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Teva v. Boehringer Ingelheim: Spiriva Inhalation Capsule Patent In Teva UK Ltd. v. Boehringer Ingelheim Pharma GmbH & Co KG, [2015] EWHC 2963 (Pat)(High Court Oct. 21, 2015)(Morgan, J.), the English trial court dealt with the validity of proposed amended claims for inhalation capsules suitable for delivery of the known drug tiotropium bromide (Spiriva) useful for the treatment of chronic obstructive pulmonary disease (COPD). A copy of Judge Morgan’s decision is attached. Regards, Hal

Neutral Citation Number: [2015] EWHC 2963 (Pat)

Case No: HP-2014-000002 IN THE HIGH COURT OF JUSTICECHANCERY DIVISION PATENTS COURT

Royal Courts of Justice, Rolls Building Fetter Lane, London, EC4A 1NL

Date: 21/10/2015

Before :

MR JUSTICE MORGAN

- - - - - - - - - - - - - - - - - - - - - Between :

TEVA UK LIMITED

Claimant

- and –

BOEHRINGER INGELHEIM PHARMA GMBH & CO KG

Defendant

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Mr Daniel Alexander QC and Mr Mark Chacksfield (instructed by Pinsent Masons LLP)

for the Claimant Mr Michael Tappin QC and Mr Douglas Campbell (instructed by Allen & Overy LLP) for

the Defendant

Hearing dates: 7 – 10 and 14- 17 July 2015 - - - - - - - - - - - - - - - - - - - - -

Approved Judgment I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this

Judgment and that copies of this version as handed down may be treated as authentic.

.............................

MR JUSTICE MORGAN

MR JUSTICE MORGAN Approved Judgment

Teva UK Ltd v Boehringer Ingelheim Pharma GMBH & Co KG

MR JUSTICE MORGAN:

The claim in outline

1. The Defendant is the patentee in respect of European Patent (UK) 1 379 220. The patent relates to capsules to be used in a dry powder inhaler for the purpose of delivering a particular active ingredient (tiotropium bromide) to the lung of a patient suffering from chronic obstructive pulmonary disease (“COPD”) or asthma.

2. On 3 June 2014, the Claimant issued a Claim Form seeking a declaration that the patent was invalid and an order for its revocation. The grounds of invalidity put forward were that the subject matter of the patent lacked an inventive step in the light of two pieces of prior art and common general knowledge. It was also said that: (1) certain integers in the claims were arbitrary; (2) there was no disclosure in the patent to suggest that the claimed capsules possessed any technical benefits or solved any technical problem; (3) there was no data in the patent to make it plausible that the claimed capsules solved any technical problem; and (4) the patent did not disclose the invention clearly enough to enable it to be performed by a skilled person. The Defence denied these allegations.

3. On 19 February 2015, the Defendant applied for permission pursuant to section 75 of the Patents Act 1977 (“the 1977 Act”) to amend the claims in the patent. The proposed amendments were extensive resulting in the Defendant putting forward 11 new claims. The amendments to the claims were sought unconditionally and it was stated that the Defendant would not contend that the original claims were valid, although the Defendant made no formal admission on that point.

4. The Claimant served notice of opposition to the proposed amendments to the claims. The opposition focussed on the new claims 5 to 11. It was said that “at least” claims 5 to 11 would be invalid. The grounds of invalidity were essentially the same as the grounds put forward by the Claimant in relation to the original claims (although the Claimant now relied on three pieces of prior art). Further, in relation to the new claim 6, it was said that the claim involved added matter. The Claimant then stated that it would not put forward a positive case of invalidity in relation to new claims 1 to 4 although it believed that those claims would also be invalid.

5. On 17 June 2015, the IPO responded to the application to amend the claims. It stated that it did not wish to be represented at the trial unless the court so directed. I did not direct it to appear at the trial. The IPO considered that claims 1 and 5 would not be allowable under sections 14(5) and 76 of the 1977 Act because they were unsupported, lacked clarity and added matter. The IPO did not refer to claim 6.

6. The trial of this action began on 7 July 2015. On 9 July 2015, the Defendant made an amended application to amend the claims in the patent. The Defendant continued to rely on its original application to amend the claims but it added conditional applications to amend. The further amendments were to introduce claim 6A or claim 6B. The application to introduce claim 6A was made in the event that claim 6 was not allowed. The application to introduce claim 6B was made in the event that claim 6 and claim 6A were not allowed.



7. The trial proceeded. As foreshadowed in its notice of opposition, the Claimant did not address claims 1 to 4 but focussed on claims 5 and 6 and claims 6A and 6B, to the extent that claims 6A and 6B raised the same issues as claims 5 and 6. By the end of the trial, the Claimant had not served a response to the amended application to introduce claims 6A and 6B. The IPO took no part in the trial although its response to the Defendant’s revised application to amend (made on 9 July 2015) was awaited. By the last day of the trial, the parties had not received a response from the IPO to that application. The parties then submitted to me the following:

(1) I should adjourn further consideration of amended claim 1 (and the claims dependent upon it) to allow the Defendant to file evidence to deal with the points raised in relation to it, unless I considered that the point could be summarily decided in favour of the Defendant;

(2) I should not finally decide the issues in relation to claims 6A and 6B and the matter should be further considered following any response from the IPO.

8. At the end of the trial, I reserved my judgment. I was later supplied with a letter dated 4 August 2015 from the IPO in response to the application to introduce claims 6A and 6B. The IPO stated that it considered that:

(1) claim 6 was clear, supported by the description and did not add matter;

(2) claim 6A also was clear, supported by the description and did not add matter;

(3) claim 6B was not clear, was not supported by the description across its full scope and added matter; and

(4) claims 6, 6A and 6B were dependent on claim 5 and because claim 5 was not allowable, for the reasons given by the IPO on 17 June 2015, the dependent claims 6, 6A and 6B were also not allowable.

9. Given the procedural background described above, this judgment deals with claims 5 and 6 and claims dependent on those claims. I will not determine the issues in relation to claim 1 and claims dependent on it. As to claims 6A and 6B, I will not formally determine the issues in relation to them but I consider that my conclusions in relation to claims 5 and 6 might be regarded by the parties as having an important bearing on the conclusion which I should reach in relation to claims 6A and 6B also. As to the legal basis for the challenge to the various claims, this judgment will focus on the questions as to whether the claims involve an inventive step and whether integers said to characterise the claims are arbitrary.

COPD

10. COPD is a diagnosis given to a person with narrowed bronchi i.e. the airways within the lungs. This narrowing is commonly caused by cigarette smoking, although it can result from other causes. Most COPD sufferers have a combination of chronic bronchitis, acute bronchitis and emphysema. The chief symptoms are cough, sputum production, breathlessness with wheeze and infective exacerbations. Together these cause disability, impaired health status and reduced quality of life. The severity of COPD is measured by spirometry, the frequency of exacerbations and the severity of



symptoms. Spirometry involves measuring the volume of air that can be expired by the patient either in one second (forced expiratory volume) or in total (forced expiratory capacity). COPD is very common, especially in patients who are over the age of 50. Rough estimates as to the prevalence of COPD in the United Kingdom population are 10 – 50 per 1,000 and as to the rate of mortality attributable to COPD are 20 – 60 per 10,000.

Asthma

11. Like COPD, asthma is a respiratory disease involving the narrowing and inflammation of the airways of the lungs. The main symptoms are breathlessness, wheeze, chest tightness and cough. The symptoms can be acute and/or chronic. The symptoms are caused by a combination of contractions of the muscles surrounding the airways, known as bronchospasm, and also inflammation of the airways which causes swelling of the airway wall and blockage by inflammatory sections.

An earlier patent

12. I was told that the preparation of tiotropium bromide was the subject of European Patent EP 0 418 716. Professor Birchall exhibited an English translation of this patent but the translation did not disclose the identity of the patentee nor the date of grant nor the priority date. I assume that the patentee was the Defendant or an associated company. I was told that the Defendant has a supplementary protection certificate in relation to this patent. The certificate (if valid) expires in March 2016. There is a dispute as to the validity of this certificate but I am not asked to resolve that dispute. I did not receive any submissions as to the significance, if any, of this patent to the present dispute but I note that the description of the compounds which are the subject of this patent refers to them being novel compounds capable of use as active ingredients in medicaments. The description also states that the compounds are strong anti-cholinergic agents which have prolonged action, with toxicity in the same range as the commercial product ipratropium, but with a stronger therapeutic effect. The description stated that the compounds are suitable for the treatment of chronic obstructive bronchitis and slight to moderately severe asthma. The patent referred to the compounds being administered in a number of ways which included administration as inhalation powders in conventional inhalation apparatus.

The patent in suit

13. The patent in suit is European Patent (UK) 1 379 220 granted to the Defendant on 29 December 2004 with a filing date of 27 May 2002. The language of the patent is German although the claims are in German, English and French. I have been provided with an English translation of the patent which is agreed to be accurate. I need to mention a small point about the spelling of “gelatine” or “gelatin”. The English

translation of the patent refers to “gelatine”. Conversely, the experts in this case

referred to “gelatin”. As the patent uses the former spelling of the word, in order to avoid confusion that is the spelling I will adopt in this judgment (except where I am quoting verbatim a passage which uses the alternative spelling).

14. The description in the patent stated:



“The invention relates to capsules for inhalation (inhalettes) consisting of specific capsule materials with a reduced moisture content, which contain the active substance tiotropium in the form of powdered preparations and are characterised by increased stability.”

15. The description then referred to the background to the invention. It referred to tiotropium bromide, said to be known from the application for patent EP 0 418 716, and then stated:

“Tiotropium bromide is a highly effective anticholinergic with

a long-lasting effect, which may be used to treat respiratory complaints, particularly COPD (chronic obstructive pulmonary disease) and asthma. By tiotropium is meant the free ammonium cation.”

16. The description then stated that for COPD and asthma it was convenient to administer the active substance by inhalation and, in particular, by administration in the form of inhalable powders containing the active substance. The description then referred to the use of an excipient with the active substance and, in order to achieve a high degree of stability, the need to ensure that the content administered remained reproducibly constant. Then it stated:

“The aim of the invention is to prepare capsules for inhalation containing an inhalable powder which contains tiotropium, which guarantees sufficient stability of the active substance.”

Further aims of the invention were stated to be that: (1) the active substance was released with a high metering accuracy; (2) the capsule would be completely emptied in the course of administration; and (3) the capsule would have good perforation qualities with good stability and low brittleness for use in inhalers.

