T 0285/14 - Patenting a drug interaction warning

Key points

• Claim 1 is directed to "Pirfenidone for use in treating a patient in need of pirfenidone therapy, characterized in that the treating comprises avoiding, contraindicating or discontinuing concomitant use of fluvoxamine."
• " The patent in suit relates to pirfenidone therapy. Pirfenidone, which has anti-fibrotic properties, had previously been approved in Japan for the treatment of idiopathic pulmonary fibrosis" 
• " According to the patent in suit, the invention is based on the discovery of an adverse drug-drug interaction between pirfenidone and fluvoxamine, which results in reduced clearance of pirfenidone and, as a consequence, increased exposure of patients to pirfenidone. The patent therefore seeks to avoid such potentially adverse interaction when administering pirfenidone therapy, and to that end proposes that the concomitant use of fluvoxamine should be avoided, contraindicated or discontinued"
• The patent is revoked as obvious because starting from D5 describing pirfenidone, the skilled person would check if CYP enzymes were involved in the metabolism of pirfenidone, found that this is the case, and would then proceed with interaction studies involving fluvoxamine, which was the only compound listed in D37 as a strong inhibitor of the CYP enzyme at issue.
• The claim suggests that the first medical use of pirfenidone is not patented, but I find it difficult to see what the non-infringing medical use is of pirfenidone. Even avoiding concomitant use of fluvoxamine is patented. So the non-infringing use is co-treatment with pirfenidone and fluvoxamine and letting the patients suffer? I'm not sure what to make of this kind of second medical use claims for evergreening. 

EPO T 0285/14 - link

Reasons for the Decision

1. Analysis of claim 1

1.1 Non-therapeutic indication

The purpose specified for pirfenidone in claim 1 - "for use in treating a patient in need of pirfenidone therapy and in need of fluvoxamine therapy" - is a therapeutic application within the meaning of Article 53(c) EPC. In this, the board takes the view that "treating a patient in need of pirfenidone therapy" explicitly does not cover the non-therapeutic application of pirfenidone, contrary to the opponent's first approach to the interpretation of claim 1.

1.2 Patients to be treated

According to paragraph [0024] of the patent in suit, a patient in need of pirfenidone therapy is a patient who would benefit from the administration of pirfenidone, i.e. one who is suffering from any disease or condition for which pirfenidone may be useful.

According to paragraph [0025] of the patent in suit, a patient in need of fluvoxamine therapy is a patient in need of selective serotonin reuptake inhibitor (SSRI) therapy, which includes patients suffering from social anxiety disorder, obsessive compulsive disorder, depression, anxiety disorders, panic disorder and post-traumatic stress disorder. The board understands from this that patients in need of fluvoxamine therapy are patients with a pathology requiring a therapy which provides a therapeutic benefit obtainable with fluvoxamine.

The patients according to claim 1 are defined by the overlap between these two patient groups.

The pathologies which can be treated with the antifibrotic agent pirfenidone (see paragraph [0024] of the patent in suit) would appear to be unrelated to those which can be treated with fluvoxamine.

1.3 Indication relating to first or further medical use

1.3.1 According to Article 54(4) EPC, novelty can be acknowledged with regard to a substance comprised in the state of the art, for use in a method referred to in Article 53(c) EPC, provided that its use for any such method is not comprised in the state of the art (first medical use).

1.3.2 According to Article 54(5) EPC, novelty can further be acknowledged with regard to a substance comprised in the state of the art, for any specific use in a method referred to in Article 53(c) EPC, provided that such use is not comprised in the state of the art (further medical use).

1.3.3 The opponent contended, in its second approach to the interpretation of claim 1 (see point IX above), that the indication defined in claim 1 was the otherwise unspecified therapeutic use of pirfenidone in the treatment of patients in need of pirfenidone therapy, which was not distinguishable from a first medical use pursuant to Article 54(4) EPC.

1.3.4 However, claim 1 actually does not relate just to pirfenidone therapy, but rather to the therapeutic treatment of patients in need of both pirfenidone and fluvoxamine, restricting both the patient group (in comparison with all patients in need of pirfenidone) and the treatment options (with regard to patients in need of fluvoxamine). The board therefore considers that the indication defined in claim 1 describes a specific therapeutic use.

