T 2059/13 (Aripiprazole against bipolar disorder/OTSUKA) 07-12-2015

I. Eight oppositions were filed against the grant of European patent No. 1 712 225. They were directed against the patent in its entirety and were based on grounds under Article 100(a)(alleged lack of novelty and of inventive step) (b) and (c) EPC.

II. The documents cited during the opposition proceedings include the following:

(D2) P. E. Keck et al., Medical Clinics of North

America, Vol. 85, No. 3 (May 2001), 645-661

(D4) C. L. Bowden, Exp. Opin. Invest. Drugs,

Vol. 10, No. 4 (2001), 661-671

(D8) G. S. Sax et al., A Postgraduate Medicine

Special Report, April 2000, 1-20

(D9) C. Guille et al., J. Clin. Psychiatry,

Vol. 61, No. 9 (September 2000), 638-642

(D11) S. Jordan et al., European Neuropsycho-

pharmacology, Vol. 11, Suppl. 3 (2001), S268

(D12) U.S. patent application No. 09/770,210

filed on 29 January 2001

(D13) T. Kikuchi et al., The Journal of Pharmacology

and Experimental Therapeutics, Vol. 274

(1995), 329-336

(D17) WO-A-02/060 423

(D24) I-Shin Shiah et al., Neuropsychobiology,

Vol. 38 (1998), 6-12

(D28) C. Cohen et al., The Journal of Pharmacology

and Experimental Therapeutics, Vol. 283

(1997), 566-573

(D29) D. S. Robinson et al., Journal of Clinical

Psychopharmacology, Vol. 10, No. 3 (Suppl.)

(June 1990), 67S-76S

(D42) Comparative Experiments, submitted with

patentee's letter dated 13 November 2008,

four pages

(D43) N. Haddjeri et al., Journal of Affective

Disorders, Vol. 51 (1998), 255-266

(D44) N. Haddjeri et al., The Journal of

Neuroscience, Vol. 18, No. 23

(December 1, 1998), 10150-10156

(D45) N. Haddjeri et al., Neuropsychopharmacology,

Vol. 22, No. 4 (2000), 346-356

(D46) I. Lucki, J. Clin. Psychiatry, Vol. 52, No. 12

(Suppl.)(December 1991), 24-31

(D47) S. M. Stahl et al., International Journal of

Neuropsychopharmacology, Vol. 1 (1998), 11-18

(D48) D. Taylor et al., The Maudsley 2001

Prescribing Guidelines, 6th edn. (2001),

Martin Dunitz Ltd., London/GB, 76

(D49) S. Bazire, Psychotropic Drug Directory

2001/02, Quay Books, Mark Allen Publishing

Ltd, Dinton/GB, 78-83

(D50) E. Vieta et al., British Journal of

Psychiatry, Vol. 187 (2005), 235-242

(D51) Comparative Pharmacological Test, enclosed

with patentee's letter dated November 5, 2012,

five pages

III. The opposition division revoked the patent; it decided that grounds under Article 100(b) EPC prejudiced the maintenance of the patent.

The opposition division stated that the tests in the application as originally filed indicated only that aripiprazole was a 5-HT1A receptor agonist. Documents (D11) and (D13) described aripiprazole as a partial 5-HT1A receptor agonist and a postsynaptic D2 receptor antagonist. It was only known that there was a relationship between 5-HT1A-agonists and depression (see page 4, lines 25-26, of the grandparent application (D17); see also documents (D29), (D46), (D47)). Only document (D24) disclosed the treatment of bipolar depressed persons with a 5-HT1A-agonist. According to document (D2), the relationship between 5-HT1A-agonism and depression could not be extrapolated to bipolar depression. A relationship between D2 antagonism and bipolar disorders was also not evident.

Additional data provided in documents (D42), (D50), (D51) and in the letter dated 19 August 2010 could not be taken into account since, at the effective date of the patent, the receptor effects (5-HT1A receptor agonism and D2 antagonism) did not reflect the claimed therapeutic treatment of both the (hypo)manic and depressed phases of bipolar disorders (see page 18, second paragraph of the decision).