17. The description then stated that “surprisingly” the problems set out above were solved

by the capsules the subject of the invention and continued:

“The capsules for inhalation (inhalettes) according to the invention are capsules which contain, as the inhalable powder, tiotropium mixed with a physiologically acceptable excipient, characterised in that the capsule material has a reduced moisture content.

The concept of a reduced moisture content within the scope of the present invention is defined as being equivalent to a TEWS moisture level of less than 15%.”

18. The description then defined what was meant by a TEWS moisture level and the possible use of a halogen drier but it is not necessary to set out those matters. The description then continued:



“Preferred capsules for inhalation according to the invention

have a TEWS or halogen drier moisture content of less than 12%, particularly preferably ≤10%.”

19. The description then referred to the capsule material and stated:

“By capsule material is meant, within the scope of the present

invention, the material from which the shell of the capsule for the inhalation is made. The capsule material is according to the invention selected from among gelatine, cellulose derivatives, starch, starch derivatives, chitosan and synthetic plastics.”

20. The description then dealt separately with some of these capsule materials. In the case of gelatine, it was stated that gelatine might be used in admixture with various plasticisers, including polyethyleneglycol (“PEG”) and the preferred amounts of PEG

were stated. The description then referred to capsules made of cellulose derivatives and stated:

“If cellulose derivatives are used as the capsule material, it is

preferable to use hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose. In this case, hydroxypropylmethylcellulose (HPMC), particularly preferably HPMC 2910 is used as the capsule material. When cellulose derivatives are used as capsule materials the level of the TEWS or halogen drier moisture content is preferably less than 8%, particularly preferably less than 5%. Most preferably, capsules for inhalation consisting of cellulose derivatives are dried to a TEWS or halogen drier moisture content of less than 4%, particularly less than 2%, before being filled with inhalable powder containing tiotropium.”

The description then referred to synthetic plastics being used as the capsule material. With those materials, the level of TEWS or halogen drier moisture content was optionally less than 3% and optionally less than 1%.

21. The description then stated that after the capsules were prepared as described earlier, they were to be produced by methods known from prior art and then filled with the inhalable powder containing tiotropium by methods known from prior art. The description stated that if the capsules did not already have a suitably reduced moisture content as a result of their storage or production then they should be dried before being filled with the inhalable powder. This drying was to be done until the moisture level corresponded to the specification of not more than 15% TEWS.

22. The description then contained details as to the tiotropium content in the inhalable powder and as to the form in which tiotropium was to be used; crystalline tiotropium bromide monohydrate was preferred.

23. Next, the description dealt with the excipient and its form and content. Examples of physiologically acceptable excipients included glucose and lactose. Lactose was the particularly preferred excipient, preferably in the form of lactose monohydrate. The



description then referred to the types of inhalers which might be used by reference to inhalers described elsewhere.

24. The description then dealt with further details as to the inhalable powder and referred again to the capsules being dried before filling with the inhalable powder to the maximum permissible level of TEWS. The description then added:

“In another preferred embodiment of the invention, the capsules for inhalation are filled with the inhalable powder containing tiotropium bromide obtained by the above process and then subjected to the dryness process described as follows.”

What followed was a detailed description of a drying process for “filled capsules”.

25. The description then continued by giving details as to the choice of tiotropium salt, and as to the preparation of the tiotropium and the excipient for use in the inhalable powder. There followed seven examples of what was involved. Some of the examples referred to the moisture content of the capsule. Examples 2 and 3 referred to a gelatine capsule with a moisture content of 9%. Example 4 referred to a HPMC capsule with a moisture content of <2%. Examples 5 and 6 referred to a polyethylene capsule with a moisture content of <1%. Example 7 referred to a gelatine capsule. The example did not specify an initial moisture content (unlike Examples 2 to 6) but then referred to the moisture content being adjusted to about 8.7% by using a procedure which plainly was the procedure, described in more detail earlier in the description, for a drying process for filled capsules.

26. The parties did not agree on one point as to the interpretation of the description in the patent. The Defendant submitted that the patent described two alternative approaches to drying the capsules. The first approach was to dry the capsule before it was filled; this approach was adopted if the capsule had a moisture content above the maximum permissible moisture content specified for the relevant capsule material in the patent. The second approach was an alternative to the first approach. The second approach involved drying the capsule after it had been filled. The Claimant agreed that the patent described the first approach but an expert witness for the Claimant, Professor Buckton, had proceeded on the basis that the second approach described in the patent involved the capsule being dried twice, once before it was filled and then, if necessary, after it was filled. My interpretation of the description accords with the Defendant’s reading of it. The second approach only involves the capsule being dried

once, that is, after it is filled. The second approach is an alternative to the first approach and is not a requirement to be complied with in addition to adopting the first approach.

27. The patent originally contained 16 claims. As the Defendant has now applied unconditionally to amend all of the claims so as to replace them with 11 claims, it is unnecessary to refer to the original claims in any detail. I will summarise the original claims by saying:

(1) claims 1 to 13 referred to “capsules” whereas claims 14 to 16 referred to the use

of capsules;



(2) claim 1 was a general claim for a capsule for inhalation with an inhalable powder of tiotropium mixed with any physiologically acceptable excipient characterised in that the capsule material had a moisture content of less than 15%;

(3) claim 2 stated that the capsule material could be a range of different materials including gelatine, cellulose derivatives and synthetic plastics;

(4) claims 5 and 6 referred to the capsule material being a cellulose derivative with a moisture content of less than 8% particularly preferably ≤5%.

28. At this point, I will draw attention to what the specification did not deal with. There was little or no technical information about capsule materials. It appears that a very wide range of capsule materials had been identified. The specification did not refer to any tests in relation to capsule materials and therefore did not discuss the results of any tests. The specification suggested that the benefits of the claimed inventions were available with gelatine as a capsule material where the gelatine is in its natural state (typically about 13% to 15% moisture). There was evidence that the average moisture content of HPMC capsules was in the range of 2% to 5%. The specification referred to cellulose capsules dried to less than 4% or preferably less than 2%. The range of moisture content from less than 4% down to 2% or more would therefore include nearly all HPMC capsules, even before drying. Conversely, there was also some evidence that the average moisture content of HPMC capsules was 4% to 6%. If that evidence were reliable, then to achieve a moisture content of less than 4% would seem to require drying. There is no demonstration in the specification that the various combinations of materials provided any particular level of physical or chemical stability, ease of piercing of the capsule or extent of drug release upon piercing and inhalation.

The proposed amended claims

29. The Defendant does not seek to defend the validity of the original claims. Instead the Defendant seeks to amend those claims by replacing them with 11 new claims. The proposed amended claims 1 to 9 refer to capsules and claims 10 and 11 refer to the use of capsules.

30. The proposed amended claim 1 is:

“1. Capsules for inhalation which contain as the inhalable powder tiotropium in admixture with a physiologically acceptable excipient, characterised in that the capsule material used is gelatine in admixture with polyethyleneglycol (PEG) 3350 in an amount of 1-10 wt. -%, preferably 3-8%, and has a reduced moisture content as a TEWS or halogen drier moisture content of ≤10% and in that the physiologically acceptable

excipient is lactose.”

31. Claim 2 refines claim 1 by specifying the amount of tiotropium in the powder. Claim 3 refines claim 2 by specifying details of the excipient. Claim 4 refines claim 3 by referring to the possible salts of tiotropium.

32. The proposed amended claims 5 and 6 are:



“5. Capsules for inhalation which contain as the inhalable powder tiotropium in admixture with a physiologically acceptable excipient, characterised in that the capsule material is the cellulose derivative hydroxypropylmethylcellulose and has a reduced moisture content as a TEWS or halogen drier moisture content of ≤5% and in that the physiologically

acceptable excipient is lactose.

6. Capsules for inhalation according to claim 5, characterised in that the capsule material has a TEWS or halogen drier moisture content of less than 2%.”

33. Claim 7 refines claims 5 and 6 by specifying the amount of tiotropium in the powder. Claim 8 refines claim 7 by specifying certain matters in relation to the excipient. Claim 9 refines claim 8 by referring to the various tiotropium salts.

34. Claim 10 refers to the use of capsules in accordance with claims 1 to 9 for preparing a medicament for inhalation. Claim 11 refers to use in accordance with claim 10 for the treatment of asthma or COPD.

The alternative amended claims

35. In view of the Claimant’s stance in relation to the proposed amended claims 5 and 6, which I have earlier described, the Defendant has in the alternative to its primary case proposed two further versions of claim 6 in these terms:

“6A. Capsules for inhalation according to claim 5,

characterised in that the capsule material has a TEWS or halogen drier moisture content of less than 2% when empty.

6B. Capsules for inhalation according to claim 5, characterised in that the capsule material has a TEWS or halogen drier moisture content of less than 2% before being filled with the inhalable powder containing tiotropium.”

36. The Defendant seeks permission to amend to include claim 6A but only if it is not allowed to amend to include claim 6. It seeks permission to amend to include claim 6B but only if it is not allowed to amend to include claim 6, alternatively claim 6A.

The principal challenge – obviousness

37. When making submissions on the law, the parties referred to the statutory provisions in the 1977 Act, rather than to the provisions of the European Patent Convention. It was not suggested that there could be any difference if one directly applied the Convention. Accordingly, I will follow the approach adopted by the parties and refer to the 1977 Act rather than to the Convention.

38. Section 1(1)(b) of the 1977 Act provides that a patent may be granted only for an invention which, amongst other things, involves “an inventive step”. Section 3 of the

1977 Act then 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 (and disregarding section 2(3) above).”

39. There is a considerable amount of case law as to how a court should go about its application of section 3 in a particular case. In Windsurfing International Inc v Tabur Marine (Great Britain) Ltd [1985] RPC 59, the Court of Appeal identified a structured approach to the application of the section. This structured approach was then elaborated and restated in Pozzoli SPA v BDMO SA [2007] FSR 37 by suggesting that it would be helpful to the court to pose for itself the following questions (see at [23]:

“(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?”

40. The Pozzoli questions were further discussed in Actavis UK Ltd v Novartis AG [2010] FSR 18. In that case, Jacob LJ also referred to the “problem and solution

approach” (“PSA”) used in the EPO both for examination and opposition, which was in these terms (taken from paragraph 11.7 of the EPO’s Guidelines for Substantive

Examination):

“11.7 Problem-and-solution approach

In practice, in order to assess inventive step in an objective and predictable manner, the examiner should normally apply the so-called ‘problem-and-solution approach’.

