Neutral Citation Number: [2008] EWHC 1422 (Pat)
`
`IN THE HIGH COURT OF JUSTICE
`CHANCERY DIVISION
`PATENTS COURT
`
`
`Case No: HC0700 572
`
`Royal Courts of Justice
`Strand, London, WC2A 2LL
`
`Date: 30/06/2008
`
`Before :
`
`THE HON MR JUSTICE FLOYD
`- - - - - - - - - - - - - - - - - - - - -
`Between :
`
`ACTAVIS UK LIMITED
`- and -
`JANSSEN PHARMACEUTICA N.V.
`
`Claimant
`
`Defendant
`
`
`
`
`
`
`
`
`
`- - - - - - - - - - - - - - - - - - - - -
`- - - - - - - - - - - - - - - - - - - - -
`
`Roger Wyand QC and Piers Acland (instructed by Bird & Bird) for the Claimant
`Daniel Alexander QC and James Whyte (instructed by Linklaters LLP) for the Defendant
`
`Hearing dates: 14th -15th May, 19th May
`- - - - - - - - - - - - - - - - - - - - -
`Judgment
`
`Mr Justice Floyd :
`
`
`
`1.
`
`Actavis UK Limited seeks revocation of European Patent No 0 334 429 (“the Patent”)
`which is in the name of Janssen Pharmaceutica N.V. (“Janssen”). The Patent
`concerns the stereochemistry of an important blood pressure drug, nebivolol. Janssen
`has applied to amend certain claims of the Patent. Actavis maintains that the Patent,
`even if so amended would remain invalid for lack of novelty and lack of inventive
`step.
`
`The background and the common general knowledge
`
`2.
`
`There is very little dispute about the relevant technical background. I set out below
`the matters which formed part of the relevant common general knowledge.
`
`Hypertension and anti-hypertensive agents
`
`3.
`
`4.
`
`Hypertension is the technical name for high blood pressure. Three main classes of
`agent were used to treat hypertension in 1988: β-blockers, diuretics and vasodilators.
`
`β-blockers are so named because they block the action of endogenous compounds
`such as adrenaline on certain receptors in the body, the so-called β-adrenergic
`receptors. There are two sub types of β-receptor: β1 and β2. The former are to be
`found in the heart and kidneys; the latter are found in the lungs.
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-1
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`Actavis v Janssen
`
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`Early β-blockers were non-selective in that the drug would block both β1 and β2
`receptors. This meant that if these early drugs were used to treat angina (in the heart
`muscle) in patients who also had asthma, there was the potential for serious side
`effects, as the receptors in the lung (undesired) would be blocked along with the
`receptors in the heart (desired). The second generation of β-blockers therefore
`focussed on drugs with β1 selectivity. Drugs with a high ratio of β1 to β2 activity were
`therefore developed.
`
`The precise mechanism of action of β-blockers in lowering blood pressure was not
`fully elucidated in 1988. It was, however, known that they reduced cardiac output
`(both heart rate and force of contraction) but were also associated, at least in the short
`term, with vasoconstriction, which acts as a drag on the blood pressure lowering
`effect of the β-blocker. So use of a β-blocker might not be associated with an
`immediate drop in blood pressure.
`
`In 1988 the focus of drug development was a third generation of β-blockers, in which
`the compound has additional pharmacological properties.
`
`Labetalol was one of the first of this third generation. It combined non-selective β-
`blockade with α-adrenergic receptor blockade (blocking the vasoconstrictor effects of
`noradrenaline). It was marketed as a racemate of four stereoisomers (see below). The
`α- and β-blockade reside principally in separate isomers. This aspect of the drug
`attracted particular interest at the time it was launched.
`
`Diuretics increase the rate at which sodium is excreted from the body in urine. This
`has the effect of reducing the amount of water and sodium in the body, which reduces
`the pressure on the walls of the blood vessels.
`
`Vasodilators dilate blood vessels. The result is that they reduce vascular resistance
`and hence blood pressure, because the diameter of the blood vessels increases.
`
`Step care management
`
`11.
`
`The treatment of hypertension with β-blockers together with a diuretic and/or
`vasodilator, known as “step care” management, was well known. The rationale of
`this approach is to alleviate the body’s natural response to a fall in blood pressure
`when treated with β-blockers alone. A vasodilator will counter this effect.
