T 0160/22 (Contraceptive regimen/BAYER) 23-07-2024

1. Claim construction

Claim 1 is formulated as a Swiss-type claim directed to the use of 20 myg of ethinyl estradiol (EE) and 3 mg of drospirenone for the manufacture of a medicament for female oral contraception characterised by a dosage regimen. The dosage regimen is the core of the invention that the patent is intended to protect and the parties disputed whether it limited the subject-matter of claim 1.

In Swiss-type claims, as in purpose-limited claims in accordance with Article 54(5) EPC, only intended uses excluded by Article 53(c) EPC can be regarded as limiting (see G 2/08, Reasons 7.1.1 and Order). Therefore, the question of whether the dosage regimen in claim 1 is limiting is directly linked to the question of whether the use for which the medicament is intended can be regarded as a method of treatment of the human or animal body by therapy excluded by Article 53(c) EPC. In other words, the question to be answered for determining whether the dosage regimen of claim 1 is limiting is whether the method of female oral contraception comprising the dosage regimen in claim 1 may be regarded as a method of treatment by therapy. This issue was controversial but can be left unanswered since, even if the dosage regimen was limiting, the subject-matter of claim 1 would not involve an inventive step, as outlined in point 2 below.

2. Inventive step (Articles 100(a) and 56 EPC)

As indicated in the paragraph above, the following assessment of inventive step assumes, in favour of the respondent, that the dosage regimen in claim 1 is limiting.

2.1 The invention in the patent belongs to the technical field of low-dose female oral contraception and relates to a particular dosage regimen. The standard regimen for low-dose oral contraceptives (OCs) is based on a 21/7-day cycle, i.e. a cycle of 21 days of daily OC administration followed by a hormone-free phase of seven days. The hormone-free phase allows withdrawal bleeding and mimics the natural menstrual cycle. However, the drop in hormone levels during the hormone-free phase may also cause menstruation-related disorders such as headaches, dysmenorrhoea, pelvic pain, acne, etc. An alternative standard regimen is based on a 24/4-day cycle. The reduction of the hormone-free phase in this regimen to only four days reduces the occurrence of menstruation-related disorders. Nevertheless, these standard regimens are not satisfactory for many women, who prefer extended cycles, i.e. cycles extending daily OC administration beyond 21 or 24 days, to reduce or completely eliminate bleeding and menstruation-related disorders (patent, paragraphs [0001] and [0002]). The problem with extended dosage regimens of low-dose OCs is that they cause bothersome breakthrough bleeding and spotting. The flexible, extended dosage regimen defined in claim 1 is aimed at managing this problem by reducing the occurrence of menstruation-related disorders while minimising breakthrough bleeding and spotting (patent, paragraphs [0020], [0022], [0024], [0026], [0031] and [0047]).

2.2 The parties presented their inventive-step arguments starting from D7 as the closest prior art.

Like the patent, D7 teaches in its introduction that the standard regimen for low-dose OCs is based on a 21/7-day cycle, and that this regimen has the disadvantage that the 7-day hormone-free phase often induces menstrual symptoms, such as bleeding, pain, breast tenderness, etc. In order to minimise the occurrence of these symptoms, a study was conducted in which it was proposed to women using the 21/7-day dosage regimen to extend the daily administration of OCs beyond 21 consecutive days with no maximum number of days. If they experienced bothersome breakthrough bleeding or spotting, they were instructed to initiate a hormone-free phase of no more than seven days, preferably three to four days (page 282, left-hand column, second paragraph). The majority of women took a hormone-free phase of four days (66%) or three days (14%) and reported an improvement in quality of life with the extended, flexible regimen (page 283, right-hand column, last full paragraph; page 285, paragraph bridging the two columns). The conclusion of the study was that, in most women, the bothersome breakthrough bleeding and spotting that occurs in extended OC regimens can be managed by initiating a three- to four-day hormone-free phase when bleeding occurs (page 287, left-hand column, first paragraph).

