T 2007/17 16-09-2022

I. Opponent 1 filed an appeal against the decision of the opposition division to reject the opposition.

II. Oral proceedings before the board took place on 16 September 2022.

III. The appellant (opponent 1) requested that the decision under appeal be set aside and that the patent be revoked.

Opponent 2, who had the status of a party as of right, did not file any requests and did not take part in the oral proceedings.

The respondent (patent proprietor) requested that the appeal be dismissed and the patent be maintained as granted.

IV. Claim 1 of the patent as granted reads as follows.

"A skin patch comprising a plurality of solid biodegradable microneedles, wherein the microneedles comprise a mixture of (i) a biosoluble and biodegradable matrix material and (ii) a purified influenza virus surface antigen vaccine, wherein the vaccine comprises hemagglutinin and 5-30 myg of detergent per myg of hemagglutinin."

Claim 2 of the patent as granted reads as follows.

"A process for preparing a skin patch comprising a plurality of solid biodegradable microneedles, comprising steps of: (i) mixing a biosoluble and biodegradable matrix material with a purified influenza virus surface antigen vaccine, wherein the vaccine comprises hemagglutinin and 5-30 myg of detergent per myg of hemagglutinin; and (ii) adding the mixture from step (i) to a mould containing cavities for forming microneedles."

Claim 3 of the patent as granted reads as follows.

"A skin patch comprising a plurality of solid biodegradable microneedles, wherein the microneedles comprise a mixture of (i) a biosoluble and biodegradable matrix material and (ii) a purified influenza virus surface antigen vaccine comprising hemagglutinin, wherein the amount of influenza virus hemagglutinin per patch is <= 16 myg per strain, wherein the patch comprises 5-30 myg of detergent per myg of hemagglutinin."

V. The following documents are referred to in this decision.

D1 Intradermal influenza vaccine delivery using skin-

penetrating dissolvable vaccine microneedles, S.

Oh et. al., Annual Meeting and Exposition, The

AAPS Journal, Vol. 8, 2006

D2 Dissolving polymer microneedle patches for

influenza vaccination, S. Sullivan et. al., Nature

Medicine 16, 915 to 920, 2010

D9 WO 2011/151726

D10 WO 2001/151723

D14 WO 2004/105729

D15 Prescribing information for FLUZONE**(®)

D16 Intradermal delivery of vaccines: A review of the

literature and the potential for development for

use in low- and middle-income countries. (2009)

Program for Appropriate Technology in Health.

D17 Summary of Product Characteristics for OPTAFLU**(TM)

D18 WO 2008/130587

D26 Flucelvax US Package Insert

VI. The arguments of the appellant may be summarized as follows.

Novelty over D9 and D10

D9 related to methods of administration of vaccines using biodegradable microneedles (page 1, line 13; page 6, lines 16 to 19 and line 27 to page 8, line 21; page 11, lines 33 to 34; claims 11 and 12). The vaccine could be an influenza vaccine (page 2, lines 8 to 9; page 4, lines 7 to 9; page 12, lines 7 to 29), for instance a purified surface antigen influenza vaccine comprising hemagglutinin, such as FLUVIRIN, AGRIPPAL and INFLUVAC (page 12, lines 12 to 16).

It was also mentioned that inactivated vaccines, i.e. whole virus, split virus and surface antigen, were suitable for intradermal injection (page 12, lines 9 to 10). Surface antigen vaccines contained fewer viral components than split virus or whole virus vaccines (page 12, lines 12 to 13). Since the person skilled in the art knew that fewer viral components reduced the risk of side effects, surface antigen vaccines would be preferred.

Hence, D9 disclosed a microneedle patch comprising a surface antigen vaccine as a preferred embodiment. Furthermore, the surface antigen vaccines mentioned in D9 contained a considerable amount of detergent (point 4.51 of the respondent's letter dated 3 April 2018).

D9 referred to detergents as a further component of vaccine products on page 20, first paragraph. In addition to a general range of detergent level (0.01 to 50 myg per myg of hemagglutinin), three examples of a high level of the detergent polysorbate 80 were explicitly mentioned (5 to 40 myg per myg, 5 to 30 myg per myg and 8 to 25 myg per myg). Hence, the person skilled in the art would have derived that the surface antigen vaccine of the microneedle patch of D9 could comprise 5 to 30 myg detergent per myg hemagglutinin, as claimed in claims 1 to 3. Since the claimed range was not narrow and not sufficiently far removed from the specific examples (5, 8, 25 and 30 myg per myg) of the whole range (0.01 to 50 myg per myg), it could not be considered as novel.

D10 contained essentially the same disclosure as D9 (page 7, lines 1 to 21; page 12, lines 14 to 31; page 20, second paragraph). With regard to the combination of claims 1, 10 or 11 and 17, D10 even disclosed a microneedle preparation from a liquid composition including a detergent. D10 also anticipated the claimed range of 5 to 30 myg per myg (page 20, lines 4 to 12). Hence, the above-mentioned conclusions also applied to D10.

Consequently, the subject-matter of claims 1 to 3 lacked novelty over D9 and D10.

Inventive step starting from D1 or D2

D1 related to administration of the influenza vaccine Fluzone by means of a biodegradable microneedle patch. According to D15 (page 5, third paragraph), Fluzone was a split virus antigen comprising hemagglutinin.

D2 also related to dissolving microneedle patches for influenza vaccination using an inactivated whole virus vaccine (page 916, left column, first paragraph; page 915, right column, last paragraph).

