“A method of evaluating a patient’s risk of developing Progressive Multifocal Leukoencephalopathy (PML), the method comprising: (i) determining, in a serum or plasma sample of the patient, an anti-JC Virus (JCV) antibody titer, wherein the anti-JCV antibody titer is determined by an ELISA assay comprising the following steps: (a) forming a reaction mixture comprising an aliquot of sample and a substrate on which is disposed Highly Purified Viral-Like Particles (HPVLPs), and (b) detecting the level of anti-JCV antibody bound to said substrate on which is disposed HPVLPs; wherein the anti-JCV antibody titer is expressed as an index value, wherein the index value is determined by normalizing an optical density (OD) value of the sample to a cut-off calibrator adjusted to have an nOD of 1, and a positive control is adjusted to have an nOD of 1.3; wherein the cut-off calibrator and positive control comprise a mixture of serum positive for anti-JCV antibodies and serum negative for anti-JCV antibodies, and wherein a negative control comprises anti-JCV antibody negative serum and has an nOD of 0.1; and (ii) determining the patient to be at high risk of developing PML if the anti-JCV antibody index value is determined to be > 1.5.” (i) determining, in a serum or plasma sample of the patient, an anti-JC Virus (JCV) antibody titer, wherein the anti-JCV antibody titer is determined by an ELISA assay comprising the following steps: (a) forming a reaction mixture comprising an aliquot of sample and a substrate on which is disposed Highly Purified Viral-Like Particles (HPVLPs), and (b) detecting the level of anti-JCV antibody bound to said substrate on which is disposed HPVLPs; wherein the anti-JCV antibody titer is expressed as an index value, wherein the index value is determined by normalizing an optical density (OD) value of the sample to a cut-off calibrator adjusted to have an nOD of 1, and a positive control is adjusted to have an nOD of 1.3; wherein the cut-off calibrator and positive control comprise a mixture of serum positive for anti-JCV antibodies and serum negative for anti-JCV antibodies, and wherein a negative control comprises anti-JCV antibody negative serum and has an nOD of 0.1; and (ii) determining the patient to be at high risk of developing PML if the anti-JCV antibody index value is determined to be > 1.5.”
“Anti-JCV antibody status identifies different levels of risk for PML in TYSABRI treated patients. Patients who are anti-JCV antibody positive are at an increased risk of developing PML compared to patients who are anti-JCV antibody negative. Patients who have all three risk factors for PML (i.e., have received more than 2 years of TYSABRI therapy, and have received prior immunosuppressant therapy and are anti-JCV antibody positive) have the highest risk of PML at approximately 9 in 1,000 patients treated. Patients should be informed about this increased risk for developing PML before continuation of treatment after 2 years. For risk stratification prior or during the treatment with TYSABRI anti-JCV antibody testing may provide supportive information.”
“Patients and Methods”, “Results” and “Discussion”
“In the final analysis, samples with nOD 450 values < 0.10 in the ELISA are considered anti-JCV antibody negative, and those with nOD 450 values > 0.25 in the ELISA are considered anti-JCV antibody positive. Samples with reactivity between nOD values 0.10 and 0.25 are further evaluated in the confirmation test. In the confirmation test, all samples exhibiting >40% inhibition are classified as anti-JCV antibody positive (see Fig 4). At nOD 450 values >0.25, the probability of observing >40% inhibition was approximately 95%.”
“Although these data are based on a small number of pre-PML samples, they suggest that patients without detectable levels of anti-JCV antibodies may have a lower risk of PML development compared to patients who have detectable anti-JCV antibodies. Further clinical studies are underway to confirm this and determine whether the assay [the validated 2-step ELISA] may be a useful tool for stratifying natalizumab-treated MS patients for higher and lower risk of PML”
“…serological assessment of anti-JCV antibody status may offer a more sensitive and practical means of identifying patients who may be infected by JCV.”
“The variation in seropositivity rates among these studies is likely due to marked differences in the sample size, demographics, and, perhaps most importantly, differences in assay methods. Our observation of 54% seropositivity is consistent with rates that have been reported in other recent large studies of healthy subjects.”
“The overall risk of developing PML in natalizumab-treated patients is rare, and is likely dependent on the convergence of multiple factors within an individual, including infection by JCV. Although the presence of anti-JCV antibodies alone may not be highly predictive of PML risk, our observation that none of the 17 pre-PML samples were classified as seronegative merits further study. Evaluation of the utility of the assay for risk stratification in the context of ongoing clinical studies will help elucidate if the risk may be significantly lower in a seronegative group compared with that of a seropositive group.”
“The false-negative rate in the assay, combined with the ~2% annual seroconversion rate observed in the STRATA cohort, suggests that periodic testing of seronegative patients is warranted in clinical practice.”
“In summary, detection of anti-JCV antibodies using this novel 2-step assay may provide a tool for stratification of patients into groups at higher risk for PML (ie, seropositive) and those at lower risk (ie, seronegative). Because the risk of PML will still be quite low in seropositive patients, it is likely that additional variables, such as the presence of viral mutations, host factors (eg, genetics and immune status), and previous therapeutic interventions may contribute to development of PML. Approaches to further stratify the risk of PML in the anti- JCV antibody positive group are being actively explored in ongoing clinical studies in the United States and in Europe. In addition, we continue to optimize the current anti-JCV antibody assay to help reduce the false-negative rate. For the time being, clinical vigilance remains the primary tool for early detection of PML. However, the clinical management of MS patients using or contemplating the use of natalizumab could be facilitated by tools, such as this assay, that may ultimately allow for a better understanding of a patient’s individual risk of this serious adverse event.”
“In one aspect, the invention features a method of monitoring PML risk in a subject, the method comprising determining the level of anti-JCV antibodies in a subject using a sample from a first date; assigning a risk of PML (e.g., high, or moderate or low risk) based on the level of anti-JCV antibodies in the subject on the first date; determining the level of anti-JCV antibodies in the subject using a sample from a second date; and assigning a risk of PML (e.g., high, or moderate or low risk) based on the level of anti-JCV antibodies in the subject on the second date.”
‘There is no data or reasoning to support a suggestion that risk may be assigned based on any particular level of antibody titre, or what would represent a “moderate” risk of developing PML. Given the absence of reasoning and the brevity of the statement, I do not believe the Skilled Team would attach any weight to it.’
‘[0002] The anti-VLA-4 (Very Late Antigen 4) antibody therapeutic natalizumab is indicated to treat relapsing forms of multiple sclerosis (MS) and moderate-to-severe Crohn’s Disease. Natalizumab treatment, however, is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection caused by the JC virus (JCV). PML occurs primarily in immunocompromised individuals and in patients receiving certain immunomodulatory therapies, including natalizumab. PML is hypothesized to be the result of a complex interaction between host and viral factors, leading to reactivation and mutation of latent archetype JCV to a neurotrophic form which can infect oligodendrocytes in the central nervous system.’
