Generics (UK) Ltd (t/a Mylan) v Richter Gedeon Vegyeszeti Gyar RT

This is a claim for a declaration that European Patent (UK) no. 1 448 207 B1 entitled “Dosage Regimen and Pharmaceutical Composition for Emergency Contraception” (“the Patent”) is invalid and should be revoked. The Patent is for a dosage regimen for use of levonorgestrel as a method of emergency contraception. The regimen for which the Patent is claimed is for use of a single dose of levonorgestrel of 1.5 mg taken within 72 hours of sexual intercourse.

Particular benefits are associated with this form of emergency contraception, in that it does not involve a physically intrusive procedure such as would be required in connection with use of an intrauterine device (“IUD”); is associated with significantly less unpleasant side-effects (such as nausea and gastrointestinal problems) than certain other forms of pill-based hormonal emergency contraceptives using other active ingredients; and is easier to use effectively than the previously established dosage regimen for levonorgestrel, which required two doses of 750 μg taken 12 hours apart. The single dose regimen is broadly equivalent in efficacy to other forms of pill-based treatment.

The grounds of invalidity relied on are (1) obviousness, in that it is claimed that the invention to which the Patent relates does not involve an inventive step (see section 1(1)(b), read with section 3, of the Patents Act 1977) and (2) insufficiency, in that it is claimed that the specification of the Patent “does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art” (section 72(1)(c) of the Act).

Section 1(1) of the Act sets out conditions which have to be satisfied before a patent can be issued. These include, at sub-section (1)(b), that the relevant invention “involves an inventive step”.

Section 3 provides:

“An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2(2) above ….”

Section 2(2) provides:

“The state of the art in the case of an invention shall be taken to comprise all matter (whether a product, a process, information about either, or anything else) which has at any time before the priority date of that invention been made available to the public (whether in the United Kingdom or elsewhere) by written or oral description, by use or in any other way.”

Section 4A provides for the grant of patents in relation to methods of treatment or diagnosis. Section 4A(3) stipulates that in the case of an invention consisting of a substance or composition for use in a method of treatment of the human body, “the fact that the substance or composition forms part of the state of the art shall not prevent the invention from being taken to be new if the use of the substance or composition in any such method does not form part of the state of the art.” Section 4A(4) makes similar provision in the case of an invention consisting of a substance or composition for a specific use in any such method.

Section 72 provides for a power to revoke patents on application, on grounds which include, at sub-paragraph (a), that “the invention is not a patentable invention”, and at sub-paragraph (c), that “the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art.”

The Claimant’s primary case is that the relevant expertise for assessment of the issues in the case, in particular that of obviousness, is that of a clinician with an interest in emergency contraception. The Claimant called as an expert witness a clinician with a strong research interest in emergency contraception, Mr Ali Kubba.

The Defendant’s case is that although the expertise of a clinician is relevant, of more importance is expert knowledge of medical statistics. Only someone with such knowledge could assess the novelty and validity of the claim in the Patent, as compared with information in the public domain before the priority date for the Patent. The Defendant did not call an expert clinician in the field of emergency contraception, but instead relied on the evidence of an expert in medical statistics, Professor Bland.

When it emerged that the Defendant would be relying on the evidence of an expert medical statistician rather than an expert clinician to defend the claim, the Claimant sought and was granted permission to adduce reply evidence from another expert medical statistician, Professor Sasieni.

Each of the witnesses had good expertise appropriate to his respective discipline. Each of them gave his evidence in a measured and neutral way, and sought to assist the court as best he could.

It is common ground that the priority date for the Patent is November 2001.

The Patent sets out the background of developing views about and research into pill-based methods of emergency contraception, focusing in particular on work carried out by A.A. Yuzpe and co-workers from the 1970s in relation to a two-dose regimen for administering levonorgestrel and ethinyl-estradiol, through to an important trial conducted by Dr Helena von Hertzen under the auspices of the World Health Organisation (“WHO”) which examined the effectiveness of a regimen involving a single dose of 1.5 mg of levonorgestrel, as follows:

“[0006] A.A. Yuzpe and his coworkers reported in The Journal of Reproductive Medicine [13(2), (1974)] the results of those studies where a pharmaceutical composition containing 100 μg of ethinyl-estradiol and 1.0 mg of norgestrel was used as postcoital contraceptive in a single dose. The composition was administered within five days of the unprotected coitus. Later the method was modified. On the one hand the period of the possible use of the composition was reduced from 5 days to 72 hours, on the other hand the dose was doubled that way that the administration was repeated 12 hours after the first one. [Fertility and Sterility, 28, 932-936, (1977), ibid. 37, 508-513 (1982); International Journal of Gynaecology and Obstetrics, 15, 133-136, (1977)]. This modification increased the success of the method.

[0007] After the studies of A.A. Yuzpe and his coworkers several other trials were carried out to prove the efficacy of this combination. In these studies the total dose of ethinyl-estradiol was 0.2 mg combined with 2.0 mg of norgestrel or 1.0 mg of levonorgestrel. The results of the studies showed that although the above administration (Yuzpe regimen) caused less side-effects than the estrogens used earlier in high doses (mainly in the sixties), the relative incidence of nausea and vomiting was still very high (50 and 20% respectively). These side-effects are due to the estrogen effect and they cause the decrease in compliance, moreover, if vomiting occurs, it decreases the efficacy of the treatment.

