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You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Hospira UK Ltd v Genentech Inc [2014] EWHC 1094 (Pat) (10 April 2014) URL: https://www.bailii.org/ew/cases/EWHC/Patents/2014/1094.html Cite as: [2014] EWHC 1094 (Pat) |
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CHANCERY DIVISION
PATENTS COURT
Fetter Lane, London, EC4A 1NL |
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B e f o r e :
____________________
HOSPIRA UK LIMITED |
Claimant |
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- and - |
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GENENTECH INC. |
Defendant |
____________________
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
____________________
Crown Copyright ©
Mr Justice Birss:
Contents | Paragraph |
Introduction | 1 |
The issues | 12 |
The witnesses | 22 |
The 115 patent | 32 |
The skilled person and the common general knowledge | 32 |
The 115 patent specification | 43 |
Claim construction | 56 |
Obviousness | 65 |
Obviousness – the FDA label | 68 |
Pharmacokinetics | 84 |
The reaction of the clinician | 114 |
Obviousness - conclusion | 118 |
Sufficiency | 119 |
Priority | 144 |
The 455 patent | 163 |
The skilled team | 163 |
Common general knowledge | 164 |
The 455 patent specification | 174 |
Claim construction | 185 |
Novelty | 194 |
Andya | 195 |
The disclosure of Andya compared to claim 1 | 202 |
Obviousness | 218 |
Waterside | 219 |
Andya – obviousness | 243 |
Obviousness over common general knowledge in general | 248 |
Obviousness over common general knowledge based on Protein A | 249 |
Declaration of non-infringement | 264 |
Conclusion | 268 |
Introduction
The issues
The witnesses
The 115 patent
The skilled person and the common general knowledge
i) 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.
ii) 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;
iii) Paclitaxel and docetaxel were approved and established cytotoxic chemotherapy drugs that were administered every three weeks when used to treat metastatic breast cancer;
iv) 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.
i) 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.
ii) 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.
iii) 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.
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.
vii) 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.
viii) 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.
ix) 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.
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.
The 115 patent specification
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.
Claim construction
Obviousness
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
Obviousness – the FDA label
Pharmacokinetics:
The reaction of the clinician
Obviousness - conclusion
Sufficiency
i) Prof Boddy had used a two compartment model whereas it would be clear from the common general knowledge Baslega paper and the way the data was reported in the FDA label that a one compartment model had been applied by Genentech.
ii) Prof Boddy's two compartment model using the 30 min infusion did not make reliable predictions yet a 30 min infusion is likely to be understood to be the way Herceptin was actually administered based on the FDA label. His predictions were based on the model using the 90 min infusion.
iii) Prof Boddy's first trough was 25 µg/ml, not far above the 20 µg/ml lower limit, and he did not know the distribution of people around this.
iv) The simulated steady state trough concentration of 17 µg/ml reported in Example 6 differed significantly from his analysis. Hospira asked rhetorically why the ordinary skilled person would reject a specific concentration based on an analysis by the patentee which if correct is rather a low trough serum concentration albeit above 10 µg/ml and prefer an analysis based on a different model from that of the FDA/Baselga and which gave an unaccountably high half life?
Priority
151. Section 5(2)(a) of the Patents Act 1977 provides that an invention is entitled to priority if it is supported by matter disclosed in the priority document. By section 130(7) of the Act, section 5 is to be interpreted as having the same effect as the corresponding provisions of Article 87(1) of the European Patent Convention. Article 87(1) says that priority may be derived from an earlier application in respect of the "same invention".
152. The requirement that the earlier application must be in respect of the same invention was explained by the enlarged Board of Appeal of the EPO in G02/98 Same Invention, [2001] OJ EPO 413; [2002] EPOR 167:
"The requirement for claiming priority of 'the same invention', referred to in Article 87(1) EPC, means that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the skilled person can derive the subject-matter of the claim directly and unambiguously, using common general knowledge, from the previous application as a whole."
153. The approach to be adopted was elaborated by this court in Unilin Beheer v Berry Floor [2004] EWCA (Civ) 1021; [2005] FSR 6 at [48]:
"48. …….The approach is not formulaic: priority is a question about technical disclosure, explicit or implicit. Is there enough in the priority document to give the skilled man essentially the same information as forms the subject of the claim and enables him to work the invention in accordance with that claim.
