Fetter Lane, London, EC4A 1NL
B e f o r e :
| (1) GENERICS (U.K.) LIMITED trading as MYLAN
(2) SYNTHON BV
|- and -
|YEDA RESEARCH AND DEVELOPMENT COMPANY LIMITED
|TEVA PHARMACEUTICAL INDUSTRIES LIMITED
Andrew Waugh QC, Thomas Hinchliffe QC and Katherine Moggridge (instructed by Bird & Bird LLP) for the Defendant and Third Party
Hearing dates: 10-12, 17 October 2017
Crown Copyright ©
MR JUSTICE ARNOLD :
|Use of MRI in MS||27-29|
|Use of disability scores||30|
|Causes of MS||31-34|
|Injection-related side effects||41|
|Clinical trials of GA||44|
|Filippi 2006 (CORAL)||49|
|Cohen 2007 (FORTE Phase II)||50|
|COMI 2008 (FORTE Phase III)||51|
|Mode of action of GA||52|
|Pharmacokinetics of GA||53|
|Background to the invention||55-56|
|Summary of the invention||57-58|
|Detailed description of the invention||59|
|The skilled person||75-78|
|The expert witnesses||79-93|
|Common general knowledge||94-133|
|US versus UK Knowledge||98-99|
|Side effects of the DMTs||100-101|
|Adherence and convenience||102-111|
|The 20 mg QD regimen for GA administration||112|
|The FORTE trials||113-127|
|Work on lower frequency administration of GA||128-132|
|New treatments on the horizon||133|
|The prior art||145-156|
|Novelty over Pinchasi||168-173|
|Obviousness over the prior art||174-190|
|Obviousness over Pinchasi||175|
|Caon and Flechter||190|
|Lack of inventive step for want of technical contribution and insufficiency||191-200|
|Summary of conclusions||213|
Diagnosis of MS
Use of MRI in MS
i) new, active sites of blood-brain barrier breakdown, and thus inflammatory demyelination within the CNS, may be visualised as Gd-enhancing areas on T1-weighted images;
ii) new MS lesions may also be visualised as hyperintense areas (i.e. bright spots) on T2-weighted images; and
iii) old lesions may appear as hypointense areas (i.e. black holes) on T1-weighted images.
i) Gd-enhancing lesions on T1-weighted images;
ii) hyperintense lesions on T2-weighted images (new or enlarging); and
iii) hypointense lesions on T1-weighted images.
Use of disability scores
Causes of MS
i) treatment with corticosteroids to accelerate recovery from acute relapses;
ii) treatment with disease-modifying agents, i.e. prophylactic therapy which reduces the number of relapses experienced by patients over a period of time and slows down, or hopefully prevents, long-term progression of the disease; and
iii) treatment of existing symptoms caused by prior injury, including fatigue, pain, muscle spasticity and visual deficits in order to relieve a variety of symptoms in the patient.
i) Interferon beta-1a (Avonex). Interferon beta-1a was first approved in the EU in March 1997 and has been available for use on the National Health Service ("NHS") since 2002 under the Department of Health's Risk-sharing Scheme (a scheme established by the Department to evaluate the long-term cost-effectiveness of DMTs after the National Institute for Clinical Excellence had concluded that it was not possible to evaluate their cost-effectiveness from the clinical trial data which was then available; the scheme enabled the price paid by the NHS to be adjusted at two year intervals to ensure cost-effectiveness). Interferon beta-1a is indicated for treatment of patients with relapsing forms of MS. Interferon beta-1a is administered by intramuscular injection once per week.
ii) Interferon beta-1a (Rebif). This form of interferon beta-1a was first approved in the EU in May 1998 and has been available for use on the NHS since 2002 under the Risk-sharing Scheme. This form of interferon beta-1a is indicated for treatment of patients with relapsing forms of MS. This form of interferon beta-1a is administered via subcutaneous injection three times per week as either a 22 µg or 44 µg dose, and the doses are administered, if possible, on the same three days each week (at least 48 hours apart).
iii) Interferon beta-1b (Betaferon). Interferon beta-1b was first approved in the EU in November 1996 and has been available for use on the NHS since 2002 under the Risk-sharing Scheme. Interferon beta-1b is indicated for treatment of patients with RRMS. Interferon beta-1b is administered via subcutaneous injection every other day ("QOD").
iv) Interferon beta-1b (Extavia). This form of interferon beta-1b was first approved in the EU in May 2008. It is indicated for treatment of patients with relapsing forms of MS and is identical to Betaferon. It is administered by subcutaneous injection QOD.