[0008] The use of levonorgestrel in emergency contraception was discovered in the 1990s. The results of the studies were reported in two well-documented publications [Lancet, 352, 428-433, (1998) and Human Reproduction, 8(3), 389-392, (1993)]. The efficacy of tablets containing only 0.75 mg of levonorgestrel and the combined tablets of Yuzpe method containing 0.1 mg of ethinyl-estradiol + 1.0 mg levonorgestrel were studied by administering the doses 12 hours apart within 48 as well as within 72 hours of unprotected coitus. The results showed that protection with two tablets containing 0.75 mg of levonorgestrel was better than with the Yuzpe regimen, but the women, who received only levonorgestrel observed less side-effects, which could be due to the lack of ethinyl-estradiol.

[0009] The mechanism of action of levonorgestrel used as postcoital contraceptive was investigated in several studies. Keserü and Garmendia showed that the antiovulatory effect probably depends partly on the time elapsed between taking the last tablet and the time of ovulation, partly on the quantity of the applied hormone [Contraception, 10, (1974)]. According to other authors besides the inhibition of ovulation, other factors can also influence the contraceptive effect [Contraception, 63, 123-129, (2001)]. Levonorgestrel administered in the follicular phase decreased the proliferation activity of the endometrium, while in the luteal phase there was no effect [Contraception, 39(3), 275-289, (1989)].

[0010] Several trials were conducted to show the effect of levonorgestrel on the cervical mucus, which could be observed a few hours after the administration. Levonorgestrel inhibits the sperms getting into the upper genital tract in such a way that it causes the thickening of the cervical mucus almost immediately after the absorption of the hormone. It was also shown that after the administration of 400 μg of levonorgestrel the alkalization of the intrauterine fluid starts already after 4 hours of administration and it lasts for approximately 48 hours. This effect can play a role in the inhibition of the movement of sperms, consequently in the contraceptive effect as well [Contraception, 11(1), (1975)].

[0011] The studies showed that two pharmaceutical compositions containing 0.75-0.75 mg of levonorgestrel used at 12 hours’ interval within 72 hours after the unprotected coitus successfully inhibited the conceptions which otherwise might have occurred. The efficacy was significantly better than the efficacy of the Yuzpe regimen used worldwide earlier. Because of the lack of the estrogen component, side effects (nausea, feeling of sickness, vomiting) leading to the decrease in compliance and the efficacy of the treatment were observed far less frequently. The results of the clinical studies showed that the efficacy was the better the earlier the treatment started after the coitus. However, according to experience, if women wanted to follow the instructions correctly, they often delayed taking the first tablet so as taking the second dose after 12 hours would not fall on an extremely inconvenient time (for example 3 o’clock in the morning). The results of the studies showed that the prescription of 12 hours’ interval between the two doses decreased the compliance. According to statistical data the majority of women took the second dose within 12 to 16 hours after the first one [Lancet, 352, 428-433, (1998)].

[0012] The results of the study of the mechanism of action of levonorgestrel used as postcoital contraceptive showed that the anti-ovulatory effect had great importance. According to the literature [Contraception, 63, 123-129, (2001)] the anti-ovulatory effect is appr. 42% of the total effect, while the rest is distributed among the effects on the cervical mucus, the migration of sperms, zygote transport through the fallopian tube, the endometrium and the implantation. The anti-ovulatory effect depends partly on the quantity of the applied hormone, partly on the time elapsed between the administration and the expected time of ovulation. This seems to support the importance of the 12-hour interval.

[0013] According to the above mentioned facts, taking 0.75 mg of levonorgestrel for emergency contraception twice at 12-hour interval within 72 hours of the coitus seemed to be reasonable. Despite of this we studied the possibility of applying the two doses at the same time within 72 hours of the unprotected coitus so as to eliminate the disadvantage of the 12-hour interval. Surprisingly it was found that the administration of two doses of 0.75 mg of levonorgestrel as an active ingredient at the same time did not cause a decrease in efficacy.

[0014] Therefore the object of this invention is a dosage regimen for emergency contraception and a pharmaceutical composition for the application of this regimen. The regimen according to this invention is that a single dose containing only 1.5+0.2 mg of levonorgestrel as active ingredient is administered to women to be treated with a pharmaceutical composition within 72 hours of unprotected coitus. Further objects of this invention are the dosage units required to carry out the above regimen.

[0015] The dosage units required to carry out the above regimen can be in solid or liquid state, and they can be for example tablets, film-coated tablets, coated tablets, capsules, pills or powder preparations. The lyophilized powder ampoule preparations – making the in situ preparation of liquid compositions possible – also belong to them. Liquid compositions can be for example solutions for injection or infusion.

[0016] The efficacy of the regimen according to this invention was compared with the known regimen administering 0.75-0.75 mg of levonorgestrel 12 hours apart in the following trials.

[0017] In a double-blind, randomized, multicentre, multinational trial 1,356 women received 0.75-0.75 mg of levonorgestrel at 12-hour interval in the traditional way, while 1,356 received in a single dose 1.5+ 0.2 mg of levonorgestrel within 72 hours of the unprotected coitus. In the group treated in the traditional way the conception rate was 1.77% while in the other group treated with a single dose it was 1.47%. The so-called “Prevented fraction” (this number shows how many percent of the conception which otherwise might happen is prevented by the treatment) was 77.3% in the group treated in the traditional way, while in the other it was 81.9%. These data support the advantage of the single dose treatment, although statistical significance can not be proven. The results of the trial proved that the conceptions which otherwise might have happened could be prevented by a single tablet containing twice 0.75 mg of levonorgestrel at least as effectively as by the known therapy.

