Embodiments and examples of the invention
51 The embodiments of the invention utilise the sandwich reaction and the competition reaction. In the sandwich reaction, the labelled reagent is a specific binding partner for the analyte. The labelled reagent, the analyte and the immobilised unlabelled specific binding reagent cooperate together in a "sandwich". Binding occurs because of the recognition of the reagent for an epitope (or binding site) on the analyte. In the embodiment involving a sandwich reaction (at page 4), it states that the two binding reagents must have specificities for different epitopes on the analyte. This suggests that the reagents should bind preferably to the analyte. However, in the embodiment involving the competition reaction (at page 4), the labelled reagent is the analyte itself, or an analyte analogue with identical specific binding characteristics to the analyte. That labelled reagent binds with the immobilised reagent. If the analyte is present in the sample, there will be competition between the analyte and the labelled reagent in binding to the immobilised reagent, so that there is a decrease in the intensity of the signal in comparison with the situation where there is no analyte. This does not import a requirement for the reagent to be mono-specific. In a competition reaction, the labelled reagent does not bind to the analyte. This requires specificity of the immobilised reagent but does not involve a concept of mono-specificity. In either reaction, the immobilised specific binding reagent in the second zone is said to be preferably a highly specificantibody and, more preferably, a monoclonal antibody. If the specific binding reagent for the analyte were necessarily mono-specific, it would not be necessary to state a preference for a highly specific antibody.
52 There are references in the specification to an "important embodiment" (at pages 7 and 8) where the carrier contains in the first zone a labelled highly-specific anti-hCG antibody and has immobilised in the second zone an unlabelled highly-specific anti-hCG antibody. The labelled and unlabelled antibodies are to have specificities for different hCG epitopes. If a specific binding reagent must be mono-specific, there is no room for degrees of specificity. Further, an "important alternative" in the same important embodiment is 'a fertile period device, essentially as described for hCG except that the analyte is LH'.
53 In an embodiment of the invention (at page 16) a labelled antibody having specificity for an epitope and a second antibody having specificity for a different epitope on the same analyte are used. As a given example of an analysis to which this can be applied, the analyte can be hCG and the reagents can be monoclonal antibodies to hCG. The specification goes on to state that an assay based on these principles can be used to determine a wide variety of analytes by choice of appropriate specific binding reagents. The analytes can be, for example, proteins, immunoglobulins, hormones, drugs or infectious diseases agents.
54 The specification describes how to produce certain examples of the invention. In the section describing the preparation of labelled reagents, the specification describes the process for coupling an anti-α hCG antibody to the dye sol label (at page 34). It goes on to state that:
Due to the structural homology between the alpha subunits of hCG and LH, [an] anti-α hCG antibody can be used to detect LH in a cross-reactive immunoassay (at page 34). Thus, a labelled antibody may be prepared for use in an LH assay in an identical manner to that described for Example 1, using an anti-alpha hCG antibody.
In the section describing the preparation of the reagent strip (at page 35), the specification provides that the immobilised protein can be a suitably selected antibody preparation such as anti-ß hCG, using a second (labelled) anti-hCG antibody in a sandwich format. However, the specification later provides (at page 36) that sandwich-type reactions may be performed for the detection of hCG in a liquid sample using an anti-hCG antibody as described earlier in the specification, that is, using an anti-α hCG antibody linked to dye sols, gold sols or coloured latex particles. It further provides that a similar embodiment can be prepared using LH instead of hCG.
55 As Inverness points out, the only difference between the MDS kits and this example in the first patent is that the antibodies are reversed in the MDS kits in that the anti-α hCG antibody is the unlabelled reagent and the anti-ß hCG antibody is the labelled reagent. Inverness says that the reverse use of the antibodies makes no difference in terms of determining whether or not there are two specific binding reagents in the MDS kits.
56 In the context of sandwich assays, the specification repeatedly uses the term specific binding reagent to describe the labelled reagent, for example:
In one embodiment of the invention, the labelled reagent is a specific binding partner for the analyte. The labelled reagent, the analyte (if present) and the immobilised unlabelled reagent cooperate together in a "sandwich" reaction (at page 4).
Another important preferred embodiment of the invention is the use of so called "direct labels", attached to one of the specific binding reagents. Direct labels such as gold sols and dye sols, are already known per se (at page 5).
The only description in the specification of the preparation of a labelled reagent for hCG detection for use in a sandwich assay utilises an anti-α hCG antibody. It describes how an anti-α hCG antibody can be labelled with dye sol for use in a sandwich assay. The most obvious conclusion is that the specification describes an anti-α hCG antibody as a specific binding reagent for hCG within the meaning of claim 1. This use of this expression to describe a reagent which binds to the α-subunit of hCG, which it shares with the other glycoprotein hormones, argues against a meaning of mono-specificity. The anti-α antibody is specific for hCG in that it will bind to hCG in a specific binding reaction; it has specificity for hCG but it is not exclusively specific for that analyte. It will also bind to the α-subunit of LH and to the other proteins with that subunit. It has specificity for LH, as well as FSH and TSH and may be used to detect those hormones. Indeed, the specification states that the anti-α hCG antibody can be used to detect LH in a cross-reactive immunoassay. The specification recognises the existence of cross-reactive immunoassays and makes reference to antibodies that will cross-react with molecules other than the target antigen. That is, the reagents are not absolutely specific.