In the problem-and-solution approach, there are three main stages:

(i) determining the ‘closest prior art’,

(ii) establishing the “objective technical problem” to be solved,

and



(iii) considering whether or not the claimed invention, starting from the closest prior art and the objective technical problem, would have been obvious to the skilled person. ”

41. As was pointed out in Actavis v Novartis at [35], the PSA does not cope particularly well where the claimed invention involves perceiving that there is a problem or in appreciating that a known problem can be solved.

42. It has been repeatedly stressed in the case law that 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. More recent statements to this effect are to be found in MedImmune v Novartis [2013] RPC 27 at [93] per Kitchin LJ and at [178] – [182] per Lewison LJ and in Novartis AG v Generics (UK) Ltd [2012] EWCA Civ 1623 at [56] per Kitchin LJ and at [76] per Lewison LJ.

43. Notwithstanding the statements referred to in the last paragraph, I ought to refer to three particular matters which can arise in the application of section 3 of the 1977 Act. The first relates to the identity of the “person skilled in the art”, the second relates to what is involved in the common general knowledge of the skilled person and the third relates to the question of whether the claimed invention is “obvious” when it would

have been obvious to try out the alleged inventive step.

44. As to the identity of the person skilled in the art, it is clear that one is entitled to assemble a notional team of skilled people who have different skills. It is also now clear that although the law involves references to a person skilled in the art when considering the scope of a patent, the sufficiency of a patent and the obviousness of a claimed invention, the skilled team may be different depending on the nature of the question posed to such a team. This is fully explained in Schlumberger Holdings Ltd v Electromagnetic Geoservices AS [2010] RPC 33 at [30] to [70]. The choice of the skilled team can be influenced by the fact that when one is considering the scope or sufficiency of a patent, one takes the patent as granted but when one is considering obviousness, one considers common general knowledge and prior art as they were before the patent was granted. As regards the composition of the skilled team for the purpose of considering obviousness, Jacob LJ said in Schlumberger at [65]:

“65 In the case of obviousness in view of the state of the art, a

key question is generally “what problem was the patentee

trying to solve?” That leads one in turn to consider the art in

which the problem in fact lay. It is the notional team in that art which is the relevant team making up the person skilled in the art. If it would be obvious to that team to bring in different expertise, then the invention will nonetheless be obvious. Likewise if the possessor of the “extra expertise” would

himself know of the other team's problem. But if it would not be obvious to either of the notional persons or teams alone and not obvious to either sort of team to bring in the other, then the invention cannot fairly be said to be obvious. As it was put in argument before us the possessors of the different skills need to be in the same room and the team with the problem must have



some reason for telling the team who could solve it what the problem is.”

45. The concept of the common general knowledge of the skilled person is elaborated in the judgement of Arnold J in KCI Licensing Inc v Smith & Nephew plc [2010] FSR 31 at [105] to [112] which was approved by the Court of Appeal in the same case: see [2011] FSR 8 at [6].

46. As to whether it is helpful to ask whether it would have been obvious to try to take a particular step to address a known problem, the law on that question is set out in MedImmune v Novartis [2013] RPC 27 at [90] to [93] per Kitchin LJ and at [179] to [186]; see also Novartis AG v Generics (UK) Ltd [2012] EWCA Civ 1623 at [55] and Regeneron Pharmaceuticals Inc and Bayer Pharma AG v Genentech Inc [2013] RPC 28 at [86]. I have also noted what was said about the necessary degree of expectation of success in Teva UK Ltd v Leo Pharma A/S [2015] EWCA Civ 779 (see at [32] – [33]), which was decided on 28 July 2015 after I reserved judgment.

The skilled team

47. The parties are agreed that for the purpose of considering the obviousness of the claimed invention in this case, I should approach that question through the eyes of a skilled team consisting of, at least, a clinician and a formulation scientist. The Defendant also submits that the skilled team should include a regulatory expert. The Claimant does not agree that the skilled team should include a regulatory expert although it accepts that its skilled team of a clinician and a formulation scientist would have access to advice on regulatory matters. I will defer considering this question until later in this judgment.

48. Although the parties are agreed that the relevant skilled team should include a clinician, there emerged at the trial some difference of view as to the level of skill expected of that clinician. I will defer consideration of that question until I have made my findings based on the evidence of Professor Geddes, an expert clinician called by the Claimant; the Defendant did not call a clinician expert.

The clinician in the skilled team

49. In relation to the information available to the clinician in the skilled team the Claimant relies on two pieces of prior art, referred to as Maesen 1995 and Barnes 2001. However, more generally, the Claimant contends that at the priority date of 1 June 2001, the clinician in the skilled team would have available certain common general knowledge as to the possibility of developing tiotropium bromide for the treatment of COPD. This common general knowledge was said to be derived from a number of sources which included Maesen 1995 and Barnes 2001 and, accordingly, I will consider the case as to the alleged common general knowledge of a clinician as at 1 June 2001 before considering the position as to the alleged prior art.

50. The Claimant called Professor Duncan Geddes to support its case as to the common general knowledge of a clinician. The Defendant instructed Professor Peter Calverley to address that topic. Each of Professor Geddes and Professor Calverley prepared two reports. Professor Calverley’s reports indicated certain areas where he disagreed with Professor Geddes. I was invited to read all four of these reports as part of my pre-



reading and I did so. In the event, Professor Geddes gave oral evidence and he was cross-examined but Professor Calverley was not called to give evidence. The Defendant accepted that his two reports were not part of the evidence before me. However, it will be necessary for me to refer to some of the points made by Professor Calverley because those points were dealt with by Professor Geddes either in his responsive report or in cross-examination.

51. Professor Geddes is a distinguished and highly experienced clinician. There was discussion as to his level of skill and how that compared with the skill of the average skilled clinician in the skilled team. Professor Calverley had in his reports divided clinicians into various groups. He referred to general practitioners and to hospital doctors, all treating patients with COPD; he then divided hospital doctors into a number of groups but in particular two groups where the distinction was between specialists in respiratory medicine who did not take an interest in academic research and specialists in respiratory medicine who did take such an interest. Professor Geddes did not accept this division into two groups of specialists in respiratory medicine; he thought that all such specialists would take an interest in academic research in the area of their specialism. I accept Professor Geddes’ evidence on this

point. Professor Calverley’s suggestion was not supported by any evidence from him and I find Professor Geddes’ evidence on the point entirely convincing. I also accept

his evidence that there were at the relevant time hundreds of hospital doctors who specialised in respiratory medicine. Professor Calverley’s reports had identified

another group of clinicians who specialised in respiratory medicine and who worked as consultants for the pharmaceutical industry. He suggested that there were four or five such people in the United Kingdom at the relevant time. He said that these were the most skilled of the specialists in respiratory medicine. He was in that group and he suggested that Professor Geddes was too. Professor Geddes explained, and I accept, that he was not in that group because he did not act as a consultant for the pharmaceutical industry. However, he did accept that his level of skill placed him in the top ten in the United Kingdom at the relevant time of specialists in respiratory medicine. He did not accept that the group to which Professor Calverley referred was limited to as few as four or five people but he accepted that the members of such a group were “super-skilled”.

52. In his report, Professor Geddes attempted to describe his instructions as to the characteristics of the hypothetical skilled clinician whom he should consider. There was argument at the trial as to what these characteristics truly were and it was suggested that Professor Geddes had not been properly instructed and had addressed himself to the knowledge of a clinician who was considerably more skilled that the average skilled clinician whom he should have been considering. I will leave that question over until I further consider the evidence which Professor Geddes gave as to common general knowledge.

53. In his report, Professor Geddes described what was involved in the trials of new drugs. He referred to the standard Phases I, II and III for such trials. This was relevant because tiotropium bromide had, as the literature demonstrated, successfully gone through Phase III trials prior to 1 June 2001.

54. Professor Geddes then described what was involved in COPD and the recognised treatments at the relevant time for COPD. I accept his evidence on those matters. Professor Calverley’s reports suggested some qualifications of Professor Geddes’



views but they were limited and in any event they were not supported by evidence from Professor Calverley. Professor Geddes referred to the anti-cholinergics which were available for prescription in 2001, namely, oxitropium and ipratropium and then stated at paragraph 5.12 of his first report:

“… at June 2001, tiotropium bromide was also known to be a

promising new anti-cholinergic in late stage development. It was understood to have a longer duration of action than oxitropium and ipratropium, in the region of 24-36 hours, and was anticipated to provide a significant advance in the treatment of COPD.”

55. Professor Geddes explained in detail his reasoning which led him to make the above statement. In particular, he referred to the literature in the period prior to 1 June 2001 which would have informed the reader as to the development of tiotropium bromide as a drug to be used in the treatment of COPD. He referred to papers by Maesen and others in 1993 and 1995, to a paper by O’Connor and others in 1996, to studies by Littner and others in 2000, by Van Noord and others in April 2000 and by Casaburi and others in November 2000. Professor Geddes also referred to disclosures as to tiotropium bromide as a treatment for COPD at professional society conferences and in the abstracts of papers at those conferences. He also referred to a number of review articles including Barnes 2001. His conclusion was expressed at paragraph 5.33 of his first report in these terms:

“The skilled clinician asked by a pharmaceutical company in

June 2001 to advise it on promising or useful avenues to pursue for the treatment of COPD and asthma would undoubtedly have advised that tiotropium bromide was a promising drug in late stage development which would be well worth taking forward. Although they would not address detailed questions of formulation, the skilled clinician would discuss with the company drug delivery and know that it was delivered by a dry powder inhaler using capsules containing 18 μg of tiotropium bromide and (as the skilled clinician would know was common) a lactose carrier.”

56. In his second report, at paragraph 4.2, Professor Geddes stated:

“Furthermore, although it is certainly true that there is a range

of interests in new medications among those active in the area, I have no doubt that any COPD specialist clinician asked to consider what products for COPD merited taking forward, would have identified tiotropium as the, or certainly one of the, leading candidates on the basis of the work that had already been done and published on it.”

57. Professor Geddes was cross-examined in detail about the literature to which he referred in his report. He was quite properly asked about the detailed contents of that literature, how far it went, how reliable it was and what the appropriate reaction to it should have been. He was also asked about the membership of the various specialist societies in the United Kingdom, in Europe and in the United States of America. He



was asked about the readership of the various journals and other publications and about attendances at conferences. It was clear that Professor Geddes reads a large number of journals and attends many conferences and applies himself diligently to many abstracts. It was also clear that the state of Professor Geddes’ knowledge and

understanding of the relevant matters was, and is, in advance of the knowledge and understanding of a more average or typical clinician who specialises in respiratory medicine. It was suggested to him that he could only speak about his own awareness of relevant matters and not about the awareness of the average skilled specialist clinician. It was also suggested that he had not considered the position of the average skilled specialist clinician at all as he had considered only the type of specialist who is a consultant to a pharmaceutical company and such a person would be super-skilled as well as being innovatory and imaginative.

