`Neutral Citation Number: [2014] EWHC 1094 (Pat)
`
`
`
`
`IN THE HIGH COURT OF JUSTICE
`CHANCERY DIVISION
`PATENTS COURT
`
`
`Case No: HC12C03487
`
`Royal Courts of Justice, Rolls Building
`Fetter Lane, London, EC4A 1NL
`
`Date: 10/04/2014
`
`Before:
`
`MR JUSTICE BIRSS
`- - - - - - - - - - - - - - - - - - - - -
`Between :
`
`HOSPIRA UK LIMITED
`- and -
`GENENTECH INC.
`
`Claimant
`
`Defendant
`
`
`
`
`
`
`
`
`
`
`- - - - - - - - - - - - - - - - - - - - -
`- - - - - - - - - - - - - - - - - - - - -
`
`Richard Meade QC, Tom Mitcheson and Jeremy Heald (instructed by Taylor Wessing) for
`the Claimant
`Michael Tappin QC and Mark Chacksfield (instructed by Marks & Clerk) for the
`Defendant
`
`Hearing dates: 6th, 7th, 10th, 11th, 12th, 13th, 14th, 18th and 19th March 2014
`- - - - - - - - - - - - - - - - - - - - -
`Approved Judgment
`I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this
`Judgment and that copies of this version as handed down may be treated as authentic.
`
`
`.............................
`
`THE HON. MR JUSTICE BIRSS
`
`
`
`
`
`
`Pfizer Ex. 1025
`Page 1 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`
`
`Mr Justice Birss:
`
`Contents
`Introduction
`The issues
`The witnesses
`The 115 patent
`The skilled person and the common general knowledge
`The 115 patent specification
`Claim construction
`Obviousness
`Obviousness – the FDA label
`Pharmacokinetics
`The reaction of the clinician
`Obviousness - conclusion
`Sufficiency
`Priority
`The 455 patent
`The skilled team
`Common general knowledge
`The 455 patent specification
`Claim construction
`Novelty
`Andya
`The disclosure of Andya compared to claim 1
`Obviousness
`Waterside
`Andya – obviousness
`Obviousness over common general knowledge in general
`Obviousness over common general knowledge based on Protein A
`Declaration of non-infringement
`Conclusion
`
`Introduction
`
`Hospira v Genentech
`
`Paragraph
`1
`12
`22
`32
`32
`43
`56
`65
`68
`84
`114
`118
`119
`144
`163
`163
`164
`174
`185
`194
`195
`202
`218
`219
`243
`248
`249
`264
`268
`
`Like all cancers, breast cancer is not a single disease. Much depends on the particular
`kind of cells which have become cancerous. The conventional therapeutic approaches
`were surgery, radiotherapy and chemotherapy or combinations of these various
`options. The agents used for chemotherapy were and are powerful drugs which are
`cytotoxic (i.e. cell killing). These drugs include Taxol (the trade name of paclitaxel),
`5-flourouracil and many others. Generally these agents attack rapidly dividing cells.
`This will include cancer cells but will also include other rapidly dividing cells in the
`body. That is why hair loss can be a side effect of chemotherapy.
`
`Some types of breast cancer can be treated with hormone therapy (such as Tamoxifen)
`but other types of breast cancer do not respond to hormone therapy. One class of
`breast cancers which was particularly difficult to treat was those in which the cells
`over-expressed a receptor known as HER2. The HER2 receptor (also known as the
`ErbB2 receptor) belongs to a class of receptors in the epidermal growth factor
`
`1.
`
`2.
`
`
`
`Pfizer Ex. 1025
`Page 2 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`Hospira v Genentech
`
`receptor (EGFR) family. 20% to 30% of breast cancers were classified as HER2
`positive. They had a poor prognosis.
`
`In general in pharmacology higher selectivity means that a drug can be given at an
`effective dose with fewer side effects. In other words the margin between safety and
`efficacy generally improves as selectivity increases. Thus an agent which could be
`targeted more closely to cancer cells in particular could be given at a higher dose in
`order to improve its efficacy, without compromising safety.
`
`A major breakthrough in breast cancer therapy in recent years has been the
`availability of an agent known as Herceptin. Herceptin is the brand name of a
`monoclonal antibody called trastuzumab. This antibody targets the HER2 receptor. It
`was developed by Genentech and Roche.