2.3 It was undisputed that the subject-matter of claim 1 differs from the teaching of D7 in the following features:

- the OC is specified as being the combination of 20 myg EE with 3 mg drospirenone,

- the minimum period of daily OC administration is of 24 days instead of 21 days,

- the maximum period of daily OC administration is of 120 days instead of unlimited,

- the hormone-free phase is of exactly four days, and

- the hormone-free phase is initiated either directly after 120 days of daily OC administration or following three consecutive days of breakthrough bleeding or spotting.

2.4 The parties did not agree on the technical effect produced by these differences. On this point, the Board shares the appellants' view that no evidence on file demonstrates that the dosage regimen of claim 1 is advantageous over that in D7.

2.4.1 The only experimental data in the patent are disclosed in the comparative example, which is not in accordance with claim 1. This example presents the results of a study on a flexible, extended OC regimen that reduces menstruation-related symptoms and manages bothersome breakthrough bleeding and spotting. The dosage regimen and the results in the comparative example appear to be those disclosed in D7 (abstract; Table 1; page 283, paragraph bridging the columns, and right-hand column, penultimate paragraph; page 286, right-hand column, penultimate paragraph).

2.4.2 The respondent relied on the results of the clinical studies reported in post-published documents D20 and D32 to demonstrate a technical effect over D7. However, as noted by the appellants, D20 and D32 do not provide conclusive evidence in that respect because the clinical studies therein do not provide a comparison with a regimen as disclosed in D7.

The clinical study in D20 compares three dosage regimens in which the OC is a combination of 20 myg of EE and 3 mg of drospirenone (abstract and page 75). First, a flexible, extended regimen as defined in claim 1, designated as "flexibleMIB". Second, a fixed, extended regimen based on a 120/4-day cycle, designated as "fixed extended". Third, a regimen based on a 24/4-day cycle, designated as "conventional 28-day". The study concluded that the flexibleMIB regimen resulted in statistically significant fewer breakthrough bleeding and spotting days than the fixed extended regimen and the 28-day conventional regimen. However, this result cannot be extrapolated to a comparison with the dosage regimen of D7 which, like flexibleMIB, is a flexible, extended regimen instead of a fixed extended or a 28-day conventional regimen.

The clinical study in D32 also compares three dosage regimens of the combination of 20 myg of EE with 3 mg of drospirenone (abstract and section 2.3). First, a flexible, extended regimen as defined in claim 1, designated as "flexibleMIB". Second, a flexible, extended regimen in which women received OC for a minimum of 24 days and initiated a four-day hormone-free phase at any time during days 25 to 120, regardless of the occurrence of bleeding. This regimen was designated as "flexibleAPC". Third, a regimen based on a 24/4-day cycle, designated as "conventional 28-day". The number of breakthrough bleeding or spotting days occurring in the flexibleMIB and flexibleAPC regimens was similar (point 3.1.2.4), although there were some differences in the median length of the bleeding episodes and the number of unscheduled bleeding days (points 3.1.2.2 and 3.1.2.3). These results are nevertheless irrelevant to the case at hand since, like the regimen of claim 1 and unlike flexibleAPC, the hormone-free phase in the regimen of D7 is initiated when breakthrough bleeding or spotting occurs. Therefore, a comparison of flexibleMIB with flexibleAPC does not allow any conclusion to be drawn on the technical effect of the regimen of claim 1 compared with that of D7.

2.4.3 The respondent argued that the clinical studies in D32 demonstrated an improvement over D7. It submitted that D7 merely proposed an extension of the standard OC regimen in which women could initiate a hormone-free phase "to meet their needs". This meant that women could initiate the hormone-free phase whenever they wanted, independently of the occurrence of breakthrough bleeding and spotting. Therefore, the teaching of D7 was represented by the regimen flexibleAPC and the comparative data in D32 demonstrated an improvement over D7. The respondent also argued that the teaching of D7 was very broad and that comparative clinical studies could not be conducted for every possible piece of closest prior art. Therefore, D32 should be accepted as evidence of an improvement.