154. In Abbott Laboratories Ltd v Evysio Medical Devices plc [2008] EWHC 800 (Pat), I added this:
"228. So the important thing is not the consistory clause or the claims of the priority document but whether the disclosure as a whole is enabling and effectively gives the skilled person what is in the claim whose priority is in question. I would add that it must "give" it directly and unambiguously. It is not sufficient that it may be an obvious development of what is disclosed. "
The 455 patent
The skilled team
Common general knowledge
The 455 patent specification
"An absorbance trace from a cation exchange column run performed as described above is shown in Figure 3. This method resolved a deamidated variant of anti-HER2 antibody that differed only slightly from nondeamidated anti-HER2 antibody. The increase in conductivity from the initial conditions to the intermediate wash began to elute the deamidated anti-HER2 antibody. However, continued washing at this conductivity was found to elute nondeamidated anti-HER2 antibody, resulting in a loss of product. Proceeding directly from the intermediate buffer to the elution buffer was observed to result in either an unacceptably low removal of deamidated anti-HER2 antibody from the product if pooling began early or unacceptably low yields of anti-HER2 antibody product if pooling was delayed until the deamidated anti-HER2 antibody was reduced. It was discovered that by going back to lower conductivity as used initially, the elution of deamidated anti-_HER2 antibody continued, without significant anti-HER2 antibody product elution."
Claim construction
A composition for therapeutic use comprising a mixture of anti-HER2 antibody and one or more acidic variants thereof,
wherein the amount of the acidic variant(s) is less than about 25%,
and wherein the acidic variant(s) are predominantly deamidated variants wherein one or more asparagine residues of the anti-HER2 antibody have been deamidated,
and wherein the anti-HER2 antibody is huMAb4D5-8,
and wherein the deamidated variants have Asn30 in CDR1 of either or both VL regions of humMAb405-8 converted to aspartate,
and a pharmaceutically acceptable carrier.
2. The composition of claim 1, wherein the amount of the acidic variant(s) is less than about 20%.
3. The composition of claim 2, wherein the amount of the acidic variant(s) is less than about 13%.
4. The composition of claim 2, wherein the amount of the acidic variant(s) is in the range of about 1 to 18%.
Novelty
Andya
The disclosure of Andya compared to claim 1
Obviousness
Waterside
• p185HER2 binding assay: peak 1 82% specific activity
peak 3 100% specific activity
• 25% of pool has deamidated Asn-30:
25% @ 82% specific activity
75% @ 100% specific activity
pool @ 95% specific activity
• Decided not to remove the deamidated material.
• Deamidation increases when HCCF is held even at 2-8C
so harvests are taken straight through to purification
i) See that the deamidated Asn30 variant existed and had a lower specific activity than native trastuzumab;
ii) See that Genentech had decided not to remove the deamidated Asn30 variant.
Andya - obviousness
Obviousness over common general knowledge in general
Obviousness over common general knowledge based on Protein A
i) The point was kept back until the middle of the cross examination. It was not actively supported by any Genentech witness and was not noticeable in Genentech's opening written skeleton. It seems to be an afterthought of the lawyers.
ii) It should be within Genentech's knowledge as to whether the particular conditions it used did have a material effect on the level of charge variants but it has adduced no evidence on this point.
iii) There is no reason to suppose that Genentech's cell line or culture conditions were in any way unusual and no suggested reason was put to Dr Gottschalk during cross examination.
iv) There is no reason to suppose that, if cell line and culture conditions do affect acidic variant levels, Genentech's parameters are at the low end of resulting acidic variants. It would seem extremely likely that other routine cell lines or culture conditions would produce acidic variant levels still lower than Genentech did. That being so, the ordinary skilled team simply using protein A purification for its known purpose with such routine cell line and conditions would produce material within the claims and the Patent is obvious.
v) If the skilled team, without knowledge of Genentech's proprietary information, would generate trastuzumab with a materially different acidic variant profile, this raises the prospect that the skilled team would not be able to reproduce Example 1 of the Patent.
Declaration of non-infringement
Conclusion