[0018] During the evaluation of undesired effects it was found that the incidence of nausea was 14.5% in the traditional group, while in the group treated with a single dose it was 13.7%. The incidence of vomiting was 1.4% in both groups. As the new regimen also has the advantageous properties resulting from the lack of estrogen component, the incidence of nausea, feeling of sickness, vomiting was apparently low. The incidence of other side-effects (diarrhoea, fatigue, dizziness, headache, breast tenderness, lower abdominal pain) was also not differing significantly.

[0019] The incidence of menstrual disorders was not increased either by the single administration of 1.5 mg dose of levonorgestrel compared to the administration of two 0.75 mg doses. The incidence of menstrual disorders was 30.9% in both groups.

[0020] The results of the comparative study show that a single dose of 1.5+ 0.2 mg of levonorgestrel surprisingly prevented the conception which otherwise might have occurred with the same success as if this amount of active ingredient were administered twice at 12-hour interval within 72 hours of the unprotected coitus. However, the single administration increases the compliance and decreases the possibility of incorrect use by women. Regarding side-effects it has the same advantageous properties as the known double dosed composition containing only levonorgestrel for emergency contraception. …”

The Claims set out in the Patent are as follows:

“1.

Pharmaceutical composition as single application dose, characterized by containing 1.5+ 0.2 mg of levonorgestrel as active ingredient in admixture with known excipients, diluents, flavoring or aromatising agents, stabilizers, as well as formulation-promoting or formulation-providing additives, commonly used in the pharmaceutical practice.

2.

Use of 1.5+ 0.2 mg levonorgestrel for the preparation of a pharmaceutical for emergency contraception.

3.

The use as claimed in claim 2, wherein the pharmaceutical is for the administration of a single application dose up to 72 hours of the coitus.”

For its obviousness case, the Claimant relies upon common general knowledge (“CGK”) and the publication in late 2000 of a report discussing interim results of Dr von Hertzen’s research for the WHO regarding the effectiveness of a regimen involving a single dose of 1.5 mg of levonorgestrel, as compared (in particular) with the two-dose regimen which was in widespread use. The report was by Professor Stephen R. Killick, the Editor-in-Chief of Gynaecology Forum, in a special issue of that journal to report the highlights of the XVI FIGO World Congress of Gynecology and Obstetrics in September 2000 in Washington DC, USA (“the Killick article”).

In his article, Professor Killick reported on a presentation by three speakers, Dr Pak Chung Ho, Dr Anna Glasier and Dr von Hertzen, who had been involved in extensive studies organised by the WHO, who summarised work of the previous 10 years. The article was short (only two pages), and only a part of it was devoted to reporting on Dr von Hertzen’s research. At three places in the article, Professor Killick referred in error to the research study being in relation to a regimen involving a single dose of 1.5 g of levonorgestrel (rather than 1.5 mg). Mr Kubba’s evidence was that this would have been appreciated to be an obvious mistake by a clinician skilled in the art relating to emergency contraception.

The Killick article included as Table II a table comparing the results to the date of the presentation from blind trials of three emergency contraception treatments: two doses of levonorgestrel, a single, larger dose of levonorgestrel and a single dose of mifepristone, as follows:

Table II: Mifepristone and two regimens of levonorgestrel for emergency contraception.

Group (code Clinical Pregnancy Relative Expected Fraction unbroken) pregnancies rate risk pregnancies prevented (%)

A 17/1241 1.37 1 99.3 83

B 18/1236 1.46 1.06 98.9 82

C 24/1244 1.93 1.41 97.8 75

All 59/3721 1.59

The text accompanying this Table in the article was as follows:

“Mifepristone is used in Shanghai as the emergency contraceptive method of choice, but its introduction into other countries will be hampered by its potential use in much higher doses as an abortifacient.

The most recent WHO study is comparing three regimens: two doses of 750 μg levonorgestrel given 12 h apart; a single dose of 1.5 g levonorgestrel; and a single dose of 10 mg mifepristone. This study is still in progress but an interim comparison between the groups was presented by Dr von Hertzen. The code has yet to be broken but there is, as yet, little difference between the groups (Table II).

There was an interesting debate after the presentations. Dr Ho confirmed that all the pregnancies in the Hong Kong study had been terminated but that there was no evidence that there was any risk of teratogenicity if the women had subsequently wished to continue with their pregnancy.

A criticism from the floor was that the session had not dealt with the use of intrauterine contraceptive devices (IUCDs) for emergency contraception. A recent Chinese study had resulted in no pregnancies after over 2000 insertions, making this method the most effective of all. Dr Glasier agreed, but made the point that total efficacy depends on availability of service and it is difficult to provide frequent IUCD insertion sessions for women who are often young, nulliparous and anxious.

The issue of providing emergency contraception without prescription was debated. Dr Glasier had given an emergency contraceptive preparation to a number of women to keep in their handbag in case of emergency. This had not increased their use of the method.