‘[0033] The methods disclosed herein are based at least in part on the discovery that anti-JCV antibody titer and other characteristics such as affinity/avidity can be indicators of a patient’s risk of developing Progressive Multifocal Leukoencephalopathy (PML). [0034] Accordingly, the invention features, a method of evaluating a patient’s risk of developing PML, comprising acquiring knowledge of a JC Virus (JCV) antibody titer (e.g., determined as described herein and expressed as normalized optical density (nOD) or index) as defined in the claims. [0035] In one embodiment, an anti-JCV antibody titer or percent inhibition is determined in a biological sample from a patient, such as a blood (serum or plasma), or CSF sample. [0036] If the titer or/and percent inhibition, or a function of both values is determined to be below a pre-determined level, the patient is determined to be at a lower risk of developing PML, and if the titer and/or percent inhibition, or a function of both values is determined to be at or above the pre-determined level the patient is determined to be at a higher risk of developing PML.’
‘[0044] The patient can be determined to have a lower risk of PML if the anti-JCV antibody titer as indicated by index value or nOD is determined to be < 0.5, the patient can be determined to have a higher risk if the anti-JCV antibody titer as indicated by index value or nOD is determined to be > 0.5 and <1.5. The patient is determined to have an even higher risk if the anti-JCV antibody titer as indicated by index value or nOD is determined to be > 1.5. [0045] If the assay indicates that the biological sample does not contain JCV antibodies above a background level, the patient can be determined to be at lower risk for PML.’ ‘[0060] The patient is determined to have a higher risk of PML if, (i) the anti-JCV antibody titer as indicated by index value or nOD is determined to be > 1.5 and the percent inhibition value is determined to be > 70%,’
‘[0073] A patient who has received an anti-VLA-4 therapy, such as natalizumab, for longer than 24 months (e.g., for 25 to 48 months, such as 26, 30, 36, 42 or 48 months or longer), and who is determined to be positive for JCV, can be determined to be at a higher risk for PML. The patient can accordingly be determined not to be a candidate to receive further treatment with an anti-VLA-4 therapy, or can be determined to be a candidate to receive treatment with an anti-VLA-4 therapy accompanied by more frequent monitoring. [0074] In an embodiment, a patient who has received an anti-VLA-4 therapy, such as natalizumab, for longer than 24 months (e.g., for 25 to 48 months, such as 26, 30, 36, 42 or 48 months or longer), and who has not received prior treatment with an immunosuppressant (other than an anti-VLA-4 therapy), and who is determined to be positive for JCV, and is determined to be at a higher risk for PML. For example, the patient can be determined to have a risk of PML of 4/1000 patients. The patient can accordingly be determined not to be a candidate to receive further treatment with an anti-VLA-4 therapy, or can be determined to be a candidate to receive treatment with an anti-VLA-4 therapy accompanied by more frequent monitoring. [0075] A patient, e.g., an MS patient, who has received prior treatment with an immunosuppressant other than an anti-VLA-4 therapy, and who is determined to be positive for anti-JCV antibodies, or JCV nucleic acid, can be determined to be at a higher risk for PML. …’
‘[0104] The invention is based, at least in part, on the discovery of new and improved methods of assessing the risk of a patient for PML that include assessing anti-JCV antibody titers or percent inhibition. The invention is based at least in part on the discovery that anti-JCV antibody titer and percent antibody inhibition can be an indicator of a patient’s risk of developing Progressive Multifocal Leukoencephalopathy (PML). [0105] Applicants have also developed an optimized assay for determining anti-JCV antibody titer levels in a biological sample, and a method for assaying the antibodies qualitatively by determining percent inhibition values, and using this information to determine the risk of a patient for developing PML. …’
"PML risk stratification tools are useful as one component in making individual benefit-risk treatment decisions for patients taking or considering taking a VLA4 inhibitor or other therapeutics known to increase risk of developing PML. Quantification of a patient's PML risk can be used, for example, in benefit-risk analysis."
“The [Gen2] assay differs from the [Gen1] assay in at least the follow [sic] ways…”
“We hypothesized that anti-JCV antibody positive patients could be further stratified for the risk of developing PML based on anti-JCV antibody titers (nOD or index) and anti-JCV antibody avidity/affinity (% inhibition). This hypothesis was derived from the observation that patients having an anti-JCV antibody titer and % inhibition below a predetermined level (“a clinical cut-point”) are at lower risk for developing PML compared to the overall anti-JCV antibody positive population.”
“I disagree that it is the teaching of EP 792 and specifically Example 6 and Figures 12 and 13 that the assay described in EP 792 should split the population 50:25:25 in the way Mr Baldwin describes. In effect, Mr Baldwin is saying that EP 792 defines ‘high risk’ as being the 25% of patients in a given population which have the highest anti-JCV antibody titers. However, this interpretation means that, if the average or distribution of anti-JCV antibody titers varies as between different populations, a different level of anti-JCV antibody titer will correspond to ‘high risk’ depending on the population tested. Instead, the Skilled IDS would understand that EP 792 provides an index value (1.5) above which MS patients are viewed as being at high risk of PML when their serum is tested using the Gen2 assay. It is made clear that this index value is being used as a measure of or proxy for an underlying antibody titer above which risk increases (although this titer is not provided). As I explained at paragraph 228 of my First Report, an index value of 1.5 is only meaningful in terms of PML risk if the ELISA from which it is obtained provides the same index value output at the same level of anti-JCV antibodies as the Gen2 assay. If the ELISA differs from the Gen2 assay in terms of the assay set up or the cut-off calibrator then an index value of 1.5 no longer represents the anti-JCV antibody titer associated with a high risk of developing PML as described by EP 792. The index value of 1.5 (and associated underlying antibody titer) was chosen by the inventors as being indicative of high risk on the basis that 87% of samples from PML patients fell above an index value of 1.5 compared to 50% of anti-JCV antibody positive patients – see paragraphs [0230]-[0231] – meaning that the risk of PML above that index value was higher than below it (where there were only 13% of PML samples and 50% of anti-JCV antibody positives). The Skilled IDS would understand that an index value of 1.5 in the Gen2 assay represents an underlying level of anti-JCV antibodies above which a patient has a higher risk of developing PML and that it had been arrived at by considering the ratio of PML samples to antibody positive patients above and below this threshold. They would not understand EP 792 to be teaching that what mattered was whether the index value was in the top 50% of the antibody-positive population (or the top 25% of the total population).”
“As I have said, in paragraphs 164 and 198 of his report, Dr Molyneux seems to attribute significance to the fact that in Example 6 the index value of 1.5 divides the anti-JCV antibody positive population into halves. In my view, the purpose of the index value being set at 1.5 is not to achieve a division of the population in that way. Instead, the purpose of the index value is to represent an underlying antibody titer which is associated with a particular level of risk of developing PML. Using the data from the particular patient population tested in Example 6, the patentee has sought to identify a threshold which groups the population into patients at higher and lower risk of developing PML. In determining that threshold, the patentee has identified an index value above which most (87%) of the pre-PML samples fell but that does not set the threshold so conservatively that the vast majority of anti-JCV antibody positive individuals who do not go on to develop PML are also deemed to be at high risk. The threshold has been set having regard to both (a) the proportions of pre-PML patients above and below the threshold and (b) the proportions of anti-JCV antibody positive but non pre-PML patients above and below the threshold. The result of that analysis is that a particular index value (1.5) is identified. That particular index value (as recorded on the Gen2 assay) represents an underlying antibody titer. If the Gen2 assay were then used to assess risk of developing PML in another study population, that risk would be assessed depending on whether or not a particular individual had an index value of greater or lesser than 1.5. In this different population, the Skilled Neurologist would not expect an index value threshold of 1.5 to divide the seropositive population 50:50 nor that 87% of the pre-PML patients would fall above the 1.5 value. That is because the distribution of the anti-JCV antibody population above and below this index value would vary depending on the particular population tested. The Skilled Neurologist would be aware that seropositivity rates would vary depending on the population tested as I mentioned above at paragraph 6. They would also expect the spread of index values to vary across different populations, and would not expect that 50% of the antibody positive patients would have an index value > 1.5 in every population tested.”