`
`Trastuzumab is different from conventional chemotherapeutic agents in a number of
`ways. Two important points stand out in the context of this case. First, it is highly
`targeted to a particular group of cancer cells, which in general terms means that the
`window between safety and efficacy is improved. Second, trastuzumab was at the
`time a new class of agent - a monoclonal antibody. Whereas conventional drug
`molecules are small, antibody molecules are large proteins. This difference has
`consequences relating to the manufacture and formulation of the drug and may also
`affect the manner in which the drug behaves in the body.
`
`Before Herceptin was approved in the USA and then later in Europe, those working in
`oncology had heard about it. The positive results of a Phase II clinical trial were
`published in March 1996 and in May 1998 the results of the Slamon trial were
`published at ASCO. In September 1998 Herceptin was approved by the FDA in the
`United States and in Europe it was approved in August 2000. Herceptin has been and
`remains a huge success. Worldwide sales from 1999 to 2013 totalled 49 billion Swiss
`Francs (£33 billion at present exchange rates) which includes European sales from
`2010 to 2013 of 8 billion Swiss Francs (£5 billion).
`
`Hospira sells generic medicines, particularly in the cancer field. It wishes to sell a
`generic form of trastuzumab in the UK. Hospira does not challenge the basic
`underlying patent held by Genentech on trastuzumab (EP 0 590 058). The
`supplementary protection certificate for that patent (SPC/GB04/015) expires on 28th
`July 2014. Hospira wishes to sell its generic trastuzumab product after that date.
`Genentech holds a number of patents of a later vintage which Hospira might infringe.
`Hospira contends that the patents are invalid and has brought this action to invalidate
`them. There is also a claim for a declaration of non-infringement in relation to one
`patent. When the case began there were three patents in suit but Genentech offered to
`surrender one of them a few months ago.
`
`The two patents in suit are EP 1 210 115 entitled “Dosages for treatment with Anti-
`ErbB2 antibodies” and EP 1 308 455 entitled “A composition comprising anti-HER2
`antibodies”.
`
`The application for the 115 patent was filed on 25th August 2000 claiming priority
`from two US applications, the first being filed on 27th August 1999. It was granted on
`5th August 2009. The claims concern a dosing regimen for trastuzumab.
`
`
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`
`
`Pfizer Ex. 1025
`Page 3 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`Hospira v Genentech
`
`
`
`10.
`
`11.
`
`The application for the 455 patent was filed on 3rd May 1999 claiming priority from a
`US filing on 6th May 1998. It was granted on 22nd March 2006. The claims concern a
`composition of trastuzumab with less than certain thresholds of certain impurities.
`
`Both patents were opposed in the EPO. In both cases the Opposition Division has
`held the patent is invalid. Both are presently under appeal before the Technical Board
`of Appeal. The parties did not know when the appeals are likely to be heard. Even if
`either appeal succeeds it may not bring the EPO proceedings to an end because in that
`event the Board may remit the case to the Opposition Division.
`
`The issues
`
`The 115 patent relates to the use of a particular dosing schedule of trastuzumab to
`treat breast cancer. The dosing schedule involves administering trastuzumab every
`three weeks whereas the existing schedule was weekly.
`
`Hospira contends that the claims of the 115 patent are not entitled to the earliest
`claimed priority date. Genentech maintains the claim to priority but accepts that if
`priority is lost the patent is invalid. Hospira also contends that even if entitled to
`priority, the patent is invalid. The invention is said to be obvious over the state of the
`art at the earliest priority date. The key item of prior art is the FDA label for
`Herceptin which was published when the product was approved by the FDA.
`Genentech accepts the FDA label is prior art but does not agree it makes the claimed
`dosing regimen obvious.
`
`Hospira’s primary case is that the invention is obvious but if the claims of the 115
`patent do involve an inventive step then Hospira contends the patent is insufficient.
`Hospira argues essentially that if it was inventive to conduct a clinical trial over what
`was known from the prior art then the same logic will apply starting from the patent
`and the result must be insufficiency. Although it is true that the patent specification
`does contain more data than was in the state of the art, Hospira point out that the
`patent specification does not contain the result of a clinical trial of the claimed dosing
`regimen. Genentech does not agree with this either as a matter of reasoning or on the
`facts. It points out that the claimed dosing regimen is in fact safe and effective to treat
`the disease. Genentech also argues that, unlike the position over the prior art, a
`skilled person reading the patent in the light of their common general knowledge will
`have sufficient confidence to conduct a clinical trial.