IV. The patent proprietor lodged an appeal against this decision.

V. The additional documents cited during the appeal proceedings include the following:

(D58) E. Mutschler, Arzneimittelwirkungen,

Wissenschaftliche Verlagsgesellschaft mbH,

Stuttgart/DE, 7th edn. 1997, 140-145, 152-153

(D59) E. Mutschler, Arzneimittelwirkungen,

Wissenschaftliche Verlagsgesellschaft mbH,

Stuttgart/DE, 8th edn. 2001, 157-172

(D61) Wikipedia Information on Risperidone,

http//en.wikipedia.org/wiki/Risperidone,

retrieved on 15 January 2014, seven pages

(D62) Wikipedia Information on Aripiprazole,

http//en.wikipedia.org/wiki/Aripiprazole,

retrieved on 15 January 2014, ten pages

(D63) F. K. Goodwin and K. R. Jamison, Manic-

depressive illness, Oxford University Press,

Oxford/GB 1990, 420-422

(D64) D. M. Hilty et al., Psychiatric Services,

Vol. 50, No. 2 (February 1999), 201-213

(D65) H.-J. Möller et al., Journal of Affective

Disorders, Vol. 67 (2001), 141-146

(D66) W. C. Drevets et al., Biol. Psychiatry,

Vol. 46 (1999), 1375-1387

(D67) Information on "RISPERDAL**(®)", "Revised:

04/2014", Janssen Pharmaceuticals, Inc.,

16 pages

(D68) P. E. Keck et al., Am. J. Psychiatry, Vol. 160

(September 2003), 1651-1658.

VI. The claims under consideration in this decision are

the following submitted during the oral proceedings of 13 June 2013 before the opposition division:

- claims 1 to 4 of the main request;

- claims 1 and 2 of the first auxiliary request;

- claims 1 and 2 of the second auxiliary request;

- claims 1 and 2 of the third auxiliary request;

- claims 1 to 3 of the fourth auxiliary request;

- claim 1 of the fifth auxiliary request;

- claim 1 of the sixth auxiliary request;

- claim 1 of the seventh auxiliary request;

and the following submitted under cover of letter dated 22 May 2015:

- claims 1 to 3 of the eighth auxiliary request;

- claim 1 of the ninth auxiliary request;

- claim 1 of the tenth auxiliary request;

- claim 1 of the eleventh auxiliary request.

a) The independent claim of the main request reads as follows:

"1. A compound which is a pharmaceutically

acceptable acid-addition salt or solvate of a

carbostyril compound of the formula (1):

FORMULA/TABLE/GRAPHIC

wherein the dotted line represents a single or a

double bond, for use in the treatment of disorders

of the central nervous system associated with

5-HT1A receptor subtype, selected from

(i) bipolar I disorder with most recent hypomanic, manic, mixed, depressed or unspecific episode, and

(ii) bipolar II disorder with recurrent major depressive episodes with hypomanic episodes, and cyclothymic disorder."

b) The independent claim of the first auxiliary request differs from that of the main request in that bipolar II and cyclothymic disorders were deleted. It reads as follows:

"1. A compound which is a pharmaceutically

acceptable acid-addition salt or solvate of a

carbostyril compound of the formula (1):

FORMULA/TABLE/GRAPHIC

wherein the dotted line represents a single or a

double bond, for use in the treatment of disorders

of the central nervous system associated with

5-HT1A receptor subtype, selected from bipolar I

disorder with most recent hypomanic, manic,

mixed, depressed or unspecific episode."

c) The independent claim of the second auxiliary request differs from that of the main request in that bipolar I and cyclothymic disorders were deleted. It reads as follows:

"1. A compound which is a pharmaceutically

acceptable acid-addition salt or solvate of a

carbostyril compound of the formula (1):

FORMULA/TABLE/GRAPHIC

wherein the dotted line represents a single or a

double bond, for use in the treatment of disorders

of the central nervous system associated with

5-HT1A receptor subtype, selected from bipolar II

disorder with recurrent major depressive episodes

with hypomanic episodes."

d) The independent claim of the third auxiliary request differs from that of the main request in that the disorders were limited to cyclothymic disorders. It reads as follows:

"1. A compound which is a pharmaceutically

acceptable acid-addition salt or solvate of a

carbostyril compound of the formula (1):

FORMULA/TABLE/GRAPHIC

wherein the dotted line represents a single or a

double bond, for use in the treatment of disorders

of the central nervous system associated with

5-HT1A receptor subtype, selected from cyclothymic

disorder."

e) The independent claims of the fourth, fifth, sixth and seventh auxiliary request differ from those of the main request, first, second and third auxiliary requests, respectively, in that

"1. A compound which is a pharmaceutically

acceptable acid-addition salt or solvate of a

carbostyril compound of the formula (1):

FORMULA/TABLE/GRAPHIC

wherein the dotted line represents a single or a

double bond,"

was replaced by

"1. A pharmaceutically acceptable acid-addition

salt or solvate of 7-{4-[4-(2,3-dichlorophenyl)-1-

piperaziny] butoxyl}-3,4-dihydrocarbostyril of the

formula (1):

FORMULA/TABLE/GRAPHIC".

f) The independent claims of the eighth, ninth, tenth and eleventh auxiliary requests differ from those of the fourth, fifth, sixth and seventh auxiliary requests, respectively, only in that the phrase

", wherein the depressive symptoms are reduced"

was inserted at the end of each of these claims.