‘18. There was no dispute about the principles which apply to the construction of patent claims. Both parties relied, as did the judge, on the summary in this court’s judgment in Virgin Atlantic v Premium Aircraft Interiors[2010] RPC 8 (‘Virgin’) at [5]: ‘(i) The first overarching principle is that contained in Article 69 of the European Patent Convention. (ii) Article 69 says that the extent of protection is determined by the claims. It goes on to say that the description and drawings shall be used to interpret the claims. In short the claims are to be construed in context. (iii) It follows that the claims are to be construed purposively – the inventor's purpose being ascertained from the description and drawings. (iv) It further follows that the claims must not be construed as if they stood alone – the drawings and description only being used to resolve any ambiguity. Purpose is vital to the construction of claims. (v) When ascertaining the inventor's purpose, it must be remembered that he may have several purposes depending on the level of generality of his invention. Typically, for instance, an inventor may have one, generally more than one, specific embodiment as well as a generalised concept. But there is no presumption that the patentee necessarily intended the widest possible meaning consistent with his purpose be given to the words that he used: purpose and meaning are different. (vi) Thus purpose is not the be-all and end-all. One is still at the end of the day concerned with the meaning of the language used. Hence the other extreme of the Protocol – a mere guideline – is also ruled out by Article 69 itself. It is the terms of the claims which delineate the patentee's territory. (vii) It follows that if the patentee has included what is obviously a deliberate limitation in his claims, it must have a meaning. One cannot disregard obviously intentional elements. (viii) It also follows that where a patentee has used a word or phrase which, acontextually, might have a particular meaning (narrow or wide) it does not necessarily have that meaning in context. (ix) It further follows that there is no general 'doctrine of equivalents.' (x) On the other hand purposive construction can lead to the conclusion that a technically trivial or minor difference between an element of a claim and the corresponding element of the alleged infringement nonetheless falls within the meaning of the element when read purposively. This is not because there is a doctrine of equivalents: it is because that is the fair way to read the claim in context. (xi) Finally purposive construction leads one to eschew the kind of meticulous verbal analysis which lawyers are too often tempted by their training to indulge.’ 19. Sub-paragraph (ix) must now be read in the light of the Supreme Court’s judgment in Actavis v Lilly[2017] UKSC 48 , which explains that, at least when considering the scope of protection, there is now a second question, to be asked after the patent claim has been interpreted, which is designed to take account of equivalents.’ ‘(i) The first overarching principle is that contained in Article 69 of the European Patent Convention. (ii) Article 69 says that the extent of protection is determined by the claims. It goes on to say that the description and drawings shall be used to interpret the claims. In short the claims are to be construed in context. (iii) It follows that the claims are to be construed purposively – the inventor's purpose being ascertained from the description and drawings. (iv) It further follows that the claims must not be construed as if they stood alone – the drawings and description only being used to resolve any ambiguity. Purpose is vital to the construction of claims. (v) When ascertaining the inventor's purpose, it must be remembered that he may have several purposes depending on the level of generality of his invention. Typically, for instance, an inventor may have one, generally more than one, specific embodiment as well as a generalised concept. But there is no presumption that the patentee necessarily intended the widest possible meaning consistent with his purpose be given to the words that he used: purpose and meaning are different. (vi) Thus purpose is not the be-all and end-all. One is still at the end of the day concerned with the meaning of the language used. Hence the other extreme of the Protocol – a mere guideline – is also ruled out by Article 69 itself. It is the terms of the claims which delineate the patentee's territory. (vii) It follows that if the patentee has included what is obviously a deliberate limitation in his claims, it must have a meaning. One cannot disregard obviously intentional elements. (viii) It also follows that where a patentee has used a word or phrase which, acontextually, might have a particular meaning (narrow or wide) it does not necessarily have that meaning in context. (ix) It further follows that there is no general 'doctrine of equivalents.' (x) On the other hand purposive construction can lead to the conclusion that a technically trivial or minor difference between an element of a claim and the corresponding element of the alleged infringement nonetheless falls within the meaning of the element when read purposively. This is not because there is a doctrine of equivalents: it is because that is the fair way to read the claim in context. (xi) Finally purposive construction leads one to eschew the kind of meticulous verbal analysis which lawyers are too often tempted by their training to indulge.’
‘Where a patentee has used general language in a claim, but has described the invention by reference to a specific embodiment, it is not normally legitimate to write limitations into the claim corresponding to details of the specific embodiment, if the patentee has chosen not to do so. The specific embodiments are merely examples of what is claimed as the invention, and are often expressly, although superfluously, stated not to be “limiting”. There is no general principle which requires the court to assume that the patentee intended to claim the most sophisticated embodiment of the invention. The skilled person understands that, in the claim, the patentee is stating the limits of the monopoly which it claims, not seeking to describe every detail of the manifold ways in which the invention may be put into effect.’
‘[15] We think it would unrealistic – indeed perverse – for the law to say that the notional skilled reader, probably with the benefit of skilled advice, would not know and take into account the explicit drafting conventions by which the patent and its claims were framed. Likewise when there is a reference to the patent being a divisional application, it would be perverse to work on the basis that the skilled man would not know what that means. A real skilled man reading a patent which, as in the case of the Patent, refers to “the parent application” would surely say “what’s a parent application?” – and he would go on to ask a man who knows, probably a patent agent.’
“A method of evaluating a patient’s risk of developing Progressive Multifocal Leukoencephalopathy (PML), the method comprising: (i) determining, in a serum or plasma sample of the patient, an anti-JC Virus (JCV) antibody titer, wherein the anti-JCV antibody titer is determined by an ELISA assay comprising the following steps: (a) forming a reaction mixture comprising an aliquot of sample and a substrate on which is disposed Highly Purified Viral-Like Particles (HPVLPs), and (b) detecting the level of anti-JCV antibody bound to said substrate on which is disposed HPVLPs; wherein the anti-JCV antibody titer is expressed as an index value, wherein the index value is determined by normalizing an optical density (OD) value of the sample to a cut-off calibrator adjusted to have an nOD of 1, and a positive control is adjusted to have an nOD of 1.3; wherein the cut-off calibrator and positive control comprise a mixture of serum positive for anti-JCV antibodies and serum negative for anti-JCV antibodies, and wherein a negative control comprises anti-JCV antibody negative serum and has an nOD of 0.1; and (ii) determining the patient to be at high risk of developing PML if the anti-JCV antibody index value is determined to be > 1.5.” (i) determining, in a serum or plasma sample of the patient, an anti-JC Virus (JCV) antibody titer, wherein the anti-JCV antibody titer is determined by an ELISA assay comprising the following steps: (a) forming a reaction mixture comprising an aliquot of sample and a substrate on which is disposed Highly Purified Viral-Like Particles (HPVLPs), and (b) detecting the level of anti-JCV antibody bound to said substrate on which is disposed HPVLPs; wherein the anti-JCV antibody titer is expressed as an index value, wherein the index value is determined by normalizing an optical density (OD) value of the sample to a cut-off calibrator adjusted to have an nOD of 1, and a positive control is adjusted to have an nOD of 1.3; wherein the cut-off calibrator and positive control comprise a mixture of serum positive for anti-JCV antibodies and serum negative for anti-JCV antibodies, and wherein a negative control comprises anti-JCV antibody negative serum and has an nOD of 0.1; and (ii) determining the patient to be at high risk of developing PML if the anti-JCV antibody index value is determined to be > 1.5.”