58. I accept that Professor Geddes was more skilled and better informed than the notional average skilled clinician specialising in respiratory medicine at the relevant time. However, I do not accept the other suggestions about the basis of the evidence which he gave. Professor Geddes was in no doubt that any skilled clinician specialising in respiratory medicine would have had the knowledge and would have formed the opinion which he described in his reports. Further, when cross-examined, he was asked about the type of presentation which a skilled clinician would give to his colleagues at a hospital clinic in relation to prospects in COPD. He said that if such a clinician had been presenting to colleagues in 2000, he would be aware of the clinical information in the literature and would be able to say not only that tiotropium bromide exists but that it was beginning to show promise.

59. Professor Geddes was also asked about other literature on COPD which did not mention tiotropium bromide and, indeed, literature which discussed other possible treatments for COPD. I accept his evidence when he said, both in his reports and in cross-examination, that the emergence of tiotropium bromide was part of the common general knowledge of the specialist in respiratory medicine because a new drug to treat COPD was rare and when such a drug was identified as a possibility it was welcomed with a high level of interest. I further accept his evidence that such a specialist would have viewed the possibility with a degree of optimism and would certainly not have dismissed the possibility. I also accept his evidence that what was known about tiotropium bromide in June 2001 showed that it was an important advance on ipratropium which was otherwise considered to be a useful drug and was indeed widely used.

60. Professor Geddes was asked about the process he undertook when he carried out a literature search in around 2015 in order to collect the literature which would have been available as at 1 June 2001. I do not think that anything which he did then, nor anything which was provided to him by the Claimant’s solicitors, calls into question any of his conclusions on the matters described above.

61. I think it likely that Professor Geddes was not given precise and clear instructions as to the level of skill assumed to be possessed by the notional skilled person in the art. However, taking his evidence as a whole, I consider that I am able to make findings as to the common general knowledge of the hundreds of specialists in respiratory medicine, working in hospitals treating patients with COPD, in relation to tiotropium bromide as at 1 June 2001. Accordingly, it is not necessary to consider whether the notional skilled person in the art would have a higher level of skill or a greater degree



of knowledge than such specialists. In the findings that follow when I refer to the skilled clinician I am referring to a person with the skills and knowledge of the hundreds of specialists referred to above.

62. In summary, based on the evidence of Professor Geddes, I find that:

(1) as at 1 June 2001, tiotropium bromide was known by skilled clinicians to be a promising new anti-cholinergic drug in late stage development and those clinicians understood that it was likely to have a longer duration of action than oxitropium and ipratropium, in the region of 24-36 hours, and those clinicians would anticipate that it would provide a significant advance in the treatment of COPD;

(2) if a skilled clinician were asked by a pharmaceutical company in June 2001 to advise it on promising or useful avenues to pursue for the treatment of COPD and asthma, the skilled clinician would have advised that tiotropium bromide was a promising drug in late stage development which would be well worth taking forward; although the skilled clinician would not address detailed questions of formulation, he would know that tiotropium bromide could be delivered by a dry powder inhaler using capsules containing 18 μg of tiotropium bromide and a

lactose carrier;

(3) a skilled clinician asked to consider what products for COPD merited taking forward, would have identified tiotropium as the, or certainly one of the, leading candidates.

63. In view of my findings as to the common general knowledge of the clinician in the skilled team, it is not necessary to analyse separately the case as to prior art as to tiotropium bromide based on Maesen 1995 and Barnes 2001.

64. I have made the above findings as to the common general knowledge of the clinician in the skilled team without mentioning a number of statements about the Defendant’s

drug, Spiriva, which appeared in the media (and not just in the technical literature) prior to 1 June 2001. The background to these statements is that prior to that date, the Defendant was developing Spiriva and promoting it, in particular, for treatment of COPD. Spiriva was a drug where the active ingredient was tiotropium bromide and the excipient was lactose and the drug was to be administered by a dry powder inhaler using a capsule made of gelatine. I was provided with a number of statements in the media concerning Spiriva. I will refer to the more important of them.

65. On 2 September 2000, Associated Press International (“API”) circulated a statement

about Spiriva extolling its virtues as a treatment for COPD and quoting a clinician at a hospital in Boston, USA, and a statement by Professor Paul Jones of St. George’s

Hospital Medical School in London; the latter described Spiriva as “a significant step

forward”. The API statement was reported in a number of newspapers or journals

internationally. By December 2000, the Defendant was in discussions with Pfizer over the marketing of Spiriva. This was picked up by the Financial Times which stated that Spiriva was expected to become a “blockbuster”. By April 2001, the Defendant had satisfactorily concluded arrangements with Pfizer. This was announced on 11 April 2001 and the announcement was reported in the Financial Times of 12 April 2001; the reference to Spiriva being a blockbuster was repeated. The future marketing of



Spiriva was announced by Pfizer in financial information it provided to the press later in April 2001. Finally, on or about 3 May 2001, the Defendant held its annual press conference to announce its financial results. A report of that conference stated that talk was dominated by Spiriva and the report described the drug and its prospects in further detail stating that interest in the drug was high and making predictions of substantial sales. Based on this material, I find that there was prior to 1 June 2001 a wide dissemination (far beyond the world of clinicians specialising in respiratory medicine) of information about the imminent future use of tiotropium bromide as a drug to be used in the treatment of COPD.

The formulation scientist

66. Both parties agree that the skilled team in this case would include a suitably qualified formulation scientist. Of course, a formulation scientist would only be relevant if someone wanted to formulate a possible active ingredient. I have already held that, as at 1 June 2001, the common general knowledge of a skilled clinician, any one of the hundreds of specialists in respiratory medicine who treated patients with COPD, would consider that tiotropium bromide showed promise as a drug for treating such patients, where such a drug was expected to provide benefits not available from pre-existing treatments. In those circumstances, it would be relevant to ask a formulation scientist for advice on formulating such a drug for administration to a patient with COPD.

67. On the questions of what a formulation scientist would already know and what he would advise when asked to formulate tiotropium bromide for administration to patients with COPD, I received a substantial body of expert evidence. The Claimant called Professor Graham Buckton and the Defendant called Professor James Birchall. Professor Buckton and Professor Birchall prepared three reports each. I was also provided with a report from Professor Graham Higson on regulatory matters and, indeed, Professors Birchall and Buckton also dealt with regulatory matters in their reports. Each of these three experts gave oral evidence and was cross-examined. Each of them was well qualified to give the evidence which he gave. This expert evidence ranged widely over a number of topics and there were many points on which the experts disagreed. However, before identifying and attempting to resolve these disagreements, I will start by setting out broad areas of agreement between the experts. Where there is a broad area of agreement and that area of agreement is sufficient for me to make progress in deciding the ultimate issue between the parties, I will not explore each and every suggested qualification of that broad area of agreement if it will not affect the ultimate outcome of this dispute.

68. There did not appear to me to be any real difference between the parties as to the level of skill and expertise of the formulation scientist in the notional skilled team.

69. In principle, there would be various ways of administering tiotropium bromide to a patient with COPD. There were three main established methods of delivering active ingredients by inhalation. These methods involved the use of a nebuliser or a pressurised metered dose inhaler or a dry powder inhaler. It was not unusual to select a dry powder inhaler as the method of delivery of an active ingredient by inhalation. There would be nothing innovative or imaginative in selecting a dry powder inhaler in order to deliver tiotropium bromide to a patient with COPD.



70. As at 1 June 2001, there were various kinds of dry powder inhaler readily available. There would be nothing innovative or imaginative in selecting a particular inhaler for the purpose of administering tiotropium bromide to a patient with COPD.

71. A formulation scientist would have to give careful attention to the mode of preparation of tiotropium bromide for use in a dry powder inhaler. For that purpose, such a scientist would use the common general knowledge available to the notional skilled formulation scientist.

72. The experts referred to a number of excipients which might, in principle, be considered to be a suitable excipient to be mixed with tiotropium bromide for this purpose. In particular, the experts considered lactose and glucose. Professor Buckton stated that the most frequently used carrier as at 1 June 2001 was lactose. Professor Birchall agreed that lactose was commonly used for the purpose of mixing with active ingredients for use in dry powder inhalers. However, he also stated that the formulation scientist would know that the only anti-cholinergic drugs then delivered by dry powder inhalers were oxitropium and ipratropium and these drugs were mixed with glucose rather than lactose. That suggested to Professor Birchall that the formulation scientist would begin by considering glucose rather that lactose but he accepted that the scientist would also consider lactose. He pointed out that lactose sometimes caused allergenic reactivity problems with some individuals but that did not stop lactose being used in the past in many instances. It does not seem to me to matter whether the scientist would ultimately choose lactose or glucose. I consider that some scientists would choose one of them and some the other. The choice would not involve an innovation or the use or imagination but rather would involve the use of the common general knowledge of the scientist. As to the mode of preparation of the excipient for the purpose of being mixed with the active ingredient, the formulation scientist would use the common general knowledge of such scientists.

73. The above conclusions mean that the last thing which the formulation scientist needed to consider was the choice of capsule material. Professor Birchall aptly described the capsule as being a container for the active ingredient and the excipient. The container was not intended to be administered to the lung. The container was to be pierced to allow the active ingredient to be carried by inhalation to the lung. The only circumstances in which any part of the container would be administered to the body would be if the inappropriate piercing of the container resulted in a piece of it getting into the throat of the patient. That was not intended to happen but it might happen. It would be more likely to happen if the container was brittle. The delivery of a piece of the container to the body might cause the patient to cough but, by reason of the likely size of the piece in question, the piece of container ought not to find its way into the lung.

74. In the above discussion, I have discussed the components (1) the inhaler; (2) the preparation of tiotropium bromide; (3) the choice of excipient; (4) the preparation of the excipient; and (5) the choice of capsule material; in that order largely because the only one which was really controversial was the last of these. However, for the avoidance of doubt, I comment that my reasons and my conclusions would be the same if the formulation scientist were to make his choice of capsule material at the second, rather than the fifth, stage of the process.



