“The skilled person would have been aware of daptomycin’s potent antibiotic activity as a matter of his common general knowledge and would not have doubted that daptomycin would be effective to treat infections in the range of doses covered by the Patent’s claims.”
“This view, that the primary benefits of once-daily aminoglycosides dosing are potentially increased efficacy and improved “ease-of-use”, is supported by the fact that clinical dosing recommendations, as set out in the BNF in September 1998, did not recommend once-daily dosing. If the once-daily dosing had been primarily driven by, or demonstrated to result in, reduced toxicity, the clinical dosing recommendations would have been revised.”
“Although aminoglycosides are generally given in 2 to 3 divided doses during the 24 hours, once-daily administration has been shown to reduce the risk of toxicity (while ensuring adequate plasma concentrations) but expert advice about dosage and plasma concentrations should be obtained”
“Numerous clinical studies demonstrate that a single daily dose of aminoglycosides is just as effective and no more (and often less) toxic than multiple smaller doses” (SCE-3 page 757, start of the third paragraph, emphasis added). As this quotation from SCE-3 makes clear, the main reference to toxicity is that it did not increase when a once-daily dosing regime is used.”
“Therefore, many authorities now recommend that aminoglycosides be administered as a single daily dose in most clinical situations.”
“… The combined skills (and mindsets) of real research teams in the art is what matters when one is constructing the notional research team to whom the invention must be obvious if the patent is to be found invalid on this ground.”
“Dr C. Rivera and Dr M. Zeckel reviewed the daptomycin project and its clinical status and issues. Mr. G. Stach and Mr. J. Wanko reviewed market economics and a financial analysis. In summary, there was uncertainty regarding the true potential for marked CPK elevations due to the small sample size. The project team recommended termination of the project should the potential for CPK levels be significant since the therapeutic index would be too narrow and the economics unattractive (based on vancomycin (sic) continued dominance in the marketplace without significant resistance).”
“The committee’s recommendation to proceed with the development of daptomycin was contingent on: (a) use of minimal resources to conduct the proposed clinical studies and (b) stipulation that the project’s future be revisited in 18 months (or following completion of the two studies) in order to assess the prevalence of vancomycin resistance in the market. The committee further suggested that the team proceed with negotiations with the FDA to conduct these studies. Studies outside of the U.S. would be considered in the event the FDA rejects the proposal.”
“because the therapeutic window between efficacy and safety was therefore thought to be small taken together with the commercial assessment at Lilly at the time that vancomycin was still reasonably able to deal with infections due to MRSA.”
“Phase II trial #1 showed safety and efficacy in treating skin and soft tissue at 2 mg/kg/day. Phase II trial #2 showed safety and efficacy in bacteraemia, but unacceptable efficacy in endocarditis at 6 mg/kg/day (3 mg/kg/q.12h). Reversible adverse muscle effects…evident in two subjects at 8 mg/kg/day (4 mg/kg/q.12h) precluding dose escalation for treatment of endocarditis. Lilly terminated development in April 1991 since daptomycin would not achieve targeted economic criteria without endocarditis, and at this time, resistant pathogens were not an epidemic.”
“Thus, for several years there was an attitude that if nothing else worked, at least vancomycin would. This illusion was shattered when the discovery of vancomycin resistant enterococci in England and France was reported in 1987.”
“Daptomycin (D), a semisynthetic lipopeptide antibiotic highly effective in vitro against gram-positive organisms, was administered i.v. once-daily in a dose of 2 mg/kg to patients with various types of susceptible gram-positive infections and compared to conventional (vancomycin etc.) therapy (C) using a double-blind, randomised study design… The results from this study showed that i.v. daptomycin in a dose of 2 mg/kg /day may be safe and effective in patients with various gram-positive infections.”
“These results suggest that D at 3 mg/kg/12h, while effective in B and non-SAE, may be less effective in SAE. Higher doses of D may be necessary to achieve improved success rates in SAE.”