The suggested summary from the floor was that a single dose of 1.5 g levonorgestrel was the preferred oral method because there was no difference between groups in the most recent WHO study, but Dr Glasier advised great caution with this assumption as the trial was still incomplete. The last few subjects could alter the data and it was wrong to try to guess which group was which, however tempting this might be.”

Since the code between the groups which had used the three different regimens had not been broken, a reader could not tell from Table II which results related to which regimen. However, they could see, as the report of the presentation noted, that there was little difference between the three regimens. The number of results available at this stage bear comparison with those in the completed study, referred to in the Patent at para. [0017].

Obviousness

On this issue, I have found the judgment of Jacob LJ in Pozzoli Spa v BDMO SA [2007] EWCA Civ 588; [2007] FSR 37 and the judgment of Kitchin LJ in MedImmune Ltd v Novartis Pharmaceuticals UK Ltd [2012] EWCA Civ 1234 of particular assistance.

It is relevant to set out the following extended passage from the judgment of Jacob LJ in Pozzoli:

“Assessing obviousness

14 The place of “inventive concept” in relation to obviousness also calls for some discussion. It will be recalled that it forms the first step of the well-known Windsurfing Windsurfing International Inc v Tabur Marine (Great Britain) Ltd] test of Oliver L.J. [1985] R.P.C. 59³ at 73. The test provides a structured approach to the problem and is often useful. I set it out adding my own numbering:

(1)

The first step is to identify the inventive concept embodied in the patent in suit.

(2)

Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question.

(3)

The third step is to identify what, if any, differences exist between the matter cited as being “known or used” and the alleged invention.

(4)

Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention.

15 I think the test requires some restatement and elaboration. First one must actually conduct the first two operations in the opposite order—mantle first, then concept. For it is only through the eyes of the skilled man that one properly understand what such a man would understand the patentee to have meant and thereby set about identifying the concept.

16 Next, that first step actually involves two steps, identification of the attributes of the notional “person skilled in the art” (the statutory term) and second identification of the common general knowledge (cgk) of such a person.

17 What now becomes stage (2), identifying the inventive concept, also needs some elaboration. As I pointed out in Unilever Plc v Chefaro Proprietaries Ltd [1994] R.P.C. 567 at 580:

“It is the inventive concept of the claim in question which must be considered, not some generalised concept to be derived from the specification as a whole. Different claims can, and generally will, have different inventive concepts. The first stage of identification of the concept is likely to be a question of construction: what does the claim mean? It might be thought there is no second stage—the concept is what the claim covers and that is that. But that is too wooden and not what courts, applying Windsurfing stage one, have done. It is too wooden because if one merely construes the claim one does not distinguish between portions which matter and portions which, although limitations on the ambit of the claim, do not. One is trying to identify the essence of the claim in this exercise.”

18 So what one is seeking to do is to strip out unnecessary verbiage, to do what Mummery L.J. described as make a précis.

19 In some cases the parties cannot agree on what the concept is. If one is not careful such a disagreement can develop into an unnecessary satellite debate. In the end what matters is/are the difference(s) between what is claimed and the prior art. It is those differences which form the “step” to be considered at stage (4). So if a disagreement about the inventive concept of a claim starts getting too involved, the sensible way to proceed is to forget it and simply to work on the features of the claim.

20 In other cases, however, one need not get into finer points of construction—even without them the concept is fairly apparent—in Windsurfing , for instance, it was the “free sail” concept. In yet other cases it is not even practical to try to identify a concept—a chemical class claim would often be a good example of this.

21 There is one other point to note. Identification of the concept is not the place where one takes into account the prior art. You are not at this point asking what was new. Of course the claim may identify that which was old (often by a pre-characterising clause) and what the patentee thinks is new (if there is characterising clause) but that does not matter at this point.

22 The third step also requires a little reformulation— Windsurfing was a case under the 1949 Act where the statutory words for the prior art were “known or used”. The European Patent Convention uses the words “state of the art”.

23 The fourth step needs no restatement, though it is worth making explicit that by invention is meant what is claimed. In the result I would restate the Windsurfing questions thus:

(1)(a) Identify the notional “person skilled in the art”;

(b)

Identify the relevant common general knowledge of that person;

(2)

Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;

(3)

Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim or the claim as construed;

(4)

Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?

Obviousness: Lions in the path and paper tigers

24 Sometimes a patentee seeks to defend his invention from a charge of obviousness by saying that there was a technical prejudice against it. Such an argument was run here. The judge said:

“[67] Mr Carr submitted that the idea of overcoming a prejudice must consist in overcoming a false prejudice; in other words a mistaken technical belief that deters the unimaginative skilled person from pursuing a particular path. Mr Carr characterised this kind of false belief as a ‘lion in the path’ (see Bunyan: The Pilgrim's Progress, The Third Stage: ‘Fear not the lions, for they are chained, and are placed there for trial of faith where it is, and for discovery of those that have none: keep in the midst of the path, and no hurt shall come unto thee.’). In such a case the patent reveals that the belief was mistaken, and thus contributes to the art. If on the other hand the perceived technical problem exists in the same form both before and after the claimed invention, then the prejudice has not been overcome at all. In such circumstances overcoming the prejudice cannot be part of the inventive concept, although the technical means for dealing with the perceived problem can be. I accept this submission.”

