mono-therapy for the reduction of intraocular pressure. Documents (7), (9) and (52) have been identified as promising springboards.

6.3 Fixed combinations as closest prior art

6.3.1 Document (4) defines a method for treating ocular hypertension or glaucoma by administration of a composition comprising an adrenergic blocking agent (beta-adrenergic antagonist) and a prostaglandin or prostaglandin derivative (claim 1). PGF2alpha isopropylester is the only example of a prostaglandin derivative in document (4). Timolol is one of the preferred beta-adrenergic antagonists. Compositions comprising PGF2alpha isopropylester and timolol are disclosed. It is stated that the combination is advantageous in that the beta-adrenergic antagonists act by reducing the secretion of aqueous humour, whereas prostaglandins act by increasing uveoscleral outflow (column 3, lines 18 to 26). By combining these two classes of actives, it is possible to reduce the concentration of each active which results in a significant reduction in the occurrence of side effects (column 3, lines 26 to 34).

6.3.2 Document (24) aims at providing an effective treatment of ocular hypertension by administration of a single-dose (i.e. once daily) of a fixed combination of latanoprost and timolol (title, abstract, paragraph bridging pages 125 and 126, page 127, right column, lines 10 to 5 from the bottom). Similar adverse events for the respective mono-therapies or the non-fixed combination were observed (page 127, right column, second paragraph).

6.3.3 The difference between the independent claims of the patent in suit and documents (4) and (24) is the choice of the second active agent. Starting from document (4) PGF2alpha isopropylester, starting from document (24) latanoprost is replaced with bimatoprost.

6.3.4 The replacement with bimatoprost allegedly leads to a reduction of side effects. However no data showing a direct comparison between compositions according to documents (4) or (24) and a composition according to the claims of the patent in suit was invoked by the respondent in appeal proceedings.

6.3.5 As a consequence, the technical problem has to be seen as the provision of an alternative fixed combination for the treatment of ocular hypertension.

In line with points 4.2 and 4.3 above, this problem is considered to be solved.

6.3.6 The opponents argued that it was obvious to replace one hypotensive active with another hypotensive active, especially since bimatoprost would have been considered by the skilled person to be a member of the same class of actives as PGF2alpha isopropylester and latanoprost.

Bimatoprost has a molecular structure that is very similar to the structures of prostaglandins, especially to the structures of PGF2alpha isopropylester and latanoprost. One difference lies in the replacement of the isopropylester moiety with an ethylamide group in bimatoprost. Bimatoprost further differs from PGF2alpha isopropylester by having a phenyl substituent instead of a n-propyl group at the end of the omega chain. A skilled person would be, however, well aware that small differences in structure may lead to major differences in activity. This general knowledge is confirmed by the mechanistic considerations as set out in the following.

Document (7) teaches that a considerable part of the activity of bimatoprost is probably due to an increase of uveoscleral humour outflow (page 723, right column, last paragraph). Document (7) then discloses that bimatoprost has no affinity to prostaglandin receptors (page 724, "Pharmacology", first paragraph, Table 1). Consequently, it cannot act, like PGF2alpha isopropylester and latanoprost, via binding to the prostaglandin receptor. Document (7) thus provides evidence that at the effective date of the patent in suit, a skilled person would not have considered bimatoprost to be a functionally equivalent derivative of prostaglandins.

Document (4) discusses in detail the mechanistic considerations that led to the selection of certain prostaglandin derivatives as suitable hypotensive actives for combined use with beta-adrenergic antagonists. Document (4) starts off by stating that prostaglandins reduce intraocular pressure by increasing uveoscleral outflow (column 1, lines 48 to 52). It is then explained that uveoscleral outflow is caused by the relaxation of the muscle part of the ciliary body, i.e. the aqueous humour passes through extracellular space between muscle fibres (column 2, lines 3 to 13). The mechanistic considerations are continued in a discussion on how prostaglandins effect this relaxation. Only one of the two possible mechanisms underlying this increase in uveoscleral outflow, on a molecular basis, is considered to be acceptable for an active that is to be combined with beta-adrenergic antagonists. This mechanism must be a molecular mechanism that is not based on the release of catecholamines but on an interaction with prostaglandin receptors (column 2, lines 14 to 36). Therefore, document (4) clearly teaches that specifically prostaglandins and derivatives of them that interact with the prostaglandin receptor are suitable for combining with beta-adrenergic antagonists. The combination of beta-adrenergic antagonists with compounds that rely on other mechanisms of action is stated to be potentially counterproductive. It is thus clear from document (4) that for the provision of effective fixed combinations mechanistic considerations on the molecular level, i.e. going beyond the inflow/outflow scheme, are decisive.