75. As at 1 June 2001, the conventional material for a capsule in a dry powder inhaler was gelatine. It was agreed that the trials which had been carried out by the Defendant and which were the subject of the literature referred to by Professor Geddes would have used capsules made of gelatine. As against that, Professor Buckton pointed out that there were only around six capsule based dry powder inhalers on the market in June 2001 and that the most recent (as at that date) previous launch of such a product was one which had received market authorisation in 1995, when HPMC capsules were not commercially available. Although gelatine was the conventional material for capsules in a dry powder inhaler, it had known disadvantages. The main disadvantage was that when the moisture content of the gelatine fell then the capsules could become brittle. This was certainly the case when the moisture content of the gelatine fell below 10%. Speaking generally, a brittle container would be less suitable for use as a capsule material.

76. The experts fundamentally disagreed as to whether the possible use of HPMC as a capsule material in a dry powder inhaler was part of the common general knowledge of a formulation scientist as at 1 June 2001.

77. Professor Buckton stated that capsule manufacturers began to make capsules from HPMC in the mid-1990s. He referred to Shionogi as one manufacturer who did so. He specifically drew attention to the Ogura article which was relied upon by the Claimant as relevant prior art. I will refer to that article in a little detail before continuing to address the question whether the possible use of HPMC as a capsule material in a dry powder inhaler was part of the common general knowledge of a formulation scientist as at 1 June 2001.

78. The prior art referred to as Ogura was an article written by Ogura, Furuya and Matsuura which appeared in the issue of Pharmaceutical Technology Europe published in November 1998. That journal was described as a trade journal. Professor Buckton said that it had a wide circulation and that the majority of formulation scientists would have their own copy of it or otherwise have access to it. Professor Birchall thought this was a considerable overstatement. He doubted whether the majority of formulation scientists would read this journal. He himself only became aware of the Ogura article much later than the priority date.

79. Professor Buckton accepted that the article was a promotional article written by various persons at Shionogi Qualicaps Co Ltd, which was a Japanese manufacturer of HPMC capsules, amongst other things. The article appeared on the pages which followed an advertisement by Shionogi Qualicaps which described that company as having a long tradition of scientific research and stated that its development of cellulose capsules was a new breakthrough. The article was also reprinted as a brochure which was used by that company, presumably for sales purposes. Professor Buckton accepted that the article was not, or probably was not, the subject of peer review. He also accepted that a scientist would regard the statements in the article with a degree of caution, at any rate at the outset.

80. The article begins with a brief summary in these terms:

“Hydroxyproplymethylcellulose (HPMC) capsules are made of

plant-derived materials and do not contain components of animal origin, eliminating problems with religious or



vegetarian dietary restrictions. Unlike gelatin, HPMC does not have chemically reactive groups, dramatically decreasing the potential for reactions between the drug and the capsule shell. HPMC capsules have a naturally low moisture content, maintain mechanical integrity under extremely low-moisture conditions and are, therefore, ideally suited for use with formulations containing water-unstable drugs.”

81. The article continues with some general remarks about the use of capsules containing the active ingredients of various types of medicaments. These remarks include a statement that in recent years capsules have been used to contain powders for inhalations. The article then lists some drawbacks in relation to capsules. The first drawback noted was that in the case of capsules made from gelatine, the gelatine generally contained 13% to 15% water and might not be suitable for use with readily hydrolysable drugs. The article went on to refer to two other drawbacks which are not relevant for present purposes; these were the possibility of the active ingredient reacting with a gelatine capsule and the possibility that gelatine might be unacceptable as a result of religious or vegetarian dietary restrictions.

82. Having described these drawbacks of gelatine capsules, the article referred to the successful manufacture of capsules from HPMC and referred to a US patent apparently for such a product. It was then stated that HPMC capsules conformed to pharmacopoeial standards applicable in the USA, Europe and Japan.

83. The article continued with a description of the manufacture of HPMC capsules and their physical characteristics. These characteristics were listed in Table I. The first line in Table I referred to moisture content and stated that the moisture content of HPMC capsules was 2% to 5% compared with that of gelatine capsules at 13% to 15%. The article then stated:

“When the moisture content of the capsule shell is decreased,

as may occur when a dessicant is added to a package of capsules containing moisture-labile drugs, gelatine capsules tend to breakage during transport and storage.”

The article then referred to the relationship between brittleness and moisture content and described a method of testing for brittleness or hardness. The article commented that the percentage of broken gelatine capsules sharply increased as the moisture content of the hard gelatine shell dropped below 10%, although the degree of brittleness could be modified by the addition of PEG during manufacture. It was then stated:

“In contrast, no brittleness was observed in HPMC capsules

even at moisture levels of only 2% … .”

The text referred to Figure 1 which supported the expressed conclusions and showed the very marked difference between the brittleness of gelatine capsules below 10% moisture content and the virtually non-brittle HPMC capsules at their average moisture content of 2% to 5 %.



84. The article then continued with a discussion of the biopharmaceutical characteristics of different capsules when taken orally. That is not material for present purposes.

85. Later in the article, when discussing the possibility of the active ingredient reacting with the gelatine in a capsule, the article stated that HPMC was chemically inert and had a lower moisture content of 2% to 5% which permitted the maintenance of a low humidity environment within the HPMC capsule shell. The article later referred to problems with the use of gelatine with readily hydrolysable drugs and stated:

“Although HPMC capsules have a naturally low moisture

content, the HPMC film does contain some adsorbed water that is readily released. For drugs that are extremely moisture sensitive, it may still be desirable to add water absorbent excipients to the formulation and desiccants to the container to enhance stability. Hydroxypropylmethylcellulose (HPMC) capsules are particularly well suited to these situations because they resist becoming brittle under low humidity conditions.”

86. Under the heading “Other applications”, the article stated:

“Capsules have also been used as unit-dose containers to administer finely divided powders with specially designed inhalation devices. In the past, such delivery systems have encountered problems, including adherence of the powder to the gelatine capsule because of static electricity and capsule breakage because of the brittleness that results from storage under very low humidity. The HPMC capsule avoids these problems and would be appropriate for use in these situations.”

87. As quoted above, the Ogura article stated that the average moisture content of HPMC was 2% to 5%. This moisture content was compared with that of gelatine which was stated to be 13% to 15%. In the evidence before me, this figure of 13% to 15% for gelatine appeared to be generally accepted without further qualification, although some of the time it was suggested that the correct range for gelatine was 13% to 16%. However, as regards HPMC, reference was made to an article published in Drug Delivery Technology in March/April 2002 (after the priority date of 1 June 2001) and written by a Mr Nagata of Shionogi Qualicaps. In his article, Mr Nagata referred to the moisture content of gelatine as being 13% to 15% and that of HPMC as being 4% to 6%, in each case when stored at 20°C to 25°C and 40% to 60% relative humidity. The Ogura article had not specified the conditions when the average moisture content was stated to be 2% to 5%. So far as amended claim 5 is concerned, it referred to a moisture content of ≤5%. The figure of 5% is either at the top of the range of 2% to 5% or in the middle of the range of 4% to 6%; it may not matter which it is. Amended claim 6 refers to less than 2%. The figure of 2% is at the bottom of the range of 2% to 5% so that less than 2% is below that range. Less than 2% is obviously below the range of 4% to 6%. So far as I understand what is meant by “the TEWS or halogen

drier moisture content”, which is repeatedly referred to in the amended claims and which is described in the patent specification, the moisture contents are not measured at any specified conditions of temperature or relative humidity.



88. Reverting to what was known about HPMC generally as at 1 June 2001, Professor Buckton explained that HPMC was at that time a well known excipient that had been used in a wide range of dosage forms for other routes of delivery. He gave the examples of a film forming polymer as a tablet coat and of a binder in wet granulated tablet formulation. HPMC was therefore a safe material for pharmaceutical use. He referred to a textbook (Remington, 19th ed., 1995) but he appeared to accept in cross-examination that the reference there to development work in relation to capsules made from methylcellulose was not relevant to HPMC. He also referred to another textbook (Aulton, 2nd ed., published 30 October 2001) which referred to capsules being manufactured from HPMC with a low moisture content and which referred to the Ogura article. However, this textbook was published after 1 June 2001 and although it would probably have been written before that date, the author was Mr Brian Jones who was retained as a consultant by Shionogi and who knew more about HPMC capsules than would have been part of the common general knowledge of a typical formulation scientist at 1 June 2001. Further, the textbook was principally dealing with capsules for oral use. Professor Buckton also referred to the fact that HPMC capsules were manufactured by Shionogi before 1 June 2001 and marketed as Qualicaps. However, these capsules were designed for oral use.

89. Professor Birchall said that there was no article, apart from the Ogura article, which had been published before 1 June 2001 which referred to the use of HPMC capsules in connection with inhalation. He placed the earliest date when the use of HPMC capsules in connection with inhalation might have formed part of the common general knowledge of a formulation scientist as being 2003.

90. Based on all this evidence, it is clear to me that the possible use of HPMC as a capsule material in a dry powder inhaler was not part of the common general knowledge of a formulation scientist as at 1 June 2001. The conventional material at that date was gelatine and the publication of the promotional Ogura article in a trade journal would not have been sufficiently widely read so as to add to the previous common general knowledge of the formulation scientist. Not enough had happened or been written or said before 1 June 2001 to change the common general knowledge of such a scientist in this respect.

91. Nonetheless, it is accepted by the Defendant that the Ogura article (the Defendant would add “for what it was worth”) was part of the prior art at that date. I therefore

need to consider the reaction of the notional skilled formulation scientist to that article on the assumption that he had read it.

92. I have described Professor Buckton’s view that a scientist would approach the

statements in this article with caution. However, it appeared from the evidence that many of the relevant statements in the article would be known to be true by a skilled formulation scientist as part of his common general knowledge. He would know about the brittleness of gelatine capsules.

93. Ogura refers to HPMC capsules having a low moisture content, even before any process of drying. At this point, I need to refer to the evidence as to the common general knowledge of a formulation scientist as to the desirability of a low moisture content for a capsule material for use in a dry powder inhaler. Professor Buckton gave evidence that it was well known that the presence of moisture was a major issue when seeking to formulate using a dry powder inhaler. He suggested that a formulation



scientist would therefore wish to use a capsule material with less rather than more moisture. The formulation scientist would know that gelatine had a comparatively high moisture content (13% to 15%) but that it was not desirable to try to reduce the moisture content of gelatine because any such attempt would create problems of brittleness.

94. It seemed to me that Professor Birchall initially agreed with Professor Buckton’s

evidence in relation to it being common general knowledge that it was desirable to choose a capsule material which had a low moisture content. However, when cross-examined, Professor Birchall sought to qualify any such agreement. He said that what was important was that the capsule material did not have an “excessive” moisture

content. He also said that it was not necessarily right to say that “drier was better”. He

stated that if one was to change the choice of capsule material to a material which was drier than gelatine, one would simply not know, until tests were carried out, whether the reduction in moisture would be beneficial.