1.4 For these reasons, the board concludes that claim 1 relates to a further medical use in conformity with Article 54(5) EPC.

2. Novelty

2.1 Document D5 is a report on the results of a regulatory review leading to the marketing approval of pirfenidone 200 mg tablets by the competent Japanese regulatory authority PMDA (Pharmaceuticals and Medical Devices Agency). According to the conclusions reached (see D5: page 4), the data and information submitted, including data from phase III clinical studies, demonstrated the efficacy and safety of the product for use in the treatment of idiopathic pulmonary fibrosis. It was common ground that D5 therefore discloses the use of pirfenidone in treating patients in need of pirfenidone therapy.

2.2 D5 does not mention patients in need of pirfenidone therapy who are also in need of fluvoxamine therapy. Since the pathologies involved are unrelated, there is no implicit disclosure of such patients.

2.3 The subject-matter of claim 1 is novel with regard to the disclosure of document D5, because claim 1 relates to a specific group of patients not disclosed in D5 and also defines certain restrictions to be observed with regard to their medication. The same applies to the other prior-art documents cited by the opponent against novelty (namely D3, D6, D7, D12, D13 and D14).

2.4 As a consequence, the subject-matter of claim 1 is novel within the meaning of Article 54(1), (2) and (5) EPC.

3. Inventive step

Patent in suit

3.1 The patent in suit relates to pirfenidone therapy. Pirfenidone, which has anti-fibrotic properties, had previously been approved in Japan for the treatment of idiopathic pulmonary fibrosis (see paragraphs [0002] to [0004] of the patent).

According to the patent in suit, the invention is based on the discovery of an adverse drug-drug interaction between pirfenidone and fluvoxamine, which results in reduced clearance of pirfenidone and, as a consequence, increased exposure of patients to pirfenidone.

The patent therefore seeks to avoid such potentially adverse interaction when administering pirfenidone therapy, and to that end proposes that the concomitant use of fluvoxamine should be avoided, contraindicated or discontinued (see claims 1 and 2 and paragraphs [0005], [0021], [0022] and [0027] to [0031]).

3.2 As acknowledged in paragraph [0003] of the patent, it was known from document D5 that pirfenidone had been shown to be metabolised by various isoforms of the cytochrome P450 (CYP) protein, specifically, the isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.

The patent in suit (see paragraph [0019]) additionally provides the information that results of in vitro experiments indicated that pirfenidone was primarily metabolized by CYP1A2 (approximately 48%). It was not contested by the opponent that this was not known from the prior art.

Furthermore, the patent acknowledges that fluvoxamine was known to be a potent inhibitor of CYP1A2 and CYP2C19 (see paragraphs [0004] and [0020] citing, inter alia, document D21).

According to data reported in the patent in suit (see Example 1 and paragraph [0022]), co-administration of pirfenidone with fluvoxamine resulted in an average sixfold increase in exposure (AUC, or area under the curve) to pirfenidone and an average twofold increase in Cmax, the mean maximum plasma concentration.

In that context it is mentioned (see paragraph [0022]) that FDA draft guidance (specifically, document D9) suggests that a drug-drug interaction is present when comparisons indicate twofold or greater systemic exposure for a drug when given in combination with the second drug, compared with when given alone.

Starting point in the prior art

3.3 It was common ground that document D5 was a suitable starting point for the assessment of inventive step.

3.4 As already mentioned (see point 2.1 above), document D5 discloses the use of pirfenidone in treating patients in need of pirfenidone therapy and relates to a regulatory approval process for pirfenidone tablets completed in Japan.

According to D5 (paragraph bridging pages 25 and 26), in vitro assay results confirmed that several cytochrome P450 (CYP) isoforms, namely CYP1A2, 2C9, 2C19, 2D6 and 2E1, were involved in metabolising pirfenidone. D5 does not however provide any information about the relative contribution of each CYP enzyme to the metabolic clearance of pirfenidone.