The respondent's arguments are not convincing. D7 is directed to the management of breakthrough bleeding in extended OC regimens and proposes initiating a hormone-free phase of three to four days when breakthrough bleeding occurs. This is apparent from the title: "Outcomes of extended oral contraceptive regimens with a shortened hormone-free interval to manage breakthrough bleeding", and is consistently taught throughout the document. For instance, the last sentence of the introduction states: "This report specifically looks at acceptability, variability and continuation rates of patients extending the active pill component with introduction of a HFI of 3-4 days when bothersome breakthrough bleeding and/or spotting occurs" (HFI means hormone-free interval). Also, the first paragraph on page 287 states: "A 3-4 day HFI interspersed in a continuous regimen when this bleeding occurs was successful in managing the bleeding in most patients". Thus, contrary to the regimen flexibleAPC in D32, the initiation of a hormone-free phase in D7 is directly linked to the occurrence of breakthrough bleeding or spotting.

With regard to the argument that comparative clinical studies cannot be conducted for every possible piece of closest prior art, the Board agrees. However, this cannot be a reason for acknowledging a technical effect over the closest prior art when there is no evidence of one.

2.5 In view of the lack of evidence of a technical effect over the dosage regimen of D7, the objective technical problem is to provide an alternative flexible, extended OC regimen.

2.6 The solution proposed in claim 1 consists of several modifications of the dosage regimen disclosed in D7 (see point 2.3 above): (i) the limitation of the OC to the combination of 20 myg EE with 3 mg drospirenone, (ii) a minimum period of daily OC administration of 24 days, (iii) a maximum period of daily OC administration of 120 days, (iv) a hormone-free phase of exactly four days, and (v) the initiation of the hormone-free phase either after the 120 days of daily OC administration or following three consecutive days of breakthrough bleeding or spotting.

The respondent argued that, even if the skilled person could combine the features in claim 1, they had no motivation do so. However, as noted by the appellants, the modifications over D7 proposed in claim 1 do not interact with each other to produce a combined effect. They are juxtaposed independent modifications with independent effects and the obviousness of each modification can be assessed separately. In this context, the respondent's arguments were primarily directed to the inventiveness of the choice of the OC, i.e. the combination of 20 myg EE with 3 mg drospirenone.

2.6.1 The limitation of the OC to the combination of 20 myg EE with 3 mg drospirenone was obvious. The dosage regimen proposed in D7 was generally applicable for managing bothersome breakthrough bleeding and spotting in any extended regimen of OCs approved and marketed (page 287, first paragraph). This is also clear from the fact that the women who participated in the study of D7 took different OCs based on an EE dose of 35 myg or less. Therefore, the results presented in D7 were not limited to any particular OC or, at most, were limited to OCs containing EE as the oestrogen component (page 282, left-hand column, last paragraph; page 283, right-hand column, last sentence of last full paragraph). D7 stated that a 24/4-day regimen of 20 myg EE with 3 mg drospirenone had been submitted to the FDA for approval (page 286, left-hand column, last sentence of last full paragraph). Therefore, it was obvious that the flexible, extended OC regimen of D7 was applicable to the available combination of 20 myg EE with 3 mg drospirenone.

The respondent contended that the skilled person would not apply the teaching of D7 to the combination of 20 myg EE with 3 mg drospirenone. This was because the dose of EE suggested in D7 was of 35 myg, and it was common general knowledge that reducing the EE dose below 30 myg increased breakthrough bleeding. In that respect, the respondent cited the paragraph bridging the columns on page 162 of D19.