‘The technical contribution is useful irrespective of where you chose to put the clinical cut-off. The Patent has taught an approach. The Patent has moved the art forward in a non-obvious way, which is the purpose of the patent system.’
‘Before the trial started, we had thought that, apart from a short point which goes only to infringement, there was no dispute about the construction of the claims. We had understood from Biogen’s pleaded case and evidence that it agreed that the Skilled Team would understand that the index value of 1.5 and the antibody titer which it represents, above which a patient is determined to be at high risk of PML according to the claims, are those determined using the Gen2 assay of the Patent. We had understood that the only dispute was whether the Patent also taught that the Skilled Team could arrive at that clinical cut-off by identifying the upper 50% of seropositive patients.’
‘132. We believe that it is common ground that the Skilled Team would understand that the index value of 1.5 in the claim and the anti-JCV antibody titer that it represents must equate to those determined using the Gen2 assay of the Patent and associated by the Patent with high risk of PML.’
‘104. Biogen contends that the Patent is not about obtaining quantitative precision. At its broadest, the technical contribution of the Patent is the teaching – on the basis of sound data – that higher anti-JCV antibody titres are associated with a higher risk of succumbing to PML while receiving natalizumab (see in particular, Example 4, Example 6 and Table 10). 105. Example 6 (as illustrated by Figures 12 and 13) teaches how the patentee draws the line between patients at high and low risk based on anti-JCV antibody titre: the approximately 50% of antibody positive patients with the lowest titres are considered to have a low or lower risk of developing PML, and the approximately 50% with the highest titres to have a high risk (this latter group being associated with 87% of PML cases). This ‘clinically relevant cut point’ corresponds with an anti-JCV antibody index value of 1.5 as measured by the Gen2 assay. Thus, in the final analysis, index values > 1.5 corresponds with high risk of developing PML when the Gen2 assay is used (Figures 12 and 13). 106. However, the technical contribution of the Patent is not confined to the particular cut point adopted by the patentee to define high risk. Sandoz themselves point out that there is an element of subjectivity in choosing such a cut point (Amended Grounds of Invalidity, §5(c)). It is common ground between the clinicians that, with the benefit of the data presented in the Patent, different cut points could sensibly be drawn (see Berger 1, §134 and Molyneux 2, §35): see, for example, Table 10 which analyses the risk associated with other, more conservative cut offs.’
‘237. As explained above, Biogen contends that the broad technical contribution of the Patent is the teaching - on the basis of sound data - that higher anti-JCV antibody titres are associated with a higher risk of developing PML while receiving natalizumab (see in particular, Example 4, Example 6 and Table 10). 238. The claim is more narrowly drawn. Anti-JCV antibody titre must be determined by means of an ELISA assay that uses HPVLPs as the capture antigen. This must be expressed as an index value obtained by normalising to a cut-off calibrator made with a mix of anti-JCV antibody positive and negative serum. The patient is then determined to be at high risk of developing PML if that index value is > 1.5. This value derives from the teaching that, when the Gen2 assay is used, an index value of > 1.5 covers approximately the upper 50% of all anti-JCV antibody positive index values but 87% of PML cases (see Example 6). 239. While the claim requires anti-JCV antibody titres associated with a high risk of PML to be expressed as index values >1.5, the use of that index value as such to identify the cut point forms no part of the inventive concept of the claim. The same cut-point could be expressed by a different index value simply by adjusting the dilution of the calibrator. To use the technical contribution of the Patent it is sufficient to use an index value to represent a clinically relevant cut point to distinguish patients at greater risk of developing PML. That is the inventive concept or core of the claim.’
‘35. One of the central issues in the case (particularly for Sandoz’s case of classical insufficiency) is one of construction: how is the index value of 1.5 in step (ii) of the claimed method to be interpreted? 36. Sandoz say that this value defines an absolute titre of anti-JCV antibody, namely that which was expressed as an index value of 1.5 when the patentee used the Gen2 assay to generate the data presented in Example 6 of the Patent. Biogen says that the value is not tied to any absolute titre of anti-JCV antibody, but is a means of expressing a dividing line between sero-positive patients at higher and lower risk of developing PML.’
‘82. Biogen’s case is that to work the claim, it is not necessary to select the exact level of risk chosen by the patentee in Example 6 based on a precise antibody titre. The Patent teaches a broad technical contribution of PML risk increasing as antibody titre increases (see for example [0033] and [0039]) and anyone who is assessing risk by reference to antibody titre is using the technical contribution of the Patent. There has been no attempt to plead or prove that this relationship does not hold across a range of antibody titres. 83. To work the Patent, therefore, it is not necessary to read into the claim any particular threshold of risk. The term “high” is a relative term: those to the right of the chosen clinical cut-off being high risk. As we understand it, there is no dispute that in these circumstances the Patent is sufficient. 84. In the alternative, if the court is of the view that a limitation is to be read into the claim, as identified in Example 6 the skilled person can work the claim by applying the median value and identifying that by reference to another population.’
‘On our construction the index value of 1.5 in the claim represents a specific anti-JCV antibody titer, namely that which equates with the titer determined using the Gen2 assay of the Patent and associated by the Patent with high risk of PML. Furthermore, on our construction this integer requires a patient to be determined to be at high risk if, and only if, their index value is > 1.5.’
‘[0033] The methods disclosed herein are based at least in part on the discovery that anti-JCV antibody titer and other characteristics such as affinity/avidity can be indicators of a patient’s risk of developing Progressive Multifocal Leukoencephalopathy (PML). [0034] Accordingly, the invention features, a method of evaluating a patient’s risk of developing PML, comprising acquiring knowledge of a JC Virus (JCV) antibody titer (e.g., determined as described herein and expressed as normalized optical density (nOD) or index) as defined in the claims. [0036] If the titer or/and percent inhibition, or a function of both values is determined to be below a pre-determined level, the patient is determined to be at a lower risk of developing PML, and if the titer and/or percent inhibition, or a function of both values is determined to be at or above the pre-determined level the patient is determined to be at a higher risk of developing PML.’
“The specification must disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these: (i) the first step is to identify the invention and that is to be done by reading and construing the claims; (ii) in the case of a product claim that means making or otherwise obtaining the product; (iii) in the case of a process claim, it means working the process; (iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims; (v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification; (vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim; (vii) the specification must be sufficient to allow the invention to be so performed without undue burden.”