VII. The appellant's arguments as far as relevant for this decision may be summarised as follows:

Late-filed documents

Documents (D63) to (D66) provided information on the role of the 5-HT1A receptor in bipolar disorders, in addition to what was disclosed in document (D43). Documents (D63) to (D68) were filed at such a late stage because the appellant had not been aware of them when submitting the statement setting out the grounds of appeal.

Priority

Bipolar disorders and cyclothymic disorder were not explicitly mentioned in the priority document, but they were implicit options in view of the discussion on postsynaptic D2 receptor antagonistic and 5-HT1A receptor agonistic activities, as bipolar disorders belonged to the 5-HT1A receptor related diseases referred to in the priority document.

Sufficiency of disclosure

The facts and circumstances of the present case differed from those underlying T 609/02 in which the chemical structure of the compounds was not identified (see T 1677/11, point 7.2, second paragraph of the reasons).

The patent in suit contained a very detailed description which disclosed in paragraphs [0016], [0022] and [0028] that there was a clear link between 5-HT1A agonism and the suitability of a drug in the treatment of bipolar disorders; the experimental part of the patent in suit demonstrated a high affinity binding of aripiprazole to the 5-HT1A receptor (see paragraph [0040]).

Any information which might be missing in the patent in suit was part of the general knowledge exemplified in documents (D2), (D8), (D43) to (D45) and (D47). The common general knowledge was not restricted to the knowledge contained in text books; it might well be represented by a multitude of scientific articles from different authors. Document (D59) was not the only document reflecting the common general knowledge, nor did this document concern bipolar disorders. Due to its limitations, the study disclosed in document (D24) did not allow the conclusion that there was no relationship between 5-HT1A receptor agonism and bipolar disorder.

The information disclosed in the patent in suit rendered the claimed therapeutic effect plausible which allowed post-published evidence (D42), (D50) and (D51) to be taken into account. Document (D2) disclosed the efficiency of antidepressants in the treatment of the depressive phase of bipolar disorders, not in the treatment of the manic phase. It was known from documents (D28), (D58) and (D9) that the manic state of a bipolar disorder could be treated with D2 receptor antagonists. Documents (D63) and (D64) showed that the use of antidepressants was known in the treatment of bipolar disorder. That aripiprazole was indeed effective for that purpose had been demonstrated in document (D50) and in the tests filed with the letter dated 19 August 2010.

Moreover, it was known from documents (D24), (D29), (D43) to (D47) and (D58) that partial 5-HT1A agonists had antidepressant efficacy. Documents (D28) and (D49) showed that D2 receptor antagonists were effective against mania. The tests (D42), (D51) and those reported in document (D68) showed the activity of aripiprazole as an antidepressant and against bipolar mania.

For these reasons, there was a well-established relationship at the filing date of the patent between

a) D2 receptor antagonism and the therapeutic effect

of the manic state of a bipolar disorder, as well

as

b) 5-HT1A receptor agonism and the therapeutic effect

on the depressive state of bipolar disorder.

VIII. Respondent 8 did not submit any arguments during the appeal proceedings. The arguments of respondents 1 to 7 as far as relevant for this decision may be summarised as follows:

Late filed documents

Documents (D63) to (D66) were not more relevant than documents (D43) to (D45). Documents (D67) and (D68) were irrelevant as they did not form part of the prior art. The appellant could have submitted these documents much earlier. Therefore, documents (D63) to (D68) should not be admitted into the proceedings.

Priority

The present claims were directed to certain compounds for use in the treatment of bipolar disorder. The priority document did not disclose bipolar disorder directly and unambiguously. Therefore, none of the claims enjoyed the priority claimed.

Sufficiency of disclosure

Sufficiency of disclosure had to be satisfied at the effective date of the patent. It was not satisfied when a second medical use was claimed unless the patent showed that the claimed therapeutic effect was obtained (see T 609/02).