95. In so far as Professor Buckton and Professor Birchall gave conflicting evidence on this point, I prefer the evidence of Professor Buckton to the effect that at the relevant time that it was well known by formulation scientists that the presence of moisture was a major issue when seeking to formulate using a dry powder inhaler and such a scientist would wish to use a capsule material with less rather than more moisture. I do not think that such a scientist would distinguish only between “excessive” moisture and “not excessive” moisture; he would see the potential benefits of achieving a lower moisture content as compared with a higher moisture content. Further, although Professor Birchall may be right that the precise performance of a particular material with a particular moisture content would only be fully known when the material was tested in connection with a particular active ingredient, that would not prevent a formulation scientist forming the view that a lower moisture content in the capsule material was highly likely to be beneficial and beneficial to a degree which was worth pursuing. Such a scientist would regard the information in Ogura about the moisture content of HPMC as particularly relevant and interesting in the context of formulating an active ingredient for delivery by a dry powder inhaler.

96. The formulation scientist would also note that Ogura specifically identified HPMC capsules for use in dry powder inhalers. He would also know that HPMC conformed to general pharmacopoeial standards. Thus, at least prima facie, a formulation scientist supplied with the Ogura article would be informed by it that the supplier of HPMC capsules was recommending them for use in dry powder inhalers and was stating that they were preferable to gelatine capsules whenever there was a concern about the moisture content of gelatine capsules. There are other things in the Ogura article to which the formulation scientist might pay less attention. I refer in particular to the identified disadvantages of gelatine capsules as regards the risk of reaction with the active ingredient and the objection to gelatine on religious or dietary grounds.

97. Thus, at the stage in preformulation when the formulation scientist was considering what material to use for the capsule in the dry powder inhaler he would know from his common general knowledge that gelatine was the conventional material and he would know from Ogura that HPMC was a possible material with claimed advantages over gelatine. Thus, at least prima facie, the mere idea of using HPMC as the capsule material does not require innovation or imagination on the part of the formulation



scientist. Conversely, there might be reasons why the formulation scientist would not follow up the idea put forward by Ogura of using HPMC as the capsule material.

98. In this case, the Defendant submits that there were reasons why the formulation scientist would not follow up the alleged idea put forward by Ogura of using HPMC as the capsule material. These reasons were:

(1) the formulation scientist, having read Ogura, would think to himself: “there is

nothing in this for me for present purposes”;

(2) the formulation scientist would have technical and practical reasons for rejecting the use of HPMC as the capsule material;

(3) the formulation scientist would be troubled by the possibility of regulatory difficulties caused by the use of HPMC as the capsule material, would involve a regulatory expert as part of the skilled team and would be advised not to use HPMC.

99. In considering whether the formulation scientist, having read the Ogura article, would consider that there was something worthwhile disclosed by the article in the context of formulating dry powder inhalation for tiotropium bromide, it is necessary to step back and consider the common general knowledge at the relevant time as to the conventional material, gelatine. In particular, I have considered the evidence as to the common general knowledge of such a scientist as to possible problems with the use of gelatine as a capsule material in connection with inhalation.

100. Professor Buckton stated that gelatine capsules had drawbacks particularly when used in inhalation products. The major issue was said to be that the gelatine contained water (typically about 13% to 15%) that was free to leave the gelatine and be taken up by the powder. Water in the powder could cause changes in product performance and stability. Professor Buckton suggested that a formulation scientist would consider reducing the amount of water in the gelatine by a drying process but he would know that if he dried the capsule too much the gelatine would become brittle and liable to fracture (particularly if the water content was below 10%). Brittleness could be a problem during the filling of the capsule. Brittleness could also affect the way in which the capsule broke when pierced by the pins in an inhaler. The change from a pin hole to a fracture of the shell would give a different air flow and would tend to alter the detachment of the active ingredient and the amount of the powder that could be removed from the capsule on inhalation. A formulation scientist would wish to achieve reproducibility of dosage with his device and not have variations in the dose. Professor Buckton also referred to a drawback with gelatine due to its animal origin. That was of limited concern with a capsule used in an inhaler where the capsule was not intended to enter the body but could be more of a concern if a brittle capsule resulted in a fragment of the capsule entering the body. Professor Buckton also referred to ethical (vegan) or religious concerns about gelatine and to the possibility of reaction between the gelatine and the excipient. I do not think that he attached much weight to these latter concerns.

101. Professor Birchall acknowledged that there were drawbacks in using gelatine as the capsule material. He said that “the main disadvantage” was when the gelatine became dry, the capsule could become brittle and could fracture during manufacture, storage,



transport or usage. However, he then paid little attention to this disadvantage because he commented that a formulation scientist knew how to deal with the problem by taking steps to avoid loss of moisture from the capsules prior to use by the patient by storing capsules in blister packs prior to patient use. However, as I see it, that would not solve the problem with brittleness during manufacture and, in any case, the suggested solution required the use of blister packs. Professor Birchall also referred to “minor issues” with gelatine in that there could be a build up of static charge such that the active ingredient could be attracted to the capsule wall and to be fully released to the patient and, further, there might be dietary and religious objections to gelatine. Professor Birchall disagreed with Professor Buckton’s statement that formulators specified a drying process for capsules.

102. Professor Birchall also referred to the possibility of moisture in the gelatine transferring to the powder and vice versa. He accepted that if that happened there could be an effect on the flow properties of the powder or on the chemical stability of the active ingredient. Conversely, he referred to a possible benefit due to the fact that gelatine had a high water sorption capacity. The gelatine could absorb water from the external environment and act as a “buffer” preventing moisture from that source

reaching the powder.

103. Professor Birchall stated that a formulation scientist would address the various problems caused by the moisture content of gelatine and its sorption capacity by using the gelatine capsule and the powder at their equilibrium moisture contents. The equilibrium moisture content of gelatine was 15%. If the gelatine and the powder were equilibrated, then the risk of the transfer of moisture would be minimised.

104. Professor Birchall also picked up the reference in Ogura to the point that the HPMC film contained some “adsorbed” water so that for drugs that were extremely moisture

sensitive it could be appropriate to add water absorbent excipients. He suggested, and I accept, that this reference to “adsorbed” water is to water on the surface of the

HPMC film. There is no reason to suppose the reference is only to the outside of the capsule so that it can include adsorbed water on the inside of the capsule, i.e. in contact with the powder when the capsule is filled. Professor Birchall said that this reference to adsorbed matter would cause concern to a formulation scientist.

105. Professor Buckton’s reaction to Professor Birchall’s concern about adsorbed water

started by doubting if Ogura meant “adsorbed” water. As I have said, there is no

reason to doubt the use of the word “adsorbed”. Professor Buckton went on to point

out that for extremely moisture sensitive drugs, a desiccant could be used. As to the movement of water from the capsule to the powder, Professor Buckton said that there was a lot more water in the case of gelatine as compared with HPMC. He said that HPMC was a “win-win” over gelatine because it had a lower moisture content in the first place and could be reduced further by use of a desiccant without creating a brittleness problem unlike the case with gelatine. Professor Buckton did not accept that prior equilibration of the capsule and the powder would be a complete answer. He stated that changes in temperature could cause movement of moisture with both capsule materials. Overall, the reference to adsorbed water would not cause concern to a formulation scientist.

106. At this point, I will address the first suggestion made by the Defendant in relation to the Ogura article that there was nothing in it for the formulation scientist. I do not



agree. The formulation scientist is working his way through the process of formulating tiotropium bromide for use in a dry powder inhaler. He has to choose a capsule material. He knows that gelatine is the conventional material. He knows that gelatine has drawbacks, principally caused by its average moisture content of 13% to 15% and the consequences as regards brittleness if it becomes dry. He has read Ogura which stresses the low moisture content of HPMC, certainly as compared with gelatine. Ogura specifically mentions capsules for use in inhalation products. I consider that the unimaginative formulation scientist would recognise that in principle it would be open to him to choose HPMC capsules instead of gelatine capsules. Of course, he would have to give more thought to the ultimate choice he made as to the capsule material but what he would get out of Ogura is that he had the option of choosing HPMC as the capsule material. I find that an unimaginative formulation scientist would show a great deal of interest in the content of Ogura in the present context.

107. The Defendant then submitted that there were practical and technical reasons why the notional formulation scientist would rule out the choice of HPMC as the capsule material. Professor Birchall pointed out that the Ogura article did not contain any information about the puncturing characteristics of HPMC. He also referred in a more general way to the fact that HPMC was not the conventional capsule material and therefore much less was known about its ability to function as a capsule material as compared with gelatine.

108. It is true that the Ogura article contains no information or comment on the puncturing characteristics of HPMC or gelatine. For that matter, the patent in suit contains no teaching on that subject either. Accordingly, the notional formulation scientist would have to use his common general knowledge in order to assess the likely behaviour of HPMC when punctured. In the remainder of this discussion, I will refer only to puncturing by pins and I will not address the position where the dry powder inhaler involves shearing rather than puncturing of the capsule; it was not suggested that different considerations arose in the case of shearing rather than puncturing.

109. The formulation scientist would know something about the behaviour of gelatine when punctured, as gelatine was a conventional capsule material. The formulation scientist would also know that gelatine could sometimes be brittle so that more force would be needed to puncture the gelatine capsule and puncturing a brittle capsule might give rise to the release of fragments. I consider that the formulation scientist would want to know more about the puncturing properties of HPMC and he would use his common general knowledge to devise and carry out appropriate tests.

110. As it happens, Professor Birchall was involved with two series of tests which addressed the puncturing characteristics of HPMC and of gelatine. These tests were carried out in 2008 and 2013. Professor Birchall summarised the results in his report and he appended the reports of the results of the tests. He stated that the tests showed that the HPMC capsule puncture was more consistent than was the case with gelatine capsules and that the gelatine capsules were more brittle, requiring more displacement of the capsule before puncturing and leading to a more severe rupture event. There was also less flap detachment with the HPMC capsules as compared with the gelatine capsules. The results of the 2008 test were again demonstrated in 2013 where the methodology used was different. These matters were not further explored in cross-examination of the experts.



111. As I understand it, the 2008 and 2013 tests showed that HPMC has advantages over gelatine in relation to its puncturing characteristics. That fact was not known as at 1 June 2001. However, it seems to me that the comparative brittleness of gelatine as compared with HPMC would suggest that this would be the position. Further, as I have said, the notional formulation scientist would wish to test the matter and he would use his common general knowledge to devise and carry out appropriate tests.

