T 0867/13 (Pompe disease/DUKE UNIVERSITY) 06-03-2018

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

Introduction

2. The invention concerns the treatment of glycogen storage disease type II (hereinafter "GSD-II"), which is also known as Pompe disease or acid maltase deficiency (hereinafter "AMD"). GSD-II is an autosomal recessive genetic disorder and is heterogenous in nature, with various molecular defects in the lysosomal acid alpha-glucosidase (hereinafter "GAA") gene, resulting in a partial or complete deficiency in GAA activity. The enzyme defect results in lysosomal glycogen accumulation in almost all tissues of the body, with cardiac and skeletal muscle the most seriously affected. The disease can manifest itself in early- and late-onset forms. The most severe phenotype is the infantile-onset form of GSD-II, originally described by J.C. Pompe. Infants suffering from Pompe disease generally die from cardiorespiratory failure before the age of one year. Juvenile and adult forms ofGSD-II are correlated with higher residual levels of GAA (see also document D73f, page 245, left-hand column, first paragraph, to right-hand column, first paragraph).

Sole claim request

Inventive step (Article 56 EPC) - claim 1

3. This decision deals with the issue of whether the claimed subject-matter involves an inventive step, all other issues having been decided in the appellant's favour in the decision under appeal.

Closest prior art

4. The opposition division held that the subject-matter of claim 1 lacked inventive step, regardless of whether document D67 or document D73f was taken as the closest prior art (see decision under appeal, points 3.5.1 to 3.5.37).

5. On appeal, both parties agreed that document D67 was the closest prior art. The board sees no reason to differ.

6. Document D67 reports that a phase II clinical trial in infantile Pompe patients with recombinant human acid alpha-glucosidase (rhGAA) produced in the milk of transgenic rabbits "has finalised with positive results" (see page 1, first paragraph). The objective of the clinical study was to obtain data on the safety and efficacy of rhGAA (see page 2, second paragraph). After 36 weeks of the study, the four infantile patients had reached the age range of 12 to 17 months, "which is well beyond the mean age of survival in untreated infantile Pompe patients" (see page 1, second paragraph).

Muscle biopsies demonstrated that the recombinant enzyme was taken up by the main target tissue, skeletal muscle, reaching normal levels of GAA activity, which were comparable to those in healthy individuals. Moreover, the enzyme was shown to be active in the skeletal muscle tissue since, on histological evaluation, lysosomal glycogen storage decreased and muscle regeneration was observed (ibid.).

According to document D67, the most prominent effect of the treatment was seen in the heart, with reduced symptoms of cardiac instability in all patients (see page 1, third paragraph). Under the heading "Clinical breakthrough" document D67 reports that "one of the infants in the trial can even walk now without help of its parents" (see page 2, fourth paragraph).

The board agrees with the appellant that the skilled person would conclude from document D67 that enzyme replacement therapy (ERT) with rabbit-milk-derived rhGAA was a technically feasible treatment for GSD-II in humans.

Technical problem and its solution

7. The subject-matter of claim 1 differs from the disclosure of document D67 in that the human rhGAA used for the treatment of GSD-II is produced in Chinese hamster ovary (CHO) cells.

8. According to the appellant, the technical effect associated with this difference is an improved treatment for GSD-II, as is derivable from paragraphs [0008], [0009], [0013] and [0043] of the patent and further supported by documents D60a and D103.

8.1 According to paragraph [0008] of the patent the infants treated "demonstrated improvement of cardiac status, pulmonary function, and neurodevelopment, as well as reduction of glycogen levels in tissues", while paragraph [0009] of the patent explains that the results seen in patient 3 were better than those seen in patients 1 and 2, because the latter developed anti-GAA antibodies. Paragraph [0043] of the patent then reports that one patient, patient 3, "has been walking independently since 12 months of age".

8.2 However, document D67 also reports an improvement in cardiac status, respiratory function and decrease in lysosomal glycogen storage in skeletal muscle tissue of the patients (see point 6). Moreover, one of the infantile patients treated with transgenic rabbit-milk-produced rhGAA could walk without help (see point 6).

Thus, no improvement over the treatment known from document D67 can be derived from paragraphs [0008], [0009] and [0043] of the patent.