In the absence of studies to evaluate pharmacokinetic interactions, the regulatory authority (PMDA) asked the company applying for regulatory approval to explain the possibility of interactions with other drugs.

The applicant company stated (see D5: page 43, third full paragraph) that pirfenidone was unlikely to have pharmacokinetic interactions with other drugs, inter alia because pirfenidone was metabolised not by a particular CYP isoform but by multiple isoforms and was therefore unlikely to be affected by CYP inhibition by concomitant drugs.

According to document D5, the PMDA accepted that response "at present", but considered that the effect of concomitant drugs actually used in clinical settings needed to be evaluated in post-marketing surveillance (see D5: page 44, first paragraph after the table).

Technical problem and solution

3.5 The subject-matter of claim 1 differs from the disclosure of document D5 by the technical features requiring that the concomitant use of fluvoxamine be avoided, contraindicated or discontinued in patients receiving pirfenidone therapy who also have a pathology which might otherwise benefit from fluvoxamine therapy.

3.6 In view of the data reported in Example 1 of the patent in suit, the board recognises that the administration of fluvoxamine concomitant with the use of pirfenidone may give rise to increased exposure to pirfenidone (presumably due to reduced clearance), which may potentially present a risk of toxicity. Hence, avoiding, contraindicating or discontinuing the concomitant use of fluvoxamine in a group of patients who might otherwise incur such a risk are measures which may serve to improve the safety of pirfenidone therapy.

3.7 The objective technical problem is thus the provision of a specific ("further") safe therapeutic use of pirfenidone.

3.8 The solution to that problem is as defined in claim 1.

Obviousness of the solution

3.9 The board does not share the patent proprietor's view that the person skilled in the art, having studied document D5 and the product insert D5a, would have desisted from investigating potential drug-drug interactions of pirfenidone based on CYP inhibition. Firstly, on the basis of the information provided in documents D5 and D5a, the occurrence of relevant interactions could not have been ruled out with any certainty, and secondly, the skilled person's common general knowledge (as represented by document D37) would have provided a strong incentive for further investigation (see points 3.11 to 3.14.5 below for detail).

3.10 Hence, the board cannot agree with the patent proprietor's contention that the claimed subject-matter should be regarded as a "problem invention", since safety, including the aspect of avoiding adverse drug-drug interactions, is a general consideration in drug development, and thus the technical problem defined in point 3.7 above would have been posed by the person skilled in the art as a matter of routine.

3.11 Conclusions from D5/D5a

3.11.1 It is usually assumed that the likelihood of drug-drug interactions with inhibitors of a metabolising pathway increases when a compound has a high affinity for a single metabolising enzyme, compared with a compound with affinity for a number of different enzymes (see D38: page 301, left-hand column, penultimate paragraph). The person skilled in the art might therefore well have estimated that pirfenidone, since it was metabolised by several CYP isoforms (see point 3.4 above), was less likely to be strongly affected by CYP inhibition by concomitant drugs.

3.11.2 This view, which is expressed in both D5 and D5a, can however only be regarded as a first approach based on likelihood, which would not have conclusively ruled out the possibility that relevant CYP-related adverse drug-drug interactions might nevertheless occur. In fact, although taking the discretionary decision not to prescribe further clinical studies prior to the regulatory approval of pirfenidone 200 mg tablets, the PMDA did not rule out the possibility of drug-drug interactions, but considered that the effect of concomitant drugs needed to be evaluated at least in post-marketing surveillance.

3.12 Common general knowledge represented by document D37

Furthermore, the board considers that document D37, which is a draft guidance published and distributed for comment by the FDA, was part of the common general knowledge of the person skilled in the art. While D37 does not establish mandatory requirements for regulatory approval, it contains recommendations relevant to the industry which a person skilled in the art would not have ignored.

3.13 Teaching of D37

- Document D37 reflects the FDA's view that the metabolism of an investigational new drug should be defined during drug development and the new drug's interactions with other drugs should be explored as part of an adequate assessment of its safety and effectiveness (see D37: lines 21 to 24).

