Neutral Citation Number: [2002] EWCA Civ 1    
Case No: A3/2000/3811
 
IN THE SUPREME COURT OF JUDICATURE
COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM CHANCERY DIVISION
MR JUSTICE LADDIE
Royal Courts of Justice
Strand, London, WC2A 2LL

Date: 23rd January 2001

B e f o r e :

LORD JUSTICE ALDOUS
LORD JUSTICE BUXTON
and 
LORD JUSTICE LONGMORE
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	LILLY ICOS LIMITED
	Petitioner/
Respondent	
	- and –
		
	PFIZER LIMITED
	Respondent/Appellant	

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David Young QC and Richard Meade (instructed by Bird & Bird for the Respondent/Appellant)
Simon Thorley QC, Andrew Waugh QC and Colin Birss (instructed by Taylor Joynson Garrett for the Petitioner/Respondent)

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JUDGMENT : APPROVED BY THE COURT FOR HANDING DOWN (SUBJECT TO EDITORIAL CORRECTIONS)

Lord Justice Aldous:

SUMMARY
1.	On 20th April 1999 the Times in an article entitled “Viagra earns Dome place as Best of British” stated – “Viagra has won a place as one of the brightest British innovations of the 1990s.”  Even so the patent for use of Viagra for the treatment of impotence was held obvious by Laddie J and his decision has been upheld by this Court.  Why the difference of opinion?  I will summarise the basis for the decision of this Court before setting out in detail my reasons.  
2.	In 1991 and 1992 Pfizer patented a series of compounds which exhibited selective inhibition of a substance known as cGMP PDEv.  Those patented compounds were perceived to be useful in the treatment of various cardiovascular disorders such as angina and hypertension.  Included within the compounds covered by the patents was a substance called sildenafil citrate.  To enable that substance to be marketed for the treatment of cardiovascular disorders, Pfizer carried out a series of long and costly trials which were needed to establish its safety and efficacy.  
3.	In 1992 and 1993 articles were published which reported, amongst other things, the work that had been carried out by a team at the Department of Pharmacology of the University of California School of Medicine.  They confirmed that nitric oxide played an essential part in the relaxation of the smooth muscle of the penis which enabled blood to fill the tissues thereby causing an erection.  Their studies showed that nitric oxide was the molecule which activated a reaction to produce a compound referred to as cGMP.  It was that compound which caused the required relaxation of the smooth muscle in the penis.  They also disclosed that another substance PDEv activated a reaction which removed cGMP: the result being that the smooth muscle returned to its normal state.  It was suggested that an inhibitor of cGMP PDEv could be useful in the treatment of impotency because that would prevent removal of cGMP, the relaxing agent for smooth muscle.  
4.	In June 1994, Pfizer applied for the Viagra patent.  It covered substantially the same products as they had patented in 1991 and 1992, but this time it claimed as the invention the use of those products as a treatment for impotency.  Amongst those products was sildenafil citrate which was subsequently marketed under the trade mark Viagra.  
5.	Thus as of the date of the Viagra patent, the product Viagra was known.  It was also known that it was a selective cGMP PDEv inhibitor.  It was also known that cGMP PDEv removed cGMP which caused or contributed towards an erection.  It had also been suggested that such inhibitors could be useful in the treatment of impotence.  Against that background this Court had to consider whether it was inventive to appreciate that Viagra, when taken orally, would cause or contribute to an erection.  This Court concluded that it was not.  The publication of the work done at the University of California was a crucial step in the Court’s reasoning.

JUDGMENT
The Proceedings

6.	On 26th February 1999, Lilly Icos LLC started proceedings for the revocation of Pfizer Limited’s European Patent No. 0702555.  That patent is entitled “Pyrazolopyrimidinones for the Treatment of Impotence”.  It is an important patent as it covers the use of the chemical sildenafil citrate, sold under the brand name Viagra, for the treatment of male erectile dysfunction (MED).  
7.	The primary attack on the patent was the allegation that the invention was obvious, but allegations of lack of novelty, insufficiency and added matter were also pleaded.  Those issues came before Laddie J in October 2000.  In his judgment dated 10th November 2000, he held that the patent was obvious and therefore should be revoked.  He rejected the allegation of lack of novelty.  Against that finding of obviousness Pfizer appealed.  Lilly supported the conclusion of the judge on obviousness, but in the Respondent’s Notice challenged his rejection of the allegation of lack of novelty, and alleged that he should also have held the patent invalid on the grounds of insufficiency and added matter.  
The Background
8.	Patent specifications have to be read and construed through the eyes of a person skilled in the art who is assumed to be possessed of the common general knowledge of such a person.  It was accepted by the parties that the judge’s statement of that knowledge was correct in so far as it went.  I therefore set out that part of his judgment in full:
2.  The following technical background is derived in part from the primer agreed by the parties and supplied to me before the trial and partly from the written reports, witness statements and oral testimony given by the witnesses at the trial. I believe it to be uncontroversial. It represents part of the common general knowledge at the priority date of the patent in June 1993.
3.  The penis, like any other living organ or tissue in a mammal, is supplied with nutrient-rich and oxygen-rich blood in vessels called arteries. The flow is maintained by allowing the exit of the blood from the organ through vessels called veins. In an adult male human the penis has to grow in length and become rigid in order to facilitate sexual intercourse. This is called erection, or tumescence. After sexual intercourse or removal of the sexual stimulation which led to tumescence, in normal males the penis will return to its more flaccid and shorter resting state. This is called detumescence. Tumescence and detumescence are caused by changes in the blood flow inside the penis. To understand how this is achieved, it is necessary to know something of the basic anatomy of the normal penis.
(a) Anatomy.
4.  Set out below is a diagrammatic representation of a cross-section of the penis. 
Figure 1:

5.  Towards the bottom of the figure the urethra is identified. This is the channel through which urine and semen can travel. Above and to each side of the urethra are two symmetrical compartments, or corpora, each of which is called a corpus cavernosum. It is changes in the blood flow inside these compartments which lead to tumescence and detumescence. The corpora cavernosa consist of vascular sinusoids. That is to say they contain a network of very small blood vessels or passages. The sinusoids are surrounded by a type of muscle known as cavernous smooth muscle which, like any other muscle, can contract or relax. The corpora cavernosa also contain a matrix of supporting connective tissue. Blood is supplied to the vascular sinusoids in the copora cavernosa through a network of arteries. The blood drains out again through a network of small veins or venules which drain into larger veins, called emissary veins. The latter veins lie on the outer surface of each corpus cavernosum. Surrounding the corpora cavernosa is a fibrous layer called the tunica albuginea. Rather like a sausage skin, it is not very elastic. The emissary veins are located between the corpora cavernosa and their respective tunica albugineas. 
(b)	function
6.  When the penis is in its flaccid resting state, the flow of blood into the corpora cavernosa is restricted or throttled back by constriction of the smooth muscle which surrounds vessels in the incoming arterial network. These muscles act rather like ligatures. When they contract they reduce the internal diameter of the vessels in the arterial network. Of course they do not completely close the arteries or the penis would be completely starved of blood. When the smooth muscles are contracted like this, less blood can flow into the corpora cavernosa. Similarly the cavernous smooth muscle is contracted to the same effect. On the other hand the venules and veins are unaffected. They continue to be able to remove blood from the penis with comparative ease.
7.  When an erection is triggered, the smooth muscles surrounding the vessels in the arterial network and the cavernous muscles relax. The arteries open up. It is now easier for them to supply blood to the corpora cavernosa. Blood floods in to the sinusoids. The sinusoids start to swell and each corpus cavernosum presses up against the surrounding tunica albuginea. The swelling of the sinusoids squeezes the venules, thereby reducing the size of their internal passages. This reduces their ability to drain blood from the corpora cavernosa. Similarly, as the corpora cavernosa expand and press against the tunica albuginea, the emissary veins located between these two tissues are squeezed and are less able to drain blood from the penis. The result is that the penis becomes engorged with blood and stiff. A state of full erection is achieved when the pressure in the corpora cavernosa equals mean systolic pressure (i.e. the pressure of the blood leaving the heart). When the erectile process works in reverse the smooth muscles contract and the arteries again become constricted. This reduces influx of blood. At the same time the smooth muscle of the sinusoids become constricted which, in turn, reduces the external pressure on the venules and the emissary veins and allows the blood to flow out. So, during an erection inflow of blood is facilitated and outflow hindered and during detumescence outflow is facilitated and inflow is hindered.
8.  It should be noticed that contraction of the smooth muscles results in relaxation or detumescence. On the other hand relaxation of the smooth muscles results in tumescence/erection. This is because the smooth muscle is being used to throttle back the blood which, if allowed to flow in at arterial pressure, would result in the penis being gorged with blood and erect.
(c)	Smooth muscles
9.  The body of a mammal contains a number of different types of muscle. For example the muscles which result in one being able to raise or lower an arm are part of the ‘voluntary’ system of the body and are under conscious control of the brain. On the other hand there  are muscles in the body which are under ‘involuntary’ control. These muscles are made to contract or allowed to relax by the background housekeeping systems which exist in mammals (and other animals). The smooth muscles which surround the sinusoids and small arteries in the corpora cavernosa are part of this ‘involuntary’ system. They are supplied and brought into operation by a separate system of nerves to those used in the voluntary system. Various types of smooth muscle are to be found in different tissues and organs of mammals.
(d)	Male Erectile Dysfunction (MED) and its treatment.
10.  A significant part of the adult male population suffers from male erectile dysfunction. An accurate figure for the numbers affected is not known, partly because some sufferers are reluctant to acknowledge the existence of the problem or to discuss it with third parties. However the sufferers of one form or another of MED in Britain may be in the millions. MED becomes more prevalent in older men. In some males MED takes the form of a total inability to achieve an erection. In others the erection may be incomplete or last insufficiently long to achieve any or satisfactory sexual intercourse. In others the penis may stay erect for a long time or permanently (priapism). It is probable that there are a number of different causes of MED, with some males having one defect and others having others. 
11.  There were, at June 1993, a number of well know treatments for men who were unable to achieve satisfactory erections. The most widely used consisted of the self administration, by injection directly into the corpora cavernosa, of various drugs. The injection had to be effected shortly before sexual intercourse was desired. The drugs deployed included phenoxybenzamine, phentolamine, papaverine and prostaglandin E1. In England papaverine was the most widely used of these agents. For obvious reasons this form of treatment did not suit everyone. Some males disliked the act of self injection and sometimes one or both partners found the treatment discouraging. Furthermore the injections were not without side effects. For example frequent injections directly into the penis cause scarring. Sometimes treatment caused pain or priapism. This form of administration of the drug is frequently referred to as intracavernosal or ‘i.c.’ As an alternative to i.c. treatment, some drugs were injected into the urethra. Again there were side effects.
12.  Another type of treatment consisted of the oral administration of a drug known as yohimbine. Although it was accepted before me by all the witnesses that the oral administration of a drug was the avenue of choice, there was much doubt as to the efficacy of yohimbine. As a result, i.c. injections were used widely not withstanding their obvious disadvantages. A number of other treatments were used in a minority of cases. These included the use of suction devices and prostheses, the use of glyceryl trinitrate patches applied to the penis and sometimes increases in arterial supply to the penis effected by surgical intervention. All suffered from some side effects even in those cases where they were effective in curing or reducing MED.
(d)	The Chemistry of Smooth Muscle Relaxation
13.  At this point it will also be convenient to explain what is going on inside smooth muscle which makes it contract and relax. All the matters set out below were known at the priority date and were common general knowledge.
14.  Muscle is made up of living cells. In the case of the type of muscles distributed in the penis, each cell is made to relax when it receives a chemical ‘messenger’ which triggers the series of chemical reactions in the cell which cause the relaxation. In smooth muscles the creation of such a chemical messenger can be traced back to the production of a short lived gas, called  nitric oxide (chemical formula: NO). Nitric oxide is produced or released from at least two sources. First smooth muscle is lined with cells called endothelium cells. It was known in the 1980’s that this produced a ‘relaxing factor’, that is to say something which affected the contraction of the muscle. Because of its source and effect this was known as EDRF (i.e. Endothelium Derived Relaxing Factor). EDRF was discovered to be  nitric oxide in the late 1980’s. 
15.   Secondly the nerves which service smooth muscle also release  nitric oxide. These nerves are sometimes called non-adrenergic non-cholinergic (to distinguish them from certain other nerves in the body which are adrenergic or cholinergic) or NANC nerves. In both cases the  nitric oxide is produced by a reaction from a chemical called L-arginine. The chemical reaction is catalysed by an enzyme called nitric oxide synthase.
16.  The  nitric oxide produced by these two methods enters the smooth muscle cells and activates another enzyme (called guanylate cyclase) which converts another chemical called guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP in turn activates certain other intracellular enzymes (called protein kinases) which cause or promote chemical reactions which relax the smooth muscle. cGMP can itself be inactivated. A group of enzymes, called phosphodiesterases or (PDEs), cause cGMP to be turned into a chemical which is ineffective to relax muscle. This ineffective chemical is known as 5’GMP. Thus turning cGMP into 5’GMP has the effect of removing the agent which causes the muscle to relax. This sequence of chemical reactions can be represented in abbreviated and diagrammatic form as follows. 
Figure 2:

17.  This is known as the NANC pathway. Notice that the agent which is believed to cause relaxation is cGMP. That agent is produced by the ‘front end’ of the pathway and is dependent, amongst other things, on the generation of NO. It is removed by the ‘back end’ of the reaction - i.e. the part which is dependent, amongst other things, on the action of the PDE enzymes. As will be recalled, relaxation of the smooth muscle results in erection. So, production of cGMP should cause or contribute towards an erection and removal of it should cause or contribute towards detumescence.
18.  What goes on in the penis is more complex than this. Penile smooth muscle is also relaxed by other agents. In particular there is another chemical called cyclic adenosine monophosphate or cAMP which relaxes the smooth muscle like cGMP does. It is produced from a different starting material to cGMP in response to different messengers. In particular the messengers which trigger the creation of cAMP are called vasoactive intestinal peptide (VIP) and prostaglandin E1 (‘PGE1’). Like cGMP, cAMP is turned into an ineffective chemical by the action of a PDE enzyme. By the priority date it was well known that there were a number of PDEs. Each one regulates the level of cGMP, cAMP or both to varying degrees. By June 1993, five different PDE enzymes or enzyme groups were recognised by scientists and a classification system was adopted to discriminate between them. By that time it was also known that some of these PDEs could be inhibited (i.e. their catalysing function could be completely or significantly blocked) by certain other chemicals, called PDE inhibitors. A table set out at the back of the primer shows the PDEs, what they acted on and examples of selective inhibitors which were known by June 1993. The relevant data are as follows: 

PDE type
	Substrate	Inhibitors	
PDEI	Hydrolyses cAMP and cGMP	None known	
PDEII	Hydrolyses cAMP and cGMP	None known	
PDEIII	Hydrolyses cAMP and cGMP	Amrinone (Sterling Winthrop)
Milrinone (Sterling Winthrop)	
PDEIV	Hydrolyses cAMP 	Rolipram (Schering)
Ro 20-1724
Denbufylline	
PDEV (including PDEV B and PDEV C)	Hydrolyses cGMP	Zaprinast (M&B22948) (although also inhibits PDEI to a lesser extent.)	