The Board cannot agree with the respondent's argument. Firstly, the EE dose tested in D7 was not 35 myg but 35 myg or less (page 282, left-hand column, last paragraph). Secondly, the dosage regimen of D7 reduces breakthrough bleeding and spotting. Therefore, the skilled person would use it for OCs likely to produce breakthrough bleeding and spotting. In addition, when D7 refers to the combination of 20 myg EE with 3 mg drospirenone, it cites D6 (reference [11]). D6 discloses the results of a clinical study on the 24/4-day regimen of the combination of 20 myg EE with 3 mg drospirenone. It concluded that the regimen was effective, acceptable, had a convenient bleeding pattern and was well tolerated (page 197, last paragraph). Therefore, the skilled person was prompted to apply the flexible, extended regimen of D7 to the combination of 20 myg EE with 3 mg drospirenone.

With respect to D19, it is an isolated scientific publication which does not represent common general knowledge and cannot demonstrate the presence of a general prejudice in the prior art. Furthermore, the passage on page 162 of D19 cited by the respondent merely states that EE doses lower than 30 myg can result in breakthrough bleeding. This does not mean that they necessarily cause breakthrough bleeding or that a dose of 20 myg EE causes significantly more breakthrough bleeding than a dose of 30 myg. Therefore, there is no reason why the skilled person would not apply the teaching of D7 to reduce breakthrough bleeding and spotting in an extended regimen based on the known combination of 20 myg EE with 3 mg drospirenone.

2.6.2 With regard to the minimum period of daily OC administration of 24 days instead of 21 days, the respondent has not put forward any particular argument. The Board agrees with the appellants that this distinguishing feature is a customary modification with no demonstrated technical effect. As noted by the appellants, the application as filed teaches that the most preferred minimum intake period is 21 to 24 days (page 7, fourth and fifth paragraphs). No technical effect is associated with the selection of 24 days. In addition, as explained in point 2.6.1 above, D7 proposes the extension of the 24/4-day regimen of 20 myg EE with 3 mg drospirenone. Therefore, the choice of a minimum period of daily OC administration of 24 days was obvious.

2.6.3 The respondent has not provided any particular argument directed to the choice of 120 days as the maximum period of daily administration, either. The Board again agrees with the appellants that this choice is customary and is not based on technical reasons. The application as filed acknowledges that, if no bleeding problems occur, the maximum cycle length can be extended for as long as desired by the woman (page 7, last paragraph). This can usually be up to two years but due to legal or regulatory requirements it may be limited to a fixed maximum. The application gives several illustrative ranges, such as 77 to 91, 112 to 126, 175 to 189 or 336 to 364 days (page 8, lines 3 to 7). For instance, in Example 1 of the application, the maximum cycle length is fixed on the basis of the study duration to 112 to 140 days, e.g. 120 days. Similarly, in Example 3 the maximum length is fixed according to the length of the proposed study to 77 to 126 days, e.g. 84 days. Furthermore, D19 discloses an extended method for administering 30 myg EE and 3 mg drospirenone with a cycle length of 42 to 126 days (page 163, paragraph bridging the columns). Therefore, the maximum length of daily OC administration of 120 days was obvious.

2.6.4 The length of the hormone-free phase of four days was by far the most preferred option in D7 and was adopted by 66% of the women. Therefore, this feature cannot provide an inventive step, either.

2.6.5 Lastly, the requirement that the hormone-free phase be initiated following three consecutive days of breakthrough bleeding or spotting is also obvious in view of the teaching in D7 that the hormone-free phase is initiated following bothersome breakthrough bleeding or spotting. The respondent has not shown that the requirement that the hormone-free phase be initiated after three consecutive days of breakthrough bleeding or spotting is critical or has any particular technical effect.

2.6.6 In an additional argument to support its case, the respondent referred to D25 to show that competitors were copying the dosage regimen of claim 1. This would indicate that the claimed dosage regimen was superior to those of the prior art.

This argument fails simply because such a consideration cannot override the outcome of the inventive-step assessment based on the problem and solution approach.

2.7 Therefore, the subject-matter of claim 1 does not involve an inventive step and the ground for opposition of Article 100(a) EPC in combination with Article 56 EPC prejudices maintenance of the patent as granted.