T 2680/19 (Alpha-1 antitrypsin for subcutaneous administration/GRIFOLS THERAPEUTICS) 05-05-2022

1. The appeal complies with Articles 106 to 108 and Rule 99 EPC and is admissible.

Auxiliary request 1

Amendments (Article 123(2) EPC) - claim 1

2. The claim, which is identical to claim 1 of auxiliary request 1 considered in the decision under appeal, is for the use of alpha1-AT in a method of treating alpha1-AT deficiency in a subject by subcutaneous administration. The effective amount of the subcutaneously administered alpha1-AT is defined by three features:

(i) it is at least about 120% of a therapeutically or prophylactically effective amount of alpha1-AT based on a dosage regimen comprising intravenously administered alpha1-AT;

(ii) it is sufficient to maintain in the subject a blood alpha1-AT trough level of at least about 80 mg/dL; and

(iii) it is about 60 mg to about 300 mg of alpha1-AT per kg of body weight of the subject.

3. It is undisputed that the application does not verbatim disclose a method in which the amount of the subcutaneously administered alpha1-AT is characterised by features (i), (ii) and (iii). The opposition division held that while the three features characterising the amount of the subcutaneously administered alpha1-AT were disclosed individually in the application, they could be combined without adding subject-matter because they were all "part of the same invention" (see decision under appeal, Reasons 11.4). On appeal, the appellant maintained that a method of treating alpha1-AT deficiency in which the amount of alpha1-AT to be subcutaneously administered was defined by the claimed combination of features (i), (ii) and (iii) was contrary to the requirements of Article 123(2) EPC.

4. It is established case law of the boards of appeal that the standard for assessing compliance with the requirements of Article 123(2) EPC is the standard set out in decision G 2/10 (OJ EPO 2012, 376, Reasons, point 4.3), also known as the "gold standard". Amendments are only permitted within the limits of what a skilled person would derive directly and unambiguously, using common general knowledge, and seen objectively and relative to the date of filing, from the whole of the application as filed.

5. It is also well established in the case law of the boards of appeal that the content of an application must not be considered to be a reservoir from which features pertaining to separate embodiments of the application can be combined in order to artificially create a particular embodiment. In the absence of any pointer to that particular combination, this combined selection of features does not, for the person skilled in the art, emerge clearly and unambiguously from the content of the application as filed (see Case Law of the Boards of Appeal, 9th edition, 2019, ("CLBA"), II.E.1.6.1).

6. The application relates to a method for providing to a subject, by a subcutaneous route, a therapeutically or prophylactically effective amount of alpha1-AT for treating or preventing a disorder or disease associated with alpha1-AT deficiency (see e.g. page 1, lines 9 to 11;

claim 1). In the section relating to the background of the invention, the application states that it is known that alpha1-AT deficiency can be treated by repeated intravenous administrations of alpha1-AT, but that this mode of administration can be associated with problems (see page 2, lines 15 to 19). There remained therefore a need "for a method for providing alpha1-AT that at least is easy to administer, is suitable for long-term administration, and achieves desirable alpha1-AT plasma bioavailability levels" (see page 2, lines 20 to 22).

7. The application then discloses three approaches for defining the amount of subcutaneously administered

alpha1-AT (see page 2, line 25 to page 3, line 4; page 6, line 30 to page 7, line 9; claim 2) as set out below.

7.1 In a first approach, termed "one aspect" (see page 2, line 25 or page 6, line 30 of the application), the amount of alpha1-AT to be administered subcutaneously is specified as being a therapeutically or prophylactically effective amount. According to "one embodiment" of this aspect, the effective amount of alpha1-AT is specified on the basis of a target blood alpha1-AT trough threshold level "sufficient to maintain a blood alpha1-AT trough level of at least 80 mg/dL" (see page 2, lines 25 to 30). This embodiment corresponds to

feature (ii) of claim 1. Further embodiments of this aspect define different target threshold levels as "at least about 10 mg/dL, illustratively, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, and 200 mg/dL" (see page 7, lines 1 to 3), and in the context of human subjects as "at least about 50 mg/dL" or "at least about 80 mg/dL" (see page 7, lines 4

to 8).

7.2 In a second approach, termed "another aspect" or "other embodiments" (see page 2, line 31 or page 7, line 10 of the application), the effective amount of alpha1-AT to be subcutaneously administered is defined by reference to a dosing regimen comprising intravenous administration of alpha1-AT to a subject and application of a dose adjustment factor of 120% to the intravenous dose (see application, page 2, line 31 to page 3, line 4; page 7, lines 10 to 16; claim 2). This approach corresponds to feature (i) of claim 1.