`
`Finally Hospira advanced a case based on added matter but by closing it became clear
`that the point does not need to be addressed.
`
`The only relevant claim of the 115 patent is claim 1. In response to the way in which
`the arguments on priority developed, Genentech made an application to amend the
`claim to include a reference to “intravenously”. By the closing this was the only
`claim to be focussed upon.
`
`The 455 patent is concerned with purifying trastuzumab and claim 1 relates to a
`composition of trastuzumab with less than about 25% of certain acidic variants of the
`antibody. Hospira argues that claims 1, 2 and 4 lack novelty over a previous
`Genentech PCT application PCT/US96/12251 (“Andya”) which was published as WO
`97/04801 on 13th February 1997 and entitled “Stable Isotonic Lyophilised Protein
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`
`
`Pfizer Ex. 1025
`Page 4 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`
`
`Hospira v Genentech
`
`Formulation”. Andya describes stability tests on various trastuzumab formulations.
`Hospira contends Andya is an enabling disclosure of a composition of trastuzumab
`with 82% native protein and therefore no more than 18% acidic variants. Genentech
`does not agree. In addition to a point about exactly what is disclosed, the main debate
`over Andya concerns enablement. Hospira also contends that Andya makes all claims
`of 455 obvious.
`
`18.
`
`19.
`
`20.
`
`21.
`
`Hospira also relies on slides presented at a conference called The Waterside
`Monoclonal Conference in April 1996 (Waterside). These slides present analytical
`data in the context of phase III trials of trastuzumab for breast cancer. Hospira
`contends that the invention in 455 is obvious starting from these slides or from the
`common general knowledge alone. Genentech denies this.
`
`The argument over common general knowledge alone has two distinct strands. One
`adds little to the obviousness argument over Andya and Waterside. At this stage it is
`enough to note that the other argument involves considering what the levels of acidic
`variants were in the starting material used in the patent, which came from a Protein A
`affinity purification step.
`
`Hospira advanced an insufficiency case on 455 but by closing it became clear that the
`point does not need to be addressed.
`
`Hospira sought a declaration of non-infringement in relation to certain trastuzumab
`formulations which they propose to sell in the UK if they cannot invalidate any or all
`claims of the 455 patent. I made the order granting the declaration during the trial,
`with reasons to be given in this judgment.
`
`The witnesses
`
`22.
`
`23.
`
`Hospira’s first witness relating to the 115 patent was Dr Robert Earhart. He has
`worked in academia and in industry as a physician and clinical pharmacologist since
`1975. In 1995 he joined Rhone-Poulenc Rorer and was responsible for clinical trials
`on the chemotherapeutic agent docetaxel (Taxotere). His evidence was concerned
`with pharmacokinetics. His view was that if a clinician had asked him to consider a
`clinical trial of a three weekly dosing regimen of trastuzumab, then based on a
`consideration of the information in the FDA label, he would advise that there was no
`reason not to conduct such a trial on pharmacokinetic grounds.
`
`Hospira’s second witness relating to the 115 patent was Professor Robert Leonard.
`He has been a practising clinician for over 40 years, with particular expertise in the
`treatment of breast cancer. Today he is Professor of Cancer Studies at Imperial
`College and a consultant (Honorary) Medical Oncologist, Imperial College NHS
`Trust. His opinion was that it would be obvious to a clinician at the relevant time to
`contemplate conducting a small clinical trial of a three week dosing regimen for
`trastuzumab and that the clinician would consult a pharmacokinetics expert about
`whether such a trial was worthwhile. If the response of the pharmacokinetics expert
`was the one advanced by Dr Earhart then the clinician would go ahead and conduct
`the trial.
`
`24.