The subject-matter of claim 1 differed from the skin patches of D1 and D2 in that the vaccine was a purified surface antigen vaccine and in that the vaccine comprised 5 to 30 myg of detergent per myg of hemagglutinin.

These two distinguishing features solved the objective technical problem of providing an alternative microneedle skin patch.

To solve this problem, the person skilled in the art would resort to the commercially available vaccine Optaflu**()(D17) (or its US-equivalent Flucelvax (D26)), which was a surface antigen vaccine comprising about 8 to 26 myg detergent per myg hemagglutinin (paragraphs [0093] and [0094] of the patent, and D26, page 7). Optaflu was prepared from viruses which were grown in cell culture. The person skilled in the art was aware that this was advantageous over viruses grown in eggs, which could be allergenic (paragraph [0032] of the patent). Apart from that, as a surface antigen vaccine, Optaflu provided the advantage that the risk of side effects was reduced. Hence, the person skilled in the art would have chosen Optaflu as an alternative to the vaccine Fluzone used in D1 or the vaccine of D2.

D14 disclosed microneedles coated with a vaccine containing a certain amount of surfactant, i.e. detergent (paragraphs [00019] and [00020]). The requirement of mechanical stability was mentioned in paragraph [00018]. Based on the teaching of this document, the person skilled in the art would have expected that a larger amount of detergent would have a positive effect also in solid microneedles.

D18 disclosed a microneedle patch, wherein the needles contained an influenza vaccine and a detergent.

Contrary to the statement in paragraph [0026] of the patent, D16 did not teach that biodegradable microneedle patches were incompatible with surface antigen vaccines having a high level of detergent. From D16, the person skilled in the art rather derived that solid, biodegradable microneedles offered several advantages and that microneedle devices had considerable promise (page 56, points 8.1 and 8.2). Furthermore, it was mentioned on page 34, first paragraph on the right, that biodegradable microneedles with sufficient strength had been achieved in preclinical studies. Thus, D16 did not convey a prejudice against a microneedle array made from a surface antigen vaccine having a large amount of detergent.

Hence, the large amount of detergent in Optaflu would not have discouraged the person skilled in the art from using this vaccine in a microneedle patch according to D1 or D2, despite D17 only disclosing the administration of Optaflu as an intramuscular injection (page 12, points 4. and 5.).

Therefore, the subject-matter of claim 1 lacked an inventive step.

VII. The arguments of the respondent may be summarized as follows.

Novelty over D9 and D10

D9 did not disclose the use of a purified surface antigen influenza vaccine, in combination with a high level of detergent, in a skin patch comprising a plurality of solid biodegradable microneedles.

To arrive at the subject-matter of the claims, the person skilled in the art would have to select features from the following three lists of equally preferred alternatives.

1. The vaccines could include no detergent at all, a low level of detergent or a high level of detergent, e.g. between 5 and 30 myg per myg (page 20, lines 1 to 3).

2. Suitable solid formulations of the vaccine could include biodegradable microneedles, coated microneedles or thin oral films (page 6, lines 18 to 29, page 6, line 26 to page 11, line 17, claims 11, 13 and 17).

3. Inactivated vaccines suitable for intradermal injection could be whole virus, split virus or surface antigen vaccines (page 12, lines 9 to 10).

D9 did not mention any advantage of a large amount of detergent over a low or zero amount, of biodegradable microneedles over coated microneedles or oral films, or of surface antigen vaccines over whole virus or split virus vaccines.

Hence, there was no specific pointer in D9 that would have led the person skilled in the art to directly and unambiguously derive the combination of features recited in claim 1 of the main request. The subject-matter of claim 1 was therefore novel over D9.

Like D9, D10 did not express any preference for the particular combination of a high detergent level and solid, biodegradable microneedles when using purified surface antigen influenza vaccines. Although D10 mentioned a microneedle formulation containing detergent, it was silent as to the amount of detergent, and there was no hint that a high level of detergent was preferred. Hence, the subject-matter of claim 1 was also novel over D10.

Inventive step starting from D1 or D2

Starting from either D1 or D2, the objective technical problem was to provide a skin patch comprising a plurality of solid, biodegradable microneedles for intradermal delivery of a further influenza vaccine.

It was surprising that the solid, biodegradable microneedle format was also effective when it was used to deliver influenza vaccines containing high levels of detergent since none of the prior art documents provided any evidence to show that solid biodegradable microneedles were effective in these circumstances.

D16 taught that preparing suitable formulations for solid, biodegradable microneedles constituted a significant challenge for intradermal delivery, requiring further development work (page vii, third bullet point; page 43, Figure 9; pages 33 to 34, Table 12). Thus, the person skilled in the art would have been aware that formulating biodegradable microneedles with sufficient strength was not straightforward.

D14 discussed the potential effects of surfactants (i.e. detergents) on vaccine formulations for coated microneedles. However, the structural properties of solid microneedles were different from those of coatings. Hence, D14 did not prompt the person skilled in the art to use a vaccine containing detergent in the range of 5 to 30 myg per myg for formulating a solid microneedle.

D18 did not teach how much detergent could be tolerated when formulating solid, biodegradable microneedles without a detrimental effect on the delivery of the vaccine.

The person skilled in the art would not consider using Optaflu since D17 did not mention that this vaccine was compatible with microneedles. Since there would have been no expectation of success with Optaflu, they would have chosen another commercially available vaccine (containing less detergent) or another administration route.

As the cited prior art did not contain any pointer towards the selection of a purified surface antigen vaccine with a high level of detergent for use in solid, biodegradable microneedles, the subject-matter of claims 1 to 3 was inventive.