“[The skilled person] must seek success. He should not be required to carry out any prolonged research, enquiry or experiment. He may need to carry out the ordinary methods of trial and error, which involve no inventive step and generally are necessary in applying the particular discovery to produce a practical result. In each case, it is a question of fact, depending on the nature of the invention, as to whether the steps needed to perform the invention are ordinary steps of trial and error which a skilled man would realise would be necessary and normal to produce a practical result.”
“It is not enough if the instructions are such that a number of equally qualified notional addressees can arrive at completely different end points, some within the scope of the claimed invention and some not. If reasonable addressees can come to different conclusions there is a conundrum as to which is right. That is not enablement. This view appears to be consistent with the approach of the Technical Board of Appeal of the EPO in Unilever/Stable bleaches (Decision T226/855) [1988] OJEPO 336, which was referred to with approval by Aldous J and the Court of Appeal in Mentor Corp v. Hollister Inc.”
“100. In the case of an invention which, ex hypothesi, is new it may not be easy to delineate the boundary with precision. In the same way as a conveyance of land may not tell you precisely where the boundary is, with the result that any dispute may have to be resolved by looking at topological features on the ground, so the boundaries of an invention may have to be determined as a matter of interpretation in the light of the common general knowledge that the skilled person would possess. But once that exercise has been carried out (these days including the possibility of equivalents), the court will be able to answer the question whether someone has crossed the boundary “yes” or “no”
‘i) The requirement of sufficiency imposed by article 83 of the EPC exists to ensure that the extent of the monopoly conferred by the patent corresponds with the extent of the contribution which it makes to the art. ii) In the case of a product claim, the contribution to the art is the ability of the skilled person to make the product itself, rather than (if different) the invention. iii) Patentees are free to choose how widely to frame the range of products for which they claim protection. But they need to ensure that they make no broader claim than is enabled by their disclosure. iv) The disclosure required of the patentee is such as will, coupled with the common general knowledge existing as at the priority date, be sufficient to enable the skilled person to perform substantially all the types or embodiments [] within the scope of the claim. That is what, [], enablement means. v) A claim which seeks to protect products or processes which cannot be performed by the skilled person using the disclosure in the patent will, subject to de minimis or wholly irrelevant exceptions, be bound to exceed the contribution to the art made by the patent, measured as it must be at the priority date. vi) This does not mean that the patentee has to demonstrate in the disclosure that every embodiment within the scope of the claim has been tried, tested and proved to have been enabled [...]. Patentees may rely, if they can, upon a principle of general application if it would appear reasonably likely to enable the whole range [...] within the scope of the claim to be performed. But they take the risk, if challenged, that the supposed general principle will be proved at trial not in fact to enable a significant, relevant, part of the claimed range to be performed, as at the priority date. vii) Nor will a claim which in substance passes the sufficiency test be defeated by dividing the [...] claim into a range denominated by some wholly irrelevant factor, such as the length of a mouse’s tail. The requirement to show enablement across the whole scope of the claim applies only across a relevant range. Put broadly, the range will be relevant if it is denominated by reference to a variable which significantly affects the value or utility of the product or process in achieving the purpose for which it is to be performed. viii) Enablement across the scope of a product claim is not established merely by showing that all products within the relevant range will, if and when they can be made, deliver the same general benefit intended to be generated by the invention, regardless how valuable and ground-breaking that invention may prove to be.’
‘To put the invention into effect, the [Skilled IDS] needs to work up an anti-JCV antibody assay which identifies essentially the same population of anti-JCV antibody patients at high PML risk as described in the Patent, using the method described in claim 1.’
‘227.1 The Skilled IDS would not be able to prepare the cut-off calibrator in EP 792 or an equivalent one. The identity of the cut-off calibrator is fundamental as all index values produced by the ELISA described in EP 792, including index values for patient samples, are measured relative to it. The cut-off calibrator is the fixed reference point of the ELISA in EP 792 against which all ODs are compared. The inability to reproduce the cut-off calibrator in EP 792 means that the Skilled IDS cannot develop an ELISA that provides equivalent results in terms of index values to the Gen2 assay in EP 792, in which the high-risk threshold of 1.5 was determined. The index value of 1.5 representing a high risk of PML in EP 792 will therefore not apply in any ELISA that the Skilled IDS produces. An index value of 1.5 in the ELISA produced by the Skilled IDS will represent a different anti-JCV antibody level, and therefore have a different clinical meaning and risk of developing PML, to an index value of 1.5 determined using the Gen2 ELISA described in EP 792. 227.2 EP 792 does not provide sufficient details regarding how to conduct an anti-JCV antibody ELISA of the type outlined in paragraph [0005] or the specific Gen2 ELISA that was used to determine the high-risk threshold of 1.5, including at least a failure to identify the capture antigen, certain reagents and assay protocol steps. The level of antibody binding and OD output of an ELISA is dependent on its set up, reagents and protocol and different samples will be affected differently by any variations in the ELISA due to the different polyclonal antibody populations in each sample. As a result, even disregarding the missing information about the cut-off calibrator, the Skilled IDS would not obtain equivalent nOD results to the Gen2 ELISA in EP 792. The cut-off threshold of an nOD of 1.5 for high risk of PML will not therefore also apply to any anti-JCV antibody ELISA that the Skilled IDS produces.’
“The cut-off calibrator (CO) is adjusted to have a reactivity index of about nOD 1.0, and a positive control (PC) is adjusted to have a reactivity index of about nOD 1.3). The CO and PC are made by mixing an anti-JCV antibody positive serum and an anti-JCV antibody negative serum. For the negative control (NC), which is typically bottle negative sera, the reactivity index target is about 0.1;. Qualitatively, the controls come from different pools of human serum, but from an assay target concentration, they are similar to the Gen 1 control levels.”
“confirm that the raw OD target for the cut off calibrator should be 1.0…and from that the raw OD of the negative and positive controls could be set at 0.1 and 1.3.”
“Such an approach would be contrary to one that the Skilled IDS would expect to have been taken based on their common general knowledge because an OD value of 4.2 is beyond the working range of most spectrophotometers. If the Gen2 assay had been designed so that the range of samples tested fell within the working range of around 0.1 – 2 or 2.5 OD, as the Skilled IDS would expect, then on considering Figure 12, the Skilled IDS would think it was likely that the Gen2 assay used a cut-off calibrator that generated a lower OD value.”
“EP 792 provides nODs for these cut-offs as determined in the Gen2 assay (i.e. at 0.2 and 0.4) but the Skilled IDS would not know which nOD values from their screening assay would represent the same anti-JCV antibody titers as nODs of 0.2 and 0.4 from the Gen2 assay. Further, the Skilled IDS would need to use a confirmatory assay to assign any indeterminate samples as positive or negative. The Skilled IDS could set up a confirmatory assay but they would not know whether their confirmatory assay would produce 45% inhibition at the same point as the Gen2 assay and therefore whether their confirmatory assay would assign indeterminate samples as positive or negative in the same way as the confirmatory step of the Gen2 assay in EP 792.”
“Paragraph 12 of Andersen explains that GenBio had access to a range of serum samples from Polpharma’s clinical trials for which it had index value results from the STRATIFY JCV DxSelect ELISA. GenBio then used these serum samples and their respective index values as determined by the STRATIFY JCV DxSelect ELISA to adjust the anti-JCV antibody assay they had developed to align the output of their assay to the STRATIFY JCV DxSelect ELISA. In the circumstances described in Andersen, in which GenBio had no access to the STRATIFY JCV DxSelect ELISA itself, this iterative process of comparing results and revising the assay was the only way in which GenBio could have developed an ELISA that provided index values that correlated with the STRATIFY JCV DxSelect ELISA.”
