T 2627/17 - Sufficiency of disclosure of 1st and 2nd medical use claim

Key points

• In this opposition appeal, claim1 is a pure compound claim defined by a Markush formula. Claim 18 is a second medical use claim specifying a relatively long list of diseases. Claim 15 is a first medical use claim.
• " The appellant [opponent] argued in respect of [first medical use] claim 15 that the alleged biological effects had not been supported across the full range of compounds claimed, and that even for the tested compounds, the data of table 11 did not allow the skilled person to identify which compounds actually provided a suitable effect in the tests employed, i.e. whether a sufficient biological effect had been achieved."
• The Board: "The relevant biological activity ascribed to the claimed compounds in the patent is the treatment or prevention of diseases or conditions which [...] involve activity at the estrogen receptor. "
• "In table 1 of the patent (pages 24-115), 453 specific compounds, many of which fall within the scope of claim 1, are disclosed. In table 11 (page 211), biological data is provided for said compounds based on IC50 activity in an "MCF7 Viability Assay" (described in examples 84 and 85; paragraphs [0810] and [0811]) and an "ER-alpha In Cell Western Assay (ski)" (described in example 86; paragraph [0813]), both assays concerning breast cancer cell lines." (link)
• In the table, either A or B is shown for the IC50 value, and + or ++ for the max response (single value), it seems for all 453 compounds.
• "In the present case, biological activity data is presented for the large number of compounds exemplified. Even accepting that not all examples fall within the scope of the present claims, as argued by the appellant in opposition proceedings with reference to D2 [] the data presented for the claimed compounds is considered sufficient to support the therapeutic application for which they were tested. 
• "As set out in T 609/02, absolute proof that a compound could be approved as a drug before it may be claimed as such (in a medical use claim) is not required. Rather, for demonstrating sufficient disclosure of a therapeutic application, the patent must provide some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if there is a clear and accepted established relationship between the shown physiological activities (in the present case, ER activity) and the disease (T 609/02, reasons, 9)."
• " Therefore, the data in table 11 of the patent sufficiently demonstrates the effect of the claimed compounds on the specific ER activity tested. Consequently, the appellant's argument that the effect would not be present for further compounds falling within the scope of the claims, but not tested, amounts to an unsubstantiated allegation, and therefore must fail. "
• " Consequently, the board found the invention defined in claim 15 to be sufficiently disclosed.' 
• Turing to the second medical use claim: 
• " Claim 18 is essentially directed to a compound (of any one of claims 1 to 10) for use in the treatment of a long list of specific conditions, including, inter alia, alcoholism, migraine, aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, deep vein thrombosis, Graves' Disease, arthritis, multiple sclerosis, cirrhosis, hepatitis B, chronic liver disease, bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis, Alzheimer's disease, Parkinson's disease, migraine, vertigo, anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder and psychosis." 
• " In T 2059/13, cited by the [opponent]  it was accepted that the compound in question (aripiprazole) successfully bound to the 5-HT1A receptor. However, there was no evidence in the patent nor in the cited prior art of any link between said receptor and bipolar disorder, the subject-matter of the second medical use claim (reasons, 4.4.4 and 4.4.5). Consequently, sufficiency of disclosure was denied. ... The situation in the present case in relation to many of the conditions listed in claim 18 is similar." 
• " With regard to a direct link between ER activity and the conditions other than estrogen-dependent cancer listed in claim 18, apart from mere verbal statements (e.g. paragraphs [0006] and [0061]), the patent is silent - both in terms of biological data demonstrating said link, and any reference to common general knowledge linking ER activity to the specific conditions listed. The situation in the contested patent is therefore similar to that underlying case T 2059/13, addressed above, in that the patent does not demonstrate the suitability of the claimed compounds for the treatment of claimed conditions other than estrogen-dependent cancer." 
• It follows that with regard to the second medical use directed to therapeutic applications other than estrogen-dependent cancer, the invention defined in claim 18 is insufficiently disclosed.
• In an auxiliary request, claim 18 is deleted. The Board turns to inventive step.
• " The objective technical problem underlying contested claims 1-14 is therefore the provision of further compounds (and corresponding compositions) with ER activity." 
• " the claimed compounds represent non-obvious alternatives to those disclosed in D4 as set out above." 
• As a comment, the present decision also illustrates the basic rule that finding one new compound with one inventive use provides for the inventive step of the product claim, thereby giving protection for all uses of the compound. The same principle applies for sufficiency of disclosure. Also the non-enabled diseases, for which the 2nd medical use claim is invalid, fall under the product claim (and the first medical use claim, for that matter).