“failures of daptomycin to cure Staphylococcal human endocarditis have been reported recently (8,14), suggesting that higher doses should be used to obtain adequate unbound concentrations of daptomycin in serum.”
“Daptomycin has recently been withdrawn from further clinical testing because of its failure against human endocarditis as well as its toxicity.”
“Daptomycin was studied in early clinical trials with a dosage of 2 mg/kg of body weight per day. These trials were terminated because of failures despite seemingly adequate levels in serum. The most recent clinical trials with daptomycin were suspended because of failures in patients treated for Staphylococcus aureus endocarditis.” … “Endocarditis represents a unique infectious process which includes difficulties existing in both antibiotic penetration, impaired immune response, high bacterial inoculum, and bacteria in both logarithmic and stationary growth Phases.”… “Despite seemingly excellent in vitro activity and in vivo efficacy in animal models, daptomycin has proved ineffective against human S. aureus endocarditis in the dosage regimens administered to date. Daptomycin has been dropped from further development in the United States because of the toxicity with higher dosage regimens. This study has demonstrated that despite the harsh environmental conditions evaluated, daptomycin was capable of producing kill rates surpassing those of vancomycin.”
“Daptomycin was shown to be well tolerated in normal human volunteers when given intravenously in a 30 or 60 minute infusion at 1 or 2 mg/kg every 24 hrs (41,57). Woodworth et al. (58) also studied the safety, pharmacokinetics and disposition of daptomycin in healthy volunteers. They showed that in single intravenous doses infused over 30 min, daptomycin was well tolerated at 0.5 to 6.0 mg/kg per day…. The authors caution that the high protein binding and large molecular size of daptomycin may limit the distribution of daptomycin out of the plasma, and so daptomycin treatment of deep-seated infections, such as bone infections and endocarditis, may have limited effectiveness.”
“At a dose of 2 mg/kg every 24 hr, daptomycin was shown to be effective in treating a variety of Gram-positive infections (59). In another study, daptomycin given at a dose of 3 mg/kg every 12 hr was shown to be effective in treating Gram-positive bacteraemias and endocarditis caused by Gram-positive pathogens (including E. faecalis) other than S. aureus (60). Only two of seven patients with S. aureus endocarditis had successful outcomes. Five patients were discontinued from the study because of adverse effects. In another study, daptomycin at 2 mg/kg once a day failed to treat two very seriously ill patients with Gram-positive infections (61). It was suggested in the latter two studies that higher doses of daptomycin would be required to treat S. aureus endocarditis and severely ill patients. However, the occasional adverse effects noted at a dose of 3 mg/kg every 12 hours seem to preclude raising the dose further, and clinical trials were stopped.”
“Daptomycin was successful in clinical trials at treating some Gram-positive infections, but it failed to treat staphylococcal endocarditis adequately. Elevated doses of daptomycin suggested that it may cause muscle toxicity in some patients, and so the clinical trials were stopped.”
“if a once-daily dosing regimen had a similar efficacy and safety profile to a twice-daily dosing regimen, the skilled person would pursue the once-daily dosing regimen due to the practical benefits.”
“SDD [single daily dosing] appears to be a safe and efficacious approach that does not prevent drug toxicity but may reduce the risk. SDD of aminoglycosides is simpler, less time-consuming, and intuitively more cost-effective than traditional MDD [multiple daily dosing] regimes.”
“The rapid increase in the incidence of gram-positive infections including those caused by resistant bacteria has sparked renewed interest in the development of novel classes of antibiotics. One such class is the lipopeptide antibiotics, which includes daptomycin.”
“Although low doses of daptomycin do not cause muscle toxicity and are effective in treating many gram-positive bacterial infections, certain types of gram-positive bacterial infections, such as deep-seated infections or those caused by certain antibiotic resistant bacterial strains, may require higher doses of daptomycin for effective treatment. For instance, certain vancomycin resistant strains of bacteria exhibit a to-24-fold higher daptomycin minimum in inhibitory concentration MIC than most vancomycin-susceptible strains. Accordingly, there is a great need to develop methods for administration of effective amounts of daptomycin that will also minimise adverse skeletal muscle effects.”