“Effect of Prior Immunosuppressant Use on Association between Index and PML Risk Further analysis of the test data set identified a different relationship between index and PML for patients based on prior immunosuppressant use (Fig 3A). In patients with no prior immunosuppressant use, the index distribution was significantly higher for PML patients than for non-PML patients (median = 2.4 vs 1.4; p<0.0001). In contrast, index distribution was similar for non-PML and PML patients with prior immunosuppressant use (median = 1.6 for both groups; p = 0.82). A similar relationship was observed for the verification data set (see Fig 3B) and the combined data set (interaction p = 0.0158; Fig 4A). Thus, subsequent analyses of index and PML risk were limited to patients with no immunosuppressant use prior to natalizumab treatment. …”
“Significant differences in index value between patients in the index cohort with and without PML were seen in patients without previous immunosuppressant use (p<0.0001) but not in those with previous immunosuppressant use (p=0.64, appendix).”
“In patients with prior IS [immunosuppressant], current data do not show an association between higher index and PML risk. The underlying biological explanation for this effect is unknown.”
“The actual contribution lies in determining a patient to be at high risk (whatever that is) of developing PML at an index value of> 1.5 (where that index value corresponds to a certain anti-JCV antibody titer, whatever that is). That is not technical in nature. It involves taking information presented by the assay and performing a mental act using that information, namely assessing risk of PML as being high. It follows that the subject-matter of the claims falls foul of the s.1(2) exclusion.”
“The method according to any one of claims 1 to 7, wherein the patient determined to be at high risk of developing PML is determined to be at higher risk of developing PML if the patient has received natalizumab for longer than 24 months and has not previously received a non-anti-VLA-4 immunosuppressant therapy, wherein the non-anti-VLA-4 immunosuppressant therapy is selected from mitoxantrone, methotrexate, azathioprine, cyclophosphamide, mycophenolate, anti-CD20 therapy, anti-CD11a therapy, and mycophenolate mofetil.”
“In an embodiment, a patient who has received an anti-VLA-4 therapy, such as natalizumab, for longer than 24 months (e.g., for 25 to 48 months, such as 26, 30, 36, 42 25 or 48 months or longer), and who has not received prior treatment with an immunosuppressant therapy other than an anti-VLA-4 therapy can be determined to be at a higher risk for PML. A patient at a higher risk for PML can have a risk of about 0.37/1000 or greater, e.g., about 4.3/1000 patients. The patient can accordingly be determined not to be a candidate to receive further treatment with an anti-VLA-4 therapy, or can be determined to be a candidate to receive treatment with an anti-VLA-4 therapy accompanied by more frequent monitoring.”
“(i) the anti-JCV antibody titer as indicated by index value or nOD is determined to be > 1.5 and the percent inhibition value is determined to be > 70%, or (ii) the patient showed an increase in index, nOD or titer by 2-fold from a previous test.”
“Prior immunosuppressant therapies, other than anti-VLA-4 therapy, that will be indicative of an increased risk of PML can include prior treatment with antineoplastics, immunosuppressants or immunomodulators, such as one or more beta-interferon or glatiramer acetate. Exemplary immunosuppressants include, e.g., mitoxantrone, methotrexate, azathioprine, cyclophosphamide, and mycophenolate, anti-CD20 therapy (e.g., rituximab), an anti-CD11a therapy (e.g., efalizumab), or mycophenolate mofetil.”
‘This oral evidence from the neurologists (coupled with the withdrawal of Dr Dugan’s report) establishes that there existed no theoretical reason in the CGK relating to the virology or immunological response to JCV, or the pathogenesis of PML, for the Skilled Team to suspect a link between anti-JCV antibody levels and the risk of PML, and no motivation to investigate such a link. To the contrary, PML was known to be associated with AIDS and the use of immunosuppressive drugs which are consistent with poor immune responses which might be expected to result in lower antibody titres. Accordingly, no such pre-existing suspicion or motivation can be ascribed to the Skilled Team when they come to the prior art.’
“First, it is relevant to consider whether at the priority date something was “obvious to try”, in other words whether it was obvious to undertake a specific piece of research which had a reasonable or fair prospect of success: Conor v Angiotech (above) para 42 per Lord Hoffmann; MedImmune Ltd v Novartis Pharmaceuticals UK Ltd[2012] EWCA Civ 1234 ;[2013] RPC 27 , paras 90 and 91 per Kitchin LJ. In many cases the consideration that there is a likelihood of success which is sufficient to warrant an actual trial is an important pointer to obviousness. But as Kitchin LJ said in Novartis AG v Generics (UK) Ltd[2012] EWCA Civ 1623 , para 55, there is no requirement that it is manifest that a test ought to work; that would impose a straightjacket which would preclude a finding of obviousness in a case where the results of an entirely routine test are unpredictable. As Birss J observed in this case (para 276), some experiments which are undertaken without any particular expectation as to result are obvious. The relevance of the “obvious to try” consideration and its weight when balanced against other relevant considerations depend on the particular facts of the case.”
“Having for a decade watched patients that I had been managing have relapses, the distress that is caused to them by that, the impact on their family life, the loss of income and slowly accumulate disability, it is incredibly helpful to have a highly efficacious drug that can meaningfully reduce the relapse rate in some pose Phase IV studies by up to 98%. So it effectively, for the majority of patients, switched their MS off. It gave patients their lives back. It had an incredibly profound effect on the cohort of patients I was privileged enough to treat.”
“Q. Okay. Do you agree with what Professor Berger says there? A. So, I would absolutely agree with what he says around the fact that a significant proportion of patients who tested JCV positive would take a decision around their own risk of PML, and either the neurologist, the very risk-averse neurologist might persuade the patient to come off treatment or the patient would take their own view. There is always a debate in terms of shared decision-making about how much the views of the neurologist would play into the decision, how that decision is played out. Broadly, I would accept that a neurologist would regard it as helpful to clarify the risk as much as was possible given the evidence of that was available. Q. Right. So you would agree with him that there was a desire to have a means to better assess a patient’s personal risk of PML and differentiate the levels of risk within the antibody positive population so that a more informed decision could be made about the risks and benefits of treatment? A. I agree, but I would caveat that by saying I am not sure the neurologist at that point would have known how to better assess the patient’s personal risk at that point.”
“…one of the limitations of the anti-JCV antibody testing provided by Biogen in April 2012 was that it could only give a positive or negative result. Although it was useful to identify anti-JCV antibody positive patients, it did not enable further differentiation between those patients in terms of their risk of PML. The Skilled Neurologist would be aware that a large proportion of the population test positive for JCV infection (over 50%). Given the high past infection rate, the rarity of PML and the limited number of other treatment options available, there was a desire among patients and clinicians to continue to use natalizumab in anti-JCV antibody positive patients. This was driven in particular by the severity of many patients’ MS symptoms, which were often life limiting and could be improved by natalizumab treatment. At the same time, treatment needed to be undertaken in the safest manner possible and therefore there was a motivation to further understand and stratify the risk of PML in JCV positive patients treated with natalizumab.”