`
`Animal models
`
`The standard animal models used for studying hypertension in 1988 included
`normotensive (normal blood pressure) and hypertensive (raised blood pressure)
`models. The blood pressure response in normotensive models would be smaller than
`the response seen in hypertensive models. There were various hypertensive models
`available. For rats, investigators would often clamp the renal arteries which had the
`effect of raising its blood pressure due to reducing blood supply to the kidney and
`increasing release of the hormone renin. Another model was a strain of rat from
`Japan known as the spontaneously hypertensive rat.
`
`12.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-2
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`13.
`
`Actavis v Janssen
`
`Tissue and organ preparations also existed and were used routinely for investigating
`β-blocker activity. The effect of the candidate drug would be assessed in its ability to
`counter the effects of a β-agonist on the tissue or organ in question.
`
`Stereochemistry
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`The underlying concepts of stereochemistry have been described in a number of
`judgments: see e.g. the summary by Kitchin J in Generics v Lundbeck [2007] EWHC
`1040 (Pat); [2007] RPC 32 at [12]-[17].
`
`This case concerns the stereochemistry of compounds with more than one chiral
`centre. In theory a structure with a number of chiral centres, (say N), will exist as 2N
`stereoisomers. So a structure such as that with which we are concerned in this case,
`with four chiral centres, could in theory have 16 stereoisomers. These stereoisomers
`consist of pairs of enantiomers, and there will be half of 2N, or 2(N-1) of these pairs.
`This is not always true, however, because in symmetrical molecules some of the
`stereoisomers will be the same.
`
`A simple example is tartaric acid which has two chiral centres, and would therefore be
`expected to have four stereoisomers. In fact it has only three. In the diagram below
`enantiomers C and D are identical, because rotating one about the vertical axis makes
`it so:
`
`
`Compunds which have chiral centres but which are in fact achiral are called meso
`compounds.
`
`It is common ground that by the priority date there was pressure from the regulatory
`bodies including the FDA in the United States and the Japanese Ministry of Health to
`provide information about individual isomers.
`
`The expert witnesses
`
`Actavis called two expert witnesses, Professor John Reid and Professor Roger
`Newton as their expert pharmacologist and medicinal chemist respectively.
`
`Professor Reid is Regius Professor of Medicine and Therapeutics and Head of the
`Division of Cardiovascular and Medical Sciences at the University of Glasgow. From
`1987 to 1993 he was Editor in Chief of the Journal of Hypertension, a well known
`international publication in the field of high blood pressure research and its treatment.
`After qualifying in Medicine from Oxford University in the late 1960s he spent over
`10 years at the Royal Postgraduate Medical School/Hammersmith Hospital in London
`training and conducting research
`in clinical pharmacology and new drug
`development. The principal interest of his group was blood pressure treatment and
`
`19.
`
`20.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-3
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`
`Actavis v Janssen
`
`21.
`
`the investigation and optimisation of β-blockers for the treatment of hypertension and
`other cardiovascular diseases. He was very well qualified to give evidence on the
`pharmacological aspects of the case.
`
`Professor Newton was employed by Glaxo from 1971 to 1996 as a medicinal chemist
`in their chemistry division. Whilst at Glaxo, his areas of research included drugs for
`the treatment of cardiovascular, central nervous system and infectious diseases. For
`eight years he directed the company's global research into respiratory diseases. He
`joined Glaxo, as a senior research chemist and eventually became the director of the
`Chemical Research Division of Glaxo. He was also the Resident Medicinal Chemist
`in the Chemistry Department at the University of Cambridge from 1996 until 2005
`and is Visiting Professor at the University of Sussex. His PhD was in the
`stereochemistry of compounds with bridgehead nitrogen atoms. Professor Newton
`has now given evidence in a large number of disputes concerning medicinal
`chemistry, a fact to which Mr Alexander QC (who appeared for Janssen with Mr
`James Whyte) drew attention in cross-examination. His evidence is not less useful as
`a result.
`
`22.