57 MDS seeks to overcome this exemplification of the anti-α hCG antibody by arguing that it was not provided as an example of a specific binding reagent. MDS argues that the body of the specification, consistently with the parent priority documents, does not limit the labelled reagent in the first zone to a specific binding reagent, although it always limits the unlabelled immobilised reagent to a specific binding reagent. It finds support for this from the use in the specification and parent priority documents of the phrase "labelled reagent", without using the word "specific" while the phrase "specific binding reagent" is always used to describe the unlabelled reagent. This, MDS says, is a deliberate differentiation between any binding reagent and a specific binding reagent, the latter meaning one that is mono-specific for the analyte. MDS says that the anti-α hCG antibody is an example of a labelled reagent which is not a specific binding reagent. It says that claim 1 is narrower than the specification in that it requires both the labelled specific binding reagent in the first zone and the permanently immobilised unlabelled specific binding reagent in the detection zone to be mono-specific.
58 In essence, MDS argues that claim 1 is not satisfied by the use of the exemplified assay involving the labelled anti-α hCG antibody. That is, of course, possible. However, it is equally likely, in my view, that the claim includes rather than excludes an exemplified embodiment of the invention. As there is an available construction that would include the exemplified use of anti-α hCG antibody as a specific binding reagent, the exemplification supports that construction. I do not accept MDS' submission that the specification deliberately differentiates between "labelled reagent" and "labelled specific binding reagent" with only the latter meaning a reagent mono-specific for the analyte. Rather, I accept Ms Boscato's evidence on the parent priority documents of the first patent, that the references to a "labelled reagent" in the context of a sandwich reaction is a reference to a labelled specific binding reagent such that the example of the labelled anti-α hCG antibody is an example of a labelled specific binding reagent.
59 The examples in the specification assist in clarifying the invention and the application of the terminology. The specification states that an assay based on the principles described can be used to determine a wide variety of analytes by choice of the appropriate specific binding reagent. The assays can be sandwich assays, for example for hCG, or competition assays. The reference in one embodiment to the fact that the analyte can be hCG and the reagents can be monoclonal antibodies to hCG suggests that the reagents are not necessarily monoclonal antibodies.
60 MDS looks to the efficacy of the device in identifying, exclusively, hCG. It points out that unless one of the binding reagents is specific only for hCG, the system will not differentiate between hCG and the other glycoprotein hormones. That is, the reagent must bind with the ß-subunit of hCG. MDS points to the definition of "specific" of 'capability of discriminating between analytes'. It says that, unless such a mono-specific reagent is used, the reagent is not so capable of distinguishing between hCG and other analytes in the sample.
61 The specification is not limited in its description to a test device for hCG. As examples of certain preferred test strip materials and reagents, the specification exemplifies the anti-α hCG antibody as an appropriate labelled reagent and the anti-ß hCG antibody as an appropriate immobilised unlabelled reagent for use in a sandwich assay for hCG. There is no example in the first patent which utilises two reagents each mono-specific for hCG.
62 The specification explains (at page 11) that 'the immobilised specific binding reagent in the second zone is preferably a highly specific antibody, and more preferably a monoclonal antibody. In the embodiment of the invention involving the sandwich reaction, the labelled reagent is also preferably a highly specific antibody, and more preferably a monoclonal antibody' (emphasis added). Highly specific does not mean mono-specific. It recognises that, while the reagent is thought specifically to target the analyte of choice, there is a possibility that it may also bind to another analyte. By directing the use of a highly specific reagent, the likelihood of cross-reaction is reduced. The patentee has used an expression that allows for a degree of specificity.
63 The degree of specificity concerns the number of different analytes with which a reagent will bind. If "specific binding reagent" already meant mono-specific, such as a monoclonal antibody, this description would be unnecessary and contradictory. Dr Sinosich acknowledged that, if "specific binding reagent" does mean exclusive specificity as advanced by MDS, a qualification that an antibody is "highly specific" is redundant.
64 MDS submits that "highly specific" contemplates analytes that will not have binding reagents that are mono-specific but this is negated by the use of the expression in the context of the detection of hCG, which has the unique ß-subunit. If the description in the specification is designed to encompass analytes that do and analytes that do not have mono-specific binding reagents, the repeated use of "specific binding reagent for the analyte" in that context is more likely to mean a reagent that binds the analyte in a specific binding reaction than a mono-specific reagent. Not all reagents will be antibodies or highly specific antibodies. As described in the specification, they are subclasses of "specific binding reagents".