v) Glatiramer acetate (Copaxone). GA was first approved in the UK in August 2000 and has been available for use on the NHS since 2002 under the Risk-sharing Scheme. GA consists of the acetate salts of synthetic polypeptides containing four naturally-occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine and L-Lysine with an average molar ratio of 0.141, 0.427, 0.095 and 0.338 respectively. The average molecular weight of GA is between 5,000 and 9,000 daltons. GA is indicated for treatment of patients with relapsing forms of MS. The recommended dose of GA in 2009 was 20 mg QD administered by subcutaneous injection.
vi) Natalizumab (Tysabri). Natalizumab was first approved in the EU in June 2006 and was made available for use on the NHS since 2007. Natalizumab is a recombinant humanised IgG4 monoclonal antibody and contains human framework regions and the complementarity-determining regions of a murine antibody that binds to α-4 integrin. This blocks entry of lymphocytes into the central nervous system across the vascular endothelial surface. Natalizumab is indicated for treatment of patients with relapsing forms of MS and also for patients with Crohn's disease. The recommended dose for natalizumab is 300 mg administered intravenously every four weeks.
Injection-related side effects
Clinical trials of GA
Mode of action of GA
i) GA administration includes a shift from Th1 to Th2 type immune response in both human and animal subjects;
ii) experiments in animal model known as experimental autoimmune encephalomyeltiies ("EAE") have shown that GA specific Th2 cells accumulate in the CNS and release anti-inflammatory cytokines in a process known as bystander suppression;
iii) non-neutralising anti-GA immunoglobulins have been suggested by some to have a therapeutic benefit;
iv) GA administration induces a broad antigen non-specific alteration of APC function and interferes with antigen presentation via MHC class II molecules;
v) GA administration results in an increase in T-regulatory cells (CD4+/CD25+ Tregs);
vi) GA administration induces GA specific CD8+ suppressor T-cells; and
vii) GA might exert a direct neuroprotective effect.
Pharmacokinetics of GA
Background to the invention
"Disclosed is an effective low frequency dosage regimen of GA administration to patients suffering from a relapsing form of multiple sclerosis, including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis"
Summary of the invention
" The invention is as defined in the appended claims. Described herein are methods of alleviating a symptom of relapsing-remitting multiple sclerosis (treating relapsing multiple sclerosis) in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis comprising administering to the human patient three subcutaneous injections of a therapeutically effective dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection so as to thereby alleviate the symptom of the patient.
 Also described are methods of increasing the tolerability of GA treatment in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis which comprises reducing the frequency of subcutaneous injections of a pharmaceutical composition comprising a therapeutically effective dose of glatiramer acetate to three times over a period of seven days with at least one day between every injection"
Detailed description of the invention
" In accordance with the invention possible injection schedules include Day 1, Day 3, Day 5; Day 1, Day 3, Day 6; Day 1, Day 4, Day 6; Day 2, Day 4, Day 6; Day 2, Day 4, Day 7; Day 2, Day 5, Day 7; or Day 3, Day 5, Day 7.
 In yet another embodiment, the therapeutically effective dose of glatiramer acetate is 40mg/ml. In a further embodiment, the therapeutically effective dose of glatiramer acetate is 40mg/0.75ml.
 In another embodiment, increasing the tolerability of GA treatment in the human patient suffering from a relapsing form of multiple sclerosis comprises reducing the frequency of an immediate post injection reaction.
 In an additional embodiment, increasing the tolerability of GA treatment in the human patient suffering from a relapsing form of multiple sclerosis comprises reducing the frequency of an injection site reaction."
"As used herein, 'tolerability' relates to the level of discomfort associated with GA treatment. Tolerability is associated with the frequency and severity of post injection reactions and injection site reactions. Tolerability influences the period that patient can follow GA treatment."
"This invention is illustrated in the Examples section which follows. This section is set forth to aid in an understanding of the invention but is not intended to, and should not be construed to, limit in any way the invention as set forth in the claims which follow thereafter."
"To assess the efficacy, safety and tolerability of Glatiramer Acetate (GA) injection 40mg/ml administered three times weekly compared to placebo in a double-blind study design."
"Treatment with 40mg s.c. GA times weekly reduces the subject population annualized relapse rate by 30% or more when compared to the placebo group. Treatment with 40 mg s.c. GA three times weekly is at least effective as 20 mg s.c. GA daily administration at reducing the subject population annualized relapse rate."