19.  It will be seen that PDEIV only acts as a catalyst for the destruction of cAMP. It can therefore be said to be a cAMP specific PDE. Similarly PDEV can be called cGMP specific. The other PDEs are not specific, but can catalyse reactions which destroy both cAMP and cGMP. However, a PDE which catalyses the destruction of both cAMP and cGMP, and therefore is not specific, may be more effective in helping to destroy one type of substrate than the other. For example PDEIII is more effective in destroying cAMP than in destroying cGMP, so it can be called a cAMP selective PDE. Similarly an inhibitor may be more effective in blocking the enzymatic activity of one type of PDE than of another. In such a case it can be said to be a selective inhibitor of the former. So zaprinast, a chemical which figures extensively in this case, is a selective PDEV inhibitor. In fact the inhibition of an enzyme is a reversible effect which is dependent on the concentration of the inhibitor used. The more inhibitor present, the greater the inhibition. For this reason, one measure of the power of an inhibitor is to find the figure which causes 50% inhibition of the enzyme activity. This is called its IC50 value.
20.  It was common general knowledge before the priority date that cGMP and cAMP also regulate a variety of functions in other organs and tissues of the body, not just the relaxation of smooth muscles in the penis.
21.  Finally I should mention that the importance of nitric oxide became so well known that in the 18 December 1992 issue of the eminent journal Science it was named “Molecule of the Year”. In the editorial of that issue, it was stated that NO “is a major biochemical mediator of penile erection” and in an article in the same issue under the heading “Molecule of the Year”, it was said:
“This year [1992], scientists proved definitively that in males, NO translates sexual excitement into potency by causing erections. Key pelvic nerves get a message from the brain and make nitric oxide in response. NO dilates blood vessels throughout the crucial areas of the penis, blood rushes in, and the penis rises to the occasion.”
22.  One of the Pfizer witnesses, Dr. Challiss, described this as tabloid journalism, and so it is, but he also said it made a nice story. I have no doubt that it reflects the excitement that the elucidation of nitric oxide’s role in the body, and in relation to male sexual activity, generated by the end of 1992.”
9.	Mr Young QC, who appeared for Pfizer, pointed out that the smooth muscle referred to by the judge in paragraph 9 of his judgment was known to be found in the vascular and bronchial systems.  He also submitted that the judge had over-simplified what happened in MED by concentrating on the NANC pathway.  The andrenergic and cholinergic pathways were also well-known.  The whole process was known to be complex and the importance of the NANC pathway in causing MED in comparison with the other pathways was not appreciated at the time.  Mr Young also submitted that the judge had failed to record that the reason why injection was the most widely used form of treatment was that it provided appropriate concentrations of drugs to the site with reduced side effects.   
10.	Mr Young is correct that the existence of other pathways would have been known to the skilled person by 1993, but the judge cannot be criticised for not explaining them.  The NANC pathway was thought to be the most important and was the one which was central to the issues to be decided.  Similar observations apply to Mr Young’s other submissions.  I have no doubt that the judge had in mind that smooth muscle occurred outside the penis and that injection delivered a drug to the relevant site.   
The Patent
11.	The specification at the outset states that the invention relates to the use of a series of pyrazolo [4,3-d] pyrimidin-7-ones for the preparation of a medicament for the treatment of impotence.  It then defines impotence in this way:
“Impotence can be defined literally as a lack of power, in the male, to copulate and may involve an inability to achieve penile erection or ejaculation, or both. More specifically, erectile impotence or dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse.”
12.	The specification then states that the efficacy of orally administered drugs for the treatment of impotence is low. It refers to the treatment current at the priority date of the patent as consisting of injection of various drugs “either alone or in combination” (page 2 line 15) which are said to have undesirable side effects, such as pain and fibrosis of the penis. Other forms of treatment are referred to. 
13.	The specification acknowledges that the compounds of the invention were known.  At page 2 line 23 it states:
 “The compounds of the invention are potent inhibitors of cyclic guanosine 3’, 5’ monophosphate phosphodiesterases (cGMP PDEs) in contrast to their inhibition of cyclic adenosine 3,5-monophosphate phosphodiesterases (cAMP PDEs). This selective enzyme inhibition leads to elevated cGMP levels which, in turn, provides the basis for the utilities already disclosed for the said compounds in [Bell I] and [Bell II], namely in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post- percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).” 
14.	There follows this statement of the inventive step made by the patentees:
“Unexpectedly, it has now been found that these disclosed compounds are useful in the treatment of erectile dysfunction. Furthermore the compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration.”
15.	After the consistory clauses, the specification describes certain preliminary investigations that had been made.  The results are summarised as follows on page 4 line 54 to page 5 line 12.
“In summary, the above investigation identified three PDE isoenzymes in human corpus cavernosum tissue.  The predominant PDE is the cGMP-specific PDEv, whilst cGMP-stimulated cAMP PDE11 and cGMP-inhibited cAMP PDE11 cAMP PDE111 are also present.
The compounds of the invention have been tested in vitro and found to be potent and selective inhibitors of the cGMP-specific PDEv.  For example, one of the especially preferred compounds of the invention has an IC50 = 6.8 nM v, the PDEv enzyme, but demonstrates only weak inhibitory activity against the PDE11 and PDE111 enzymes with IC50 = > 100μM and 34μM respectively.  Thus relaxation of the corpus cavernosum tissue and consequent penile erection is presumably mediated by the elevation of cGMP levels in the said tissue, by virtue of the PDE inhibitory profile of the compounds of the invention.
Furthermore, none of the compounds of the invention tested in rat and dog, both intravenously (i.v.) and orally (p.o.) at up to 3 mg/Kg, has shown any overt sign of adverse acute toxicity.  In mouse, no deaths occurred after dose of up to 100 mg/Kg i.v..  Certain especially preferred compounds showed no toxic effects on chronic p.o administration to rat at up to 10 mg/Kg and to dog at up to 20 mg/Kg.  
In man, certain especially preferred compounds have been tested orally in both single dose and multiple dose volunteer studies.  Moreover, patient studies conducted thus far have confirmed that one of the especially preferred compounds induces penile erection in impotent males.”
16.	There follows statements that the compounds of the invention may also be used for the treatment of female sexual dysfunction, and for veterinary use.  The specification concludes with this paragraph:
“Moreover, the invention includes the use of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic oral treatment of erectile dysfunction in man.” (page 5 lines 23 to 25)
17.	There are 11 claims of which claims 1, 5, 6, 7, 9, 10 and 11 are relevant.  They are in this form:
“Claim 1.	 The use of a compound of formula (I):

(I)