`
`Janssen called only one expert, Professor Caldwell, who is the Dean of the Faculty of
`Medicine in the University of Liverpool. He played an important role in the re-
`emergence of stereochemistry as a factor in drug development. Since 1980 he has had
`an extensive consulting practice concerned with aspects of drug discovery and
`development including several programs related to hypertension and β-blockers.
`
`23. Mr Wyand QC (who appeared for Actavis with Mr Piers Acland) said that there was a
`contrast between the oral evidence of Professor Caldwell and his expert report. There
`is some force in that, in that points taken firmly in his report seemed to dissolve under
`cross-examination. An example is his challenge in his second report to Professor
`Newton’s assertion that the ratio of RSSS to SRRR isomers would be 1:1. Under
`cross-examination he said that if it were anything other than a racemate it would be
`surprising. Whilst I have not ignored his report, I have relied primarily on the oral
`evidence Professor Caldwell gave where there is a dispute between him and
`Professors Reid or Newton.
`
`Witnesses of fact
`
`24.
`
`25.
`
`Actavis served fact witness statements from Professor Stephen Curry and Mr Martin
`Barkworth. Only the former was cross-examined (by video-link). He was a good
`witness.
`
`Jannssen called Mr Woestenborghs to give evidence about a prior disclosure. He had
`no real recollection of the relevant events, and was understandably reluctant to accept
`that he had disclosed the invention, with the consequences that might entail. This led
`him, I thought, to cling on to somewhat unlikely explanations as to what might have
`happened.
`
`Nebivolol
`
`26.
`
`Although not part of the relevant common general knowledge, it is worth noting what
`nebivolol is.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-4
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`27.
`
`The general chemical structure of nebivolol is as follows:
`
`Actavis v Janssen
`
`
`
`
`
`
`
`28.
`
`This structure contains four chiral centres:
`
`29.
`
`
`If all R and S combinations were distinct, the structure would embrace eight pairs of
`enantiomers. However, owing to the symmetry of the molecule around the central
`nitrogen atom, some of these configurations are duplicative. In summary, there are
`four pairs of enantiomers and two meso forms, a total of ten enantiomers.
`
`30.
`
`Nebivolol comprises a 1:1 mixture of two isomers: the SRRR and the RSSS. The
`former is referred to as d-nebivolol and the latter as l-nebivolol.
`
`The Patent
`
`31.
`
`32.
`
`The Patent has an unchallenged priority date of 23rd March 1988. It is entitled
`“Agents for lowering the blood pressure”.
`
`The Patent begins by saying that United States Patent No 4,654,362 (the “362 patent”
`cited as prior art in this case) describes a class of 2,2’-iminobisethanol derivatives
`having β-blocking activities. It identifies the discovery underlying the Patent in the
`following terms:
`
`It has now been found that a certain class of isomers of said
`bisethanol derivatives potentiate the activity of blood pressure
`reducing agents.
`
`33.
`
`There follows a clause describing the invention in similar terms to the “use” claim of
`claim 1. The compounds for use in the invention are defined by a general formula (I)
`indicating the stereochemistry of the four chiral centres with the letters R and S:
`
`
`The invention is said to be concerned with the use for the manufacture of a
`medicament for potentiating the effects of blood pressure reducing agents having
`
`34.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-5
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`
`Actavis v Janssen
`
`35.
`
`36.
`
`37.
`
`adrenergic and/or vasodilating activity, other than the agents of formula (I), of a
`compound of formula (I).
`
`The complex wording is the result of a desire to claim the invention in so called
`“Swiss” form. In short it is saying: use of an RSSS to potentiate blood pressure drugs
`(other than another RSSS).
`
`The compounds for use in the invention are therefore the RSSS isomers of the class of
`compounds. The most preferred compound at page 2 lines 35-36 is the compound in
`which R5 and R9 are fluoro-, with the remaining substituents all hydrogen. That
`compound is l-nebivolol:
`
`
`The specification then proceeds to explain in detail how the compounds of formula (I)
`can be prepared by stereo-specific synthesis. The final step in the synthesis is to react
`an RS oxirane with an SS amine (or an SS oxirane with an RS amine). Examples 1-3
`describe the synthesis of l-nebivolol.
`
`38.