"Accordingly, the subject application discloses an effective low frequency dosage regimen of GA administration to patients suffering from a relapsing form of multiple sclerosis, including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Based on the performance of the dosage regimen in these studies, the administration of three s.c. injections over a period of seven days with at least one day between every injection is also expected to work in the treatment of patients who have experienced a clinically isolated syndrome (CIS). This is based on the fact that the 20mg daily s.c. injection has been shown to work in PCT International Application PCT/US2008/03146 …"
"Glatiramer acetate for use in a regimen of three subcutaneous injections of a 40mg dose of glatiramer acetate every seven days with at least one day between each subcutaneous injection for use in treating a patient who is suffering from a relapsing form of multiple sclerosis or who has experienced a first clinical episode and is at high risk of developing clinically definite multiple sclerosis and wherein the pharmaceutical composition further comprises mannitol."
"Glatiramer acetate for use according to claim 1, wherein the tolerability of glatiramer acetate treatment in the human patient is increased by reducing the frequency of an immediate post injection reaction or an injection site reaction."
The skilled person
The expert witnesses
"… as a general matter, it is highly undesirable for a party to adduce evidence from two different experts on the same issue. It is likely to lead to an increase in the cost and complexity of the case and to provide no corresponding benefit to the court in dealing with the case justly and in accordance with the overriding objective. Moreover, it is likely to create practical difficulties for the party faced with the evidence of precisely the kind which the appellants say arise in this case. But that party should raise the issue with the judge, preferably before or, at the latest, during the trial, and seek appropriate directions as to whether the party seeking to rely upon the evidence should be permitted to do so and, if he is, the appropriate course to be adopted in relation to it. …"
"I think it is going to be a recipe for trouble if you have different human beings covering both the clinical aspect and the neurological aspect. If you have read my judgments over the past couple of years where you have multiple expert cases, you will see that time and time again I have commented on difficulties that are caused by having experts that overlap with each other. It really is not helpful."
Common general knowledge
US versus UK knowledge
Side effects of the DMTs
"In all clinical trials, injection-site reactions were seen to be the most frequent adverse reactions and were reported by the majority of patients receiving Copaxone. In controlled studies, the proportion of patients reporting these reactions, at least once, was higher following treatment with Copaxone (70%) than placebo injections (37%)."
Similarly, the Patient Information Leaflet stated that ISRs were "very common (more than 1 in 10 patients)".
Adherence and convenience
"All currently approved drugs for multiple sclerosis are administered parenterally. However, long-term treatment with injected drugs is not without problems. These include patient discomfort and the occurrence of adverse events associated with frequent injections, such as local injection site reactions. These issues, through reduction of patient compliance, probably negatively affect patients' use of all available drugs. Thus, there is a strong rationale for assessment of whether drugs that are known to be effective when given parenterally also exert positive effects on clinical and MRI measures of disease activity when given orally."
It was on this basis that the CORAL Phase III trial was undertaken.
"In my experience, for most of my patients the frequency of injections was an important factor in selecting which treatment to take. For [patients with mild RRMS] Avonex was a popular choice because it was administered once weekly (albeit via intramuscular injection which can be more painful than sc injections) and led to fewer ISRs than the more frequently administered interferons."
The 20 mg QD regimen for GA administration
The FORTE trials
"Objective: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40 mg daily vs. the approved 20 mg formulation in relapsing remitting multiple sclerosis. Methods: Eligibility criteria included clinically definite multiple sclerosis, expanded Disability Status Scale score 0 to 5.0, no previous use of GA, at least one relapse in the previous year, and 1 to 15 gadolinium-enhancing (GdE) lesions on a screening MRI. MRI was repeated at months 3, 7, 8, and 9, and neuralgic examinations were performed at baseline and months 3, 6, and 9. Results: Of 229 subjects screened, 90 were randomly assigned to GA 20 mg (n = 44) or 40 mg (n= 46). The groups were well matched at baseline for demographic, clinical, and MRI characteristics. The primary efficacy endpoint, total number of GdE lesions at months 7, 8 and 9, showed a trend favouring the 40-mg group (38% relative reduction, p = 0.0898). A difference between the two dose groups emerged as early as month 3 (52% reduction; p = 0.0051). There was a trend favouring the 40-mg group for relapse rate with benefit on proportion of relapse-free subjects (p = 0.0183) and time to first relapse (p = 0.0367). GA 40 mg was well tolerated, with an overall safety profile similar to that of 20 mg. Some features of injection site reactions and immediate postinjection reactions were more common and severe with the higher dose. Conclusions: Glatiramer acetate (GA) 40mg was safe and well tolerated. The overall efficacy results suggested that a 40-mg dose of GA may be more effective that the currently approved 20-mg dose in reducing MRI activity and clinical relapses."