wherein	

R1 is H; C1-C3 alkyl; C1-C3 perfluoroalkyl; or C3-C5 cycloalkyl;
R2 is H; C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl; C1-C3 perfluoroalkyl; 
or C3-C6 cycloalkyl;
R3 is C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl; C1-C6 perfluoroalkyl; C3-C5 cycloalkyl; C3-C6 alkenyl; or C3-C6 alkynyl;
R4 is C1-C4 alkyl optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7; C2-C4 alkenyl optionally substituted with CN, CONR5R6 or CO2R7; C2-C4 alkanoyl optionally substituted with NR5R6; (hydroxy)C2-C4 alkyl optionally substituted with NR5R6; (C2-C3 alkoxy)C1-C2 alkyl optionally substituted with OH or NR5R6; CONR5R6; CO2R7; halo; NR5R6; NHSO2NR5R6;NHSO2R8; SO2NR9R10; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;
R5 and R6 are each independently H or C1-C4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R11)-piperazinyl or imidazolyl group wherein said group is 
optionally substituted with methyl or OH;
R7 is H or C1-C4 alkyl;
R8 is C1-C3 alkyl optionally substituted with 
NR5R6;
R9 and R10 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperdino, morpholino or 4-N(R12)-piperazinyl group wherein said group is optionally substituted with C1-C4 alkyl, C1-C3 alkoxy, NR13R14 or CONR13R14;
R11 is H; C1-C3 alkyl optionally substituted with phenyl; (hydroxy)C2-C3 alkyl; or C1-C4 alkanoyl;
R12 is H; C1-C6 alkyl; (C1-C3 alkoxy)C2-C6 alkyl; (hydroxy)C2-C6 alkyl; (R13R14N)C2-C6 alkyl; (R13R14NOC)C1-C6 alkyl; CONR13R14; CSNR13R14; or C(NH)NR13R14;
and		
R13 and R14 are each independently H; C1-C4 alkyl; (C1-C3 alkoxy)C2-C4 alkyl; or (hydroxy)C2-C4 alkyl.
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man.
Claim 5:	“The use according to claim 4 wherein the compounds of formula (1) is selected from. …”  There follows a list of 9 chemical compounds.
Claim 6:	“The use according to claim 5 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.”
Claim 7:	“The use according to claim 5 wherein the compound of formula (I) is 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.”
Claim 9:	“The use according to any one of claims 1 to 8 wherein the medicament is adapted for oral treatment.”
Claim 10:	“The use of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic oral treatment of erectile dysfunction in man.”
Claim 11: 	“The use according to claim 10 wherein the inhibitor is a cGMP PDEv inhibitor.””
18.	The patent is what has become known as a second medical use patent.  The compounds claimed in claim 1 were known.  They had been found to be useful in the treatment of angina and other complaints and had been patented in two patents of Pfizer called Bell I and Bell II.  Claim 1 is worded as a Swiss-type claim (see Bristol Myers Co. v Baker Norton Pharmaceuticals [2000] IP&T 908).  Thus the invention of claim 1 is the use of the known compounds “for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man.”
19.	Claim 5 contains the “especially preferred” compounds set out at page 3 line 56 to page 4 line 14.  The first is the compound claimed in claim 7 and the third is that claimed in claim 6.  
20.	Claim 6 is of interest as it is sildenafil (which salt is not identified), the compound sold by Pfizer under the trade mark Viagra.  Claim 7 is confined to the compound which may be produced and sold by Pfizer.  
21.	Claim 9 covers use of the compounds in the previous claims provided that the medicament is adapted for oral treatment.  
22.	Claim 10 is an independent claim.  It is not confined to the compounds of the formula of claim 1.  The claimed compounds are defined by their action.  They are cGMP PDE inhibitors for the curative or prophylactic oral treatment of MED.  Claim 11 is similar, but the inhibitor is a cGMP PDEV inhibitor.  It is important to realise that those claims do include the use of inhibitors which do not fall within the formula of claim 1.  Thus the statement which appears at page 2 line 23 (see paragraph 13) does not apply as it is directed at the compounds of claim 1.  
23.	Construction – Before the judge a number of issues of construction arose.  He summarised his conclusions in this way:
“58.  My findings on the construction of the claims are therefore as follows:
(A)	Claim 1 covers the use of a Formula I compound (a) either alone or with some other agent, (b) by any means of administration, (c) for the purpose of treating male animals who have the inability to obtain or sustain an erection and (d) where such use is effective, at least in some cases, in treating that disorder. 
(B)	Claim 10 covers the use of (a) any compound which inhibits cGMP PDE enzymes (whether selective or not), (b) either alone or with some other agent, (c) by oral administration, (d) for the purpose of treating males who have the inability to obtain or sustain an erection and (e) where such use is effective, at least in some cases, in treating that disorder. 
(C)	Claim 11 is of the same scope as claim 10 save that it is restricted to compounds which inhibit cGMP PDEV.”
24.	Lilly accept those conclusions of the judge.  Pfizer challenged two conclusions relating to claims 10 and 11.  As claim 10 was of no commercial  importance to Pfizer, their submissions were specifically directed to claim 11.  They submitted that when claim 11 claimed use of cGMP PDEV inhibitors, it was limited to use of inhibitors which were cGMP PDEV selective.  They also submitted that the inhibitor had to be causative of the effect.  
25.	There is no need to decide whether those submissions are correct as they are only relevant to issues raised in the Respondents’ Notice, upon which the Court did not hear argument in view of the conclusion reached that the patent was invalid as it was obvious.  
Obviousness
26.	The judge held that the patent was invalid as it was obvious having regard to the disclosure in an article by Rajfer and others published in the New England Journal of Medicine in January 1992.  It reported work done at the Department of Pharmacology of the University of California School of Medicine.  He also held the patent invalid having regard to an article by Dr Murray of Smith Kline Beecham Pharmaceuticals in the April 1993 issue of DN&P.  That article reviewed a number of papers, including that of Rajfer.  A thesis by Dr Bush, a member of the University of California team, was also relied on.  The judge held that it made some of the submissions advanced on behalf of Pfizer difficult to sustain.  Also pleaded were the Bell patents.  Having regard to the submissions of the parties, it is not necessary to deal with the Bush thesis.  I will therefore concentrate on Rajfer and Murray which, it was agreed, should be read together, and the Bell patents.  
27.	Mr Young in his submissions placed considerable emphasis upon claim 5.  That did not reflect the submissions the judge recorded had been made to him, nor the detailed conclusions he reached. 
28.	This new twist to the case was not available to Pfizer in this Court for two reasons.  First, Pfizer had made it clear before the trial started that they were not contending that claim 5 had independent validity.  In a notice to admit facts dated 23rd April 1999, Lilly requested Pfizer to admit that none of the claims 2-11 were independently valid.  The reply was that claims 1, 6, 7, 9, 10 and 11 were independently valid.  Thus claims 3, 4 and 5 were not sought to be defended, if claim 1 was invalid.  
29.	Second, Pfizer accepted that no undue or inventive effort was required to screen for and identify useful orally active PDEv inhibitors.  That concession was recorded in a letter dated 21st June 2000 written by Pfizer’s solicitors.  It arose from an allegation of insufficiency.  
30.	Lilly’s re-amended particulars of objection included allegations of insufficiency against claims 1, 2, 3, 4, 7, 9, 10 and 11.  One of those allegations stated that if and insofar as the patentee sought to distinguish the prior art, then Lilly would contend that the specification did not disclose the invention, the subject matter of claims 10 and 11, sufficiently for it to be performed by a person skilled in the art.  In essence, the specification did not contain information enabling the skilled person to produce and select the inhibitors claimed in those claims.  
31.	The concession in the June letter was relied on by Pfizer at a hearing before Pumfrey J on 22nd June 2000 to persuade the judge to refuse to make an order for disclosure relating to the allegation of insufficiency.  Mr Waugh QC, Lilly’s counsel at that hearing, submitted to the Court that it would be unacceptable if it was open to Pfizer to run a case of non-obviousness based on any suggestion that there was something within a screening programme for suitable PDEv inhibitors.  That submission was put by the judge to counsel for Pfizer who said – “What we hope to accomplish by the statement [the statement in the letter of 21st June 2000] that we have drafted is this.  Once you know what you are looking for, you can get it and screening does not involve inventive effort or undue labour.”  The judge then queried whether identification of the ones that were suitable for oral administration was inventive.  To that counsel replied: - “No, my Lord, the invention is the appreciation that PDEv inhibitors are useful for the oral treatment of impotence.”  Upon that basis the judge refused the application for disclosure.  He said:
“I think that having regard to the statement which Pfizer is prepared to make, set out in paragraph 4 of Mr Meade’s skeleton argument [the same as in the June letter], and having regard to what he told me in response to a direct question from me this morning – which will appear on the transcript – that screening forms no part of any positive case of inventiveness which is being made on behalf of Pfizer, the process of screening forms no positive case which would be advanced in support of the contention of non-obviousness, it seems to me that it would be wrong for me, on this aspect of the objection, to make the order for disclosure which is sought.”	
That conclusion was recorded in the court’s order of 17th August 2000.  
32.	Consistent with the concession made, Pfizer’s skeleton argument concentrated on claims 1, 9, 10 and 11.  However their closing written submissions did assert that there was a complete absence of evidence that it would be obvious to pick the compounds claimed in claims 5 and 6.  That may be right, but the reason was clear.  Independent validity was not claimed for claim 5 and it was accepted that no inventive effort was required to screen for and identify orally active PDEv inhibitors.
33.	The concession made in the letter of 21st June 2000 and repeated by counsel at the hearing on 22nd June 2000 was inevitable.  The patent refers to the compounds of formula (I) of claim 1 as the compounds of the invention.  It is those compounds which Pfizer said they unexpectedly found to be active in the treatment of MED.  Within that category were the “preferred” compounds of claim 4 and the “especially preferred” compounds of claim 5.  At page 4 line 57 the specification states that “the compounds of the invention have been tested in vitro and found to be potent and selective inhibitors of cGMP-specific PDEv.”  There follows information on one of the “especially preferred” compounds claimed in claim 5.  The specification does not say which compound; nor does it give any information as to how the skilled person who read the specification would know how to select PDEv inhibitors.  