8.3 Paragraph [0013] of the patent discloses that CHO-cell-derived rhGAA is preferred and further that it "is assumed that the glycosylation differs from that of GAA that is produced in transgenic mouse and rabbit milk (...)". In the board's judgement, it does not follow directly and unambiguously from this statement that the assumed difference in glycosylation leads to an improved treatment if CHO-cell-derived rhGAA is used rather than transgenic rabbit-milk-produced rhGAA.

8.4 Documents D60a and D103 - both published after the priority date - relate to effects seen in Pompe mice (document D60a; see left-hand column, second paragraph under the heading "Results", and right-hand column, first paragraph under the heading "Conclusions") and GAA knockout mice (see document D103, page 452, right-hand column, fourth and fifth paragraphs, and Figures 3 and 4). However, these results obtained in mice do not establish that CHO-cell-derived rhGAA is better than rabbit-milk-derived rhGAA at effecting glycogen clearance in humans. Moreover, the alleged effect - an improved treatment for GSD-II - could only be taken into account when determining the problem underlying the invention for the purpose of assessing inventive step, if it can be deduced by the skilled person from the patent considered in relation to the closest prior art (see also Case Law of the Boards of Appeal, 8th edition 2016, I.D.4.4.2 and I.D.4.4.6). In the present case, no improvement over the treatment known from document D67 is derivable from the patent (see points 8.1 to 8.3).

8.5 In the board's judgement, the subject-matter of claim 1 can thus not be considered to provide an improved treatment over the treatment disclosed in document D67.

9. Therefore, starting from the closest prior art document, D67, the objective technical problem to be solved is the same as formulated by the opposition division, namely the provision of an alternative treatment for human GSD-II or its associated cardiomyopathy (see decision under appeal, Reasons, point 3.5.12).

Obviousness

10. The opposition division held that the claimed solution was obvious in light of the teachings of the available prior art documents, in particular document D73f (see decision under appeal, Reasons, points 3.5.18 to 3.5.30).

11. To determine whether the claimed invention, starting from the closest prior art and the objective technical problem, would have been obvious to the skilled person, the boards of appeal apply the "could-would approach". When considering whether or not claimed subject-matter constitutes an obvious solution to an objective technical problem, the question to be answered is whether or not the skilled person, in the expectation of solving the problem, would have modified the teaching in the closest prior art document in the light of other teachings in the prior art so as to arrive at the claimed invention (see Case Law of the Boards of Appeal, 8th edition 2016, I.D.5.). Accordingly, what the skilled person, starting from the closest prior art and faced with the objective technical problem, would or would not do depends not solely on the disclosure of the closest prior art document, but also on the state of the art in the relevant technical field (see also decision T 939/92, OJ EPO 1996, 309, Reasons, point 2.4.3).

Furthermore, in accordance with the case law of the boards of appeal, a course of action can be considered obvious within the meaning of Article 56 EPC if the skilled person would have carried it out in expectation of some improvement or advantage. In other words, obviousness is not only present when the results are clearly predictable but also when there is a reasonable expectation of success (see Case Law of the Boards of Appeal, 8th edition 2016, I.D.7.1).

12. The appellant submitted that, in view of the disclosure of document D67, which reported a successful treatment for a lethal disease for the first time, the skilled person was not motivated to look for an alternative treatment, i.e. the skilled would not have been motivated to modify the treatment disclosed in document D67.

13. However, it is established case law that it is the normal task of a skilled person working in a certain field not to remain inactive but to seek alternatives, to be constantly occupied with the elimination of deficiencies, with the overcoming of drawbacks and with the achievement of improvements of known devices and/or products (cf. inter alia, decisions T 247/11 of 24 February 2017; Reasons, point 25; T 1102/00 of 1 June 2004, Reasons, point 14; T 455/91, OJ EPO 1995, 684, Reasons, point 5.1.3.2). In the board's view, it is not conceivable that in the case of the treatment of a potentially lethal disease the motivation of the skilled person to search for further - or alternative - treatments stops, solely because one treatment exists - even if it is perceived as satisfactory at the time. Indeed, when document D67 was published, alternative treatments were already pursued in clinical trials (see

below, point 14) and there is no evidence that these were stopped in view of the success reported in document D67.