- D37 acknowledges that the cytochrome P450 (CYP) family of enzymes is known to be responsible for the metabolic clearance of many drugs and that metabolic routes of elimination can be inhibited or induced by concomitant drugs. Thus CYP inhibition by concomitant medication is a known cause of drug-drug interactions (see D37: lines 58 to 88 and Appendix B; also see D40: abstract and page 410, sentence bridging columns 1 and 2).

- In contrast to earlier approaches which focused on specific drugs likely to be co-administered, D37 takes a more general approach and recommends early screening for drug-drug interactions during drug development, in particular with regard to CYP-related interactions (see D37: lines 333 to 339).

- In testing an investigational drug for the possibility that its metabolism is inhibited by interacting drugs, the selection of the potentially interacting drugs should be based on studies identifying the enzyme systems that metabolise the investigational drug. The choice of interacting drug can then be based on known important inhibitors of the pathway under investigation (see D37: lines 398 to 404).

- In vitro studies can frequently serve as a screening mechanism to rule out the importance of a metabolic pathway and the drug-drug interactions that occur through this pathway, so that subsequent in vivo testing is unnecessary (see D37: lines 168 to 171).

- A Decision Tree for CYP-based drug-drug interaction studies is presented in Appendix B on page 24 of D37, as reproduced below (see page 24 of this decision).

- The situation in which the drug to be investigated (also called NME or "new molecular entity" in D37) is a substrate of CYP enzymes is reflected in the first two arms (from the left) of the decision tree.

- It can be seen that in a first step (shown at the top of the decision tree), the CYP enzymes metabolising the drug are identified in in vitro studies.

- If the drug is a substrate of a CYP enzyme and the contribution of the pathway to its elimination is major or unclear, further testing is required (second arm of the decision tree).

FORMULA/TABLE/GRAPHIC

3.14 Conclusions from D37

3.14.1 The patent proprietor argued that, since document D5 did not identify any CYP enzyme as a major contributor to the metabolic elimination of pirfenidone, the person skilled in the art would have inferred that no single CYP was a major contributor and that, according to the decision tree of D37 (first arm), further tests were not required, because there was no particular risk of important drug-drug interaction. This was moreover entirely consistent with the statement made by the applicant company in document D5 (page 43).

3.14.2 The board does not reach the same conclusion. While document D5 identifies five CYP enzymes as contributors to the metabolic clearance of pirfenidone, their relative contribution is not indicated or discussed in D5. Thus there is nothing that would suggest to the reader that none of the CYP enzymes is a major contributor: information on that subject is simply not available in D5. This corresponds to the situation mentioned in the second arm of the decision tree, where the contribution of the metabolic pathway to the elimination of the drug is "either major or unclear". In that situation, document D37 recommends in vivo studies with potent inhibitors of the CYP enzymes involved.

3.14.3 The opponent argued that D37 clearly implied that the skilled person's next step should be the identification of any CYP enzyme(s) with a high (or "major") relative contribution to the metabolism of pirfenidone.

3.14.4 The board agrees that this would appear to be the logical next step. It was not contested that the person skilled in the art would be able to identify the relative contributions of different CYP enzymes. In that way, the skilled person would have established by experiment that CYP1A2 was the major contributor, and would have proceeded with interaction studies involving fluvoxamine, which was the only compound listed in D37 as a strong inhibitor of CYP1A2 (see D37: Tables 6 and 2).

The second arm of the decision tree also encompasses the alternative option of conducting interaction studies with inhibitors of each relevant CYP enzyme without first identifying the relative contribution of each enzyme in the elimination of pirfenidone. Again, fluvoxamine would have been included as a potent inhibitor of CYP1A2 (also known to inhibit CYP2C19, CYP2C9 and CYP2D6; see D37: Tables 6 and 2 and paragraph [0020] of the patent).

3.14.5 Thus the person skilled in the art, proceeding according to the second arm of the decision tree, would inevitably have identified the drug-drug interaction of fluvoxamine and pirfenidone and would have arrived at the subject-matter of claim 1 without the exercise of inventive skill.

3.15 As a consequence, the subject-matter of claim 1 does not involve an inventive step within the meaning of Article 56 EPC.

Order

For these reasons it is decided that:

1. The decision under appeal is set aside.

2. The patent is revoked.