25 I would not analyse it that way myself. There is an intellectual oddity about anti-obviousness or anti-anticipation arguments based on “technical prejudice.” It is this: a prejudice can only come into play once you have had the idea. You cannot reject an idea as technically unfeasible or impractical unless you have had it first. And if you have had it first, how can the idea be anything other than old or obvious? Yet when a patent demonstrates that an established prejudice is unfounded—that what was considered unfeasible does in fact work, it would be contrary to the point of the patent system to hold the disclosure unpatentable.

26 I put it this way in Union Carbide Corp v BP Chemicals Ltd [1998] R.P.C. 1 , 13:

“Invention can lie in finding out that that which those in the art thought ought not be done, ought to be done. From the point of view of the purpose of patent law it would be odd if there were no patent incentive for those who investigate the prejudices of the prior art.”

27 Patentability is justified because the prior idea which was thought not to work must, as a piece of prior art, be taken as it would be understood by the person skilled in the art. He will read it with the prejudice of such a person. So that which forms part of the state of the art really consists of two things in combination, the idea and the prejudice that it would not work or be impractical. A patentee who contributes something new by showing that, contrary to the mistaken prejudice, the idea will work or is practical has shown something new. He has shown that an apparent “lion in the path” is merely a paper tiger. Then his contribution is novel and non-obvious and he deserves his patent.

28 Where, however, the patentee merely patents an old idea thought not to work or to be practical and does not explain how or why, contrary to the prejudice, that it does work or is practical, things are different. Then his patent contributes nothing to human knowledge. The lion remains at least apparent (it may even be real) and the patent cannot be justified.

29 This analysis does not require a different way of looking at the inventive concept depending on whether or not the patentee has shown the prejudice is unjustified as the judge thought at [67]. It is simply that in the former case the patentee has disclosed something novel and non-obvious, and in the latter not. The inventive concept, as I have said, is the essence of what is in the claim and not dependent on any question about a prejudice being overcome.”

I have directed myself with particular regard to paras. [83]-[95] in the judgment of Kitchin LJ in MedImmune. In relation to step (4) in the Pozzoli analysis, it is pertinent to set out paras. [89]-[93] here:

“89.

It is step (4) which is key and requires the court to consider whether the claimed invention was obvious to the skilled but unimaginative addressee at the priority date. He is equipped with the common general knowledge; he is deemed to have read or listened to the prior disclosure properly and in that sense with interest; he has the prejudices, preferences and attitudes of those in the field; and he has no knowledge of the invention.

90.

One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.

91.

For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way. Lord Hoffmann summarised the position in this way in Conor at [42]:

"In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case."

92.

Moreover, whether a route is obvious to try is only one of many considerations which it may be appropriate for the court to take into account. In Generics (UK) Ltd v H Lundbeck, [2008] EWCA Civ 311, [2008] RPC 19, at [24] and in Conor [2008] UKHL 49, [2008] RPC 28 at [42], Lord Hoffmann approved this statement of principle which I made at first instance in Lundbeck:

"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."

93.

Ultimately the court has to evaluate all the relevant circumstances in order to answer a single and relatively simple question of fact: was it obvious to the skilled but unimaginative addressee to make a product or carry out a process falling within the claim. As Aldous LJ said in Norton Healthcare v Beecham Group Plc (unreported, 19 June 1997):

"Each case depends upon the invention and the surrounding facts. No formula can be substituted for the words of the statute. In every case the Court has to weigh up the evidence and decide whether the invention was obvious. This is the statutory task."

I turn, then, to apply this guidance to the facts in this case.

At step (1) in the Pozzoli analysis, there was an issue between the parties regarding who should be regarded as the person skilled in the art for the purposes of the Patent. Such a person may in certain circumstances be regarded as a composite of a team of scientists or experts, all of whose disparate skills would be required to make sense of and put into practical implementation the invention for which the patent protection is claimed - see Teva UK Ltd v Astrazeneca AB [2012] EWHC 655 (Pat) at [2] per Arnold J:

“A patent specification is addressed to those likely to have a practical interest in the subject matter of the invention, and such persons are those with practical knowledge and experience of the kind of work in which the invention is intended to be used. The addressee comes to a reading of the specification with the common general knowledge of persons skilled in the relevant art, and he or she reads it knowing that its purpose is to describe and demarcate an invention. He (or she) is unimaginative and has no inventive capacity. In some cases the patent is addressed to a team of persons with different skills.”

Here, the parties agreed that the relevant scientific team would include a formulation scientist, but nothing turned on that role. They disagreed about the other member or members of the relevant team.

In my judgment, the relevant person skilled in the art for the purposes of this case is a clinician working in the field of specialist contraceptive services (including emergency contraception), with the normal level of interest in keeping themselves up-to-date with important research in that field which one would expect such a clinician to have and with the level of understanding of basic medical statistics which such a clinician would have. I do not accept the submission of the Defendant that the teaching in the Patent is addressed to a team which would include a clinician and a specialist medical statistician:

A further issue relates to the CGK of the relevant clinician. The number of clinicians practising in the field of specialist contraceptive emergency contraception is large. In Mr Kubba’s opinion, which I accept, the relevant person skilled in the art would have been a medical practitioner working in the delivery of specialist contraceptive services who would have been awarded the basic Diploma or the Membership of the Faculty of Family Planning and Reproductive Health Care of the Royal College of Obstetricians and Gynaecologists (“the FFPRHC”, which changed its name in 2007 to the Faculty of Sexual and Reproductive Healthcare) and would have had at least five years’ hands-on experience in the management of emergency contraception. In 2001 the FFPHRC had approximately 14,000 members, most of whom were general practitioners.