`
`Genentech’s first witness on the 115 patent was Professor Peter Barrett-Lee. He
`qualified as a doctor in 1982 and is now Medical Director & Consultant Clinical
`
`
`
`Pfizer Ex. 1025
`Page 5 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`
`
`Hospira v Genentech
`
`Oncologist of Velindre NHS Trust, and Professor of Oncology in the School of
`Medicine at Cardiff University. He has been a consultant oncologist at Velindre in
`1994, specialising in breast and skin cancer and is the lead specialist in breast cancer
`and skin cancer at Velindre and Cardiff University. His opinion was that at the
`relevant time a trial of a three weekly dosing regimen for trastuzumab was not
`obvious. It would not occur to the skilled clinician to consider such a trial and if it did
`occur to him, he would dismiss the idea and he would not consult a pharmacokinetics
`expert about it. If the clinician did consult a pharmacokinetics expert and their
`response was the response Genentech contended would emerge from considering the
`prior art, then he would not conduct a trial of a three weekly dosing regimen. On the
`other hand if a skilled team was presented with the patent, then based on Prof Boddy’s
`analysis of the pharmacokinetics using the data in the patent, Prof Barrett-Lee would
`carry out the clinical trial.
`
`Genentech’s second witness relating to the 115 patent was Professor Alan Boddy. He
`obtained a PhD in pharmacokinetics in 1986 and today is Professor of Cancer
`Pharmacology and Team Leader of the Pharmacology group at the Northern Institute
`for Cancer Research at Newcastle University. His opinion was that based on the
`information made available to the public in the prior art, a pharmacokineticist would
`not support a trial of three weekly dosing of trastuzumab. In relation to the issue of
`sufficiency, Prof Boddy’s view was that the pharmacokinetic data in the patent
`coupled with the information publicly available at the time would lead a
`pharmacokineticist to support a three weekly dosing trial.
`
`Hospira’s expert witness on the 455 patent was Dr Uwe Gottschalk. He trained as a
`biochemist and has a PhD in Chemistry from the University of Münster. He worked
`at Bayer from 1991 to 2004 as a research and process development biochemist and
`from then until today Dr Gottschalk has worked at Sartorius Stedim Biotech which
`supplies process technology to the biopharmaceutical industry. He is currently Group
`Vice-President of Purification Technologies.
`
`Dr Gottschalk’s opinions supported Hospira’s case that the 455 patent lacked novelty
`and did not involve an inventive step. He addressed the characteristics of various
`trastuzumab compositions and expressed the view that trastuzumab could be separated
`from the relevant acidic variants on an analytical scale and that purifying trastuzumab
`on a larger scale was obvious, albeit that the separation of the acidic variants from the
`native protein might involve sacrificing yield.
`
`Hospira also served a witness statement from Rekha Patel, the Regulatory Affairs
`Product Manager for Global Biologics Development at the claimant. She verified the
`contents of Hospira’s Statement of Case which dealt with Hospira’s trastuzumab
`product and was relevant to the declaration of non-infringement. She was not cross-
`examined.
`
`Genentech’s witness on the 455 patent was Professor Nigel Titchener-Hooker. He
`graduated from UMIST in 1983 with a degree in chemical engineering and is now
`Professor of Biochemical Engineering and the Head of the UCL department of
`Biochemical Engineering. He is also the Director of the EPSRC Centre for Innovative
`Manufacturing in Emergent Macromolecular Therapies. Prof Titchener-Hooker
`addressed the scaling up of protein purification. He explained that separating
`trastuzumab from the acidic variants on a large scale was difficult and not obvious.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`
`
`Pfizer Ex. 1025
`Page 6 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`Hospira v Genentech
`
`
`
`30.
`
`31.
`
`Genentech had served reports from a second expert in relation to the 455 patent,
`Professor Zhaohui Sunny Zhou, but during the trial decided not to call the Professor.
`
`Each of the witnesses at trial were good witnesses who gave their evidence fairly,
`seeking to help the court. Neither side criticised the other’s witnesses.
`
`The 115 patent
`
`The skilled person and the common general knowledge
`
`32.
`
`33.
`
`34.
`
`It was common ground that the skilled addressee of the Patent would be a team and
`that the team would comprise a clinician, specifically an oncologist, and an expert in
`pharmacokinetics. At one stage there appeared to be a dispute about whether the
`skilled clinician would be a “pure” clinician with no research interest (Genentech) or
`a practising clinician who is part of a team investigating new dosing regimens
`(Hospira). I find that the relevant skilled clinician would not necessarily be someone
`already working in a team investigating new dosing regimens, but they would be a
`clinician who was prepared to contemplate and propose new dosing regimens. There
`was clear evidence that clinicians in this field would regularly do this.