EPO T 2627/17 

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

https://www.epo.org/law-practice/case-law-appeals/recent/t172627eu1.html

2. Sufficiency of disclosure - claims 15-18

The patent is concerned with compounds to treat, prevent or diagnose diseases or conditions that are estrogen sensitive, estrogen receptor dependent, or estrogen receptor mediated (patent, paragraph [0002]).

The appellant's objections in relation to sufficiency of disclosure solely concerned the invention defined in medical use claims 15-18.

2.1 First medical use claim 15

Claim 15 is directed to a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, or N-oxide thereof, for use in medicine.

2.1.1 The appellant argued in respect of claim 15 that the alleged biological effects had not been supported across the full range of compounds claimed, and that even for the tested compounds, the data of table 11 did not allow the skilled person to identify which compounds actually provided a suitable effect in the tests employed, i.e. whether a sufficient biological effect had been achieved. According to the appellant, the conclusion of the opposition division that the requirements of sufficiency of disclosure were met in this regard was incorrect, since the relevant case law had not been correctly applied.

2.1.2 More specifically, the appellant submitted that the "relevant test" in view of decision T 609/02 and decisions citing it such as T 1592/12 and T 2059/13, was whether the patent application as filed disclosed the suitability of the product (in the present case, the claimed compounds) for the claimed therapeutic applications to the skilled person using common general knowledge. The conclusion of the opposition division was incorrect since, in the case underlying T 609/02, the fact that no data was presented in the application as filed demonstrating an impact of the relevant hormone on the listed diseases, did not automatically mean that the issues addressed therein could not be applied to the present case. Specifically, as pointed out in both T 1592/12 (reasons 15-17) and T 2059/13 (reasons 4.2.1-4.2.4), the points of law presented in T 609/02 applied to the therapeutic use of chemical compounds in general, and thus also to the facts of the present case.

Similarly, the appellant submitted that the conclusion of the opposition division regarding the applicability of the facts underlying T 488/16 was also incorrect. This view was supported by inter alia the statement in T 2059/13 (reasons 4.2.3) that "differences are normal and the usefulness of case law is not confined to similar or identical facts, but lies in the principles or guidance which can be extracted from earlier cases". Thus, the appellant argued, in view of T 488/16 (reasons 4.10), when opponents had provided technically sound and persuasive arguments as to why an alleged effect had not been made plausible, which raised doubts as to whether the technical problem had been solved at the filing date, they had discharged their burden of proof.

2.1.3 The board's view is as follows.

The relevant biological activity ascribed to the claimed compounds in the patent is the treatment or prevention of diseases or conditions which are estrogen sensitive, estrogen receptor dependent, or estrogen receptor mediated (paragraph [0002]), i.e. involve activity at the estrogen receptor. Such activity is described differently in the various submissions of the parties, as well as in the cited prior art. Since the exact nature of the activity at the estrogen receptor was not a matter of discussion nor dispute in the present proceedings, for ease of reference the board in the following employs "estrogen receptor activity", abbreviated as "ER activity", as representative of all terminology employed in relation to the alleged effect of the claimed compounds.

In table 1 of the patent (pages 24-115), 453 specific compounds, many of which fall within the scope of claim 1, are disclosed. In table 11 (page 211), biological data is provided for said compounds based on IC50 activity in an "MCF7 Viability Assay" (described in examples 84 and 85; paragraphs [0810] and [0811]) and an "ER-alpha In Cell Western Assay (ski)" (described in example 86; paragraph [0813]), both assays concerning breast cancer cell lines.

Thus, the patent comprises biological data in relation to specific breast cancer cell lines for a wide range of compounds falling within the scope of claim 1.

The situation in the decisions cited by the appellant was however different, as set out in the following.

In T 609/02, not only was no evidence presented in the patent that the alleged effect took place, but the patent was also silent with regard to the identification of a specific steroid hormone allegedly providing said effect (reasons, 5). Thus, in view of the lack of information provided in the patent, sufficiency of disclosure was denied.

In T 1592/12, the relevant claims concerned a specific dosage regimen. Since the patent provided no data, and the half-life of the active compound in question (a specific antibody) would have provided the skilled person with serious doubt that the claimed administration would suffice (reasons, 28), the suitability of the claimed dosage regimen to obtain the required therapeutic effect was deemed not to be sufficiently disclosed in the patent (reasons, 41).

Similarly, in T 0488/16, no data was provided in the application as filed to support the allegation that the sole claimed compound provided a particular therapeutic effect. Although the relevant issue in that case was inventive step, the considerations relevant to sufficiency of disclosure remain the same (see e.g. T 116/18, reasons 13.3.1). Specifically, in T 0488/16, the application as filed was found to lack any evidence at all that any of the very broadly defined compounds of the claims of the application as filed, let alone the single compound claimed (dasatinib), was active as an inhibitor of the specific protein kinase inhibitors concerned.