Clearly, only a tiny fraction of the relevant pool of clinicians would have attended the presentation at the FIGO World Conference in Washington DC in September 2000. However, the Killick article was available in a leading journal in the field and I accept the evidence of Mr Kubba that leaders in the United Kingdom in the field of emergency contraception were giving lectures and seminars in late 2000 and throughout 2001 in which the fact of the WHO research study and a broad outline of its preliminary findings were cascaded down to those clinicians with an interest in the subject of emergency contraception. In my view, on the evidence, an awareness that there was such a WHO research study and that its preliminary findings had been reported in the Killick article, to which reference could easily be made, formed part of the CGK of the person skilled in the relevant art for the purposes of this case. Also, by virtue of section 2(2) of the Act, the Killick article formed part of the state of the art.

The Claimant did not in its pleadings or at trial seek to go beyond this, to assert that things which may have been said in greater detail or with greater clarity in the presentation by Dr von Hertzen itself formed part of the relevant CGK or state of the art. This has a bearing on the approach which should be adopted with respect to the error in the Killick article in setting out the level of dose of levonorgestrel in the single dose regimen at 1.5 g rather than 1.5 mg. In my view, the strong probability is that this error crept in when Professor Killick wrote up the presentation for his report. It is very unlikely that the research leader herself, deeply familiar with all the details of the study, would have made such an egregious error when making her presentation at the conference, and much more likely that it was a simple error of transcription by Professor Killick from notes taken by him listening to the presentation. However that may be, the relevant CGK and state of the art has to be assessed by what was contained in the Killick article, rather than by reference to what was in fact probably stated in the presentation.

Mr Kubba suggested that a relevant clinician looking at the Killick article would realise that the reference to a dose of 1.5 g of levonorgestrel was an obvious slip, and that what was meant was a dose of 1.5 mg. I think that in this part of his evidence, however, Mr Kubba was influenced by his own personal knowledge regarding the dose level tested in the study, probably informed by his having actually attended the presentation and by his reading of the subsequent publication of the detail of the research study. I do not accept that a clinician of the relevant type who read the Killick article would immediately know, and would proceed with confidence on such an understanding, that “1.5 g” of levonorgestrel necessarily meant “1.5 mg”.

However, I do accept that, because (as explained by Mr Kubba) a dose of 1.5 g of levonorgestrel would have been so far out of line with the usual level of dose which such a clinician would be familiar with and would expect, a clinician reading the Killick article would immediately think that there was something highly questionable and likely to be wrong with the amount of the dose stated as part of the single dose regimen. It would have been obvious that the dose amount was suspect, and a clinician wishing to understand what was being reported in the Killick article would have thought that the obviously sensible course would be to get in touch with him (or with those identified as having made the presentation in September 2000) to check on the true amount. Had anyone done this, there is little doubt that he (or they) would have checked with Dr von Hertzen and would have reverted with a correction and the information that the true dose amount for the single dose regimen which was the subject of the research was 1.5 mg of levonorgestrel.

This is relevant to the discussion of obviousness, in particular in relation to steps (3) and (4) in the Pozzoli analysis. As Arnold J held in KCI Licensing Inc v Smith & Nephew Plc [2010] EWHC 1487 (Pat); [2010] FSR 31 at [112] (having reviewed the relevant authorities at [105]-[111]):

“… even if information is neither disclosed by a specific item of prior art nor common general knowledge, it may nevertheless be taken into account as part of a case of obviousness if it is proved that the skilled person faced with the problem to which the patent is addressed would acquire that information as a matter of routine. For example, if the problem is how to formulate a particular pharmaceutical substance for administration to patients, then it may be shown that the skilled formulator would as a matter of routine start by ascertaining certain physical and chemical properties of that substance (e.g. its aqueous solubility) from the literature or by routine testing. If so, it is legitimate to take that information into account when assessing the obviousness of a particular formulation. But that is because it is obvious for the skilled person to obtain the information, not because it is common general knowledge.”

Arnold J’s review of the law, and in particular para. [112], was approved by the Court of Appeal on the appeal in that case: [2010] EWCA Civ 1260; [2011] FSR 8, at [6].

In my view, in the present case, a clinician with the characteristics of the relevant person skilled in the art would immediately have appreciated that the reference in the Killick article to a dose of 1.5 g of levonorgestrel was very likely to be a mistake in the article; that it was very possibly a slip for 1.5 mg; and that it would require to be checked with an obvious available source (Professor Killick or the presenters at the meeting), which would have disclosed that it was indeed a slip and should have stated “1.5 mg”. I think this is properly described as the course which would have been followed to acquire relevant information “as a matter of routine”, within the guidance given in KCI. In any event, it was the obvious course which would have presented itself to the relevant person skilled in the art to obtain information obviously relevant to dealing with the problem to which the Patent is addressed, and is in my view relevant to be taken into account in assessing the case on obviousness.