`
`The common general knowledge can be divided between that possessed by the
`clinician and that possessed by the pharmacokinetics expert.
`
`The important elements of the common general knowledge of the clinician member of
`the skilled team at the priority date are the following:
`
`i)
`
`ii)
`
`iii)
`
`iv)
`
`Breast cancers could be classified in a number of ways, including by stage
`(early, late or locally advanced) and by receptor status (HER2-positive,
`oestrogen receptor (ER) positive etc.). Early stage breast cancer was regarded
`as operable (curable by surgery); late stage disease (metastatic disease) was
`regarded as incurable but was still treated; locally advanced disease was
`regarded as inoperable but could potentially be rendered operable by
`treatment. Clinical trials of new cancer agents would generally have been
`conducted in patients with metastatic disease who had not responded to other
`treatments for risk/benefit and ethical reasons, although positive results in such
`patients would be expected to lead to a greater response rate in other patient
`settings.
`
`There were three established categories of non-surgical breast cancer therapy –
`endocrine (hormone) therapy, cytotoxic chemotherapy and radiotherapy – and
`antibody therapy had recently been introduced as a further category;
`
`Paclitaxel and docetaxel were approved and established cytotoxic
`chemotherapy drugs that were administered every three weeks when used to
`treat metastatic breast cancer;
`
`In September 1998 trastuzumab, alone or in combination with paclitaxel, was
`approved by the FDA (as Herceptin) for the treatment of metastatic breast
`cancer. The FDA label is a formal document which forms part of the approval
`process of any drug. The FDA label for Herceptin was part of the common
`general knowledge.
`
`
`
`Pfizer Ex. 1025
`Page 7 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`Hospira v Genentech
`
`
`
`35.
`
`Another aspect of the common general knowledge of the skilled clinician related to
`convenience. The primary consideration of any therapy is safety and efficacy.
`However Prof Leonard’s view was that, although it was a secondary consideration,
`nevertheless it was desirable to administer therapies in a manner as convenient as
`possible for the patient and medical staff and that increased convenience could be
`achieved by alternative routes of administration, less frequent dosing and co-
`administration. Prof Barrett-Lee’s view expressed in his report was that this was very
`much a subsidiary matter. In cross-examination he accepted that it was a factor in all
`patients and that clinicians always have to take into account how drug treatments will
`be given and what impact this will have. He agreed it was a factor in wanting to
`modify a treatment. Papers looking carefully at quality of life and convenience in the
`context of cancer treatment were put to Prof Barrett-Lee. They spanned a period from
`1983 to 1998.
`
`36.
`
`I find that at the relevant date (1999) convenience was an important factor for cancer
`treatment in general and treatment of metastatic disease in particular. To the skilled
`clinician in oncology it would be routine to think about improving quality of life by
`looking at how drugs were administered. Tests would then be carried out to ensure
`safety and efficacy.
`
`37.
`
`The important elements of the common general knowledge of the pharmacokinetics
`expert member of the skilled team at the priority date are the following:
`
`i)
`
`ii)
`
`iii)
`
`A drug effect arises from a pharmacodynamic interaction between a drug and
`its target within the body and generally depends on the concentration of the
`drug at the site of action.
`
`Pharmacokinetic methods model the effects of four general processes:
`adsorption, distribution, metabolism and excretion and allow the concentration
`of a drug at the site of action (or toxicity) to be modelled over time after a dose
`is administered.
`
`The rate of elimination of a drug from the body is commonly first-order (i.e.
`proportional to the first power of the concentration of the drug) but may also
`be zero-order (i.e. a constant/proportional
`to
`the zeroth power of
`concentration).
`
`iv) Where the relevant elimination process may be saturated by a high
`concentration of drug the drug will exhibit dose-dependent pharmacokinetics
`(i.e. zero order above the saturation level, first order below it).
`
`v)
`
`There are three categories of pharmacokinetic model: classical compartmental
`models, physiologically-based compartmental models and non-compartmental
`models.
`
`vi)
`
`Regarding compartmental models:
`
`a)
`
`In a one-compartment model the body is modelled as a single central
`compartment into which the drug distributes and the concentration of
`the drug at the site of action is assumed to be the concentration in this
`single compartment.