7.3 As a third approach, the dose of alpha1-AT to be subcutaneously administered is directly specified in terms of possible dose ranges as follows: "In one embodiment, the dose to be subcutaneously administered is at least about 1 mg per kg of body weight of the subject per subcutaneous administration, illustratively, about 1 mg to about 1000 mg, about 10 mg to about 900 mg, about 20 mg to about 800 mg, about 30 mg to about 700 mg, about 40 mg to about 600 mg, about 50 mg to about 500 mg, about 60 mg to about 400 mg, about 70 mg to about 300 mg, about 80 mg to about 250 mg, about 90 mg to about 200 mg, and about 100 mg to about 150 mg per kg of body weight of subject per administration. In another embodiment, the dose is about 60 mg to about 300 mg per kg of body weight of the subject" (see page 7, lines 19 to 26 of the application). The embodiment termed "another embodiment" corresponds to feature (iii) of claim 1.

8. The three features (i), (ii) and (iii) defining the subcutaneously administered amount of alpha1-AT in claim 1 are disclosed in the application explicitly as distinct "aspects" and separate "embodiments" of alternative methods for providing to a subject, by a subcutaneous route, a therapeutically or prophylactically effective amount of alpha1-AT; they are not disclosed as combined features within a single alpha1-AT administration method (see application, page 2, lines 25 and 31; page 6, line 30; page 7, lines 4, 6, 10, 19 and 25).

9. None of the passages of the application disclosing features (i), (ii) and (iii) of claim 1 links an embodiment of one aspect to a different aspect or to an embodiment of a different aspect (see application,

page 2, line 25 to page 3, line 4; page 6, line 30 to page 7, line 26).

10. The application furthermore discloses that one factor that may be considered when determining a therapeutically or prophylactically effective amount of alpha1-AT for subcutaneous administration is the pharmacology of alpha1-AT. Pharmacokinetic parameters or measures of alpha1-AT levels in the blood are said to include the area under the curve (AUC), Cmin (= trough level), and Cmax, the trough level being the lowest blood level of alpha1-AT during a fixed dosing period (see page 6, lines 8 to 16). However, the application does not provide any information on how the trough levels, dose adjustment factor and dose ranges generally - or features (i), (ii) and (iii) specifically - interact to achieve a therapeutically or prophylactically effective amount of alpha1-AT upon subcutaneous administration.

11. In Example 1, the plasma bioavailability of subcutaneously administered alpha1-AT was determined in rabbits. A single injection of two subcutaneous (SC) dose levels, 200 mg/kg body weight (SC-1) and 240 mg/kg body weight (SC-2), were examined and compared with a single intravenous (IV) administration of alpha1-AT

(200 mg/kg body weight). The results were summarised as follows: "The fractional availability (F) derived from the area under concentration curve's (AUC's) of SC-1 (i.e., 100% IV dose) and SC-2 (i.e., 120% of IV dose) group were, respectively, 27% lower (P<0.05) and

8% lower (not statistically significant) compared to the IV group" (see page 14, lines 22 to 25). Accordingly, Example 1 provides a rationale for

feature (i) but not for combining it with features (ii)

and (iii).

12. In Example 2, plasma bioavailability after three repeated subcutaneous administrations of alpha1-AT was examined. Groups of rabbits were dosed on day 0, 2, 4 and 6 at 50mg/kg (SC-3), 60mg/kg (SC-4) and

70mg/kg (SC-5). The fractional availability, determined by comparing the AUC to the single-dose IV group from the experiment described in Example 1, was 0.71 ± 0.03, 0.89 ± 0.04 and 0.91 ±0.07 for SC-3, SC-4 and SC-5, respectively. A trough level of at least

80 mg/dL was not reached in any of the three SC groups (see Figure 2). Accordingly, Example 2 does not provide a rationale for combining features (i), (ii) and (iii) either.

13. While the claims as filed disclose subject-matter corresponding to feature (i) of claim 1 (see claim 2 as filed), they provide no link between that feature and features (ii) and (iii). In fact, subject-matter corresponding to features (ii) and (iii) is not disclosed in the claims as filed.

14. The board concludes from the above analysis (see

points 6. to 13.) that the application discloses features (i), (ii) and (iii) as distinct, alternative embodiments of three different methods of providing to a subject, by a subcutaneous route, a therapeutically or prophylactically effective amount of alpha1-AT, not as features within a single administration method.

The application does not provide any technical information as regards the trough level corresponding to feature (ii), the dose range corresponding to feature (iii) or their interaction with feature (i) in providing to a subject, by a subcutaneous route, a therapeutically or prophylactically effective amount

of alpha1-AT. No other technical information linking features (i), (ii) and (iii) is provided in the application either.

Accordingly, the application provides no incentive or pointer for the skilled person to combine a blood alpha1-AT trough level of 80 mg/dL and a dose range of about 60 mg to about 300 mg of alpha1-AT per kg of body weight of the subject with a dose adjustment factor of at least about 120% within a single method of subcutaneous alpha1-AT administration.

15. The board is not persuaded by the respondent's line of reasoning that claim 1 does not relate to an undisclosed combination of features because the skilled person would immediately understand that the trough level and dose adjustment factor were not alternative embodiments but merely a specification of what "the invention also entails" and the dose range was "part of another embodiment of the same invention".