14. As to teachings in the prior art (see point 11) other than the teaching in document D67, at the priority date of the patent, the skilled person was aware of the teaching of document D73f, a review article entitled "Towards a molecular therapy for glycogen storage disease type II (Pompe disease)". This document discloses that ERT and gene therapy are being pursued for the treatment of GSD-II (see page 246, right-hand column, second paragraph). The document also reports that rhGAA has been produced "in its precursor form in Chinese hamster ovary (CHO) cell lines and in transgenic mouse and rabbit milk" (see page 247, left-hand column, third paragraph).

As regards the CHO-cell-derived rhGAA, document D73f then summarises the pre-clinical results disclosed in references 19, 20 and 25, which are documents D2, D1 and D3 respectively in these appeal proceedings (see references on pages 250 and 251 of document D73f).

Thus, document D73f reports with regard to those documents that "[i]ncubation of the precursor form of rhGAA with primary fibroblasts derived from patients with infantile-onset GSD-II resulted in the uptake of the enzyme and normalization of GAA activity and glycogen levels in the fibroblasts. This uptake is inhibited by M-6-P, suggesting mediation of uptake by M-6-P receptors. Injection of purified rhGAA into guinea pigs resulted in increased GAA activity levels in liver, heart and skeletal muscle" (see page 247, left-hand column, third paragraph).

Document D73f further reports that in vivo efficacy has been studied in Japanese quail with acid maltase deficiency (AMD quail). AMD quail "cannot fly, lift their wings or right themselves from the supine position", but intravenous treatment with rhGAA "resulted in the ability of the quail to both right themselves and flap their wings". Moreover, GAA activity had increased in most tissues examined and glycogen levels and histopathology had been restored to normal levels in the heart and liver (see page 247, left-hand column, fifth paragraph).

Document D73f then notes that "[s]imilarly, rhGAA purified from the milk of transgenic mice and rabbits has been shown to correct GAA deficiency and reduce glycogen storage in heart and skeletal muscle of GSD-II knockout mice. The dose of the milk enzyme required to correct the enzyme deficiency as well as the glycogen storage in the mouse model was larger than the dose of the CHO-derived enzyme that had been used in the quail model. The duration of the treatment required to see a therapeutic effect with the milk enzyme was also longer than with the CHO enzyme. Furthermore, no clinical improvement was seen in the mouse model following treatment with the milk-derived enzyme" (see page 247, right-hand column, second paragraph).

Furthermore document D73f reports that "the observation that rhGAA improves muscle strength (in the quail model) and histopathology and biochemical parameters (in both quail and mouse models) suggests that rhGAA is a promising enzyme replacement therapy for human GSD-II. Based on these results, two clinical trials using different enzyme sources have recently been initiated to investigate the potential of rhGAA to safely treat GSD-II patients. A phase II study is being conducted in the Netherlands (...) using GAA purified from the milk of transgenic rabbits and a Phase I/II study using rhGAA purified from CHO cells is being conducted in the USA (...)" (see page 247, right-hand column, third paragraph).

Document D73f adds that, although no efficacy data is yet available for the two ongoing clinical trials of rhGAA replacement therapy, "pre-clinical data suggest that enzyme replacement therapy will be successful" (see page 249, right-hand column, third paragraph).

14.1 The board considers that the evidential value of document D73f is not lessened because it is authored by the inventor of the patent, as it is co-authored by another expert in Pompe disease who is not an inventor on the patent. Moreover, document D73f is a scientific article, published in an academic journal. In the board's opinion, it is therefore not conceivable that the authors of document D73f were not objective in their assessment of the pre-clinical data in the primary literature they reviewed merely because one of the authors was also an inventor on what, at the time, was a patent application.

14.2 While document D73f summarises the information that was already known in the prior art, in the board's opinion, it does indeed also add to this information by expressing the joint opinion of two experts on the significance of the pre-clinical data in the primary literature, i.e. it gives the clear statement that these data "suggest that enzyme replacement therapy will be successful".

14.3 In the board's opinion, the skilled person also understands that, to the extent document D73f refers to problems, these might arise - i.e. will not necessarily arise in all patients - only if the treatment is successful. Indeed, document D73f states that "[a] successful treatment might unmask the underlying neurologic problem. Furthermore, immune responses could limit the efficacy" (see page 249, right-hand column, third paragraph; emphasis added by the board).