"Injection site reactions were the most frequent adverse event for both doses, occurring in 38 (86.4%) subjects in the 20-mg group and 39 (84.8%) in the 40-mg group. Injection site manifestations reported with at least 5% higher incidence for GA 40 mg included burning, mass, pass, and urticaria (table 3). Skin necrosis and lipoatrophy were not observed. Thirty-nine IPIRs occurred in 10 (22.7%) subjects on GA 30 mg vs 52 IPIRs in 15 (32.6%) subjects on GA 40 mg. The incidence in the 200mg group was consistent with previous large studies of GA. IPIRs were categorized most often as moderate severity in the 40-mg group and mild in the 20-mg group. All IPIRs resolved without sequelae, although one in the 40-mg group led to hospitalization and subsequent discontinuation from the study. The greatest difference in IPIR component symptoms … was in palpitations."
"In the present study, an advantage of the 40 mg dose on suppressing GdE lesions was already evident at month 3 and, in fact was more prominent compared with months 7, 8, and 9. Similarly, results based on the first relapse, e.g. time to first relapse and proportion of relapse free subjects, were more robust than measure based on the 9 month study period, e.g., relapse rate. These results suggest that the onset of action of the 40 mg dose is more rapid compared with 20 mg. A larger, longer study will be necessary to confirm the sustainability of the efficacy advantage of the higher dose.
GA at the currently approved 20 mg dose has been safe and well tolerated in previous trials and post-marketing experience. The overall safety and side effect profile of the 40 mg dose in this trial was similar, although it was associated with greater incidence of certain adverse effects. For example, although the overall incidence of injection site reactions was similar, some aspects were more common with the higher dose, and the injections seemed to be somewhat more painful. IPIRs also were somewhat more common and severe. Qualitatively, both side effects were similar what has been seen previously."
"Background: Results from a phase II study showed that 40mg dose of glatiramer acetate (GA) was possibly more effective than the currently approved 20mg dose in reducing MRI activity and clinical relapses. Objective: To evaluate the safety, tolerability, and efficacy of GA 40mg compared to the 20mg dose. Methods: Patients with definite MS (revised McDonald criteria), with at least one documented relapse in the 12 months prior to screening, or at least two documented relapses in the 24 months prior to screening, and EDSS score 0–5.5, were enrolled. Subjects were evaluated at screening, baseline, and at months 1, 2, 3, 6, 9, and 12. The primary endpoint was the rate of confirmed relapses observed during the study. Results: A total of 136 centers in 20 countries participated in the trial. Of the 1262 subjects screened, 1155 were randomized to GA 20mg (n=586) or 40mg (n=569). The groups were well-matched at baseline on demographic, clinical, and MRI characteristics. Annualized relapse rate (ARR) in the last year prior to study was 1.498. The primary efficacy endpoint was similar in both groups (relative risk=1.07, p=0.4859) with mean ARR of 0.33 for the 20 mg and 0.35 for the 40 mg group and 0.27 for those who completed one year treatment. Seventy-seven % of the patients remained relapse-free in both groups. Both groups showed a reduction in the mean number of gadolinium-enhancing and new T2 lesions over time with a trend for a faster reduction in the first trimester in the 40mg dose compared with 20mg dose. Both doses were well-tolerated with a safety profile similar to that observed in previous studies of 20mg GA. Conclusions: In RRMS patients, both GA 40 mg and the currently approved 20mg doses were safe and well-tolerated, and were equally effective in reducing clinical relapses and MRI activity."
"* Three pivotal trials support the efficacy, tolerability, and safety of GA 20 mg dosing in RRMS patients
* Results from a phase II study showed that 40mg dose of glatiramer acetate (GA) was possibly more effective than the currently approved 20mg dose in reducing MRI activity and clinical relapses".
"* Safety profile similar to that observed in previous studies of GA 20mg; both doses were well-tolerated; increased treatment discontinuation due to injection site reactions with the higher dose
* No safety concerns in both doses with regards to Laboratory Results, ECG and Vital signs".
