T 0725/11 - Industry journal article as CPA

Key points

• The Board decides that a claim for essentially a tablet with  combination of two active ingredients for HIV therapy, was obvious over an announcement of patentee of a clinical trial of that combination therapy in D24, an article in the industrial journal "BioWorld® Today." 
• The patentee argued that D24 did not form the closest prior as " D24 was silent on important issues such as efficacy. Also [D24] provided no actual technical information". 
• The Board does not agree. " D24 is a public statement of intent made by Gilead's CEO and its executive vice president of research and development. It therefore carries weight and would not be dismissed by the skilled person as mere speculation. Instead, a skilled person would regard this plan of co-formulating FTC and TDF as a promising approach." 
• The Board finds the claimed formulation to be obvious. " Any effects related to synergy are inherent to the two active ingredients used in the co-formulation and thus already covered by the disclosure of the two specific active agents to be combined, TDF and FTC, in the closest prior art [D24]."

EPO T 0725/11 -  link

Reasons for the Decision

1. The appeal is admissible.

Oral proceedings were held and the proceedings were continued in the absence of the duly summoned respondent 2 in accordance with Article 15(3) RPBA and Rule 115(2) EPC.

The main request and auxiliary requests 1 and 5 are admitted into the proceedings. Compared to the corresponding requests previously on file they contain minor amendments in the dependent claims that do not raise any new issues (Article 13(3) RPBA).

2. Inventive step (Articles 52(1) and 56 EPC)

2.1 The present invention is directed to a pharmaceutical co-formulation in the form of a tablet comprising tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) for the treatment or prevention of the symptoms or effects of an HIV infection. The pharmaceutical composition should provide enhanced therapeutic safety and efficacy, impart lower resistance, and lead to higher patient compliance (see patent in suit, paragraph [0010]). Concerning the efficacy, synergy is mentioned (paragraphs [0003] and [0011]). It is intended to provide a "one pill, once daily" dosage regimen (paragraph [0054]). An important issue is the chemical stability of the composition (paragraph [0011]). In sum, a physically acceptable, chemically stable and effective composition is to be provided.

2.2 Closest prior art

Document (24) represents the closest prior art. Document (24) is an issue of BioWorld® Today. According to document (37), BioWorld® Today is read by biotechnology professionals (first complete paragraph). It publishes information that is researched and written by the top business and science reporters in industry (second complete paragraph).

Document (24) reports on the intention of the biopharmaceutical company Gilead Sciences, Inc., citing both the President and CEO of Gilead and the firm's executive vice president of research and development, to start developing a co-formulation of Coviracil (FTC) and Viread (TDF), to be dosed as one pill, once daily. Apart from stating this intention, preliminary and optimistic statements about compatibility in view of resistance mutations and physical chemical properties of the drugs are made. The co-formulation work is described as "currently ongoing"; testing of FTC and TDF in combination for HIV is "under way" (document (24), page 6, right column, paragraphs 2 to 5).

A skilled person working in the field of antiviral therapy, especially HIV therapy using reverse transcriptase inhibitors, would consult all available literature dealing with this topic, including literature providing information on the research pipelines of companies working in this field. Such information is essential in order to keep abreast of the latest developments.

The appellant argued that document (24) did not qualify as closest prior art because its content was remote from the purpose of the patent in suit. Furthermore, document (24) was silent on important issues such as efficacy. Also, according to the appellant, it provided no actual technical information.

Indeed, document (24) does not provide any technical details on how the co-formulation is actually put into practice. Document (24) discloses a project. It clearly states that the company having in its portfolio the two active pharmaceutical ingredients under consideration, FTC and TDF, is about to develop a co-formulation of these two actives for the treatment of HIV. Such a statement by a pharmaceutical company implicitly amounts to a concrete plan to develop a commercially viable product. A commercially viable product is one that has the stability required for transport together with a certain shelf life and having a usable level of efficacy. Further, document (24) is a public statement of intent made by Gilead's CEO and its executive vice president of research and development. It therefore carries weight and would not be dismissed by the skilled person as mere speculation. Instead, a skilled person would regard this plan of co-formulating FTC and TDF as a promising approach. In summary, document (24) relates to providing a co-formulation for the same purpose as the patent in suit and its content would be considered by the skilled person.

The appellant has stated that it considered document (4) to be more suitable as the closest prior art document. Document (4) describes the use of TDF for the treatment of HIV infections and discusses in particular the pharmacological properties of TDF. The results of pharmacokinetic drug interactions of TDF and other antiretroviral drugs are examined, and presented in table VIII. Document (4) is therefore a document a skilled person trying to treat HIV infections would consult. However, the board considers that document (24) is even closer, since it relates to both claimed active ingredients in the context of HIV infections and explicitly mentions co-formulations of TDF and FTC. The appellant has agreed to follow the problem-and-solution approach starting from document (24) as the closest prior art.

2.3 Main request

2.3.1 Claim 1 of the main request defines a pharmaceutical co-formulation in the form of a tablet comprising carriers or excipients and TDF and FTC in a weight ratio from 1:10 to 10:1.