For step (2) in the Pozzoli analysis, the focus is on the claim made by the patentee: MedImmune Ltd v Novartis Pharmaceuticals UK Ltd [2012] EWCA Civ 1234, [86]-[87]. In this case, there was a dispute about the true interpretation of what the patentee claimed in the Patent. The Defendant argued that the words “for emergency contraception” used in Claim 2 and incorporated by reference in Claim 3 mean that the regimen in fact has to be effective in producing contraception in emergency situations. This was related to the Defendant’s argument, which I have rejected above, that the relevant person skilled in the art would have been a composite including an expert medical statistician. The suggestion, as I understood it, was that since the claim in the Patent is for a dose regimen which is in fact effective, a clinician wishing to understand the teaching in the Patent would have needed to call on the assistance of an expert in medical statistics to confirm the claim that the regimen is indeed effective.

Up to a point, I accept the thrust of the submission of Mr Silverleaf QC for the Defendant regarding the proper interpretation of Claims 2 and 3 in the Patent. The words “for emergency contraception” bear their ordinary meaning as understood by a relevant person skilled in the art, as construed in the context of the whole Patent and having regard to the purpose of the invention: see Virgin Atlantic Airways Ltd v Premium Aircraft Interiors Group [2009] EWCA Civ 1513; [2010] RPC 8 at [5]. The dose regimen covered by the Claims is for the purpose of providing emergency contraception to a level which provides sufficient reasonable assurance that a pregnancy will be avoided after unprotected intercourse to allow it to be recommended clinically for use by a patient.

I did not find at all persuasive the analogies drawn by Mr Acland QC for the Claimant with cases reviewed by Arnold J in Eli Lilly v Janssen Alzheimer Immunotherapy [2013] EWHC 1737 (Pat); [2014] RPC 1 at [190]-[204],in which the words “for treating cancer” were found to mean only “has a beneficial effect in the treatment of cancer” (Bristol-Myers Squibb Co. v Baker Norton Pharmaceuticals Inc [2001] RPC 1), the words “for the curative or prophylactic treatment of erectile dysfunction” were found to mean only that the treatment would work in at least some individuals (Re Pfizer Ltd’s Patent [2001] FSR 16), the words “for the treatment of a non-neoplastic disease or disorder characterised by undesirable excessive neovascularisation” were found to mean only that the treatment would improve the patient’s condition by treating the angiogenic component of the disease from which the patient is suffering (Regeneron Pharmaceuticals Inc v Genentech Inc. [2013] EWCA Civ 93) and the words “a pharmaceutical composition [etc] … for use in preventing or treating a disease characterised by amylid deposit in a patient” were found to mean only that there had been success in a Phase 2 clinical trial (Eli Lilly itself). The meaning given to such claims in those patents simply reflected the particular contexts in which they fell to be construed. For example, clinicians and others would not expect treatments for cancer to be successful, in the sense of securing a high rate of cure of the disease. By contrast, the point of emergency contraception is actually to achieve avoidance of pregnancy with a reasonable degree of confidence. Such an interpretation of the phrase “for emergency contraception” is reinforced by the background understanding given by CGK, namely that there already existed one very highly effective emergency contraceptive procedure (insertion of an IUD) and other somewhat less effective, but still highly effective, forms of pill-based emergency contraception.

In my judgment, against that background, the claim that the new regimen is “for emergency contraception” involves a claim that it will provide a reasonable level of effectiveness in achieving prevention of pregnancies, broadly comparable to other existing treatments which are available for that purpose, such as would make it potentially worthwhile to use it for that purpose, taking into account the other possible benefits associated with its use (such as avoidance of physically intrusive intervention, lesser side effects, greater prospect of successfully finishing the treatment etc). But, on proper interpretation, the claim does not go further than this.

Read in context and bearing in mind the intended addressee of the Patent (a relevant clinician), the words “for emergency contraception” do not carry the connotation of statistically exact correspondence in effect between the proposed one dose regimen using levonorgestrel and the existing two dose regimen. It is common ground that use of an IUD is a form of emergency contraception with a better proven level of efficacy in preventing pregnancy than use of pill-based regimes, so the claim in the Patent that the invention of the one dose regimen using levonorgestrel is “for emergency contraception” could not be taken to be a claim that it is, judged according to rigorous statistical standards of equivalence, equally effective as use of an IUD. Tolerance of some degree of reasonable variance in terms of efficacy in preventing pregnancy as between the new regimen and other existing treatments (both IUD and pill-based treatments) is thus inherent in the proper interpretation of the claim, which supports the interpretation I have arrived at.

Moreover, and again in line with that interpretation, a clinician seeking to use the teaching in the Patent would be concerned with clinical effectiveness of the treatment in a broad, holistic sense, taking into account both the efficacy profile of the proposed new regimen and the benefits it could offer as compared with other treatments for emergency contraception. It might be clinically appropriate to use the new regimen by reason of those benefits, even if it was somewhat less effective than another treatment, provided that – all things considered – it still offered a reasonably high level of assurance that it would work.

Mr Silverleaf’s argument regarding the proper interpretation of the Claims in the Patent therefore does not take him very far. In particular, it does not lead to the conclusion that the relevant person skilled in the art to whom the Patent is addressed should be taken to be a composite including an expert in medical statistics. If anything, consideration of step (2) reinforces the conclusion arrived at under step (1). It does not undermine the points set out under step (1).

The state of the art at the priority date in November 2001 included the CGK about existing methods of emergency contraception, including the two dose regimen using levonorgestrel. It also included the Killick article, which made available to the public information about use of levonorgestrel in an on-going WHO research project including the one dose and two dose regimens and about the interim results obtained from that study: see section 2(2) of the Act. The Killick article included the mis-statement of the dosage of levonorgestrel used in the one dose regimen in the project as 1.5 g rather than 1.5 mg, referred to above.