“The invention is characterised by a pharmaceutical composition comprising a high dose of the antibiotic that causes skeletal muscle toxicity at a dosage interval of 24 hours to once weekly. In one embodiment of the invention, daptomycin is administered at a dose of 3 to 75 mg/kg at a dosage interval of 24 hours to once weekly.”
“Without wishing to be bound by any theory, skeletal muscle effects appear to be related to the duration of time at low plasma concentrations of daptomycin available for repair of subclinical damage to the myofibers. Therefore, the data suggest that the dosing interval is the key determinant of muscle toxicity, rather than just the magnitude of the dose itself. Further, since Cmax and/or AUC were found to be the key pharmacokinetic parameters associated with eradication of infection [refs cited] the pharmacological activity of daptomycin is optimized by once-daily dosing. These results suggest that once-daily dosing can minimize daptomycin muscle toxicity, while potentially optimizing its antimicrobial efficacy (Figure 3).”
“The results demonstrate that administration of daptomycin to eight patients at a 4 mg/kg dose every 24 hours or to nine patients at a 6 mg/kg dose every 24 hours did not cause an increase in serum CPK levels above the normal range… Furthermore, even in the few patients who experienced some elevation in CPK levels above normal, the elevation was not considered to be related to daptomycin treatment… Similarly, administration of an initial dose of 6 mg/kg daptomycin followed by 3 mg/kg every 12 hours to three human patients did not cause an increase in CPK levels above normal.”
“1a) Does the requirement of the “same invention” in Article 87(1) EPC mean that the extent of the right to priority derivable from a priority application for a later application is determined by, and at the same time limited to, what is at least implicitly disclosed in the priority application? 1b) Or can a lesser degree of correspondence between the priority application and the subject-matter claimed in the later application be sufficient in this respect and still justify a right to priority?”
“If the invention claimed in a later European patent application constitutes a so-called selection invention - i.e. typically, the choice of individual entities from larger groups or of sub- ranges from broader ranges of numerical values - in respect of the subject matter disclosed in the first application whose priority is claimed, the criteria applied by the EPO with a view to assessing novelty of selection invention over the prior art must also be considered carefully when assessing whether the claim in the European patent application is in respect of the same invention as the priority application within the meaning of Article 87(1) EPC. Otherwise, patent protection for selection inventions, in particular in the field of chemistry, could be seriously prejudiced if these criteria were not thoroughly complied with when assessing priority claims in respect of selection inventions. Hence, such priority claims should not be acknowledged if the selection inventions in question are considered “novel” according to these criteria.”
“Muscle toxicity was investigated most thoroughly in dogs, where it was found that repeated daily intravenous administration of high doses of daptomycin caused a pattern of acute degenerative and regenerative myopathy in the skeletal muscle. Muscle toxicity was dose-related in both incidence and severity, as shown in the table below.”
“The results of these new experiments indicate that the frequency of administration is an important variable in determining the muscle toxicity of daptomycin. Rather than being strictly related to the dose level (or the corresponding serum drug level), the degree of muscle damage appears to be related to the time between treatments. Muscle toxicity could be reduced by administering the drug in larger, less frequent doses, rather than small, frequent doses. It is possible that a certain interval between treatments is necessary for the repair of acute muscle damage. This is an unexpected conclusion that would not be anticipated on the basis of prior toxicology data.”
“P argued that the claimed range of 3-10 mg/kg of claim 1 of the main request is not a novel selection over the range 2 to 10 mg/kg disclosed in P1. The two ranges are thus allegedly the “same invention” in the sense of G2/98 and consequently, P holds that the priority claim based on P1 is valid.”