112. As to the fact that much less was known about HPMC, as compared with gelatine, as a capsule material for inhalation products, I do not consider that the notional formulation scientist would be put off from considering and then testing HPMC when he was asked to devise a formulation of tiotropium bromide.

113. In 2015, the Defendant carried out a range of experiments. It may be that these experiments were designed to show the benefits which flowed from a reduced moisture content in the capsule material. The facts which the Defendant asked the Claimant to agree in its notice of experiments would suggest that that was their purpose. The notice of experiments did not suggest that the Claimant was asked to agree that routine trials of HPMC capsules would show that there was significantly greater chemical degradation with HPMC capsules as compared with gelatine capsules. However, it was pointed out at the trial that one of the experiments, involving Protocol 2 showed a higher level of chemical degradation with HPMC capsules as compared with gelatine capsules. As to that result, Professor Buckton regarded the extent of chemical degradation for both HPMC capsules and gelatine capsules as disturbing and not itself a reason for rejecting HPMC as a capsule material and restricting oneself to gelatine capsules. He pointed out that Protocol 2 involved reducing the capsule material to powder and mixing it with tiotropium bromide in proportions which placed the capsule material in far more intimate contact with the active ingredient that would be the case in actual use. Further, Protocol 2 was conducted in conditions of 40°C and 75% relative humidity which suggested a real possibility that both the HPMC and the gelatine would be in a different physical form to that which would exist at ambient conditions. Further, the water content in the tiotropium/HPMC mix would be in the region of 12%. In the light of this evidence, which I accept, I do not consider that the result of Protocol 2 as regards chemical degradation would produce the result that a formulation scientist doing routine trials in 2001 would have rejected HPMC, and would have restricted himself to gelatine, as a capsule material even if he had carried out tests in accordance with Protocol 2, amongst the tests he carried out.

114. As noted above, the Defendant submitted that a consideration by the notional formulator of regulatory matters would have persuaded him in 2001 not to pursue HPMC as a possible capsule material but instead to take the straightforward route, involving no regulatory concerns, of adopting the conventional material, gelatine.

115. This submission requires me to consider the relevant legal principles and, possibly, the evidence on this point. First, the legal principles.

116. The Claimant relies on the legal principles stated by Jacob J and by the Court of Appeal in Re Richardson-Vicks Inc’s Patent [1995] RPC 568 at 579-580 per Jacob J and [1997] RPC 888 at 895 and 896-897 per Aldous LJ and again stated by Lewison J in Ivax Pharmaceuticals UK Ltd v Akzo Nobel NV [2006] EWHC 1089 (Ch). The Defendant suggested that these principles needed to be reconsidered in the light of



what was said about the possible composition of the skilled team in Schlumberger Holdings Ltd v Electromagnetic Geoservices AS [2010] RPC 33 and in the further light of what was said about the relevance of commercial conditions in Dyson Appliances Ltd v Hoover Ltd [2001] EWCA Civ 1440. Reference was also made to the comments of Birss J about the possible relevance of regulatory matters in Teva UK Ltd v Leo Pharma AS [2014] EWHC 3096 (Pat) at [81] – [83], which was said not to be affected by the Court of Appeal’s later reversal of his conclusion that the

claimed invention was obvious: see [2015] EWCA Civ 779.

117. With the guidance given by Re Richardson-Vicks Inc’s Patent in particular it does not seem to me ultimately to matter whether the skilled team includes a regulatory expert or where the skilled team has access to the advice of a regulatory expert or whether the formulation scientist on the skilled team would himself know about regulatory matters without feeling it necessary to call on a regulatory expert. What matters is whether the alleged delay or difficulty in obtaining regulatory approval was an obstacle to the manufacture (as distinct from the marketing and the sale of the product once manufactured) of the product resulting from the claimed invention. In this case, it is not said that the alleged delay or difficulty in obtaining regulatory approval was such an obstacle and would not therefore justify a finding that the invention was not obvious in a case where the invention is obvious from a technical and practical point of view. I do not find anything in Schlumberger Holdings Ltd v Electromagnetic Geoservices AS [2010] RPC 33 or in Dyson Appliances Ltd v Hoover Ltd [2001] EWCA Civ 1440 which affects this part of the decision in Re Richardson-Vick Inc’s

Patent. Further, I do not think that the comments of Birss J in Teva UK Ltd v Leo Pharma AS [2014] EWHC 3096 (Pat) at [81] – [83] are directed to this point and, in any case, I find that there is clear authority on the point which binds me in the shape of the decision of the Court of Appeal in Re Richardson-Vicks Inc’s Patent. The patent does not say anything about regulatory matters; it is not suggested that the claims involved an inventive step because they would assist in some way in obtaining regulatory approval. I would not have expected the patent to do so.

118. In case I am wrong on the legal principles which apply to suggested difficulties in relation to regulation, I will make brief findings based on the evidence as to that matter. The Defendant contended that the idea of using HPMC as the capsule material, instead of the conventional gelatine, would not appeal to the skilled team because it would expect the use of HPMC to result in delay and expense in obtaining regulatory approval. It was not suggested that the use of HPMC as the capsule material would result in a refusal of regulatory approval; in fact, Mr Higson expected that it would be approved by the regulator. HPMC had been previously widely used in a wide range of medicaments and foodstuffs. It had been used in medicaments to be applied to sensitive organs such as the eye. When used as a capsule material in a dry powder inhaler, it was not intended that HPMC would be delivered to the lung. HPMC might conceivably be liberated from the inhaler if a piece of the capsule broke off on puncturing and entered a patient’s throat. The amount involved in such a case

was likely to be very small, possibly even trivial. Such a piece might induce a cough in the patient. That would cause little or no concern. HPMC was an authorised food additive so there would not be a concern on that score.

119. The Defendant’s case as to regulatory considerations was part of a wider case which

sought to demonstrate that a formulation scientist asked to formulate tiotropium



bromide in a dry powder inhaler would have had no motivation to select HPMC as the capsule material. The Defendant emphasised that gelatine was the conventional material. The Defendant submitted that gelatine was wholly satisfactory and in so far as any special steps needed to be taken in relation to the moisture content of gelatine there were well established steps which were routinely taken in the form of equilibrating and the use of blister packs. To this, the Defendant added the submission that the choice of a new material, HPMC, instead of the conventional material, gelatine, would cause delay and expense. I do not accept this submission. Gelatine was the conventional material but it was not considered to be wholly satisfactory. The description in Ogura of HPMC as a capsule material, with a low moisture content, would have been very interesting to an unimaginative formulation scientist. That property of HPMC would have been attractive to him. That would provide a motivation for him to include HPMC as a possible capsule material. I do not consider, on the facts, that he would have been put off by regulatory considerations from continuing his pre-formulation on that basis.

120. In relation to the question whether it would have been obvious in the light of Ogura, and in the light of common general knowledge about the general properties of HPMC, to try HPMC as a potentially suitable capsule material, I consider that the evidence establishes that it was obvious to try HPMC with a high prospect of success.

Was the alleged invention obvious?

121. Having made the above findings, I will now consider whether the amended claims 5 and 6 involved an inventive step for the purposes of section 3 of the 1977 Act.

122. For this purpose, I will first follow the structured approach identified in Pozzoli. I have made my findings as to the notional team involving a clinician and a formulation scientist. I have also made findings as to the common general knowledge of those skilled persons. I next need to identify the alleged inventive step. I will first consider the position where the alleged inventive step is the use of tiotropium bromide in particular, in a dry powder inhaler, where the capsule material is HPMC. As to the alleged differences between, this alleged invention and the former state of the art, I conclude that the possible use of tiotropium bromide in a dry powder inhaler as a treatment for COPD and asthma would have been within the common general knowledge of a skilled clinician and the choice of HPMC as a capsule material was pointed out by the prior art, Ogura. On that basis, viewed without any knowledge of the alleged invention, I consider that the possible use of tiotropium bromide in a dry powder inhaler using HPMC as the capsule material for the treatment of COPD and asthma did not require any degree of invention and was obvious.

123. I will next apply the PSA approach favoured by the EPO. For this purpose, I have identified the common general knowledge of the skilled clinician and the prior art, Ogura. As to the alleged objective technical problem, it might be suggested that the technical problems were to devise a treatment for COPD and/or to choose an appropriate capsule material. As to those suggested problems, I again consider that the possible use of tiotropium bromide in a dry powder inhaler using HPMC as the capsule material for the treatment of COPD and asthma did not require any degree of invention and was obvious.



124. It was stressed by Kitchin J in Generics (UK) Ltd v H Lundbeck A/S [2007] RPC 32 at [72], in a passage approved many times subsequently, that the question of obviousness must be considered on the detailed findings of fact in each case. In this case, having considered the matters mentioned by Kitchin J, such as the motive to find a solution to any formulation issues arising, the nature of the alternatives and the expectation of success, I conclude that it would have been obvious, to a skilled but unimaginative formulation scientist in or before June 2001, to identify HPMC as a capsule material when he was asked to formulate tiotropium bromide for use in a dry powder inhaler for the treatment of COPD and asthma. Similarly, standing back as recommended in MedImmune v Novartis, in the light of all of my earlier findings, I consider that such a use would have been obvious to such a person.

125. The Defendant submitted that I would be assisted when considering the question of obviousness by asking why no one had before 1 June 2001 used HPMC as a capsule material in a dry powder inhaler. It was pointed out that the prior art, Ogura, was published in 1998. It was also submitted that this consideration should carry even more weight in view of the suggested fact that HPMC was not used in this way for some time after 2001. I do not think that I am in the end much assisted by asking this question. I have held that the suggestion in Ogura that HPMC be used as a capsule material in a dry powder inhaler was not part of the common general knowledge of formulation scientists at 1 June 2001. So this is not a case where the averagely skilled formulation scientist knew of the suggestion and had discounted it. Further, the evidence was not precise as to whether, and in particular, when the idea of using HPMC as a capsule material in a dry powder inhaler did become part of the common general knowledge of formulation scientists. The evidence referred to a publication in 2003 and the fact that Professor Buckton used HPMC as a capsule material for inhalation purposes in 2005.

126. Thus far, when considering the obviousness of the claimed invention, I have approached the matter on the basis that the claimed invention related to the use of HPMC as the capsule material. However, the relevant claims describe the use of HPMC as the capsule material in more closely defined terms so that the question becomes whether the closer definition in the relevant claims gives rise to an invention, that is, something which was not obvious by reference to the common general knowledge and the prior art.