`
`
`
`Pfizer Ex. 1025
`Page 8 of 47
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`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`
`
`Hospira v Genentech
`
`b)
`
`In a two-compartment model the drug is modelled as diffusing rapidly
`in the blood and highly perfused organs and that, at a slower rate,
`distributing to other tissues that are less well perfused.
`
`These models are theoretical and do not relate to actual compartments in the
`body. An important point is that the choice of model is determined by the data
`and not a physiological theory as to how the drug will behave in the body.
`
`In classical compartmental models the volumes of the compartments are
`apparent volumes derived from measurements of variation
`in drug
`concentration, whereas in physiologically-based models the compartment
`volumes are based on estimates of the real volumes in the human body that
`they represent.
`
`A commonly stated pharmacokinetic parameter for a drug is the serum half
`life. This is the time the serum concentration will drop by one half. In a one
`compartment model there is a single half life whereas in a two compartment
`model there are two distinct half lives.
`
`vii)
`
`viii)
`
`ix)
`
`x) When a drug is administered repeatedly the concentration in the body
`approaches a steady state concentration.
`
`xi)
`
`For drugs given by repeat dosing, an initial higher dose (loading dose) was a
`commonly used method to reach steady state concentrations more rapidly.
`
`xii) Doses may be expressed in absolute dose levels (mg) or weight-adjusted dose
`levels (mg/kg). It is a standard assumption that the average patient weighs
`70kg. Unless specific patient weight data is available, the weight-adjusted
`dose level is obtained by dividing the absolute dose level by 70kg.
`
`38.
`
`One kind of dose dependent non-linearity arises when a compound exhibits
`Michaelis-Menten kinetics. In general terms Michaelis-Menten kinetics relate to a
`situation in which there may be a given quantity of an enzyme to act on a substrate.
`For example there could be an enzyme which catalyses the breakdown of a drug. The
`rate of the reaction will increase as the concentration of substrate (i.e. the drug) rises
`from zero but that increase will reach a maximum once the substrate is in large excess
`relative to the enzyme. At low substrate concentrations the elimination may be
`approximately first order but when the substrate is in large excess the elimination is
`zero order because the given quantity of enzyme is in effect working flat out.
`
`39. When a drug is administered repeatedly the serum concentration rises to a peak
`sometime after dosing and falls to a trough just before the next dose is given. An
`assessment will be made of the target trough serum concentration which is needed for
`the drug to be efficacious. From the point of view of achieving efficacy the aim will
`be to have a dosing regimen which keeps the trough serum concentration above the
`target. Just as the trough is relevant for efficacy, the peak may be relevant to toxicity
`and the risk of side effects.
`
`An issue between the parties was the extent to which the pharmacokinetics expert
`would take into account views they might have about the behaviour of antibodies in
`general: when the antibodies were in circulation in the body and when they were
`
`40.
`
`
`
`Pfizer Ex. 1025
`Page 9 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`Hospira v Genentech
`
`
`
`41.
`
`42.
`
`eliminated. Dr Earhart thought the expert would know about this and take it into
`account and Prof Boddy thought the expert would not. Although I preferred Dr
`Earhart’s view on this point, I do not think it plays a major part in the issues I have to
`decide and I will assume the point in Genentech’s favour.
`
`The skilled clinician would regard pharmacokinetics as a province of experts in that
`field but that does not mean they had no appreciation of general concepts. They
`would understand drug half lives and the idea of a trough serum concentration for a
`drug.
`
`In reality the members of the skilled team would consult and work together however
`for the purposes of analysis it is useful to consider a slightly stilted choreography
`between the two members of team in order to illuminate and address the issues. That
`choreography is reflected in the sections on obviousness and sufficiency below.
`
`The 115 patent specification
`
`43.
`
`Claim 1 in the amended form sought by Genentech is to:
`
`Use of the anti-ErbB2 antibody huMab4D5-8
`
`in the manufacture of a medicament for use in a method for
`treating a human patient diagnosed with a breast cancer
`characterized by overexpression of ErbB2,
`
`said method comprising the steps of
`
`administering intravenously to the patient an initial dose of
`8mg/kg of the anti-ErbB2 antibody; and
`
`administering intravenously to the patient a plurality of
`subsequent doses of the antibody in an amount that is 6 mg/kg,
`wherein the doses are separated in time from each other by
`three weeks.