The skilled person would thus have been well aware that mechanisms on a molecular basis were decisive when deciding on the combination of two hypotensive compounds.

When assessing issues relating to the mechanisms of action, post-published documents (such as documents (40) to (42)) are disregarded by the board, since they cannot elucidate the knowledge of the skilled person before the effective date of the patent in suit.

The opponents emphasised on the disclosure of document (9). They explained that document (9) taught that bimatoprost was a new advantageous development in the line of prostaglandin derivatives that would consequently have been used by the skilled person as a replacement for the prostaglandin derivatives of documents (4) or (24). In fact, document (9) discloses a group of compounds that are potent ocular hypotensives and particularly suitable for the treatment of glaucoma (column 1, second paragraph). The compounds are presented as an advantageous development in view of the related art, e.g prostaglandin derivatives, such as PGF2alpha isopropylester and latanoprost (column 2, lines 33 to 53). The inventive compounds of document (9) replace the carboxylic acid group, presumably of the related prostaglandin, with a non-acidic substituent. Good potency and lower ocular surface hyperemia than the parent compounds were found (column 3, lines 9 to 19). Several specific compounds, some esters and some amides, are disclosed and some of them are synthesised and used in examples. Bimatoprost, which is neither synthesised nor used in the examples, is listed by its chemical formula as compound (9) in column 7 and defined in a list of specific compounds in claim 10. Document (9) is, however, completely silent on the mechanism of action of its new class of compounds.

6.3.7 The provision of a fixed combination in the specific case of treating ocular hypertension is not per se trivial. The skilled person would be aware that careful considerations concerning the choice of the active agents have to be made to avoid effects that may be counterproductive in view of the condition to be treated. Consequently, the skilled person, in the specific case of the treating ocular hypertension, would not simply combine any active agent with any other active agent. When trying to provide an alternative fixed combination the skilled person would take particular care to replace one active only with another active known to act by exactly the same mechanism on a molecular basis. Since there is evidence that PGF2alpha isopropylester/latanoprost act via different receptors than bimatoprost, the skilled person would not have replaced PGF2alpha isopropylester or latanoprost with bimatoprost when aiming at the provision of an alternative fixed combination.

6.3.8 Starting from either document (4) or document (24) the claimed subject-matter is a non-obvious alternative.

6.4 Mono-therapies and non-fixed combinations as the closest prior art

6.4.1 Document (7) focuses entirely on bimatoprost. The title indicates that the author considers bimatoprost to belong to a class of actives which differs from known classes, it reads: "Bimatoprost: a member of a new class of agents, the prostamides, for glaucoma management". Document (7) teaches that bimatoprost influences humour outflow by increasing tonographic outflow facility by approximately 35% and by increasing pressure-independent outflow, probably corresponding to uveoscleral outflow, by approximately 50% (page 723, right-hand column, last paragraph). Under the heading "Pharmacology", it is indicated that bimatoprost is not a prodrug, i.e. it acts directly as an amide. It has also no affinity for the prostaglandin receptor (page 724, left-hand column, first paragraph and Table 1).

Document (9) concerns a new class of compounds suitable for the treatment of glaucoma (column 1, second paragraph). The compounds are presented as an advantageous development in view of the related art, e.g. prostaglandin derivatives, such as PGF2alpha isopropylester and latanoprost (column 2, lines 33 to 53). The inventive compounds of document (9) contain a replacement of the carboxylic acid group, presumably of the related prostaglandin, with a non-acidic substituent. Good potency and lower ocular surface hyperemia than the parent compounds were found (column 3, lines 9 to 19). Several specific compounds are disclosed and some of them are synthesised and used in examples. Bimatoprost, which is neither synthesised nor used in the examples, is listed by its chemical formula as compound (9) in column 7 and defined in a list of specific compounds in claim 10. In document (9), column 11, lines 48/49, a combination with "other of the known vasodilator drugs" is taught. This passage has to be read in combination with the preceding paragraph dealing with the treatment of various pathophysiological diseases relating to heart conditions. This preceding paragraph is the only paragraph in document (9) that mentions an effect of vasodilation. This passage does thus not concern the treatment of ocular hypertension.