127. For convenience I will set out again the relevant claims. The proposed amended claim 5 is:

“5. Capsules for inhalation which contain as the inhalable powder tiotropium in admixture with a physiologically acceptable excipient, characterised in that the capsule material is the cellulose derivative hydroxypropylmethylcellulose and has a reduced moisture content as a TEWS or halogen drier moisture content of ≤5% and in that the physiologically

acceptable excipient is lactose.”

128. The proposed amended claim 6 is:



“6. Capsules for inhalation according to claim 5, characterised in that the capsule material has a TEWS or halogen drier moisture content of less than 2%.”

129. The proposed amended claims 6A and 6B are:

“6A. Capsules for inhalation according to claim 5, characterised in that the capsule material has a TEWS or halogen drier moisture content of less than 2% when empty.

6B. Capsules for inhalation according to claim 5, characterised in that the capsule material has a TEWS or halogen drier moisture content of less than 2% before being filled with the inhalable powder containing tiotropium.”

130. The features of these claims which I have not so far considered are:

(1) Claim 5 refers to the capsule material being HPMC with a reduced moisture content of ≤5%;

(2) Claim 6 refers to the capsule material being HPMC with a reduced moisture content of less than 2%;

(3) Claim 6A refers to the capsule material being HPMC with a moisture content of less than 2% when empty; and

(4) Claim 6B refers to the capsule material being HPMC with a moisture content of less than 2% before being filled with the inhalable powder tiotropium bromide.

131. Before considering the law, I make the following comments. Ogura referred to the average moisture content level for HPMC capsules as being 2 to 5%. Nagata referred to the average moisture content as being 4% to 6%. I do not think that either party proved that one of these ranges was correct and the other was wrong. The patent contains a number of statements about the moisture content of the capsules. I will collect those statements together here:

(1) the patent referred to “specific capsule materials with a reduced moisture

content”;

(2) the concept of “a reduced moisture content” was defined in the patent as

“being equivalent to a TEWS moisture level of less than 15%”;

(3) preferred capsules had a moisture content of “less than 12%, particularly

preferably ≤10%”;

(4) for gelatine capsules, the preference was for a moisture content of “less than

12%, particularly preferably ≤10%”;

(5) for cellulose capsules, the preference was for “less than 8%, particularly

preferably less than 5%. Most preferably, capsules for inhalation consisting of cellulose derivatives are dried to a TEWS or halogen drier moisture content of



less than 4%, particularly less than 2%, before being filled with inhalable powder containing tiotropium”;

(6) for plastic capsules, the preference was for “optionally less than 3%, optionally less than 1%”;

(7) the proposed amended claim 1 refers to a moisture content of ≤10”.

132. I also comment that the patent identifies a fairly wide range of capsule materials and does not discuss the relative merits of them. The patent does not refer to any tests of any of the materials nor to any performance criteria. The patent defines “reduced moisture content” as being less than 15% but does not indicate what advantages, if

any, might or would accrue if the moisture content is reduced to the various other figures referred to in the patent. The patent does not attempt to justify the choice of different figures by describing, much less demonstrating, the consequences of making a product which conforms to such figures. The patent does not contain any information about the sensitivity of tiotropium bromide to moisture. There is no reference to any particular level of physical or chemical stability, ease of piercing of the capsule or extent of drug release on piercing and inhalation by reference to moisture levels.

133. The Claimant submitted that the figures for moisture levels in the claims were arbitrary. That led to an extensive citation of authority said to be relevant to this submission. The principal authorities cited were T939/92 AGREVO/Triazoles [1996] EPOR 171, T1329/04 John Hopkins University School of Medicine [2006] EPOR 8, Conor Medsystems Ltd v Angiotech Pharmaceuticals Ltd [2008] RPC 28, Dr Reddy’s

Laboratories (UK) Ltd v Eli Lilly & Co [2010] RPC 9, Sandvik Intellectual Property AB v Kennametal UK Ltd [2011] EWHC 3311 (Pat) at [180] to [185], Human Genome Sciences Inc v Eli Lilly & Co [2012] RPC 6 at [149]

134. I will attempt my own summary of the principles established by the authorities. This summary is largely drawn from Generics (UK) Ltd trading as Mylan v Yeda Research and Development Co Ltd [2012] EWHC 1848 (Pat) at [335] to [352] but adapted to suit the circumstances of the present case.

(1) The following principles apply regardless of the field of invention but the application of the principles can vary according to the circumstances, including the field of invention.

(2) An arbitrary selection from the prior art is not inventive, regardless of the field.

(3) Where it is suggested that the claimed invention is an arbitrary selection, the key question is whether the specification passes the threshold test of disclosing enough to make the invention plausible, that is, to make it plausible that the claimed invention has the technical significance claimed for it.

(4) “Plausible” conveys the sense that there is some real reason for supposing that

the statement is true.



(5) If something is inherently unlikely, the burden of proof is on the party who wishes to persuade the court that it is indeed the case.

(6) When the disclosure of the patent, read in the light of the skilled person’s

common general knowledge, did not disclose enough to make the invention plausible, i.e. that it solved a technical problem, that was the end of the matter; it was not open to the patentee to rely on post-dated evidence to demonstrate the technical effect.

(7) When the disclosure of the patent, read in the light of the skilled person’s

common general knowledge, did disclose enough to make the invention plausible, i.e. that it solved a technical problem, it was not open to the party challenging the patent to rely on post-dated evidence to show that the invention was obvious.

(8) Post-dated evidence may be relied upon to confirm that the disclosure in the patent does or does not make it plausible by showing that it solved a technical problem.

135. The patent identifies the suggested technical problem in fairly limited terms. It states that a capsule material with “a reduced moisture content” helps to increase the

stability of the active ingredient, tiotropium bromide. The patent adds:

“The concept of a reduced moisture content within the scope of

the present invention is defined as being equivalent to a TEWS moisture level of less than 15%.”

136. It was well known as at 1 June 2001, that gelatine had an average moisture content of 13% to 15%. Therefore the concept of a reduced moisture content to achieve sufficient stability of the active ingredient to create the allegedly invented product was achieved by the use of the conventional capsule material, gelatine. As earlier explained, the patent then proceeded to refer to a number of different moisture levels below 15%. It said that the lower moisture levels were “preferable”. The patent

specified a large number of alternative moisture levels. Amongst other things, it specified levels of less than 12% and less than 1% and a number of other figures between 12% and 1%. The patent did not offer any explanation of what would be achieved by using a capsule material with those different moisture levels. As regards HPMC specifically, with an average moisture content of 2% to 5% (or possibly 4% to 6%), no explanation was offered as to what the technical advantage would be if one used HPMC capsules with their average moisture content instead of gelatine with a higher moisture content or what technical problem if any was created by using HPMC without drying it (apparently within amended claim 5) and what technical advantage would be achieved by drying it to less than 2% (within amended claim 6). Of course, it might be said that the teaching of the patent was the basic message that a drier capsule would be better than a more moist capsule. If that is the teaching of the patent, I have already held on the basis of Professor Buckton’s evidence that that was

common general knowledge. I referred earlier to Professor Birchall’s attempt to

qualify Professor Buckton’s evidence by suggesting that one would not know

precisely what the effect would be of using a capsule material (other than gelatine) with less moisture than gelatine. If I were to accept that evidence, it seems that it weakens further the Defendant’s position in relation to the point that the moisture



levels in the patent are purely arbitrary. If Professor Birchall were right, then the patent gives one no cause to think that the chosen moisture levels have been chosen for technical reasons. It is even more likely that they were chosen without a technical justification and were accordingly arbitrary.

137. I referred earlier to the fact that the Defendant carried out certain experiments in this case. As I understand it, the intention was to show that the lower moisture levels in HPMC capsules as compared with higher moisture levels in capsules demonstrated a technical benefit as regards the stability of the active ingredient. I will assume for the moment that the experiments did indeed demonstrate such a technical benefit. As is clear from the statements of principle summarised above, if the moisture levels in the claims were arbitrary then the claims are obvious and invalid and the results of later experiments, not referred to in the patent, cannot save the claims. In any event, the results of the experiments were not all that clear. The comparison between a case using a HPMC capsule with a moisture content above 5% and a HPMC capsule with a moisture content below 5% did not demonstrate that there was a benefit which was achieved when the moisture content was below 5% and which was not achieved if the moisture content rose above 5%. Nor did that experiment show that there was an advantage in drying an HPMC capsule which was within the average range of 2% to 5% or even 4% to 6%. The most that could be said for the experiment was that a marked difference in the moisture content of a HPMC capsule produced some improvement in the stability of the active ingredient. However, based on Professor Buckton’s evidence which I have accepted, that is exactly what one would expect if one used the common general knowledge of a formulation scientist as at 1 June 2001. Further, I do not consider that the experiments proved anything which would not have been part of that common general knowledge in relation to a HPMC capsule with a moisture content of less than 2%. Further, the experiments did not suggest that tiotropium bromide was particularly sensitive to moisture.

138. I conclude that the use of HPMC as a capsule material in a dry powder inhaler for the delivery of tiotropium bromide was obvious and the specification of specific moisture levels in amended claims 5 and 6 and 6A and 6B was arbitrary. There was no inventive step in any of these claims.

139. In view of my conclusions that claims 5 and 6 lacked an inventive step, I find that the inventions claimed in those claims were obvious. Accordingly, I will not permit the Defendant to amend its patent to include claim 5 or claim 6.

Other matters

140. This conclusion means that it is not necessary to address a number of other submissions made by the parties as to sufficiency or plausibility or added matter. In this case, I do not see an advantage in my considering these further submissions on the assumption that I might be wrong on obviousness, just in case there is an appeal against that finding. If the case is considered by the Court of Appeal it will have my findings of fact on the expert evidence in this case and will be able to deal with any of these further points if they need to be decided on appeal. Further, if I were to deal with them at this stage I would have to proceed on the basis that some part of my reasoning in relation to obviousness is wrong but I would not know which part of my reasoning to reject for the purpose of considering these further points.



141. I was asked by the Defendant to adjourn the determination of the issue in relation to claim 1 unless I felt able to decide it summarily in the Defendant’s favour. I do not

feel able to decide the issue summarily in that way. This provides a further reason why I would not wish to decide the further issues as to claims 5 and 6. Some of these further points may need to be addressed in relation to claim 1 and if they do then need to be decided I would prefer to decide them in that context rather than in the present context where I consider that they do not arise.

The result

142. I will not allow amendments to introduce claims 5 and 6. The inventions claimed in those claims lacked an inventive step and the characterising integers in relation to moisture content are arbitrary.

143. I will hear counsel on the consequences for the other issues which have been raised and as to the orders which should now be made.

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