As can also be taken from document D73f, an immune response was more likely to develop in infantile patients carrying a null mutation, but not in juvenile and adult patients with residual enzyme activity which might render them immunologically tolerant (see page 248, left-hand column, first paragraph), which thus suggests successful therapy at least in the latter patient groups.

14.4 In the board's opinion, the skilled person would have perceived the "outstanding questions" formulated with regard to ERT in document D73f in the table on page 250 to be rather academic ones and the answers to them not crucial to the success of the therapy. They would therefore not have led to any concerns as regards the suitability of CHO-cell-derived rhGAA because (i) the mechanism underlying an effective therapy does not have to be known for there to be a reasonable expectation of success, (ii) the prevention of further damage would in itself be considered an improvement, and (iii) neurological and immunological issues would arise only if the treatment was successful (see also point 14.3).

14.5 In the board's judgement, the teaching of document D73f would therefore motivate the skilled person to choose CHO-cell-derived rhGAA as an alternative for the treatment of GSD-II in humans in that it indicates that it may be clinically superior to the milk-derived enzyme on at least three accounts (see page 247, right-hand column, second paragraph) and given the background that milk-derived rhGAA was already known at the priority date to be effective in human GSD-II therapy (see document D67 and point 6 above).

14.6 Based on the pre-clinical work summarised in document D73f, which established that CHO-cell-derived rhGAA targets muscle and heart cells and enters the correct cell compartment, reducing glycogen storage there, i.e. having a direct effect on the cause of GSD-II, the board considers that the skilled person also had a reasonable expectation that enzyme replacement therapy based on CHO-cell-derived rhGAA would be efficacious in treating GSD-II or its associated cardiomyopathy in humans.

14.7 In the board's opinion, the skilled person would have been further motivated by the disclosure of document D67 in this regard since, at the priority date of the patent, the skilled person was aware from document D67 that one of the two clinical trials mentioned in document D73f, namely the clinical trial with rabbit-milk-derived rhGAA, had been completed and had indeed been successful (see document D67 and point 6 above). In other words, the pre-clinical data obtained in in vitro and in animal models with rabbit-milk-derived rhGAA had indeed translated into successful enzyme replacement therapy for GSD-II in human infants - as predicted in document D73f.

14.8 In the board's opinion, the "potentially cheaper production in milk of transgenic animals" (see document D73d, page 1820, right-hand column, lines 10 to 6 from the bottom) would not have deterred the skilled person from pursuing CHO-cell-derived rhGAA for the treatment of GSD-II, not least because it was perceived to be better than milk-derived rhGAA (see point 14 above). Moreover, the board notes that - according to the appellant's expert - CHO cells "are easier and less expensive to work with than rabbits" (see declaration D99, paragraph 33).

15. The board is not persuaded by any of the appellant's other lines of argument, based on documents D73f, D73d, D10, D27, D25 and D95 to D97 and expert declarations D8, D45, D99 and D100, to the effect that, on the priority date, the skilled person had doubts about the suitability of CHO-cell-derived rhGAA for the treatment of GSD-II, as will be explained in the following.

15.1 In the board's opinion, the observation that hGAA isolated from placenta and CHO-cell-derived rhGAA have a similar glycosylation pattern but that hGAA extracted from placenta is not functional (see document D73d, page 1818, left-hand column, second paragraph, to right-hand column, second paragraph) would not have raised any doubts as to the expectation of success. At the priority date the skilled person not only knew that hGAA extracted from placenta was not functional (see document D10, abstract) but also that this was due to a lack of M-6-P groups (see document D1, page 903, right-hand column, and document D73f, page 246, right-hand column, first paragraph). Importantly, he also knew that the CHO-cell-derived rhGAA was appropriately phosphorylated such that uptake via the M-6-P receptor could take place; see document D1 (page 908, paragraph bridging columns), document D2 (see page 69, right-hand column), document D3 (see page 831, right-hand column) and document D73f (page 247, left-hand column, second full paragraph).

15.2 The finding that one particular enzyme, alpha-L-iduronidase, is not properly glycosylated (see document D27, page 210, right-hand column, second paragraph) would not have influenced the skilled person's expectation as regards therapy with CHO-cell-derived rhGAA, since it is established in documents D1 to D3 (see preceding point) that CHO-cell-derived rhGAA is indeed appropriately phosphorylated such that uptake via the M-6-P receptor can take place.