`
`The words underlined were sought to be added by amendment in the application
`notice dated 3rd March 2014.
`
`The claim is in the familiar Swiss type form. Claim 4 is written in the “product for
`use” form but is otherwise in the same terms. I will focus on claim 1. The antibody
`referred to is trastuzumab.
` The disease is breast cancer characterised by
`overexpression of ErbB2 (i.e. HER2). The method involves an 8mg/kg loading dose
`and subsequent doses of 6mg/kg on a three weekly schedule. This regimen can be
`summarised as 8 + 6 q3w. For what it is worth there must be a plurality (i.e. at least
`two) subsequent doses. The dependent claims 2 and 3 (and correspondingly 5 and 6)
`combine the antibody treatment with a chemotherapeutic agent in general (claims 2/5)
`or with paclitaxel or docetaxel in particular (claims 3/6).
`
`Despite the relatively narrow terms of claim 1, the specification of the 115 patent as a
`whole is written in broad terms. The first paragraph, entitled Field of the Invention,
`explains that the disorders the document relates to are those characterised by
`overexpression of ErbB2 or disorders expressing EGFR. This includes but is not
`
`44.
`
`45.
`
`
`
`Pfizer Ex. 1025
`Page 10 of 47
`
`

`

`THE HON. MR JUSTICE BIRSS
`Approved Judgment
`
`
`
`Hospira v Genentech
`
`limited to cancer. There is a reference to cancer but it is not limited to breast cancer.
`Any antibody which binds ErbB2 is covered. There is a general reference to front
`loading the dose of the antibody. The cancer treatment may involve combining the
`antibody with a chemotherapeutic agent such as paclitaxel or docetaxel or an
`anthracycline derivative. In the latter case there may also be treatment with a
`cardioprotectant. This reflects the fact that trastuzumab combined with anthracycline
`derivative chemotherapeutic agents had been linked to cardiotoxicity. The paragraph
`ends with a wide reference to “infrequent dosing” of the antibodies.
`
`The remainder of the specification is also written in similarly wide terms. The
`Summary of the Invention section (paragraphs 13 to 33) starts with a reference to
`front loading in order to achieve early attainment of the target trough serum
`concentration, again written in broad terms. Very wide ranges for peak and trough
`serum concentration are given in paragraph 16. A range of periods for the first
`subsequent dose is mentioned in paragraph 16 from 4 weekly to “most preferably one
`week or less”. Initial doses of 12mg/kg and 8mg/kg are mentioned with subsequent
`maintenance doses of 6mg/kg three weekly but also (paragraph 20) 8mg/kg every
`week, or 2 or 3 weekly.
`
`Paragraph 19 refers to “still another embodiment” as an 8mg/kg initial dose and a
`three weekly 6mg/kg maintenance dose. This corresponds to claim 1 albeit there is no
`reference in this paragraph to the disease to be treated.
`
`Paragraph 25 includes a long list of cancers to be treated. They are characterised by
`overexpression of ErbB2. Breast cancer is the first in the list of over twenty cancers.
`Paragraph 26 refers to antibodies. Trastuzumab is not the only one mentioned. A
`combination with other chemotherapy drugs, including paclitaxel and docetaxel is
`mentioned in this Summary section.
`
`The Detailed Description of the Preferred Embodiments section comes next along
`with the drawings. This section runs from paragraphs 34 to 177. Part V of this
`section is concerned with Treatment with Anti-ErbB2 Antibodies. Paragraph 168 in
`this part contains another reference to the 8 + 6 q3w dosing schedule, again without
`reference to a particular disease or antibody and again among a number of other
`dosing proposals.
`
`From paragraph 177 onwards are six examples. Example 1 presents the results of a
`clinical trial of the 4 + 2 q1w dosing regimen of intravenous Herceptin in metastatic
`breast cancer patients in combination with chemotherapy consisting of either Taxol
`(paclitaxel) or a combination of anthracycline and cyclophosphamide. The results are
`positive for the combination with paclitaxel. The combination with anthracycline
`derivatives is contraindicated due to the cardiac side effects.
`
`Example 2 presents pharmacokinetic and pharmaco