"* No significant differences in efficacy measures between GA 20mg and GA 40mg
* Both doses demonstrated remarkable reduction compared to baseline in clinical and MRI activity
* Good safety and tolerability profile; no unexpected adverse effect with the higher dose
* Trend for an earlier effect of high dose on MRI activity".
i) There was no statistically significant difference in efficacy between the 40 mg dose and the 20 mg dose in terms of MRI activity or reduction in relapses.
ii) There was some evidence in both FORTE Phase II and Phase III of an earlier onset of activity as measured by MRI with the 40 mg dose than with the 20 mg dose; but the evidence was weak, in particular because of the problem with the randomisation of the frequent MRI cohort in Phase III which meant that the apparent difference at three months could be an artefact. Moreover, there was no discussion of the clinical significance of an earlier onset of action if there was one. Dr Green and Prof Zajicek were disagreed as to whether the skilled person would consider that an earlier onset of action would be clinically beneficial, and I conclude that the skilled person would regard this as uncertain.
iii) In terms of efficacy, therefore, there was no disadvantage in administering a 40 mg dose rather than a 20 mg dose, and there was a possible, but unproven, short-term advantage of uncertain clinical significance.
iv) In the Phase II trial, there had been no real difference in the rate of ISRs between the 40 mg dose and the 20 mg dose, although there was a suggestion that injections were more painful; whereas there was an increase in both the rate and the severity of IPIRs, although it is not clear whether this was statistically significant. In the Phase III trial, there had been a statistically significant increase in early terminations due to adverse events, which were mainly due to ISRs. So far as one can tell from Comi 2008B, this was due to an increase in the frequency of ISRs, rather than their severity. There was also an increase in the frequency of IPIRs, although it is not clear whether this was statistically significant. There is no mention in Comi 2008B of the IPIRs having been more severe.
v) Nevertheless, both the 40 mg and the 20 mg doses were safe and well tolerated.
vi) In terms of tolerability, therefore, there was a disadvantage in administering a 40 mg dose rather than a 20 mg dose, mainly in terms of the frequency of ISRs, albeit that it remained well tolerated.
Work on lower frequency administration of GA
i) Flechter et al, "Comparison of glatiramer acetate (Copaxone®) and interferon ß-1b (Betaferon®) in multiple sclerosis patients: an open-label 2-year follow-up", J. Neurol. Sci., 197, 51-55 (2002) ("Flechter 2002A");
ii) Flechter et al, "Copolymer 1 (Glatiramer Acetate) in Relapsing Forms of Multiple Sclerosis: Open Multicenter Study of Alternate-Day Administration", Clin. Neuropharmacol., 25, 11-15 (2002) ("Flechter 2002B"); and
iii) Khan et al, "Randomized, prospective, rater-blinded, four-year pilot study to compare the effect of daily versus every-other-day glatiramer acetate 20mg subcutaneous injections in relapsing-remitting multiple sclerosis", Multiple Sclerosis, 14, S296 (2008) ("Khan 2008"). Khan 2008 is the abstract from a presentation by Prof Khan at WCTRIMS in September 2008.
"In summary, although our study is an open-label one, it shows that IFNß-1b injected subcutaneously on alternate day, and Copaxone injected subcutaneously either daily or on alternate day, may modulate disease activity in a similar way and to a similar extent.
The choice of the appropriate medication for each patient still remains an individual decision since the effects of IFNß-1b and Copaxone seem to be similar. The fact that Copaxone injected on alternate day seems to be equally effective as the Copaxone injected daily is important to patients with injection-related adverse events and, from an economic point of view, as a cost-effective measure. Moreover, considering that there is no available data supporting daily vs. alternate-day Copaxone injection, in our view a well-designed post-marketing study is required, in order to confirm or refute the results obtained in our study."
"The results of this trial suggest that alternate-day treatment with Copolymer 1 [i.e. GA] is safe, well tolerated, and probably as effective as daily Copolymer 1 in reducing relapse rate and slowing neurologic deterioration. However, these preliminary observations will have to be examined in larger studies, preferably comparing daily with alternate-day administration of Copolymer 1 in a blinded manner."
"Background: The recommended dose of GA in RRMS is 20 mg subcutaneous (SC) daily (QD) although the optimal dose remains unknown. There is considerable interest in alternate dosing regimens of GA in RRMS. Daily SC injectable therapy can be challenging for long-term patient compliance. Objective: We conducted a pilot trial to compare the effect of GA 20 mg SC daily versus every other day (QOD) in RRMS. The primary endpoint was based on a composite of clinical, MRI, and immunologic outcomes. Methods: Treatment naïve RRMS patients were randomized to GA 20 mg SC QD or QOD and followed prospectively for 2 years. After 2 years, patients in each group were given the option to continue or switch to the other group, and followed for an additional 2 years. EDSS was recorded every 6 months by a rater blinded to dosing allocation. Brain MRI scans were obtained at baseline, and years 2 and 4. Blood for immunologic testing was obtained at baseline and multiple time points after randomization. Results: 30 patients were randomized to GA 20 mg SC given QD or QOD. Both groups were well-matched for age, disease duration, EDSS, relapse rate, T2W and gadolinium (Gd) enhancing lesions. After 2 years, there were no differences in the relapse rate, disease progression, Change in T2W lesion volume, or Gd enhancing lesions between the two groups. In vitro proliferation of GA-responsive T-cells and Th1/Th2 cytokine expression did not differ between the two groups at any time point after randomization. After 2 years, all patients in the QD group opted to switch to QOD. After a total of 4 years of prospective follow-up, there was no difference between the QD-QOD cross over group and the always QOD group. Additional data on imaging and immunologic outcomes will be presented. Conclusions: This pilot study suggests that GA 20 mg SC administered QD or QOD may be equally effective in RRMS. This may have implications for the long-term use of GA. However, large multi-center studies are warranted to confirm our findings and to identify the optimal dose of GA in RRMS."