2.1.4 Thus, in contrast to the facts underlying the present case, in the above-mentioned decisions, no evidence had been presented demonstrating a biological effect for the claimed compounds. In the present case, biological activity data is presented for the large number of compounds exemplified. Even accepting that not all examples fall within the scope of the present claims, as argued by the appellant in opposition proceedings with reference to D2 (letter dated 16 August 2017, point 10), the data presented for the claimed compounds is considered sufficient to support the therapeutic application for which they were tested. As set out in T 609/02, absolute proof that a compound could be approved as a drug before it may be claimed as such (in a medical use claim) is not required. Rather, for demonstrating sufficient disclosure of a therapeutic application, the patent must provide some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if there is a clear and accepted established relationship between the shown physiological activities (in the present case, ER activity) and the disease (T 609/02, reasons, 9).

2.1.5 Therefore, the data in table 11 of the patent sufficiently demonstrates the effect of the claimed compounds on the specific ER activity tested. Consequently, the appellant's argument that the effect would not be present for further compounds falling within the scope of the claims, but not tested, amounts to an unsubstantiated allegation, and therefore must fail.

2.1.6 The appellant also argued that even for the tested compounds, the data of table 11 did not allow the skilled person to identify which compounds actually provided a suitable effect in the tests employed, i.e. whether a sufficient biological effect had been achieved. The board notes however that with regard to the minority of compounds tested in table 11 achieving a "B" rating in the respective assay in table 1 ("B" denoting an IC50 > 100nm), it can only be concluded that these compounds are less active than compounds rated "A", but not that they are "inactive", as implied by the appellant, and therefore unsuitable for the claimed therapeutic indication. The data in table 11 shows that even if some of the claimed compounds display less strong ER activity, they still reduce the viability of breast cancer cells in vitro. Furthermore, although the appellant labelled the in vitro tests of the patent as "very rough", the results in table 11 clearly reflect therapeutic applications in diseases and conditions involving ER activity, as set out above. There is therefore no reason to doubt that the biological tests in the patent demonstrate the suitability of the claimed compounds for therapeutic application in ER-regulated conditions.

2.1.7 It is established case law that a successful objection of lack of sufficiency of disclosure presupposes that there are serious doubts, substantiated by verifiable facts. In the present case, no such facts have been submitted by the appellant. Furthermore, the board found the appellant's arguments based on the case law of the Boards of Appeal to be unconvincing.

Consequently, the board found the invention defined in claim 15 to be sufficiently disclosed.

2.2 Second medical use claim 18

Claim 18 is essentially directed to a compound (of any one of claims 1 to 10) for use in the treatment of a long list of specific conditions, including, inter alia, alcoholism, migraine, aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, deep vein thrombosis, Graves' Disease, arthritis, multiple sclerosis, cirrhosis, hepatitis B, chronic liver disease, bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis, Alzheimer's disease, Parkinson's disease, migraine, vertigo, anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder and psychosis.

2.2.1 The appellant's objections in relation to claim 18 included those outlined above in relation to claim 15, which failed to convince the board.

The appellant also argued in relation to the second medical use claims, citing in particular decision T 2059/13, that the biological tests of table 11 of the patent (demonstrating ER activity against specific breast cell lines as set out above), were not sufficient to support the effectiveness of the claimed compounds against all conditions claimed, in particular those listed above.

2.2.2 The respondent counter-argued that the patent rendered it plausible that the estrogen receptor is involved in all of the conditions listed in claim 18. Evidence was provided in the patent, in which it was stated that the estrogen receptor can interact with DNA either directly or indirectly (paragraph [0055]), thus indicating its versatility in the regulation of processes in the body.

2.2.3 The board's view is as follows. In T 2059/13, cited by the appellant, it was accepted that the compound in question (aripiprazole) successfully bound to the 5-HT1A receptor. However, there was no evidence in the patent nor in the cited prior art of any link between said receptor and bipolar disorder, the subject-matter of the second medical use claim (reasons, 4.4.4 and 4.4.5). Consequently, sufficiency of disclosure was denied.