15.3 In the board's opinion, the pursuit of alternative treatments for GSD-II after the priority date, as apparent from documents D95 and D96, cannot be taken to imply a rejection or the failure of the CHO-cell-based rhGAA technology and certainly not at the priority date. Indeed, at the relevant date, CHO-cell-based rhGAA was also being pursued, even in clinical trials (see document D73f, page 247, right-hand column, second full paragraph).

15.4 The board considers that the passages relied on by the appellant from document D25 (see column 3, lines 12 to 47) and document D97 (paragraph [0009]) are unsuitable to establish that the "experts in this field at the time of the invention had no expectation that CHO produced GAA would result in a therapy for GSD-II disease" as they merely confirm what was already known at the priority date of the patent, namely that lysosomal enzymes require adequate amounts of M-6-P to bind to M-6-P receptors to be transported to the lysosome. However, the cited passages neither address

CHO-cell-derived rhGAA specifically nor question the results obtained in documents D1 to D3 and summarised in document D73f.

The board notes in this context that the statement (see declaration D8, paragraph 25) that document D25 concluded that "the CHO-produced enzyme would be inefficiently targeted to affected cells and (...) of limited effectiveness in the treatment of [GSD-II] (id. at col. 3, lns 41-43" is incorrect because document D25 does not address CHO-cell-derived rhGAA in column 3, lines 41 to 43, but hGAA extracted from placenta, which was well known at the priority date of the patent in suit not to be efficiently internalised by cells due to a lack of M-6-P (see point 15.1 above).

15.5 Moreover, the board notes that, at the priority date, the skilled person was not aware of the phosphorylation results reported in document D25 (see column 20, lines 44 to 47) and document D97 (see example 27 and Table 1). The appellant's argument that these documents

showed "the real world disbelief" in the invention and that the doubts of the experts must translate into doubts of the notional skilled person thus also fails.

15.6 Finally, the board notes that the results reported in document D60a were also only available after the priority date and could therefore not have possibly influenced the skilled person's expectation of success at the relevant date.

15.7 To summarise, none of documents D10, D25, D27, D60a, D73d, D73f, D95, D96 and D97 establishes that, at the priority date, the skilled person would have had any reason to think that CHO-cell-produced rhGAA could not be used successfully for the treatment of GSD-II. Thus, the positive expectations the skilled person had based on the disclosure of document D67 in combination with the teaching of document D73f would not have been lessened by the teaching of any of these documents.

16. As regards the various further doubts formulated by the appellant's expert Dr Cummings (see declaration D8, paragraphs 6 to 44), the board considers that the notional skilled person, aware of the teaching of documents D1 to D3, had in fact no reason to doubt that CHO-cell-produced rhGAA reaches the target cells (muscle and heart), is internalised by the target cells and delivered to its final site of action within the lysosomes of those cells and is functional there. The reasons for this are as follows.

16.1 That recombinant production in CHO cells yields rhGAA which is properly glycosylated to allow M-6-P receptor-mediated endocytosis of such rhGAA is shown in documents D1 to D3 (see point 15.1 above). Document D2 (see abstract and page 68, left-hand column, last paragraph) discloses that CHO-cell-derived rhGAA is "efficiently taken up by fibroblasts from Pompe patients" such that intracellular levels reach intracellular levels seen in normal fibroblasts, restoring normal levels of GAA and glycogen. Moreover, CHO-cell-derived rhGAA is also shown to be "endocytosed efficiently by cultured muscle cells of an infantile GSD-II patient" and to clear the stored lysosomal glycogen (see document D1, page 907, paragraph bridging left- and right-hand columns).

16.2 The distribution of CHO-cell-derived rhGAA to target cells was specifically addressed in the animal models described in documents D2 (see abstract) and D3 (see abstract), where the enzyme was in fact shown to reach the target cells, including in the skeletal muscle and heart, after intravenous injection.