`
`At page 4 line 15 the specification says this:
`
`
`The patentee is acknowledging in this passage that one of the RSSS compounds is not
`novel. The RSSS compound in question is the RSSS isomer of the preferred
`compound of the 362 patent. That compound is the one in which all the substituents in
`the general formula 1 are hydrogen. Its RSSS isomer is specifically characterised in
`362.
`
`The specification gives a long list of blood pressure reducing agents which are
`potentiated by the compounds of formula (I). A particular group is said to be the
`compounds of the cited 362 patent. The SRRR enantiomers are singled out and d-
`nebivolol specifically mentioned.
`
`At page 4 line 55 a further aspect of the invention is described, namely a composition
`comprising an amount capable of potentiating the effects of blood pressure reducing
`agents of a compound of formula (I) together with a blood pressure reducing agent. A
`favoured ratio of the two ingredients is said to be 1:1.
`
`In addition to examples describing the synthesis of the RSSS compounds, the
`specification also contains pharmacological examples. These experiments comprised
`blood pressure and heart rate measurements on the spontaneously hypertensive rat – a
`well known animal model. They compared the effect of administering (a) l-nebivolol
`alone (b) known hypertensive agents and (c) the combination. The experiments were
`done at two dosage rates. The results show that whilst, on the whole, l-nebivolol alone
`had little or no effect, it greatly improved the performance of the known agents.
`
`39.
`
`40.
`
`41.
`
`42.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-6
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`The claims
`
`43.
`
`Claim 1 is to
`
`Actavis v Janssen
`
`The use for the manufacture of a medicament for potentiating
`the effects of blood pressure reducing agents having adrenergic
`and/or vasodilating activity, other than the agents of formula (I)
`as defined hereinafter, of a compound of the formula (I)… or a
`pharmaceutically acceptable acid addition salt, wherein
`[definitions follow]
`
`44.
`
`45.
`
`I have set out formula (I) above, and nothing turns on the definitions of the various
`generalised radicals R1 to R10.
`
`Claim 3 claims the use according to claim 1 wherein the compound used is l-
`nebivolol.
`
`46.
`
`Claim 4 is for
`
`A pharmaceutical composition comprising a pharmaceutically
`acceptable carrier, a compound of formula (I) as defined in any
`of claims 1 to 3, and a blood pressure reducing agent having
`adrenergic and/or vasodilating activity, said agent being other
`than the said compound of formula (I).
`
`47.
`
`48.
`
`49.
`
`50.
`
`Claim 5 claims a claim 4 composition where the blood pressure agent is selected from
`a list of known agents.
`
`Claim 6 claims a claim 4 composition where the agent is d-nebivolol. So here the
`claimed composition is the RSSS and SRRR enantiomers of the same structural
`formula.
`
`Claim 7 claims the claim 5 or 6 composition when the molar ratio is 1:1.
`
`Claim 7, as dependent on claim 6, as dependent on claim 4, as dependent on claim 3 is
`a claim to a 1:1 mixture of RSSS and SRRR nebivolol. This is the mixture of isomers
`which is marketed as nebivolol. Only claims 4, 5, 6 and 7 (not claim 3) are defended
`as independently valid.
`
`Construction
`
`Use … for potentiating
`
`51.
`
`Claims 1-3 are use claims. In G2/88 MOBIL/Friction reducing additive [1990] EPOR
`73, the Enlarged Board of Appeal of the EPO held that:
`
`In relation to a claim whose wording clearly defines a new use
`of a known compound, depending upon its particular wording
`in the context of the remainder of the patent, the proper
`interpretation of the claim will normally be such that the
`attaining of a new technical effect which underlies the new use
`is a technical feature of the claimed invention.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-7
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`52.
`
`Actavis v Janssen
`
`Later the Board explained what might be meant by the technical effect being “a
`technical feature of the invention”. It was that
`
`“the compound actually achieves the particular effect.”
`
`53.
`
`54.
`
`In the present case I see no difficulty in construing claim 1 as restricted to the use of
`the RSSS isomers in such a way as actually to achieve the technical effect, namely the
`potentiation of another (non RSSS) blood pressure drug. I would have done so
`whether the claim related to a “new use of a known compound” or not. That latter
`issue is something that I consider in its proper place, under the heading of novelty
`below.