Document (52) provides information on the medicament Lumigan**(TM), a 0.03% bimatoprost ophthalmic solution. Bimatoprost is identified as being a prostamide, which is a synthetic structural analogue of prostaglandin. The ocular hypotensive activity is achieved by increasing outflow of aqueous humour through both the trabecular meshwork and uveoscleral routes (page 1, "Mechanism of Action"). As a major adverse reaction, conjunctival hyperemia is identified (page 5, "Adverse Reactions", first paragraph). In contrast to documents (7) and (9), document (52) mentions in very general terms the use of a further active agent for the treatment of ocular hypertension. Under the heading "Dosage and Administration" on page 6, it is stated in the third paragraph that Lumigan**(TM) may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure, when keeping administration at least five minutes apart. A similar statement can be found on page 4, paragraph 8. Despite the fact that no suggestion as to the identity of the other topical ophthalmic drug is made, the disclosure in document (52), which in view of the considerations above is closer to the claimed subject-matter than the disclosure of documents (7) or (9), constitutes the closest prior art for the problem-solution approach starting from non-fixed combinations.

6.4.2 The difference between the independent claims of the patent in suit and the disclosure of document (52) is the addition of a further compound capable of reducing intraocular pressure in form of timolol in a fixed combination.

6.4.3 The technical problem may thus be seen as the provision of a safe and effective composition leading to a further reduction, in compared with the reduction achieved by the sole administration of bimatoprost, of intraocular pressure in the treatment of ocular hypertension.

6.4.4 There is no doubt that the addition of timolol leads to a further reduction of intraocular pressure compared with the administration of bimatoprost alone. Reference is made to the data of the patent in suit, e.g. as presented in Figure 1.

6.4.5 Information representing the common general knowledge on the treatment of ocular hypertension and in particular on the provision of drug combinations for such a treatment can be found in documents (44) to (46).

Document (44) relates to antiglaucoma drugs. It states that a myriad of pharmacologic agents is available to decrease intraocular pressure through distinctly different mechanisms. Because of their unique mechanisms of action, these drugs may be used both alone and in combination (page 183, left-hand column, second paragraph).

Document (45) contains a section dealing explicitly with the "Combination of Antiglaucoma Drugs". The combining of drugs from different classes involving different modes of action can be employed when the application of one drug does not lower the intraocular pressure sufficiently (page 245, left column, third paragraph). Several combinations are discussed, including PGF2alpha isopropylester with timolol for patients that responded poorly to timolol (page 245, right-hand column, fifth paragraph). The next paragraph (page 245, right-hand column, sixth paragraph) relates to "proper" combinations and teaches that they lead to an enhanced reduction in intraocular pressure and cause longer-lasting effects. No details are mentioned.

Document (46), cited in the written procedure, confirms that prostaglandins lower the intraocular pressure in patients whose pressures are inadequately controlled by timolol alone (page 96, left-hand column, middle paragraph).

However, it is not clear whether any of documents (44) to (46) refers to fixed combinations. The provision of a fixed combination requires considerations on at least two levels. Firstly, the skilled person would have to choose two active agents that are suitable for combination. In the present case of hypotensive active agents the selection criteria would focus mainly on mechanisms of action and side effects. Furthermore, for a fixed combination, the possibility of interaction/reaction/influence of respective stabilities of the two actives when they are provided in the same composition would also play a role. A second aspect concerns the matrix of the fixed composition. It must ascertain a suitable shelf life and provide safe and effective delivery of the combined agents. Further issues may also arise, e.g. relating to dosage regimens. Guidance would thus be needed as to which two actives are promising from both a therapeutic and a formulation related point of view.

The opponents selected a document essentially relating to a mono-therapy by bimatoprost or vaguely proposing a further active agent to be administered at a time interval of at least 5 minutes as the closest prior art. It is questionable whether a skilled person starting from this point would have consulted documents relating to combinations not including bimatoprost for guidance. Documents not including bimatoprost provide neither guidance as to the suitability of the combination for achieving the therapeutic effect nor information on formulation related issues.