“The results of Studies A and B suggest that the pharmacokinetic parameter defining daptomycin-associated skeletal muscle toxicity in dogs is not related to Cmax AUC or an intrinsically toxic plasma concentration, but is related to the dosing interval or percentage of time below particular plasma concentrations. Therefore, the data suggest that dosing interval had a greater influence on muscle toxicity than did dose itself. Further, studies in animal efficacy models have demonstrated that effectiveness of daptomycin is optimised by once-daily dosing because Cmax was found to be the key pharmacokinetic parameter associated with eradication of infection (J. Leggett et al., ICAAC abstract, 1987). These results suggest that once-daily dosing can minimise muscle toxicity, while optimizing its antimicrobial efficacy.”
“Daptomycin exhibited a favourable side-effect profile in clinical trials completed to date and will be administered as a once-a-day therapy.”
“…such claims are generally regarded as novel over a mere proposal to administer the drug to patients in the manner claimed. This is because the mere proposal does not disclose that the treatment is indeed efficacious. If it was obvious that the treatment would be efficacious, or at least it was obvious to conduct a trial of the treatment which would involve treating patients, then the claim is likely to lack inventive step but that is another matter.”
“123…All the "bits and pieces" of the invention were known separately for many years. The question "why was it not done before" is always a powerful consideration when considering obviousness, particularly when all the components of a combination have been long and widely known. Sometimes there is a good answer (e.g., no demand, not worth the expense, prior art only recent).”
“77. It generally only comes into play when one is considering the question “if it was obvious, why was it not done before?”
“Q. Right, and although it does not say specifically what support they have for the Phase III trials, they must have done or had in hand Phase II work to support doing the Phase III trial? A. Yes, you would anticipate they have some or they may have been able to re-analyse what Lilly did and discuss that with the FDA and get approval. I really cannot say from looking at this. But what it means is that the FDA has accepted that they can do these studies. Q. Yes, and therefore the reader of this would think first of all that daptomycin is very well worth taking forward for these indications and in these doses? A. They would assume so, yes. Q. That that is supported by Phase II work? A. Yes.”
"Daptomycin demonstrated in vivo antibacterial activity against all three test strains [methicillin-susceptible S. aureus ATCC2679, methicillin-resistant S. aureus or E. faecalis 3123], with the greatest activity observed against methicillin-resistant S. aureus. The predicted MIC for all three strains was approximately 13 µg/ml, corresponding to total (bound plus unbound) drug. On the basis of the drug’s pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be effective."
"Six volunteers were administered daptomycin in successive single doses of 2, 3, 4 and 6 mg/kg. Each dose was given as a 30-min constant-rate infusion of daptomycin in 50 ml of a 5% glucose solution. At least 72 h separated each dose. Blood samples for daptomycin analysis were collected at 0 and 30 min following the beginning of infusion and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h post infusion."
"Most notable is the limited CLR [renal clearance] of daptomycin, with possibly safer use in renally impaired patients, and the drug’s longer half-life, allowing once- or twice-daily administration with proper doses."
“our data suggest that good antibacterial activity would be produced from single doses of 4 to 6 mg/kg. However, the extended t½ of daptomycin predicts the accumulation of drug upon multiple dosing. Effective antibacterial activity may be produced by 2 to 3 mg/kg given every 12 hours, depending on the susceptibility of the organism.”
“In an even more preferred embodiment, daptomycin is administered in a dose of 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg/kg once every 24 hours.”
“The rapid increase in the incidence of gram-positive infections – including those caused by antibiotic resistant bacteria – has sparked renewed interest in the development of novel classes of antibiotics. One such class is the lipopeptide antibiotics, which includes daptomycin.”
“It became apparent that the widely shared view that the equilibrium between daptomycin and its impurities would prevent purification above a particular level was in fact a misconception. I consider that this misconception could have arisen for one of a number of reasons, for example, because Lilly had only used repeated HIC to purify daptomycin in the presence of aceto-nitrile, or because the Lilly process resulted in traces of catalytic species being present in the composition.”