16. The property of belonging to the same invention does not set the embodiments on which features (i), (ii) and (iii) are based apart from all other embodiments of the invention. Accordingly, being part of the same invention cannot act as a pointer to the claimed combination of features (see point 5. above). For the same reasons, the opposition division's reasoning (see point 3. above) cannot hold either.

17. The respondent's further argument that it was an "overly formalistic, semantic approach" to say that the words "embodiments" and "aspects" constituted a strict separation and that there was a reason why this information was provided in one document - the application - likewise fails. This argument ignores the fact that the content of an application must not be considered to be a reservoir from which features pertaining to separate embodiments of the application can be combined in order to artificially create a particular embodiment (see point 5. above).

18. The respondent furthermore submitted that the required bioavailability for a subcutaneous administration of alpha1-AT to be therapeutically or prophylactically effective acted as a pointer, meaning that the skilled person, after being told in the application that sufficient bioavailability was important for the subcutaneous therapy (see page 2, lines 20 to 22 of the application), would recognise that the definitions corresponding to features (i), (ii) and (iii) could be used in combination to define a suitable subcutaneous therapy, and that satisfying all three features "was of course the best way and hence preferred".

19. However, as set out above (see points 7. to 8.), the application discloses three alternative approaches for defining the amount of the subcutaneously administered alpha1-AT, with the first approach (based on target blood alpha1-AT trough threshold levels) and the third approach (based on alpha1-AT dose ranges) encompassing several alternative embodiments. Even if it were accepted that "achieving bioavailability" could serve as a pointer towards combining the three alternative approaches into a single method, the skilled person would require an incentive or pointer to choose the particular combination of embodiments corresponding to

features (i), (ii) and (iii) from among all the other possible combinations of embodiments.

20. The respondent's submission in this context that features (i), (ii) and (iii) were disclosed as being preferred and could therefore be combined is not found persuasive.

In the application, the embodiment corresponding to feature (ii) (i.e. blood alpha1-AT trough level of at least about 80 mg/dL) is disclosed as "one embodiment", and the feature corresponding to feature (iii) (i.e. 60 mg to about 300 mg of alpha1-AT per kg of body weight) is disclosed as "another embodiment" (see points 7.1

and 7.3). Neither embodiment is stated as being "preferred". Nor does the application disclose that the embodiments corresponding to features (ii) and (iii) are particularly advantageous or optimised in terms of ensuring sufficient bioavailability compared with all the other trough levels and dose ranges disclosed (see also point 10. above).

21. The respondent's further argument that a preference was implied because the skilled person would have understood that an "embodiment" was narrower than an "aspect" cannot succeed because the application discloses several embodiments for the trough level (see point 7.1) and several embodiments for the dose range (see point 7.3).

Furthermore, if it were accepted that "being narrower" implied a preference, then the application would point to different embodiments; 80 mg/dL is not the narrowest option for the trough level (see point 7.1 above),

and 60 mg to about 300 mg of alpha1-AT per kg of body weight is not the narrowest option for the dose range (see point 7.3 above).

In sum, a preference for features (ii) and (iii), and hence a pointer towards combining them with feature (i) in the context of bioavailability, is not derivable from the application.

22. Lastly, as regards the respondent's reliance on established case law for assessing novelty, the board notes that also when contesting novelty, the content of a document must not be treated as something in the nature of a reservoir from which features pertaining to separate embodiments may permissibly be drawn in order to create artificially a particular embodiment which would destroy novelty, unless the document itself suggests such a combination of features (see CLBA,

section I.C.4.2).

23. The board concludes that the subject-matter of claim 1 relates to subject-matter that is not directly and unambiguously derivable from the application as filed

(Article 123(2) EPC).

Auxiliary requests 2 to 6

24. The respondent requested that the opponent's appeal be rejected, implying that the patent be maintained on the basis of auxiliary request 1, but did not refer to its lower-ranking claim requests, i.e. auxiliary requests 2 to 6 submitted with the reply to the statement of grounds of appeal. In case the respondent implicitly wished to maintain the lower-ranking claim requests, the board notes the following.

25. Claim 1 of each of auxiliary requests 2 to 6 contains the same combination of features, (i), (ii) and (iii), as claim 1 of the main request (see section VI.). The reasoning set out above for claim 1 of the main request (see points 2. to 23.) therefore applies mutatis mutandis to the subject-matter of claim 1 of each of auxiliary requests 2 to 6. This was not disputed by the respondent. Consequently, the subject-matter of claim 1 of auxiliary requests 2 to 6 does not meet the requirements of Article 123(2) EPC.

Reimbursement of the appeal fee

26. As stated under section X. above, the patent proprietor withdrew its appeal before the decision was announced at oral proceedings. As a consequence, the appeal fee paid by the patent proprietor is to be reimbursed

at 25% in accordance with Rule 103(4)(a) EPC. A separate order for the reimbursement has been issued.