34.	Claim 11 covers compounds that may or may not fall within claim 1.  It follows that claim 11 had to be insufficient, due to the absence of any information as to how to select PDEv inhibitors, unless the ability to make and select them was within the capacity of the ordinary skilled person.  
35.	Mr Thorley reminded us of the statements of Lord Bingham, Lord Hoffmann and Lord Scott in Designers Guild Limited v Russell Williams (Textiles) Limited [2001] FSR 113.  He submitted that the approach of the judge had been correct and that therefore it would be inappropriate for us to come to a different conclusion on obviousness which was a jury-type question.  It is settled law that this Court will exercise extreme caution before reversing a conclusion of a judge on obviousness, but there is no need to do so in this case as I believe the judge was right.  
36.	The parties in their submissions adopted the structured approach advocated by Oliver LJ in Windsurfing International Inc v Tabur Marine (Great Britain) Limited [1985] RPC 59 at page 73:
“There are, we think, four steps which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as [forming part of the state of the art] and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention.”
37.	As independent validity of a number of claims was alleged by Pfizer, it is necessary to consider them in turn.  
38.	Claim 1-  There was no dispute as to what was the inventive concept of claim 1.  It was the use of the formula (I) compounds for treatment of MED.  
39.	I have already set out the relevant common general knowledge and can therefore turn to the third step of Windsurfing, namely to decide what are the differences between the pleaded prior art and the inventive concept of claim 1.  The parties accept that the Rajfer and Murray papers should be read together.  In those circumstances I believe it is appropriate to start first with Murray which is a review article.  
40.	The first words of Murray are “Looking Ahead”.  The article is headed “Phosphodiesterase VA inhibitors”.  It also states:
“The therapeutic potential of PDE VA inhibitors as, for example, vasodilators, bronchodailtors and producers of gastrointestinal motility, is largely based on the effects of one compound, Zaprinast, and a clearer picture will be obtained when other rationally designed inhibitors become available.”
Clearly the author is suggesting that other PDEv inhibitors should be investigated.  
41.	The article opens with a concise review of the interest that has developed in PDEs caused by the recognition that there were 5 distinct PDE families.  It states at page 150 that the purpose of the review was to discuss briefly the PDE families and to describe the physiological and pharmacological effects of PDEv and the potential therapeutic indications.  
“Cyclic nucleotide phosphodiesterases (PDEs) have long been regarded as potential targets for therapeutic agents. More recently, interest in this area has been renewed by the recognition that there are five distinct PDE isoenzyme families, and that tissues have different complements of these isoenzymes. There is, therefore, a logical foundation for selective PDE inhibitors to be used to increase cyclic nucleotide levels in specific target tissues or organs. Indeed selective PDE III inhibitors (see below for nomenclature) are currently used clinically for the treatment of congestive heart failure and as antithrombotic agents, and this success has given hope that inhibitors of other PDE isoenzymes will also be useful drugs. The purpose of this review is to discuss briefly the PDE isoenzyme families and to describe one of these isoenzyme families, PDE V. The physiological and pharmacological effects of PDE VA inhibitors are reviewed and their potential therapeutic indications discussed.” 
42.	The article goes on to set out what was known about Zaprinast, which Murray says was the most frequently studied PDEv inhibitor, and two other inhibitors made by May & Baker and SK & F respectively.  The effect of those inhibitors on a number of in vitro smooth muscle preparations is described and shown in Table V.  The article continues:
“The effects of zaprinast have also been studied in a number of other smooth muscle types. With strips of human corpus cavernosum, zaprinast alone caused a relaxation and enhanced the relaxation caused by nitric oxide or electrical stimulation.  [At this point there is a footnote reference to the Rajfer paper.]
…
Zaprinast is a weak relaxant of lower esophageal sphincter muscle from a number of species, including humans, but potently relaxes guinea pig colon and Taenia coli preparations. Contracted rat gastric fundus is also relaxed by zaprinast, and the compound potentiates the sodium nitroprusside (SNP)-induced relaxation of this tissue.
In vivo studies of PDE VA inhibitors have largely been on the effects of zaprinast on mean arterial blood pressure (MABP) in anesthetized rats or dogs, and again, the results give a reasonably consistent picture. Zaprinast lowered MABP mainly by decreasing total peripheral resistance, and there is evidence for selective vasodilatation. Zaprinast increased cardiac output and also caused a marked natriuresis, but had little effect on heart rate. In a rat aortavenocaval fistula model of cardiac failure, infusion of zaprinast caused natriuresis with little effect on MABP. Treatment of spontaneously hypertensive rats with zaprinast caused a fall in MABP to control levels. SK&F-96231 did not affect heart rate or MABP in conscious dogs, whereas bronchodilating effects of the compound were observed in anesthetized guinea pigs.”
43.	The article ends with these three important paragraphs:
“To date, the only PDE VA inhibitor that has been clinically evaluated is zaprinast. In adult asthmatics, zaprinast reduced bronchoconstriction induced by exercise, but not that provoked by histamine51. In contrast, zaprinast had no effect on exercise-induced asthma in children52. However, when evaluating these results, it should be remembered that these were small clinical trials using a compound that may have actions other than PDE VA inhibition. Therefore, at present, PDE VA inhibitors must be considered to be compounds with potential rather than established clinical use.
Smooth muscle relaxation appears to be the most promising of the potential uses of PDE VA inhibitors, and possible therapeutic utilities could include vaso dilatation, bronchodilatation, modulation of gastrointestinal motility and treatment of impotence. Although PDE VA inhibitors will relax most smooth muscle types in vitro, this does not necessarily mean that a nonselective action will be seen in vivo. Selective actions could be achieved by virtue of the fact that many of the effects of PDE VA inhibitors in a particular tissue are dependent on the level of guanylate cyclase activity. Thus, PDE VA inhibitors will have the greatest effect in cells and tissues that have a high guanylate cyclase activity, and there could be considerable value in a therapeutic agent that has little activity in its own right, but potentiates the effects of endogenous mediators. An example of this has been demonstrated in the rat model of cardiac failure described above, where the operated animals were more sensitive to the effects of zaprinast than their sham-operated controls. An explanation for this is that higher levels of the guanylate cyclase-activating ANP are found in the former group.”
… At present the therapeutic potential of PDE VA is largely based on the effects of … zaprinast, and a clearer picture will be obtained when other rationally designed PDE VA inhibitors become available.”
44.	There is a clear disclosure in Murray: (i) that use of PDEv inhibitors elevate cGMP, but not cAMP levels; (ii) that smooth muscle relaxation appears to be the most promising of the potential uses of PDEv inhibitors; (iii) possible uses of PDEv include, amongst others, the treatment of impotence; (iv) a clearer picture will be obtained when other rationally designed inhibitors become available.
45.	Rajfer was, as I have said, an article which set out work carried out at the University of California.  The article played a part in making the magazine “Science” declare nitric oxide the “Molecule of the Year”.  
46.	The abstract in Rajfer records that:
“Nitric oxide has been identified as an endothelium – derived relaxing factor in blood vessels.  We tried to determine whether it is involved in the relaxation of the corpus cavernosum that allows penile erection.”	
47.	It is recorded in the results section of the abstract:
“The relaxation [of human corpus cavernosum tissue] caused by either electrical stimulation or nitric oxide was enhanced by a selective inhibitor of cyclic guanosine monophosphate (GMP) phosphodiesterase (M&B 22,948).” [i.e. by a selective cGMP PDE inhibitor]
48.	The judge accurately summarised the relevant parts of Rajfer in this way:
“71. Under the heading ‘conclusions’ in the abstract, the authors say that defects in the NANC pathway may cause some forms of impotence. The main text of the paper records that failure of penile erection could be due to impaired relaxation of the smooth muscle of the corpus cavernosum (p. 90 left column) and states that the purpose of the study it reports was to ascertain whether nitric oxide plays a part in relaxation of the corpus cavernosum in humans and therefore in penile erection (p. 90 right column). It then reports a series of experiments. It is not necessary to go into the detail of those experiments but they can be split into two broad groups. In the first, the effect of modification of the nitric oxide generating part of the NANC pathway was examined. For example the generation of nitric oxide was impaired by swamping the tissue samples with an analogue of L-arginine which is not turned into NO. This had the effect of preventing L-arginine from being turned into NO (see step 1 in the flow diagram at paragraph 16 above). The second was concerned with looking at the chemical processes by which the cGMP produced by NO was removed from the tissue. To do this it used a cGMP PDE inhibitor identified as M&B 22,948 – this is the pharmaceutically active molecule known as zaprinast produced by May & Baker (see the table at paragraph 18 above). The authors report that they took strips of fresh human corpus cavernosum tissue and subjected them either to electrical field stimulation (i.e. to emulate the effect of the nerves when a man is sexually aroused) or to treatment with a chemical called SNAP which liberates NO. In both cases the NO released made the corpus cavernosum relax. The authors then applied the selective cGMP PDE inhibitor, zaprinast, to the tissue samples to see what effect it had on the NO-generated relaxation. It records that the inhibitor augmented or enhanced the relaxant responses. For example under the rubric “Preliminary Observations in Men without Impotence” Rajfer says:
“Corporal tissue from two men without impotence and tissue from impotent patients responded similarly with regard to the … enhancing effects of M&B 22,948 on electrically elicited relaxation. … M&B 22,948 … caused increases of 72 to 86 percent and 84 to 96 percent, respectively, in the relaxation response of corporal strips from 2 normal patients and 11 impotent patients.”
72.  In the discussion section of the paper, Rajfer says:
“… the addition of nitric oxide … caused similar rapid relaxant responses that were … enhanced by M&B 22,948 … M&B 22,948 is a selective inhibitor of cyclic GMP but not cyclic AMP phosphodiesterases…” [i.e. it is a selective inhibitor of cGMP PDE but not cAMP PDE]
and ends by concluding that the NANC pathway 
“…may be involved physiologically in mediating penile erection. It is conceivable that impairment of this pathway could account for the impairment in relaxation elicited by electrical-field stimulation that has been described in certain impotent men. Smooth-muscle relaxation is the mechanism by which papaverine and prostaglandin E1, when injected intracavernosally, cause tumescence in impotent men. … interference with the L-arginine-nitric oxide pathway could be one cause of impotence that is treatable by the administration of direct-acting vasodilators.”
73.  There is one other passage in Rajfer which should be referred to. It is on the second page of the paper in the detailed description of the experimental procedure being used. It reads as follows:
“When [zaprinast], an experimental drug prepared by May and Baker (Dagenham, United Kingdom) was tested, it was added to the strips at a concentration of either 1 or  3 mol per liter (whichever caused a relaxation of 10 to 15 percent, sufficient to ensure that enough [zaprinast] had been added).””
49.	Mr Young criticised the way the judge had categorised the experiments into two categories.  That he submitted was only possible once the invention was known.  I reject that submission.  The conclusion of the judge was apparent from the article.  
50.	Rajfer elucidated the NANC pathway and suggested that interference with the pathway could be one cause of impotence.  It taught that smooth muscle relaxation,  necessary for an erection, was indirectly induced by nitric oxide and was mediated through an increase in cGMP concentration.  Further, Zaprinast was a selective inhibitor of cGMP PDE and also potentiated relaxation.  
51.	Mr Young submitted that the difference between the Murray and Rajfer articles and the concept of claim 1 was that there was no teaching that any cGMP inhibitor would be effective in the treatment of MED as opposed to the suggestion that cGMP PDE or PDEv inhibitors were potentially useful in the treatment of MED.  
52.	The fourth step is to consider, without knowledge of the invention, whether the difference between the prior art and the invention of claim 1 was obvious.  In my view it was.  Anybody who read Murray and Rajfer would have realised that PDEv inhibitors were likely to be effective in the treatment of MED.  There was nothing inventive in trying them out for that purpose.  The work involved to identify those that worked was routine and, in any case, it was conceded that the screening process did not involve invention.  Further any search for selective cGMP PDE inhibitors would have found the Bell patents which disclosed as their inventions oral or intravenous use of such inhibitors for the treatment of such complaints as angina and hypertension.  Bell I claimed in claim 1 the compounds of claim 1 of the patent.  There were 8 compounds “especially preferred” in Bell I.  They included sildenafil citrate (Viagra) and four other compounds claimed in claim 5 of the patent.  There were 5 “especially preferred” compounds in Bell II.  They included the compound of claim 7 of the patent and three others included in claim 5.  The judge was right when he concluded:
“138. I accept Mr Thorley’s arguments of obviousness. If anything, the case of obviousness based on Murray is even stronger than in relation to Rajfer. It could be said that Pfizer’s patent is little more than a putting into practice of the recommendations and suggestions of Dr Murray. Those recommendations and suggestions would have been appreciated by a man skilled in the art at the priority date as being sound and worth trying.”
53.	Mr Young submitted that the judge’s conclusion was arrived at as a result of hindsight reasoning which was unfair to inventors (see Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] RPC 346 at 362).  I disagree that the judge fell into that error.  It is always difficult for a judge to place himself back in time to the priority date of the patent; a time when the invention had not been published.  But in this case, the Murray article explicitly provided the way forward.  PDEv inhibitors were said to be potentially useful for the treatment of MED and that a clearer picture would be obtained when inhibitors, other than the three mentioned, became available.  There could be no invention in doing what was suggested.  
54.	The reaction of those who gave evidence is also inconsistent with the submission that the conclusion reached by the judge was infected with hindsight reasoning.  Dr Gristwood read Rajfer in or about February 1993 and appreciated that PDEv would potentiate the relaxant effect of EDRF.  He also appreciated that impotence was a new therapeutic possibility for PDEv inhibitors.  That of course was the reaction recorded by Dr Murray in his article.  Dr Hyafil, who worked for Glaxo Wellcome, attended a conference in Basle at which Professor Ignarro spoke about the work described in Rajfer.  Shortly afterwards he prepared a report which said that nitric oxide was almost certainly the neurotransmitter which caused penile erections and that relaxation of the corpus cavernosum was accompanied by an increase in cGMP levels which was potentiated by the same PDEv inhibitor that Glaxo Wellcome was investigating, namely Zaprinast.  Dr Silver of Sterling Winthrop gave a talk at a conference that took place in April 1994, before Pfizer’s invention was made public, in which he said that the therapeutic uses for PDEv inhibitors included impotence.  Dr Ringrose of Pfizer saw Rajfer in late January or early February 1992.  He sent a copy of the paper to this colleagues with this note on it: “Should we not try out UK 92480 [sildenafil citrate] on impotence?  Have we seen any beneficial side effects?”
55.	It is difficult to believe that the idea of testing PDEv inhibitors for the treatment of MED was arrived at by hindsight reasoning in the light of evidence that people at the time came to the same conclusion when Rajfer and Murray became known.  
56.	Mr Young submitted that it was not correct to conclude that the skilled person would arrive at the conclusion that PDEv inhibitors were effective to treat MED.  To do that he would need to do trials which might or might not establish effectiveness.  When considering what was obvious, the skilled person was not presumed to carry out trials for the sake of doing them.  In the present case the only PDEv inhibitor on the market was Zaprinast.  That product had not proved successful during in vivo tests.  Thus if the skilled person had done what Dr Kruse said would have been done, namely use Zaprinast as a starting point to develop PDEv inhibitor compounds, the invention of claim 1 would not have been achieved without a prolonged research programme which, upon the evidence of Dr Ellis, would have extended over many years.  That did not point to a conclusion of obviousness. 
57.	Mr Young is correct that when considering what is obvious it cannot be assumed that the skilled person would try every possible permutation or carry out extensive research (see Hallen Co v Brabantia (UK) Ltd [1991] RPC 195 at 212). What would have been obvious will depend on all the circumstances.  As I said in Norton Healthcare Ltd v Beecham Group Plc CA (unreported)19th June 1997.
“When deciding whether a claimed invention is obvious, it is often necessary to decide whether a particular avenue of research leading to the invention was obvious.  In such circumstances the extent of the different avenues of research and the perceived chances of any one of them providing a successful result can be relevant to the decision whether the invention claimed was obvious.  Whether the subject matter was obvious may depend upon whether it was obvious to try in the circumstances of that particular case and in those circumstances it will be necessary to take into account the expectation of achieving a good result.  But that does not mean that in every case the decision whether a claimed invention was obvious can be determined by deciding whether there was a reasonable expectation that a person might get a good result from trying a particular avenue of research.  Each case depends upon the invention and the surrounding facts.  No formula should be substituted for the words of the statute.  In every case the Court has to weigh up the evidence and decide whether the invention was obvious.  This is the statutory task.”
58.	There was every reason to expect a good result in the treatment of MED by using cGMP PDEv selective inhibitors.  Such had been suggested in Rajfer and Murray.  It was appreciated to be likely by others who became aware of the work described in those articles.  Once Rajfer and Murray were published it would be routine for the skilled person to screen and test cGMP PDEv inhibitors in the way suggested by Dr Kruse in his witness statement.  That would have included studies, including oral bioavailability studies on the more promising compounds.   
59.	Mr Young also relied on the way that Pfizer came to make the invention.  He drew attention to the fact that they were testing sildenafil citrate to treat complaints such as hypertension.  Erections were reported as a side effect.  That led to the realisation that it could be used for the treatment of MED.  
60.	That history does show that the invention of claim 1 of the patent was a surprise to Pfizer and that could have indicated invention.  However account must be taken of the Rajfer and Murray articles.  As the judge said:
“90. … What is clear from the evidence is that the Pfizer workers involved did not know, to use Dr Ellis’ words, that the mechanism of action of cGMP PDE inhibitors is fundamentally different from other direct acting vasodilators. They had not appreciated that the production of cGMP is not increased by an inhibitor but that its breakdown is countered. However these are matters which a skilled man in the art would have understood from Rajfer (and from Murray or Bush). It should be remembered that even the abstract at the beginning of the Rajfer article points out the different mode of action because it states that 