“The Skilled Neurologist would have wanted to review further data from a larger number of patients (both PML and non-PML) than were evaluated in Gorelik, which would have been collected as a matter of good clinical practice in any case…This would essentially be a continuation of the studies described in Gorelik”
“..would also want to conduct longitudinal testing of seropositive patients to see if any pattern could be seen in their antibody levels over time, particularly in patients who went on to develop PML as this might also provide a way to stratify patient risk within the anti-JCV antibody positive group.”
“To better understand whether epidemiologic factors, including geography, gender, age, immunosuppressive pretreatment, and duration of natalizumab treatment influence the seroprevalence and levels of anti-JCV antibodies and the utility of serostatus for PML risk stratification, a large cohort of German patients with MS treated with natalizumab was investigated for anti-JCV antibodies. In addition, samples available from 10 natalizumab-treated patients collected before or at PML diagnosis were analyzed in a blinded fashion.”
“There is no data or reasoning to support a suggestion that risk may be assigned based on any particular level of antibody titre, or what would represent a “moderate” risk of developing PML. Given the absence of reasoning and the brevity of the statement, I do not believe the Skilled Team would attach any weight to it.”
“I think the easiest way, of course, is to expand the cohort to show, and I think that was also the point that I was making before, that the meaningfulness of this paper also turns into clinical routine meaningfulness.”
‘The Skilled Neurologist would have wanted to review further data from a larger number of patients (both PML and non-PML) than were evaluated in Gorelik, which would have been collected as a matter of good clinical practice in any case (as I mentioned at paragraph 66 above), to determine whether the hypothesis that risk of PML would be associated with antibody levels was borne out.’
‘12. … If the Skilled Neurologist could not obtain nOD values for patient samples from Unilabs (or another laboratory testing samples with the STRATIFY JCV assay), conducting this investigation would involve preparing an anti-JCV antibody assay, measuring antibody levels with that assay, recording the results and analysing whether there was a correlation with PML risk. I understand from Bristows that Mr Scrimshaw’s evidence is that such an assay could have been prepared by the Skilled IDS, although it would be different to that used in Gorelik. It would take time to collect the patient data but it would be straightforward to collect and analyse.’
‘Clinicians in the UK will do no more than interact with the patient’s body to obtain a sample for diagnostic purposes and/or conduct the intellectual exercise of using the results of the Assay to determine whether a patient’s anti-JCV antibody status is such that treatment with natalizumab is appropriate.’
“If the host computer is situated in Antigua and the terminal computer is in the United Kingdom, it is pertinent to ask who uses the claimed gaming system. The answer must be the punter. Where does he use it? There can be no doubt that he uses his terminal in the United Kingdom and it is not a misuse of language to say that he uses the host computer in the United Kingdom. It is the input to and output of the host computer that is important to the punter and in a real sense the punter uses the host computer in the United Kingdom even though it is situated in Antigua and operates in Antigua. In those circumstances it is not straining the word "use" to conclude that the United Kingdom punter will use the claimed gaming system in the United Kingdom, even if the host computer is situated in, say, Antigua. Thus the supply of the CD in the United Kingdom to the United Kingdom punter will be intended to put the invention into effect in the United Kingdom.”
“156. I agree with RIM that asking and answering Aldous LJ's questions in this case leads to a different answer. Who uses the method of operating a messaging gateway system that has the claimed features? The answer is RIM. Where do they operate it? The answer is in Canada.”
“A detection method performed on a maternal serum or plasma sample from a pregnant female, which method comprises detecting the presence of a nucleic acid of foetal origin in the sample, wherein said nucleic acid is a paternally inherited sequence which is not possessed by said pregnant female.”
“A method for performing prenatal diagnosis of a foetal chromosomal aneuploidy in a biological sample obtained from a female subject pregnant with a foetus, wherein the biological sample is maternal plasma or serum and wherein the sample includes cell-free nucleic acid molecules from the female subject and the foetus, the method comprising: performing a random sequencing on at least a portion of a plurality of the nucleic acid molecules contained in the biological sample to obtain a pre-determined number of sequences, wherein the sequences represent a fraction of the human genome; aligning, with a computer system, each sequence to a human genome; determining a first amount of sequences identified as being aligned to a first chromosome; determining a second amount of sequences identified as being aligned to one or more second chromosomes; determining a parameter from the first amount and the second amount; wherein the parameter represents a relative amount between the first and second amounts; and comparing the parameter to one or more cut-off values, to determine a classification of whether a foetal chromosomal aneuploidy exists for the first chromosome.”
“In my judgment, the crucial question is where, in substance, is the Alternative Proposed Process to be used? The answer is the United Kingdom. In substance, the ‘method of detecting a nucleic acid of foetal origin in a sample’ (Lo 1), the ‘method of detection of foetal aneuploidy’ (Quake) and the ‘method for performing prenatal diagnosis’ (Lo 2/3) would be performed by laboratories in the UK. The blood test would be taken in the UK, the sequencing machine would be operated in the UK and the information so obtained would be transmitted to Taiwan for a pre-determined set of automated computer processes to be applied to it. The output of the computer processing would be sent back to the United Kingdom for use in the United Kingdom. As Aldous LJ said in Menashe, it does not matter where the computer is situated. The process is operated, in substance in the UK. I accept Illumina’s submission that any other result would make it far too easy to avoid infringement of patents of this nature, given the ease of digital transmission and the ability to off-shore computer processing.”
“It should not be thought, however, that the claims do not continue to have an important function. It is variants from the claim which have to achieve substantially the same effect in substantially same way as the invention. The claims remain the starting point for the subsequent analysis of variants. Although we may have edged closer to it, the new approach does not transgress the second of the outlawed approaches in the Protocol, which treats the claim merely as a somewhat vague guideline.”
“the inventive concept is the new technical insight revealed by the invention as claimed, in the context of the specification as a whole, as it would have been perceived by the skilled person at the priority date.”
‘Anti-JCV antibody titre must be determined by means of an ELISA assay that uses HPVLPs as the capture antigen. This must be expressed as an index value obtained by normalising to a cut-off calibrator made with a mix of anti-JCV antibody positive and negative serum (fn:The ELISA must also use positive and negative controls that comprise positive and/or negative serum and have defined index values, but nothing discrete turns on these). The patient is then determined to be at high risk of developing PML if that index value is > 1.5. This value derives from the teaching that, when the Gen2 assay is used, an index value of > 1.5 covers approximately the upper 50% of all anti-JCV antibody positive index values but 87% of PML cases (see Example 6). While the claim requires anti-JCV antibody titres associated with a high risk of PML to be expressed as index values >1.5, the use of that index value as such to identify the cut point forms no part of the inventive concept of the claim. The same cut-point could be expressed by a different index value simply by adjusting the dilution of the calibrator. To use the technical contribution of the Patent it is sufficient to use an index value to represent a clinically relevant cut point to distinguish patients at greater risk of developing PML. That is the inventive concept or core of the claim.’
‘….the inventive concept of the claim is a method of assessing PML risk by determining whether the patient has a level of anti-JCV antibodies which is above that represented by an index value of 1.5 using the Gen2 assay of the Patent.’
“… Diluents can include, in non-limiting examples, solutions that include BSA, phosphate buffered saline (PBS), or PBS containing Tween.”