`
`The parties also debated the meaning of “potentiating”. I think “potentiating”
`probably means no more than “improving the effect of”. Obviously the blood
`pressure reducing drug is not required to be inactive in the absence of the potentiating
`agent. Further, I do not think that the word says anything about what the potentiating
`agent does in the absence of the other drug. It could be active in some way in its own
`right, or it might not. I do not think the precise meaning of “potentiate” has a bearing
`on the outcome of the dispute however.
`
`Other components
`
`55. Mr Alexander submitted that the pharmaceutical composition claims (before
`amendment) were limited to a compound of formula (I) and a single blood pressure
`reducing agent. He sought to draw an analogy with the construction of the claim to an
`enantiomer (and a pharmaceutical composition containing it) adopted by Kitchin J in
`Generics v Lundbeck [2007] EWHC 1040 (Pat); [2007] RPC 32 at [60]. Seeking to
`draw analogies with decided cases about different claims in different patents is not a
`fruitful or legitimate use of authority. It is sufficient to say that in Generics v
`Lundbeck the whole point of the invention was the isolation of the enantiomer from its
`counterpart. In the present case the object of the invention is quite different: using the
`enantiomer to potentiate other agents, which expressly include the counterpart
`enantiomer. If SRRR is allowed to be present as a blood pressure reducing agent, why
`not other isomers or indeed anything else which fits the description “a blood pressure
`reducing agent”?
`
`The analogy apart, Mr Alexander submitted that the Court should not, if it can help it,
`arrive at a construction of the claim which has the result that the claim will read on to
`prior art referred to in the patent. That is a valuable canon of construction which has
`been relied on in a number of cases: see Beloit Technologies Inc v Valmet Paper
`Machinery [1995] RPC 705 at 720 lines 30-33, and Ultraframe v Eurocell Building
`Plastics [2005] EWCA Civ 761; [2005] RPC 36 at [47], but it is not a rigid rule: see
`Lewison J’s discussion of the principles in the Ultraframe case at first instance [2004]
`EWHC 1785 at [72] to [73].
`
`In the present case, Mr Alexander argues that 362, which is referred to in the Patent,
`would anticipate the composition claims unless they are construed as limited to
`mixtures of a compound of formula (I) and one (and only one) blood pressure
`reducing agent. 362 discloses a preferred compound which includes an RSSS isomer
`and multiple other isomers (i.e. compound 76 which must include RSSS as well as a
`number of isomers which have adrenergic activity). That mixture inevitably falls
`
`56.
`
`57.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-8
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`
`Actavis v Janssen
`
`within the claim (widely construed) once made into a pharmaceutical composition,
`which is something expressly taught by 362. Mr Alexander develops the argument by
`pointing out that in claim 4 the patentee has appreciated the need not to claim a given
`RSSS in combination with itself – how could he have overlooked the need to disclaim
`combinations of RSSS with more than one other blood pressure reducing drug?
`
`58. Mr Alexander supplements this argument with the further point that claim 5 refers to
`“the blood pressure reducing agent of claim 4”: implying, he says, that there is only
`one of them. I do not think there is anything in this supplementary point: the
`implication is not a necessary one.
`
`59. Mr Wyand submits that the word “comprising” in claim 4 is the term conventionally
`used to indicate the threshold requirements of the claim: the word “consisting”
`generally being used when a negative requirement is what is meant. So much is
`recognised by the application to amend. Thus, claim 4 requires a mixture which may
`have more than one of each of the following: a pharmaceutically acceptable carrier, a
`compound of formula (I) and a different blood pressure reducing agent.
`
`60.
`
`I prefer Mr Wyand’s submissions. Whilst, when confronted with the effect of 326 on
`the composition claims, the patentee might wish his claims to be limited to a
`compound of formula (I) and a single blood pressure reducing agent (or at least to a
`single agent of same structural formula), I cannot see in general why he would wish
`his claims to be so circumscribed. The discovery on which the invention is based,
`that RSSS will potentiate a wide range of blood pressure reducing agents would apply
`as much to compositions with a single agent to compositions with multiple agents. I
`cannot see any way of writing into the claim a specific exclusion when the other
`agents are those which occur when 362 is carried out.