“The relaxation caused by either electrical stimulation or nitric oxide was enhanced by a selective inhibitor of cylcic guanosine monophosphate (GMP) phosphodiesterase.” (emphasis added)
91.  That message is reinforced by the rest of the document. It explains that the inhibitor does not produce the muscle relaxing factor (cGMP) but enhances or amplifies its action if it is already there. Dr Ellis is correct to say that the different mode of action of cGMP PDE inhibitors to NO donors makes it clear why the experiment did not work. However once Rajfer (or Murray or Bush) was published and had been read carefully, that difference was no longer a matter of hindsight.”
61.	Mr Young also relied upon the fact that Glaxo filed a patent application on 21st January 1994 for potent and selective cGMP PDE inhibitors for the treatment of impotency. It contained the statement “that the patentees had unexpectedly found that the claimed compounds were useful in the treatment of MED.” That patent application was put to Dr Hyafil (Ev. 4 at page 470).  The suggestion, never put to the witnesses, was that the statement was correct and that it was not obvious until 1994 that such compounds were effective.  That patent application does not impugn the evidence of Dr Hyafil that he realised that cGMP PDEv inhibitors might be used to treat impotence in April 1992.  
62.	Claim 5 -  As I have already pointed out, this claim was not included in the claims which were said to have independent validity.  Even so, Mr Young sought to reinstate it as a claim which was inventive, even if claim 1 was invalid.  To do that he suggested that there was invention in selecting the 9 compounds in claim 5 from other cGMP PDEv inhibitors.  That submission cannot be sustained for two reasons.  First, there is no basis in the specification for a selection patent.  The claim 5 compounds are said to be especially preferred, but there is no indication as to why they are preferred or whether they have any quality not enjoyed by the other compounds in claims 1, 2, 3 or 4.  Second, they are the especially preferred products in the Bell patents.  It was obvious for the skilled person to find the Bell patents and to use some of the compounds disclosed and the most obvious ones to start with were the “especially preferred” ones.  There was nothing inventive in using the compounds of claim 5.  
63.	Claims 6 and 7 -  These claims add nothing to claim 1.  They cannot be supported because of selection, as there is nothing in the specification which suggests that they have any different qualities to the other compounds in claim 5 or claim 1.  Further there could be nothing inventive in using the especially preferred compounds of the Bell patents.  In fact the claim 7 compound would probably have been a preferred one to try in view of its good selectivity shown in the Table in Bell II.  
64.	Claim 9 -  Mr Young placed considerable emphasis upon this claim.  He submitted that oral administration would not have been obvious for six reasons.  First, oral administration would have been thought to interfere with a considerable number of other smooth muscles.  Second, to achieve an effect upon the smooth muscle of the penis, it would have been expected that massive doses would be necessary which would cause side effects.  Third, the accepted way of providing the drug to the site was injection.  Fourth, there was no reason to believe that any acceptable oral dose would have sufficient bioavailability to achieve the desired effect.  Fifth, the only oral treatment was use of a drug called Yohimbine.  It was rarely used due to lack of efficacy.  Sixth, there was little published on oral treatment of MED and Dr Eardley, at least, thought in 1992 that effective oral treatment of MED was some years away.  
65.	Mr Young relied upon the evidence of Dr Ellis and Dr Eardley to support those reasons.  He also referred us to paragraph 43 of Dr Eardley’s witness statement.  There he referred to the Murray article which had been provided to him as part of the collection of prior art documents.  He said – “My first thought would be that if one was going to use such compounds [PDEv inhibitors], one would have to inject the drug …”.  Dr Eardley went on to give as his reasons for that statement that it was difficult to image how you could have an effect on the penis with a product taken orally, and it was hard to believe that one could administer drugs systemically, whilst only having therapeutic effects on the penis.  
66.	As Mr Young demonstrated, there are reasons for doubting the ability to administer orally a drug to treat MED.  However that does not mean that it was inventive to decide to do so.  In my view it was not.  Oral was the obvious route of administration and there is nothing in the specification which suggests that there was any difficulty to be overcome to adapt the compound for oral use.  If it was obvious to try, it seems that success was within the reach of the skilled person carrying out routine procedures.  The fact that it was obvious is demonstrated by statements in all the 25 patents produced in a prior art search for cGMP PDE inhibitors, including the Bell patents, that the compounds were suitable for oral treatment.  
67.	The judge rightly held:
“99. … The starting point in considering this issue is an awareness of what those in the art thought of oral treatment of MED at the priority date. In my view this was an area in which there was close to consensus between the witnesses. There is no doubt that a high priority in the search for any new treatment of MED was that it should be administered orally. This was considered to be the ideal form of treatment by Dr. Gristwood. Dr. Challis, said that oral delivery was clearly the preferred route of administration and, under cross-examination, he said:
“…if you can achieve oral administration I am sure that there are a myriad of reasons why you would pursue it” (Day 5 Transcript page 659 –660)
100.  Some of those reasons were given by Dr. Kruse in a passage in his report which was not seriously challenged:
“The ultimate aim of most drug research program is to produce a drug which can be taken orally. … Oral administration is the preferred and most widely used route of administration for the simple reason that it best ensures patient compliance and can be used at home, as opposed to in a hospital setting. Oral drugs can easily be self-administered by a patient. Swallowing a pill is a relatively non-invasive and non-threatening event for most patients and it is a fairly easy task to ensure one is taking the correct quantity of the drug, i.e. it is easier to count pills than say measure out a quantity of solution to take intravenously. Of course there are some circumstances where other routes of administration (e.g. intravenous or intramuscular) might be preferred, for example for the administration of a very potent, short acting drug following a stroke or an anaphylactic shock. Non-oral methods of administration might also be preferred for certain organs, for example administration directly into the eye for the treatment of glaucoma. However, in the vast majority of cases of drugs being administered to treat non-life threatening conditions the oral route of administration is the best and the most widely used. In a disease such as erectile dysfunction, where male self-image, and perceptions of performance are important, oral activity is almost certainly a requirement for a commercially successful drug. It is difficult to imagine an injectable or other mode of administration competing effectively with the discretion and simplicity of an orally acting therapeutic.”
101.  Similar evidence was given by Mr Pryor, a urologist called by Lilly who was a most impressive witness. He said that by early 1993 the vast majority of clinicians had recognised the disadvantage of penile injection therapy and the desirability of having an oral preparation and that he would have advised any company involved in finding a new treatment for MED that it should make it a priority to develop an orally active drug. He said:
“The oral route of administration is generally the most convenient and most acceptable to a patient for any drug. It enables the patient to manage easily and in the safest way possible the treatment of his particular disorder. It is suitable for acute, chronic or prophylactic treatment. With respect to the treatment of erectile dysfunction, oral administration of a medicament was generally recognised as being the obvious goal to aim for since it would overcome the unpleasant and potentially hazardous procedures associated with intracavernosal injections. In fact, at the NIH consensus meeting in 1992 it was stated that amongst the needs and directions for future research was the development of new therapies, including pharmacologic agents, and with the emphasis on oral agents that may address the cause of male erectile dysfunction which greater specificity (page 194)”. (Pryor Expert Report paragraph 5.4)
(The NIH referred to in that passage is the American National Institute of Health which held a meeting on impotence in December 1992.)
102.  I accept Mr Pryor’s evidence as fair and reliable. Indeed Pfizer accepts that at the priority date an effective oral treatment for impotence was known to be desirable “in the abstract”.”
68.	After citing a passage from  his judgment in Bourns Inc. v Raychem (Judgment 12th June 1997) he continued:
“105. However, there are additional reasons why Mr Kitchin’s arguments must be rejected. On the facts here there was overwhelming pressure on workers in the field to try oral administration with any new pharmaceutical candidate for MED treatment. I have already referred to the very unpleasant nature of the primary treatment for male impotence, namely self injection into the penis immediately before sexual intercourse, and the general appreciation by 1992 if not before that oral treatment was what was needed. Pfizer suggests that the perceived risks of oral administration of a PDE inhibitor were so great that they would not even be tried. This argument reached its high point in Professor Ignarro’s warning that oral administration risked killing the patients. Because some PDE inhibitors were known to have an effect on the peripheral vascular system which could result in lowered blood pressure, so any systemic treatment would be likely to be potentially life-threatening.