Claim 1 of the main request differs from the disclosure of document (24) in the definition of the weight ratio between the two active pharmaceutical ingredients and the specific galenic form of a tablet. Also, document (24) does not disclose an actual and reworkable pharmaceutical composition comprising FTC and TDF.

2.3.2 Technical problem

The problem to be solved may be defined as putting into practice the co-formulation taught by document (24).

2.3.3 Proposed solution

The solution proposed by the subject-matter defined in claim 1 of the main request consists in the selection of a tablet and the requirement of a certain weight ratio of the two active pharmaceutical ingredients. The problem has been solved. This has not been contested. Evidence is found in document (35).

2.3.4 Obviousness

The skilled person, faced with the task of providing an actual formulation comprising TDF and FDC, will look for guidance in the prior art, i.e. in documents relating to actual formulations in the field of reverse transcriptase inhibitors, and especially to formulations comprising TDF or FDC.

One of the active agents, TDF, has already been formulated as a tablet, comprising 300 mg of TDF, and is available under the trade name "Viread" (document (10), page 2, second last paragraph; document (31), page 2, "2. Qualitative and quantitative composition"). The form of a tablet and the amount of 300 mg are thus highlighted and constitute a starting point for the skilled person's routine developments.

The second active pharmaceutical agent, FTC, has been tested in various amounts. For once-daily use 100 mg and 200 mg have been tested and 200 mg has been identified as the optimal dose (document (20), figure 1 and sentence bridging pages 86 and 87). Consequently, a weight ratio close to 300:200, or 3:2, i.e. within the range 1:10 to 10:1, would have been considered by a person skilled in the art as a starting point for routine tests.

The selection tablet form and of a weight ratio of TDF to FTC within 1:10 to 10:1 is thus the result of the routine approach taken by the skilled person when formulating a pharmaceutical composition comprising these two actives. No inventive step can be acknowledged.

2.3.5 Further arguments

Any effects related to synergy are inherent to the two active ingredients used in the co-formulation and thus already covered by the disclosure of the two specific active agents to be combined, TDF and FTC, in the closest prior art document (24). The appellant's arguments concerning reservations by the skilled person about combining TDF and FTC, due to expected stability problems, can be disregarded. The combination of TDF and FTC is already part of the disclosure of the closest prior art and would thus not be questioned by the skilled person.

The appellant has further argued that tabletting would exacerbate the stability problems arising from the combination of TDF and FTC, since in a tablet the two incompatible active agents were situated in intimate proximity and during the tabletting very harsh conditions applied. Thus, according to the appellant, a skilled person was aware of the stability problems of TDF and FTC and would have avoided the galenic form of tablets. TDF and FTC were inherently incompatible due to the free acid group in TDF which would lead to a degradation of FTC.

Documents (51) and (53) relate to degradation of cytidine derivatives and show the degradation rates of certain cytidine derivatives under acidic conditions. When considering table 1 of document (51), it can be seen that the actual conditions are important. The pH values influence the degradation considerably, as does the temperature. Also of great influence is the actual structure of the hexopyranosyl-like unit. The rate of degradation or-to put it another way-the stability thus depends both on the actual compound and on the reaction conditions, such as pH and temperature. Table 4 of document (53) gives the rate constants for the deamination of cytidine and several of its derivatives. The deamination rate constant depends on the actual structure of the compound. Both the cytosine-like part of the structure (compare for example compounds (1), (2) and (4)) and the substitution on the 6 position (compare compounds (1) (as there is no data for compounds (6)) and (7)) influence the deamination rate. For lamivudine, a compound differing from FTC by the absence of a fluorine substitution in ortho position of the amino group, stability problems in tablets comprising TDF have been observed in document (57) by the appearance of a brown colour (paragraph bridging pages 8 and 9). However, none of these documents directly concerns FTC.

In view of the fact that Gilead's executive vice-president of research and development has advertised the co-formulation of TDF and FTC, the board cannot follow the argumentation that a skilled person, having in mind stability problems of other, albeit structurally related substances, would not follow the teaching of document (24). It is a matter of routine for a skilled person to carry out stability tests and to find an adequate galenic form. The mere speculation that tabletting might exacerbate potential stability problems would not deter a skilled person trying to realise the teaching of the closest prior art as a tablet, which is one of the most common and convenient galenic forms and comprised by the term "pill".

The disclosure of document (61) concerning the rapid absorption of TDF and FTC is post-published. It has thus not been established that at the priority date of the patent in suit the skilled person would have been aware of problems possibly arising from the rapid absorption of both drugs (document (61), page 24, "5.2 Pharmacokinetic properties"). Consequently, the arguments based on document (61) cannot be taken into account.

The board notes that the appellant has neither argued that the invention lies in the field of galenics, nor invoked any effects due to concentrations or other technical features that may be considered to pertain to the field of galenics.

2.3.6 In view of the disclosure of HIV therapy in document (24), the same reasoning applies mutatis mutandis to claim 12 of the main request.

2.3.7 Conclusion

The subject-matter of claims 1 and 12 of the main request does not involve an inventive step (Article 56 EPC).