“… as at any date between31 May 2011 and31 May 2012 inclusive, the PCT did not disclose an in vitro JCV assay clearly enough and completely enough for a person skilled in the art to perform such assay to determine the anti-JCV antibody titer of a serum or plasma sample from a patient expressed as an index value (nOD) and, from that index value, to determine the level of risk of that patient of developing PML wherein high risk of developing PML corresponds to an index value of >1.5 or wherein a particular risk of developing PML corresponds to any other index value disclosed in the PCT.”
“15. In Fujifilm Kyowa Kirin Biologics Co., Ltd. v AbbVie Biotechnology Limited and another[2017] EWCA Civ 1 , [2017] R.P.C. 9 [‘Fujifilm’] this court examined for the first time whether Arrow declarations were available in principle, or whether there existed fundamental obstacles to their grant. Thus it was contended on behalf of the patentee inter alia that: (i) an Arrow declaration was in effect a challenge to validity of a patent which could only be made once a patent was granted in the proceedings identified ins.74 of the Patents Act 1977 ; (ii) such declarations were in substance a collateral attack on proceedings within the EPO, which the English court would not permit; (iii) to allow declarations in the Arrow form would be to open the floodgates; (iv) if the Arrow declaration does raise issues of validity, then it would be a way of undermining the system of allocation of jurisdiction under the recast Brussels Regulation in ways which the courts have striven to prevent; (v) the Arrow case itself had therefore been wrongly decided. 16. The court dismissed all these objections to the grant of Arrow declarations. At [93] the court explained that the existence, following grant, of the statutory remedy for revocation (and, I would add, declarations of non-infringement) needed to be borne in mind. The course envisaged by the Patents Act is that parties should wait and see what patent is granted before resorting to Arrow declaratory relief. However the statute did not create a bar to the grant of relief “in appropriate cases”
““[Merck] says this court should not be making declarations in respect of the validity of patent applications because they are subject to examination by the EPO and their claims can change. For the court to start anticipating the examination process would be to usurp the function of the EPO and this is inconsistent with the framework of the EPC and the Act. I agree with all of these submissions. I find it hard to conceive of any circumstances in which it would be appropriate for this court to grant a declaration that no valid patent could be granted on a divisional application which is being prosecuted before the EPO. But that is not what is sought. Arrow only seeks declarations that its own product was obvious at the priority date.”
“There is no dispute that the declaration must be formulated with clarity. The facts ultimately declared by the court must be clear, otherwise the declaration will simply give rise to further dispute and defeat the purpose for which it is granted. The declaration must also be clear so that the court can know what technical issues it has to decide. The declaration must therefore identify the combination of features of the products and processes in question on which the assessment of obviousness is to take place.”
“The proposed declaration is concerned not with the novelty or obviousness of a product or process independent of any pending patent application, but with what is and what is not enabled by the disclosure of the PCT. That disclosure is the subject of ongoing prosecution in the EPO. Accordingly (1) the claim for [the declaration sought] is a premature attack on the validity of a patent application prior to grant contrary tos.74 of the Patents Act 1977 and/or (2) a collateral attack on proceedings within the EPO and/or (3) would involve the Court improperly usurping the function of the EPO examiner.”
“84. AbbVie's real complaint, as it seems to us, is that the declarations, by asserting that the dosing regimen is old or obvious, are making it clear that a future patent claim to that regimen would be invalid. Accordingly, if AbbVie were to obtain the grant of claims in that form, the resulting patent would have been pre-emptively adjudged invalid. There is therefore, implicit in the Arrow declaration, an inter partes declaration of invalidity of a putative patent, not yet granted, having those claims. 85. Does the scheme of the EPC and the Act preclude a pre-emptive determination of the validity of a putative patent which has not been granted? If so, then FKB must wait and see whether such a patent is indeed granted and avail themselves of the remedies by way of opposition in the EPO or revocation before the national court. That may never happen. In the meantime there will be continuing commercial uncertainty over whether their product will be held to infringe. 86. In our judgement there is nothing in the scheme of the EPC and the Act to prevent such declarations in cases where there is a real justification for their grant. It is necessary to examine quite carefully the ways in which it is suggested that the grant of such a declaration would conflict with that scheme. 87. So far as the EPO is concerned, the following considerations are relevant. Firstly, the declaration has no direct impact on what the EPO can or cannot do in relation to any given application. The EPO will apply its own internal legal order and procedures irrespective of any decision of the national court. Secondly, the court is not being asked to review or adjudicate on past action within the EPO, as it was in Lenzing or Virgin. It is, however, correct to say that the court is being asked to adjudicate on an issue which may arise in proceedings in relation to one or more applications proceeding in the EPO. 88. We do not think that this latter consideration means that the declaration is a collateral attack on the proceedings in the EPO. On the contrary it is an inevitable feature of the scheme set up under the EPC that national courts will have to decide whether combinations of features are old or obvious, and that they will have to do so while possible divisional applications are still pending in the EPO (or indeed in the national patent office). Whenever a national court decides that a claim with features A, B and C is old or obvious in the course of revocation proceedings against a granted patent, it is deciding an issue which may arise in relation to a pending application. That is exactly what happened in the Arrow case itself, when divisionals were prosecuted in relation to essentially the same idea as had been held obvious (albeit in normal revocation proceedings) by Jacob J and the Court of Appeal. Because of the structure of the EPC, the EPO cannot be insulated from findings by national courts which may run contrary to applications which it is in the process of examining. The EPO is considered by the scheme to be capable of deciding its cases in accordance with its own legal order. 89. For similar reasons, the grant of an Arrow declaration is not inconsistent with the abolition of the right to oppose a patent in pre-grant opposition proceedings. The declaration will not prevent the EPO from granting any patent.”
“I do not accept that it is clear at this stage that either the general declaration or the PPD declaration is so unclear that it could not be granted. In each case GSK would have to establish that the relevant features were old or obvious at the level of generality at which they are pitched.”
“…[performing] an assay to determine the anti-JCV antibody titer of a serum or plasma sample from a patient expressed as an index value (nOD) and, from that index value, to determine the level of risk of that patient of developing PML wherein high risk of developing PML corresponds to an index value of >1.5 or wherein a particular risk of developing PML corresponds to any other index value disclosed in the PCT”
“Some of Mr Speck's submissions, in his skeleton argument at least, treated the declarations sought here as if they were patent claims. In the conventional approach to interpretation of patent claims, the claimed features are treated as the limit of what is required in order to infringe, in the absence of some express indication to the contrary. Additional features in the defendant's product will not avoid infringement. Thus, argued Mr Speck, the declarations in the present case covered a vast array of different products, such as the combination of ze or yf with every known lubricant, or additional refrigerant. It was quite wrong to pre-judge the obviousness of such combinations. Alternatively, if that was not the effect of the declaration, then it lacked clarity. I do not think it is correct to construe declarations such as those sought by Mexichem as if they were patent claims, so that every conceivable product which could fall within the declaration is being declared to be obvious. Sensibly understood, what Mexichem is seeking is a declaration that the mere idea of using Inagaki's disclosure of ze and yf as a refrigerant in a MAC is obvious. The declaration, being silent on lubricants and other refrigerants, says nothing about whether combinations of the cited refrigerants with such materials are obvious or not.”