i) There was considerable interest in less frequent administration of GA, in particular because of the adherence issue with QD administration.
ii) The studies in Flechter 2002A and Flechter 2002B suffered from methodological flaws which reduced the weight that could be placed on them, but would not lead the skilled person to disregard them altogether.
iii) Each of the studies suggested that 20 mg QOD might be as effective as 20 mg QD, but given their small scale and open-label (i.e. unblinded) nature, no firm conclusions could be drawn and larger, blinded studies were required to confirm the findings.
New treatments on the horizon
The prior art
"The safety profile of the 40 mg/d dose is essentially similar to the currently available 20 mg/day dose with a slight tendency of higher incidence of IPIR."
"The increased efficacy observed with 40 mg/day GA in reducing MRI-measured disease activity and relapse rates indicates that it is well tolerated and can improve the treatment of RRMS patients. The improvement in efficacy, however, is not accompanied by a corresponding increase of adverse reactions which would be expected upon a doubling of the administered dose.
Also observed was the accelerated rate at which the 40 mg/day dose became effective as compared to the 20 mg/day dose. This was unexpected. Specifically, the 40 mg/day dose showed efficacy, as measured by MRI, by the third month, whereas the 20 mg/day dose did not show efficacy until the sixth month. The results at three months comparing the 40 mg/day dosage are shown in Figure 3 and Table 2 above."
"OBJECTIVE: We conducted a pilot trial to compare the effect of GA 20 mg SC daily to every other day (QOD) on clinical, MRI, and immunologic outcomes in RRMS. BACKGROUND: The recommended dose of glatiramer acetate (GA) for the treatment of RRMS is 20 mg SC daily though the optimal dose remains unknown. Recent studies failed to show improved efficacy with higher than the recommended dose. DESIGN/METHODS: Treatment naïve RRMS patients were randomized to GA 20 mg SC QD or QOD and followed prospectively for 2 years. After 2 years, patients in each group were given the option to continue or switch to the other group, and followed for an additional 2 years. EDSS was recorded every 6 months by a masked-rater. Brain MRI scans were obtained at baseline, years 2 and 4. Blood for immunologic testing was obtained at baseline and multiple time points after randomization. RESULTS: 30 patients were randomized to GA 20 mg SC given QD or QOD. Both groups were matched for age, disease duration, EDSS, relapse rate, and T2W lesions. After 2 years, there were no difference in the relapse rate, disease progression, or any MRI outcome. In vitro GA-proliferative responses and Th1/Th2 cytokine expression did not differ between the two groups at any time point after randomization. After 2 years, all patients in the QD group opted to switch to QOD. After a total of 4 years of prospective follow-up, there was no difference in the clinical efficacy between the 'QD-QOD cross over' and the 'always QOD' groups. Injection related lipoatrophy was significantly less in the QOD group. CONCLUSIONS/RELEVANCE: This pilot study suggests that GA 20 mg SC administered QD or QOD may be equally effective in RRMS. Larger, multi-center studies are warranted to confirm our findings and identifying the optimal dose of GA in RRMS."
"1. Treatment with 20mg Cop 1 in alternate day injections subcutaneously is safe and well tolerated.
2. Relapse rate decreases significantly and stabilises at lower levels.
3. Patients' disability, as measured by EDSS, does not deteriorate during the first year of treatment, although deterioration is observed during the second year. It may very well be that the natural history of the disease is attenuated by Cop 1.
4. The results obtained in this open-label study, with alternate day injection of Cop 1, showed safety and efficacy as well, as the daily injection studies reported in several controlled trials."