2.2.4 The situation in the present case in relation to many of the conditions listed in claim 18 is similar. In paragraph [0005] of the patent, it is stated that the compounds of the invention are useful in the treatment or prevention of diseases or conditions in which the actions of estrogens or estrogen receptors are involved. ER activation in various cancer cells is described in the patent paragraphs [0045] to [0050] and [0055] to [0068], and references to the prior art are provided demonstrating the link between ERs and specific estrogen-dependent cancers (e.g. paragraphs [0055]-[0057]). Existing treatments based on the link between ER activity and said cancers (e.g. paragraph [0057]) are also described. Biological data is presented demonstrating the activity of the claimed compounds in breast cancer cell lines (examples 84-87 and table 11), thereby credibly linking the ER activity of the claimed compounds with diseases and conditions having a direct link to said activity. This data however only relates to (estrogen-dependent) breast cancer cell lines. With regard to a direct link between ER activity and the conditions other than estrogen-dependent cancer listed in claim 18, apart from mere verbal statements (e.g. paragraphs [0006] and [0061]), the patent is silent - both in terms of biological data demonstrating said link, and any reference to common general knowledge linking ER activity to the specific conditions listed. The situation in the contested patent is therefore similar to that underlying case T 2059/13, addressed above, in that the patent does not demonstrate the suitability of the claimed compounds for the treatment of claimed conditions other than estrogen-dependent cancer.

A similar line was taken in T 0488/16 (reasons, 4.5), in which the board stated "... a mere verbal statement that 'compounds have been found active' in the absence of any verifiable technical evidence is not sufficient to render it credible that the technical problem the application purports to solve ... is indeed solved".

Also in T 609/02 (reasons, 9), addressed above, it was stated that "showing a pharmaceutical effect in vitro may be sufficient ... if there is a clear and accepted established relationship between the shown physiological activities and the disease" (emphasis added by the present board). In the present case, there is no such established relationship between the ER receptor and many of the conditions listed in claim 18.

2.2.5 The respondent also cited D9 and D10, (referenced in paragraphs [0055] and [0056] of the patent) to support its position that the invention defined in claim 18 was sufficiently disclosed in relation to all of the conditions listed therein. Specifically, D9 and D10 confirmed the skilled person's general understanding that the estrogen receptor plays a role in a wide variety of processes in the body. This information, in combination with the evidence in the patent rendered it credible that the claimed compounds could be applied in all of the therapeutic uses claimed.

According to D9:

"Estrogens regulate many cellular processes in a wide variety of target tissues during growth, development, and differentiation. Estrogens are mainly involved in the regulation and development of the female reproductive tract but also play a role in the central nervous system, cardiovascular systems, and in bone metabolism..." (page 1073, left hand column, first paragraph), and

"The NF-kB family of transcriptional factors are involved in the immune and skeletal systems and inflammatory response ... NFkB binds to kB elements and regulates the expression of target genes ... [the estrogen receptor alpha] has been shown to inhibit NF-kB in an E2-dependent manner." (page 1074, paragraph bridging left and right columns)

Similarly, according to D10:

"Estrogens exert a wide variety of effects on growth, development, and differentiation, including important regulatory functions within the reproductive systems of both females and males, in mammary gland development and differentiation, as anti-atherosclerotic agents, in central nervous system functions, and in the regulation of hypothalamic-gonadal axis" (page 227, left hand column, first paragraph).

2.2.6 The board does not agree. These general statements in D9 and D10 are not sufficiently specific to conclude that the pharmaceutical effect observed in the patent against breast cancer reflects a therapeutic application for all of the conditions listed in claim 18. More specifically, that estrogens may be generally known to play a role in the various processes in the body cannot be equated to direct and unambiguous evidence of a specific effect of ER activity on the metabolic mechanisms of many of the diseases and conditions listed in claim 18, let alone a positive effect required for therapy. Such diseases and conditions include for example, but not limited to, alcoholism, migraine, aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, deep vein thrombosis, Graves' Disease, arthritis, multiple sclerosis, cirrhosis, hepatitis B, chronic liver disease, bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis, Alzheimer's disease, Parkinson's disease, migraine, vertigo, anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder and psychosis.

2.2.7 In this context the respondent furthermore argued that neither the board nor the appellant had shown that there were serious doubts, substantiated by verifiable facts, regarding the alleged link between ER activity and the diseases and conditions listed in claim 18. However, a parallel can be drawn between this argument and that raised in T 488/16 (reasons, 4.10) in which the proprietor argued that the burden of proof lay with the opponent. The board in that case decided that since persuasive arguments had been put forward by the opponent, its burden had been discharged. Similarly, in the present case as set out above, there is no credible evidence on file directly linking the ER activity of the claimed compounds with all of the conditions listed in contested claim 18. In view of this, and since those conditions are totally different from ER-dependent cancers, it must be assumed that the therapeutic effects claimed (the treatment of those diseases) cannot be obtained.

2.2.8 It follows that with regard to the second medical use directed to therapeutic applications other than estrogen-dependent cancer, the invention defined in claim 18 is insufficiently disclosed.

2.3 In conclusion, the invention defined in contested claim 18 is not disclosed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art.