The application as filed did not show that there was a clear and established relationship between the 5-HT1A receptor agonism of aripiprazole and its suitability for the treatment of bipolar disorders. The statement in paragraph [0022] of the patent in suit was merely an assertion and did not suffice to establish sufficiency of disclosure, as was evident from decisions T 609/02 and T 801/10. This was all the more true in view of the disclosure of document (D4), according to which the "inherent complexity of bipolar disorder" had been a barrier to the study of new agents (see page 668, bottom paragraph of the left-hand column).

Documents (D2), (D8), (D43) to (D45) and (D47) were patent applications or journal articles and did not - in contrast to the general textbook (D59) - reflect the common general knowledge of the skilled person. Tables 1-5 and 1-11 of document (D59) showed that neuroleptica had effects on a multitude of receptors, the 5-HT1A receptor not even being mentioned in this document. The only prior art document cited which dealt with the 5-HT1A receptor and bipolar disorder was (D24) which, however, suggested that the subsensitivity at this receptor only occurred in unipolar, not in bipolar depression. Documents (D43) to (D45) did not relate to 5-HT1A agonism in general, but to tests of certain drugs which had no direct agonistic effect at this receptor. Document (D47) concerned unipolar depression only. As disclosed in document (D2)(see page 650 and the penultimate paragraph on page 657), drugs effective against unipolar depression might induce hypomania, mania and cycle acceleration in bipolar depression. Hence, the therapies of bipolar and unipolar depressions differed considerably. Therefore, it was not generally known at the filing date of the patent that bipolar disorders were linked to the 5-HT1A receptor.

Consequently, the patent in suit, if combined with the knowledge disclosed in the prior art, did not provide the information necessary to carry out the subject-matter of the claims. It was not justified to fill this gap with the disclosure of post-published evidence.

Grounds under Article 100(b) EPC thus prejudiced the maintenance of the patent in suit (see decisions T 609/02, T 63/06 and T 491/08). As stated under point 7.11 of the decision under appeal, the burden of proof lay with the patentee to show that the disclosure was sufficient.

It was doubtful whether the mechanism of unipolar depression was the same as for bipolar depression (see (D2), page 649, under the heading "Bipolar Depression"). None of the documents (D63) to (D68) disclosed the suitability of 5-HT1A receptor agonists for the treatment of bipolar or unipolar depression. As stated in document (D59), there was no clear relationship between serotonin reuptake inhibition of a drug and its antidepressant activity.

Document (D61) showed that risperidone had effects on a multitude of receptors (see the table on page 4). Hence it was doubtful whether aripiprazole was suitable for treating bipolar depression and bipolar mixed states.

Document (D59) disclosed that neuroleptics used to treat mania not only had a D2 receptor antagonist component, but also an alpha1, 5-HT2, muscarine and H1 receptor blocking activity. Thus, there was no clear link between D2 receptor antagonism and the treatment of mania. Nor did this document show that it belonged to the common knowledge that the therapeutic effect of antipsychotics and antidepressants was based on an affinity to the 5-HT1A receptor.

Document (D24) mentioned that the findings must be interpreted with caution and might mean that 5-HT1A receptor subsensitivity only occurred in unipolar but not in bipolar depression.

None of the further documents cited by the appellant in its grounds for appeal, nor the prior art cited in paragraphs [0009] to [0017] of the patent in suit established a link between the 5-HT1A receptor and bipolar depression.

The invention was that aripiprazole showed 5-HT1A agonism (see the only example). Hence the appellant had to demonstrate that the suitability of this drug for the treatment of bipolar disorder was based on this effect. For this reason, the appellant could not rely on documents (D2), (D9), (D13), (D28), (D48) and (D49) because the effect shown in these documents was based on the D2 antagonistic effect of the drug, as was evident from (D59).

IX. The appellant (patent proprietor) requested that the decision under appeal be set aside and that the case be remitted to the department of first instance on the basis of the main request or of any of auxiliary requests 1 to 7, filed on 13 June 2013, or of auxiliary requests 8 to 11, filed on 22 May 2015, should the board find one of the requests to comply with the requirements of Article 83 EPC.

Respondents 1 to 7 requested that the appeal be dismissed. Respondent 7 further requested not remit the case to the department of first instance should the board find one of the requests to comply with the requirements of Article 83 EPC. Respondents 1, 3 and 5 further requested that the appellant's request for remittal be rejected and that documents D63 to D68 not be admitted into the appeal proceedings.

Respondent 8 did not take an active part in the proceedings and did not file any requests.

X. Respondent 8 was duly summoned but did not attend the oral proceedings before the board. In accordance with Rule 115(2) EPC, the oral proceedings were continued in the absence of respondent 8.

XI. At the end of the oral proceedings, the Chairman announced the decision of the board.