"22. … the matter relied upon as prior art must disclose subject-matter which, if performed, would necessarily result in an infringement of the patent. That may be because the prior art discloses the same invention. In that case there will be no question that performance of the earlier invention would infringe and usually it will be apparent to someone who is aware of both the prior art and the patent that it will do so. But patent infringement does not require that one should be aware that one is infringing … It follows that, whether or not it would be apparent to anyone at the time, whenever subject-matter described in the prior disclosure is capable of being performed and is such that, if performed, it must result in the patent being infringed, the disclosure condition is satisfied. …
24. Although it is sometimes said that there are two forms of anticipatory disclosure: a disclosure of the patented invention itself and a disclosure of an invention which, if performed, would necessarily infringe the patented invention … they are both aspects of a single principle, namely that anticipation requires prior disclosure of subject-matter which, when performed, must necessarily infringe the patented invention."
"i) Notwithstanding that it is not within the literal meaning of the relevant claim(s) of the patent, does the variant achieve substantially the same result in substantially the same way as the invention, ie the inventive concept revealed by the patent?
ii) Would it be obvious to the person skilled in the art, reading the patent at the priority date, but knowing that the variant achieves substantially the same result as the invention, that it does so in substantially the same way as the invention?
iii) Would such a reader of the patent have concluded that the patentee nonetheless intended that strict compliance with the literal meaning of the relevant claim(s) of the patent was an essential requirement of the invention?"
If questions (i) and (ii) are answered yes, and question (iii) is answered no, then there is infringement.
"4.5. Taking equivalents into account
The case law of the boards of appeal is based on a narrow concept of novelty, i.e. the disclosure of a prior document does not include equivalents of the features which are explicitly or implicitly disclosed; equivalents can only be taken into account when it comes to considering inventive step (T 517/90). This narrow concept of novelty, which excludes equivalents, is of particular importance for the application of Art. 54(3) EPC. In T 167/84 (OJ 1987, 369) the board commented that conflicting applications within the meaning of Art. 54(3) EPC 1973 were included in the state of the art solely from the point of view of novelty, but were considered in the light of their 'whole contents'. In order to mitigate the harsh effects of the 'whole contents approach', its application was confined to novelty. Further, in order to reduce the risk of 'self-collision', it had always been considered justified to adopt a strict approach to novelty. For this reason, the Guidelines expressly stated that 'when considering novelty, it is not correct to interpret the teaching of a document as embracing well-known equivalents which are not disclosed in the document; this is a matter of obviousness' (Guidelines G-VI, 2 – November 2015 version). According to the case law of the boards of appeal the 'whole contents' of an earlier document did not also comprise features which were equivalents of features in the later document (see also T 928/93, T 1387/06).
In T 652/01 the appellant was of the opinion that although the relevant prior-art document did not explicitly mention a particular feature, that feature could be derived from the document by applying the document's teaching mutatis mutandis. The appellant had referred to T952/92 (OJ1995,755), which, in its first headnote, stated that 'availability' within the meaning of Art. 54(2) EPC 1973 involved not only availability of the disclosure but also availability of information accessible and derivable from the disclosure, which meant that 'derivable equivalents' were included. However, the board held that, when reading the cited phrase from T 952/92 in the context of the present decision, it was clear that the term 'derivable' had been employed in the sense of "obtainable by chemical analysis of a sample" and that it was used with the same restriction as expressed in opinion G 1/92 (OJ 1993, 277), namely that it had to be 'directly and unambiguously derivable'."
Novelty over Pinchasi
i) Pinchasi teaches administration of 40 mg GA QOD to treat patients with relapsing forms of MS;
ii) over a seven-day period, that regimen would be identical to the regimen claimed in the Patent; and
iii) over a longer period, that regimen would be identical to the regimen claimed in the Patent every other week, while in the intervening weeks it would result in the administration of one additional dose.
Obviousness over the prior art
Obviousness over Pinchasi
"The accumulated data showing that GA acts as an immunomodulating drug, and the results of the FORTE study showing that a higher dose of GA does not increase the efficacy of the drug, encouraged the Sponsor to further explore the optimal dose and dosing regimen of GA and to study the safety and efficacy of GA administered in a reduced injection frequency. This rationale is further supported by the current situation where all the currently approved treatments for RRMS are administered parenterally and frequent injections affect the long-term adherence to treatment.20
Hence, the next natural step is to reduce the dosing regimen of GA and find the optimal regimen that will improve the convenience of treatment and reduce the burden and adverse events associated with daily subcutaneous injections.