`
`61. Mr Alexander argued rather more faintly for a similar limitation in claim 1, the use
`claim. Here, it seems to me, he is on weaker ground still. The use is:
`
`“for potentiating the effects of blood pressure reducing agents”.
`
`62.
`
`The use of the plural is particularly ill-adapted to limit the claim to a singular blood
`pressure reducing agent. Moreover Mr Alexander cannot ask his forensic (Beloit)
`question about 326 here. In addition to acknowledging 326 as prior art, the Patent
`acknowledges that the preferred compound of 326 is old: see page 4 lines 15-17. The
`skilled person would therefore understand that the patentee thought that he was
`overcoming the effect of 326 on the novelty of claim 1 by claiming the invention in
`use form. He would see no reason to read limitations into the claim to create further
`distinctions with 326 based on what is (or rather is not) present in the medicine.
`
`The proposed amendment
`
`Janssen has applied to amend claim 4 to substitute the words “consisting of” for
`“comprising”. The amendment has a corresponding narrowing effect on claims 5, 6
`and 7.
`
`Actavis does not oppose the amendment. Moreover, it accepts that the amendment
`has an effect, as it no longer argues that claims 4, 6 and 7 lack novelty. Actavis
`contends that the claims as so amended remain obvious.
`
`63.
`
`64.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-9
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`The validity attacks
`
`Actavis v Janssen
`
`65.
`
`The grounds on which validity is attacked are lack of novelty and obviousness. There
`are two main starting points for these attacks. The first is an earlier Janssen patent in
`the field (“the 362 Patent” or “362”). The second is an alleged oral (or more precisely
`oral and visual) disclosure at a meeting in Guildford (“the Guildford Forum”). A
`further attack based on the disclosure of a written version of the oral and visual
`disclosure for the purposes of its inclusion in the conference proceedings, was not in
`the end pressed on me as an independent starting point.
`
`The 362 Patent
`
`66.
`
`362 discloses a class of derivatives of 2,2’-iminobisethanol. In column 1 it is pointed
`out that:
`
`67.
`
`The general formula for the compounds is shown below:
`
`
`
`68.
`
`
`All the compounds actually prepared in the examples have a core structure where the
`variables A1 and A2 simply close the ring structures with a direct bond. So the core
`structure is as shown in the formula below, in which the chiral centres are marked 1-
`4:
`
`69.
`
`
`362 points out (column 4 lines 34-39) that “it is evident” that the compounds of the
`invention may have several asymmetric carbon atoms. At lines 40-58 it continues:
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-10
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`
`Actavis v Janssen
`
`70.
`
`
`362 does not go to the extent of determining the absolute stereochemical
`configurations of the compounds and their precursors. Instead, it uses its own
`nomenclature by identifying the first isolated material from a separation as “A” and
`the second as “B”. So a final compound put together from an A oxirane and B amine
`would be designated “AB”. Professor Newton considered that 362 would convey to
`the skilled reader that the AB configuration was favoured. I accept his evidence on
`this point.
`
`71.
`
`At column 5, 362 elaborates on the properties of the compounds as follows:
`
`
`It is common ground that the reference to “disorders of the coronary vascular system”
`in the passage quoted above would be read as “disorders of the cardiovascular
`system”.
`
`Thus the compounds of 362 are put forward as being strong β- blockers and
`importantly selective β1- blockers which combine with vasodilating properties to
`produce a useful antihypertensive activity. It is important to bear in mind that the
`
`72.
`
`73.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-11
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`
`Actavis v Janssen
`
`reader is not told anything about where, amongst the various enantiomers present, the
`activity lies.
`
`74.
`
`The specification goes on to say that
`
`In view of their useful properties in the treatment and the
`prevention of disorders caused by the coronary vascular
`system, the subject compositions may be formulated into
`various pharmaceutical forms.
`
`75.
`
`76.
`
`77.
`
`78.
`
`Accordingly, there can be no doubt that the specification of 362 discloses the use in
`the manufacture of a medicine of the compounds which 362 specifically describes. It
`also describes pharmaceutical compositions which comprise the specific compounds.