16.3 Moreover, the board finds no support in the prior art for the assertions that, at the priority date, "it was therefore widely believed that CHO cells were not suitable for the production of GAA for the treatment of GSD-II" (see declaration D8, paragraph 13) and "the prevailing belief was that an enzyme produced in CHO culture either would not reach, or would not be taken up by, the target cells in sufficient quantities to produce a therapeutic effect" (see declaration D8, paragraph 14 to 29). On the contrary, a group of experts, the authors of documents D1 (see page 908, right-hand column, last sentence), D2 (page 69, right-hand column, last paragraph) and D3 (see end of abstract), all considered CHO-cell-derived rhGAA to be a promising candidate for the treatment of GSD-II in humans, as did the authors of document D73f (page 247, right-hand column, second paragraph, and page 249, right-hand column, third paragraph). Moreover, this positive assessment was not contradicted by any negative reappraisal of the pre-clinical data in the peer-reviewed scientific literature.

16.4 Of course, to establish that CHO-cell-derived rhGAA reaches the target cells in vivo too required clinical studies in humans. Such clinical trials were indeed ongoing at the priority date, and in the board's opinion the skilled person had every reason to be optimistic about their outcome. Firstly, the skilled person was aware that rhGAA from a different non-human source, namely the rabbit-milk-derived rhGAA, had been shown to reach the target cells in vivo in humans (see document D67 and point 6). Secondly, several CHO-cell-derived recombinant proteins, including a lysosomal protein, Cerezyme**(TM), had been successfully used in human therapy before (see declaration D73, paragraphs 37 and 38), indicating that there could have been no generally applicable technical prejudice against the use of CHO cells in the production of pharmaceutical products for human use.

16.5 In the board's opinion, declaration D45 by Dr Koeberl does not help the appellant's case either because, by basing its analysis on the statement that "in the specific case of enzyme replacement therapy ("ERT") for GSD-II, human clinical trials had universally failed for more than 30 years" (see paragraph 5), it ignores the successful treatment of GSD-II with rabbit-milk-derived rhGAA reported in document D67.

16.6 In the board's opinion, the renewed assertion in

Dr Cummings' second declaration, D99, that "CHO cells were thought to be an extremely unlikely source for a replacement enzyme to treat GSD-II" (see paragraph 18) carries no weight as the only literature referred to in support was post-published (document D25 and document D60a), and the assertion is contradicted by the uniformly positive assessment of the suitability of CHO-cell-derived rhGAA for ERT for GSD-II in the published scientific literature (see points 14 to 14.5).

16.7 Since document D73f is read by the skilled person with the knowledge of document D67 (see point 14.7 above), the assertion that a person skilled in the art would not conclude from either document D67 or document D73f, when considered alone, that CHO-cell-produced rhGAA would be likely to prove a successful treatment for GSD-II therefore misses the point (see declaration D99, paragraphs 30 to 40, and declaration D100, paragraphs 10 to 21).

16.8 The board agrees with the respondent that the appellant's position is inconsistent in relying on evidence from Dr Chen (in the case of declaration D98) while asserting that Dr Chen's status as an inventor invalidates his objectivity as an author of a peer-reviewed article (in the case of document D73f).

16.9 In any case, declaration D98 does not help the appellant's case because the attempt to reinterpret the clear statement in D73f that "the pre-clinical data suggest that enzyme replacement therapy will be successful" to mean "the very limited preclinical data in AMD quail did, in fact, "suggest" the hope that the therapy would succeed, and that is why human clinical trials were undertaken" (see paragraph 22) fails because the meaning of the statement in D73f is clear and in line with teachings in the prior art. Thus, the pre-clinical data presented in the primary literature was also regarded as positive by the authors in each of documents D1 (see page 908, right-hand column, last sentence), D2 (page 69, right-hand column, last paragraph), D3 (see end of abstract) and D73d (see page 1820, right-hand column).

The assertion that the scientific community reacted "with astonishment to the ability of CHO-produced GAA to provide an effective treatment of the disease" (declaration D98, paragraph 24) is not corroborated by any objective evidence and thus is not persuasive.

17. The board concludes that the prior art motivated the skilled person to use CHO-cell-derived rhGAA for the manufacture of a medicament for the treatment of human GSD-II or its associated cardiomyopathy and that, based on a scientific evaluation of the facts available (see decision T 207/94, OJ EPO 1999, 273, Reasons, point 31), the skilled person also had a reasonable expectation of success. Therefore, the subject-matter of claim 1 is considered to be obvious and thus to fail to meet the requirements of Article 56 EPC.