Further support for this rationale was provided by several small-scale, investigator initiated studies, which explored a reduced injection frequency of GA.21,22,23 These studies employed a dose of GA 20mg, given either on alternate days or twice weekly, with follow-up periods which ranged from two to four years. These studies included between 30 and 68 subjects, and employed an open label design. The results of these studies demonstrated effects in relapse rate reduction which were comparable to daily injections of GA 20mg, suggesting a lower injection frequency can be considered. In two of these studies,22, 23 these comparable effects were also supported by MRI data. These results of these studies also suggest that participating subjects found the reduced frequency regimens preferable and associated with a lower of injection related adverse events. The authors of all three studies highlighted the need for larger, multi-center studies to confirm their findings.
While it is important to note that all the above mentioned studies were clearly too small and underpowered to show a significant effect on clinical end-points, they do provide additional support to the rationale of the current proposed study.
The dose regimen that was selected for the trial is GA 40 mg injected subcutaneously three times a week.
In the absence of data about the efficacy of lower frequency administration of GA 20mg in large, well controlled studies, the sponsor has decided to take a more conservative approach. Therefore the subjects will receive approximately the same weekly dose, given by 3 subcutaneous injections instead of with a daily injection frequency of 7 injections.
The 40 mg dose has been previously explored as a potential formulation for daily injection in two clinical studies (see Section 22.214.171.124). While no superiority of the GA 40 mg dose over the GA 20 mg was demonstrated, the GA 40 mg formulation showed similar quality, safety and efficacy profile compared to that of the GA 20 mg dose. The use of the 40mg dose in this study would allow a gradual approach where reduction in injection frequency would be offset by the use of a higher dose, already shown to be effective and safe in daily use.
Three weekly doses of 40 mg GA would give a cumulative weekly dose of 120mg, approximately similar to the 140 mg cumulative weekly dose given today with daily injections of 20 mg. This would serve as an opportunity to explore the increased convenience of three injections a week, without substantially reducing the total GA dose administered. If this dose regimen is indeed found to be effective, RRMS patients will benefit from a much more convenient injection schedule, and the enhanced compliance resulting from this will help maintain the long term efficacy of this treatment.
It should also be noted that considering the reduced injection frequency, and the fact that in the GA/9016 study, local reactions at the injection sites and immediate transient reactions following injection were reported with a similar incidence for both doses,15 one may certainly expect a reduction in the frequency of such reactions with this new dose regimen, further enhancing subject adherence to treatment."
References 21 and 22 are Flechter 2002B and Khan 2008. (Reference 23 is another abstract from Prof Khan's group comparing 20 mg QD with 20 mg twice-weekly published in 2009, I presume after the priority date of the Patent. It is not suggested, however, that this would have affected the skilled person's attitude to the proposal.)
Caon and Flechter
Lack of inventive step for want of technical contribution and insufficiency
"… we do not consider that there is any issue of principle which prevents the granting of Arrow declarations in appropriate cases. Drawing the threads together:
(i) A declaration that a product, process or use was old or obvious at a particular date does not necessarily offend against s.74 of the Act.
(ii) Such a declaration may offend against the Act where it is a disguised attack on the validity of a granted patent.
(iii) Such declarations do not offend against the scheme of the EPC or the Act simply because the declaration is sought against the background of pending divisional applications by the counter-party.
(iv) On the other hand the existence of pending applications cannot itself be a sufficient justification for granting a declaration.
(v) Whether such a declaration is justified depends on whether a sufficient case can be made for the exercise of the court's discretion in accordance with established principles."
i) justice to the claimant;
ii) justice to the defendant;
iii) whether the declaration will serve a useful purpose. The attainment of commercial certainty in patent cases can constitute a useful purpose. The spin-off value of a judgment in other states may be such a factor, but a declaration sought solely for the benefit of foreign courts will rarely be justified; and
iv) whether or not there are any other special reasons why the court should or should not grant the declaration.
"A declaration that the use of the Claimants' Product for treating a patient suffering from relapsing forms of MS wherein the Claimants' Product comprises glatiramer acetate for administration in a regimen of three subcutaneous injections of a 40mg dose of glatiramer acetate every seven days with at least one day between each subcutaneous injection would have lacked novelty and/or been obvious as at 20 August 2009 insofar as the dosing regimen is concerned."
Summary of conclusions
i) claims 1 and 3 of the Patent are novel over Pinchasi;
ii) claims 1 and 3 of the Patent are obvious over Pinchasi, and therefore invalid;
iii) if claims 1 and 3 were not obvious over Pinchasi, then they would not be obvious over Caon or Flechter;
iv) if claim 3 was not obvious, then it would lack plausibility and thus be invalid on the grounds of lack of inventive step and insufficiency, but the same does not apply to claim 1 as I have construed it; and
v) it is not appropriate to grant the Claimants an Arrow declaration.