`
`362 itself concentrates on a preferred compound, compound 76, in which all the
`substituents are hydrogen. 362 discloses that the individual enantiomers of that
`compound have been made and tested.
`
`Actavis focuses attention on a different compound, compound 84. Compound 84 has
`the same structural formula as nebivolol. The isomeric form is listed as AB. It is
`common ground that the skilled person would understand from the disclosure of 362
`that compound 84 was a mixture of two pairs of enantiomers. The two pairs are (1)
`SRRR and RSSS (in fact d- and l- nebivolol) and (2) two further isomers, namely
`RSRR and SRSS.
`
`Table 1 in column 25 of the ‘362 Patent shows the biological activities of a selection
`of the final compounds, some of which are individual stereoisomers and others are
`mixtures. The data are based on the guinea pig atrium model which provides a
`measure of β1-receptor blockade and the guinea pig tracheal ring model which
`provides a measure of the effect on β2-receptors. The ED50 ratio for β2/β1-antagonism
`provides a measure of cardioselectivity – the higher the value the better. Compound
`84 is one of the top 4. It has the favoured AB configuration. Compound 79, which is
`a single stereoisomer of the preferred compound, is not far behind.
`
`79.
`
`Table 1 does not provide any information to back up the claim to vasodilating
`properties.
`
`Lack of novelty over 362
`
`80.
`
`The law of novelty has recently been reviewed by the House of Lords in Synthon v
`SmithKline Beecham [2006] RPC 10. Lord Hoffmann, having reviewed the authorities
`said:
`
`If I may summarise the effect of these two well-known
`statements, the matter relied upon as prior art must disclose
`subject-matter which, if performed, would necessarily result in
`an infringement of the patent.
`
`Does 362 disclose subject matter which, if performed, would necessarily infringe
`claim 1 of the Patent? Actavis rely exclusively on Compound 84. The manufacture
`of a pharmaceutical composition (a medicament) using compound 84 as active
`
`81.
`
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1049-12
`IPR2016-00379
`
`

`
`THE HON MR JUSTICE FLOYD
`Approved Judgment
`
`
`
`Actavis v Janssen
`
`82.
`
`83.
`
`ingredient is disclosed in 362. Compound 84 will contain the RSSS isomer, as well as
`the SRRR isomer and the other stereoisomeric pair of RSRR and SRSS. The
`composition will have adrenergic and/or vasodilating properties as required by claim
`1 and as taught by 362.
`
`There is clearly no express teaching in 362 that the RSSS isomer is potentiating the
`effect of any of the other isomers as blood pressure reducing agents. In the light of the
`way I have construed claim 1, a first question is whether, if compound 84 is used in
`the manufacture of a medicine, the RSSS isomer will in fact potentiate the effects of
`another blood pressure reducing isomer.
`
`The starting point is that we know (now) that when a medicine is made from only
`RSSS and SRRR the former does potentiate the latter. So much is clear from the data
`in the Patent. There is no direct evidence as to what happens when all four isomers
`are present. Professor Caldwell was of the view that it was not possible to predict for
`certain, from the behaviour of one pair of enantiomers, what would happen if all four
`were tested together:
`
`A. Yes, but the reason that I am being less than direct in
`answering, not answering your question directly, is that to me
`you are assuming that the other pair is completely inert of any
`activity at all. If I tested all four together, yes, I see beta-
`blockade. I have no evidence that if I tested, in the same way
`that we have here -- set aside semantics for the moment -- a
`potentiation, an interesting interaction between those two
`enantiomers, one looks like it does not do very much until you
`put it in with the other one. We must not assume that the other
`two enantiomers that to my knowledge have not been
`examined, we must not assume that they are silent and of no
`consequence. You are assuming that when you test compound
`84 that you will get this nice division of activity and so on, and
`I just do not know anything at all about the other enantiomers
`that enables me to... You know, I can quite understand
`experimenters would hope that we would have the situation that
`you have got but we are talking here about testing a mixture of
`four compounds together. We have seen how mixtures of two
`can have interesting effects but teasing those things apart, and I
`am asked to predict the kind of answers I might expect to see, I
`just do not know. I have seen far too many instances of
`interactions of a whole variety of types between enantiomers to
`do anything other than raise it as an issue at this stage.
`
`These remarks