106.  It is all too easy in a case like this to raise a lurid fear and for that to obscure the issues. That, in my view, is what Pfizer have done here. It is well known and not in dispute that regulatory authorities exercise immense care before they will license drugs for human use. The prospect of an orally administered impotence treatment being allowed on the market which has a significant risk of killing patients or even causing them significant harm must be regarded as very small indeed. As Mr Kitchin is anxious to point out, most drugs go through extensive testing, including testing on live animals, before they are allowed even to be clinically tested on humans. The risk, if there is one, therefore is not a risk of killing patients so much as of failing to make it through the trials which always have to be undertaken to prove efficacy and lack of relevant or unacceptable toxicity and side effects. The question is, therefore, whether it would be obvious to try to use a cGMP PDE inhibitor in oral treatment or were the risks of failing so great as to deter the notional skilled worker before he set off down that path. Whether something is obvious to try depends to a large extent on balancing the expected rewards if there is success against the size of the risk of failure. Here it was apparent that the rewards for finding an oral treatment would be substantial. The risk was not, as indicated above, the risk of killing anyone, but the risk that trying oral administration would not work so that the research would be unproductive. …
107.  I have come to the conclusion that the skilled team would not have been put off trying oral administration of a PDE inhibitor. On the contrary, on balance there is much in the evidence which suggests that trying oral administration was a worthwhile, and perhaps the first, avenue to pursue. The skilled team would have included PDE expertise. It would have known that the oral administration of PDE inhibitors was already being tried in a number of fields. As Dr. Challis agreed, it was well known by 1993 that a number of PDE inhibitors were bioavailable orally. Further Lilly produced a document (X17) which referred to 25 patents to PDE inhibitors applied for before the priority date of the patent in suit. The patentees included Warner-Lambert Co., SmithKline Beecham, Pfizer and Schering – all well known names in the pharmaceutical field. Every one of them suggested that the inhibitors should be administered orally. In some cases they contain a suggested daily dose for human ingestion. Even by the time of Rajfer in January 1992, it would have been apparent that it was worth trying oral administration of any candidate compound. The reasons for this are not difficult to understand. On the one side there was the pressure to find an oral treatment for MED. On the other there was nothing to suggest that these inhibitors as a class were necessarily ineffective or toxic when so administered. Dr. Gristwood gave evidence on this issue. He said:
“Having read Rajfer et. al., there was nothing to deter me from pursuing an oral delivery of a selective PDE V inhibitor as a treatment of impotence. Although cardiovascular effects have been reported in anaesthetised rats and dogs with intravenous administration of zaprinast, I was not then, and still am not, aware of any reported adverse side effects associated with oral administration of zaprinast to humans. I was aware in 1993 that zaprinast had been administered orally in humans (both adults and children) without adverse side effects. I would expect most people working in the field to have been aware of this.” 
108.  I accept that evidence. The fact that zaprinast (May & Baker’s PDEV inhibitor) which was discussed and used in Rajfer was the subject of clinical trials and had been administered orally for that purpose would have been known to all those involved in the potential use of PDE inhibitors as a drug candidate. Anyone who had any fears about the use of it, or other PDE inhibitors, for oral administration would have found that out from the published literature. Furthermore, even if the skilled man was not aware that PDE inhibitors had actually been used in such clinical trials, he would not have been put off trying oral administration. He would have been unable to predict whether there would be a problem associated with oral administration, or if there was its nature and magnitude and he would be reassured that if any significant problem did exist it would surface during the course of the tests necessary for regulatory approval, that is to say tests specifically designed as a filter to ensure no appreciable risk to the public. The result is that the skilled man or team in the art would not have been put off from trying to use a PDE inhibitor for oral administration. 
109.  The evidence supports the view that any worries about possible side effect or contra indications would not have been sufficient to prevent a worker in the field from trying out PDEs for administration to man, whether orally or otherwise. For example Dr. Challis’ evidence was:
“Q. 	Coming back again to paragraph 46 you are unable to point my Lord to any known PDE5 as at 1993 which was known to have life-threatening side-effects. 
A.	I am sorry, I have gone to the .... We are on 46? 
Q. 	Did I say 46. I should not have done. …
MR. THORLEY: I do apologize; it is my fault. Paragraph 65, top of page 29, you were talking about life-threatening consequences. That is what we were talking about and I am trying to ensure that I have got your evidence accurately. Do you want me to put the question again? 
A.	No. I am quite happy. I am saying that, I think the point that I am trying to get across there is that if one is thinking about the treatment of MED one has a good idea of what the patient population is going to be. It is going to be generally more elderly. I think the incidence of impotence increases essentially exponentially beyond the age of around 40, so we are dealing here with a group of patients that have potentially other health problems in their lives. We are dealing with a disorder that is in itself not life-threatening and, therefore, I think that anyone developing drugs in this area is going to be acutely aware of any side-effects, never mind life-threatening side-effects, but there is the potential of these drugs, I think, to cause life-threatening effects in people with particular other complicating disorders. 
Q. 	Are you saying that that concern would deter you from doing any development work in the field or are you saying that you would conduct development research with caution? 
A.	The latter.” 
(Day 5 Transcript page 700)
110.  He returned to the same theme on the next day:
“MR. THORLEY: … doctor, you said, if I recall rightly that because of these complications there could be no guarantee that a beneficial therapy could be produced. 
A.	No. 
Q.	By pursuing any particular route of potential treatment. 
A.	That is absolutely the case, yes. 
Q.	That is the point that you are seeking to make. 
A.	The point is that I believe .... The sildenafil example gives us a clear example of where, despite all of my provisos, a drug is extremely effective. Therefore, all I am doing is trying to make you aware of the complexities of the field. I am not saying that there was no point in travelling towards that therapeutic goal at all.” (Day 6 Transcript page 720)
111.  In addition to these points, I should refer to the evidence of Dr. Dennis Smith, the Senior Director of Pfizer’s Drug Metabolism Department and whose entire industrial career has been in the area of Drug Metabolism and Pharmacokinetics. He was asked by Pfizer to comment on what procedures would have formed a routine part of drug development programmes  in order to assess the oral bioavailability of a compound, as at June 1993 .  In particular, he was asked to comment on the use of conscious animals for this purpose as at that date. 
112.  He stated that oral bioavailability assessment of compounds using animals, such as the dog had certainly become a well known and routine part of drug development programmes by 1992.  He said that this was due to fundamental similarities between animals and man in the processes governing absorption of compounds from the gastrointestinal tract and subsequent appearance in the systemic circulation (from where the drug molecule exerts its pharmacological effect). He also said that such assessments are a routine aspect of selecting the appropriate drug molecules for clinical development. He supported that view by a reference to numerous published articles from various workers, from a large number of pharmaceutical companies. His report also contains the following:  
“I should say that in practice, oral bioavailability studies are not carried out on the full range of compounds studied in the course of a drug discovery programme, but only those which are considered to be the more promising candidates for further development.  For each compound being tested, such studies normally took approximately two to three weeks to carry out in 1993.  I should also point out that species differences in bioavailability between man and animal species, including dog, have been identified, which may mean that the data needs interpretation for prediction to man.  However, the assessment of oral bioavailability in animal species in 1993 and today remains an essential element of the preclinical assessment of novel drug candidates.  Increasingly in vitro systems have been put into place which facilitate this interpretation, but these are used alongside data on bioavailability in conscious animals.  Other animal species are used in addition to the dog in the assessment of oral bioavailability.  These include mice, rats and monkeys.  However, the extensive use of the dog in pharmacology studies and in drug safety evaluation within the pharmaceutical industry, results in the dog being amongst the most commonly used of the animal species.”
113.  Unsurprisingly, Lilly chose not to cross examine this witness. His evidence supports the view that it would have been a matter of course to try out any potential anti-MED candidate by oral administration to conscious animals, including dogs, and that any such testing would have taken a comparatively short time. That is what the skilled man in the art would have done.”
69.	Claims 10 and 11 -  If claim 11 is obvious, it is accepted that claim 10 must also be obvious.  It is therefore appropriate to consider claim 11 and when doing so to assume that the claimed inhibitors must be effective and causative in the treatment.  
70.	Claim 11 adds nothing inventive to claim 1.  The Murray article is concerned with the effect of PDEv inhibitors and in particular the reported effect upon vascular smooth muscle.  The suggestion was – “Smooth muscle relaxation appears to be the most promising of the potential uses of PDE VA inhibitors, and possible therapeutic utilities could include vasodilatory bronchodilation, modulation of gastroinestinal motility and treatment of impotence.” 
71.	The reasons for holding claim 1 obvious apply equally to claim 11.  
72.	Conclusion.  The judge was right to conclude that this patent was invalid as being obvious.  That being so, there is no need to consider the other objections to validity.  The appeal should be dismissed.  

Lord Justice Buxton:
73.	I agree.

Lord Justice Longmore:
74.	I also agree.