The inventive concept of the Claims in the Patent involved the one dose regimen based on a 1.5 mg dose, supported by a claim of efficacy in light of the completed WHO study.

As explained above, the mis-statement about the single dose amount in the Killick article would have been obviously doubtful to a relevant person skilled in the art and the means of resolving that doubt (by contacting Professor Killick, as the author or the article, or any of the researchers identified in the article as having made the presentation, to check the position), would also have been obvious. Therefore, I consider that there would have been steps available which were obvious to a person skilled in the art which would have led to correction of the mis-statement of the dose amount for the single dose regimen as stated in the Killick article.

Although there was some debate at the hearing regarding whether there was a prejudice in the CGK against use of a single dose of levonorgestrel for emergency contraception, as discussed in Pozzoli, that seems to me to be inapposite as a way of thinking about the matter in this case. Prior to the WHO research, there was no settled understanding or prejudice among practitioners that a single dose of levonorgestrel would not be effective for emergency contraception. It was simply that the precise mechanism by which levonorgestrel had effect as a contraceptive was unknown, so absent research one could not be sure what dosage regimens might work.

Accordingly, this is more a case that without research into other dose regimens it could not be known whether they would or would not be effective. In my view, therefore, the more helpful guidance is that given in MedImmune at [90]-[93], set out above. The question is, was this a case in which, after the Killick article, it was obvious to investigate the regimen using one dose of 1.5 mg of levonorgestrel within 72 hours after intercourse, on the basis that it would be thought to have a reasonable or fair expectation of success judged in the light of all the circumstances? However, having said this, I do not think that the difference between the approach explained in MedImmune and the approach to cases of prejudice in the CGK explained in Pozzoli is significant in the context of consideration of step (4) in this case.

In my judgment, the report in the Killick article about the WHO research project, as read by a relevant person skilled in the art, made it obvious that use of a single dose of 1.5 mg of levonorgestrel within 72 hours of intercourse was likely to be a viable method of emergency contraception. From that report, it was obvious that such a regimen could be pursued and investigated with a reasonable or fair expectation of success.

The summary of the comments from the floor set out at the end of the article is, in my view, revealing. The persons who attended the presentation are likely to have included clinicians interested in the field of emergency contraception, with the sort of knowledge and understanding comparable to that to be ascribed to the relevant person skilled in the art in this case. The general reaction was immediately to see that use of the one dose regimen was now likely to be a viable form of emergency contraception (indeed, the general view was that this should be the preferred oral method of emergency contraception).

I accept the evidence of Mr Kubba, the only expert clinician called to give evidence in the case, that from the report of the presentation in the Killick article it was obvious to a clinician representing the relevant person skilled in the art that a regimen involving one dose of 1.5 mg of levonorgestrel would be likely to provide an effective treatment for emergency contraception. Even an unimaginative person with relevant clinical expertise would have appreciated that such a single dose regimen was now an obvious candidate in the range of available treatments for emergency contraception.

Looking at the matter more broadly in terms of the kind of contribution to human knowledge that the patent system is intended to incentivise and reward (cf Pozzoli at [25]-[29]), as a cross-check for my conclusion, I consider that the additional research work (finalising the study which was already well advanced as reported at the time of the presentation in September 2000) and additional information (confirmation of the preliminary findings presented in September 2000) were not of the character or extent that one could reasonably describe them as a significant additional contribution to human knowledge such that one would expect them to attract protection in the form of a patent monopoly of exploitation. The possibility of using the single dose regimen involving levonorgestrel for emergency contraception had already been substantively revealed and attested by the extant research findings reported in September 2000 as an obvious likely way forward in the field of emergency contraception, notwithstanding the caveat regarding the need to finish the study mentioned at the end of the Killick article.

I also observe, by way of comment, that the presentation of detailed information in September 2000 was not some kind of slip or unfortunate “own goal” by researchers who were trying to do research to establish a patent. The research study was funded by the WHO, World Bank and UN organisations, with the Defendant public spiritedly providing levonorgestrel and placebo tablets for use in the research. The WHO researchers were carrying out their research for the public benefit, and clearly wished to communicate as much as they reasonably could at their presentation in September 2000 to inform the world about the latest advances in available information about effective emergency contraception treatments.

For the reasons I have given, the challenge to the validity of the Patent on the ground of obviousness succeeds.

Lack of sufficiency

On the basis of my finding on obviousness, the insufficiency challenge does not arise. Mr Acland’s submission on insufficiency in the statement in the Patent was an alternative submission predicated on failure for the Claimant on the issue of obviousness - on which, in the event, it has succeeded. It is sufficient here simply to note that on this alternative ground of challenge to the validity of the Patent, I was impressed by Mr Silverleaf’s submission, supported by authority, that there is a difference between the test for sufficiency of specification in a patent and the test for obviousness, with a lower standard being applicable in relation to the former. That being so, it would by no means necessarily have followed that, if the inventive step specified in the Patent had not been obvious, the Patent must inevitably have failed by reason of insufficiency of specification. As it is, however, it is unnecessary and inappropriate to say anything further about this.

The claim that the Patent is invalid, on grounds of obviousness, succeeds.