Document (52) itself does not give any clear guidance concerning concrete combinations. It provides information on the concomitant administration of two hypotensive actives, but without indicating which second hypotensive active would be suitable. Document (7) is silent on combinations. Document (9) discusses combinations for a different therapeutic purpose. There is no information on fixed combinations including bimatoprost and further hypotensive actives on file. Thus, there is no guidance for the skilled person on which hypotensive actives would be advantageous in combination, especially in a fixed combination, with bimatoprost.

Consequently, the question to be answered is whether the skilled person would simply use any of the known hypotensive actives which is acting by a physiological mechanism other than increasing aqueous humour outflow in combination with bimatoprost.

The opponents argued that timolol was "the" hypotensive active used for reducing intraocular pressure and that timolol was well established in combination treatments. Specific combinations were disclosed in documents (4) and (24) (see above) and in documents (2) (timolol + carbonic anhydrase inhibitor), (3) (timolol + brinzolamide), (5) (timolol + 15-deoxy-prostaglandin compound), (6) (timolol + (13,14-dihydro-15-ketoprostaglandin compound), (10) (see above) and (20) (timolol + glutamate antagonist). The skilled person would thus automatically consider timolol when aiming at providing a fixed combination.

However, the closest prior art document discloses the use of bimatoprost essentially for mono-therapy and does not mention further specific hypotensive actives. Starting from such a disclosure involves an ex post facto analysis to rely on the teaching of documents referring to the second claimed active in combination with further actives, which are irrelevant in the context of the patent in suit.

Furthermore, in analogy to the considerations under point 6.3.6 above, the skilled person would have reservations when combining bimatoprost with a beta-adrenergic antagonist such as timolol. The skilled person would have in mind the caveat from document (4) that, depending on the mechanism underlying the uveoscleral outflow, a combination with a beta-adrenergic antagonist could be counterproductive.

In the absence of a clear mechanistic explanation, on a molecular basis, of the activity of bimatoprost, the skilled person would not have combined bimatoprost with timolol when aiming at providing a safe and effective fixed combination leading to a further reduction of intraocular pressure in the treatment of ocular hypertension. Therefore, the provision of a combination of bimatoprost and timolol for the treatment of ocular hypertension involves an inventive step.

6.4.6 Having thus come to the conclusion that the subject-matter of claims 1 and 6 involves an inventive step when considering the technical problem defined in point 6.4.3 above and also when considering the technical problem defined in point 6.3.5 above, it is not necessary to establish whether a technical problem involving the reduction of the side effect of conjunctival hyperemia may be formulated.

6.4.7 Further arguments

(a) The opponents further argued that the skilled person would have combined any prostaglandin derivative with timolol and have expected an at least additive effect in the decrease of intraocular pressure. The subject-matter of the patent in suit would thus be the result of the normal next step in the development of prostaglandin derivative based products.

The board cannot concur with this argument, since the skilled person would not have considered bimatoprost to be a member of the prostaglandin class at the effective date of the patent in suit.

(b) The opponents have further argued that it was a well-known fact that fixed combinations improved patient compliance. The skilled person, following the teaching in document (52) (page 6, "Dosage and Administration") to concomitantly administer other topical ophthalmic drug products to lower intraocular pressure, would have opted for a fixed combination knowing from its general common knowledge that timolol was the most commonly used agent to be combined with prostaglandin derivatives.

It has been established above that the skilled person would not have considered bimatoprost to belong to the class of hypotensive prostaglandin derivatives. The provision of a fixed combination having patient compliance in mind has to be seen as a further step, once the two actives to be combined have been decided on. Consequently, the board cannot accept the opponents' argument.

(c) It was also argued that a skilled person would have been aware of the teaching of document (4) that the combination of two actives would allow for the same hypotensive effect while leading, due to the administration of a reduced amount of each of these two actives, to less severe side effects. Consequently, when starting from a mono-therapy by a compound having severe side effects, the skilled person would have simply added a second active, knowing that the reduction of the concentration of both of the two now present actives would have led to a reduction of side effects.

Having come to the conclusion that in the case of the provision of fixed combinations for the treatment of ocular hypertension the skilled person would not have simply combined any two actives, the question of concentrations and side effects does not arise for the board in the present case.

6.5 The subject-matter of claims 1 and 6 of the patent in suit involves an inventive step and, therefore, the ground for opposition under Article 100(a) and Article 56 EPC does not prejudice the maintenance of the patent.

Order

For these reasons it is decided that:

The appeal is dismissed.