“Question: So Tom Kelleher from Cubist contacted you sometime before June 1999 to look into some optimisation and scale-up work for the daptomycin manufacturing process. Correct? Answer: Yes Question: And generally speaking, what you were tasked to do was use your standard approach that we discussed this morning to look at what chromatography techniques would be best suited for purifying daptomycin. Is that correct? Answer: Yes Question: And so based on your initial preliminary work on the daptomycin molecule, characterising it using the standard approach we discussed earlier, it was determined that pH range, salt, urea, temperature and loading were five factors to look into for further study. Is that correct? Answer: Yes Question: So is it fair to say then that based on screening the resins and optimising the pH variables, the specific resin used and the denaturant, you were able to come up with a process for purifying daptomycin? Answer: We came up with the best conditions with our products, yes. Question: Early this morning we talked about the standard approach that you adopted in determining purification methods for purifying proteins. Do you remember that? Answer: Yes Question: I understand that daptomycin is not a protein, but you didn’t take a different approach to determining the purification method to purify daptomycin did you? Answer: No”
“A. From our point of view we did not know what he considered standard. There was proprietary information that Perseptive held. We did not lay out an experimental plan to him. We gave him the material and said, can you purify this. We also did not do a great deal of explaining to Paul Lynch that we had this equilibrium issue. We just let him go and see what he found.”
“Normally, however, one has to combine several chromatographic methods to achieve complete purification of a protein from a crude biological extract. With the wide variety of chromatographic media available today, this can normally be done in a short period of time.”
“Anion exchange chromatography was (and still is) the most commonly used purification technique because the buffers were readily available and easy to make up and use. I have never worked in a laboratory that did protein purification that did not have an ion exchange chromatography column, nor am I aware of having visited one.”
“A. In answer to your question, certainly one will consider all separation methods, including ion-exchange chromatography in looking to develop a separation method for a given compound. Q. Including daptomycin? A. Yes.”
“Ion exchange chromatography is an excellent complement to such high-resolution techniques as reverse-phase chromatography.”
“Q. And the reason techniques like this are considered complementary is because if you simply keep doing one step after another all focusing on charge, it very much limits what you can achieve. A. That is correct. Q. Whereas if you do one separation based on charge and then another one based on hydrophobicity, you are looking at two different characteristics of the molecule. A. That is correct. Q. And that gives you better results. A. It should.”
“Q. And this use of the anion exchange column in that way is just exactly what is in the contemplation of the common general knowledge that we have been looking at over the last few minutes in those textbooks, is it not? A. In terms of the fact that the amount of solvent is reduced, I would agree. Q. And concomitantly, to use a word from one of those books, I think you would expect to get purification at the same time if you designed things adequately? A. If you did, that is correct.”
“A. …I would say that the use of chaotropic aggregations, particularly of the urea, it is so commonly known that I found it difficult to find a clear instance of it being used. It was referred to in this particular paper for the purposes of dissolving aggregates. The use of chaotropic agent to get rid of aggregates is common in protein purification, and urea is one of the oldest biological molecules known. It has been used for a very long time.”
“A. I believe that the use of chaotropic agents was common general knowledge and urea was a common chaotropic agent, so I would have to agree with that.”
“A technical prejudice must be general: it is not enough that some persons actually engaged in the art at the material time labour under a particular prejudice if a substantial number of others do not. A prejudice which is insufficiently widespread for it properly to be regarded as commonly shared will not, in my view, be attributed to the notional skilled person.”
“So it all depends on the conditions at which you prepare your solution. The time it takes and the rates of reaction compared to the equilibrium”
“Just because the focus of the specification is on larger scale operations, that is not a reason to read limitations into the claims which are not there. The claims contain no language which the reader would think was an attempt to limit them to material made on any particular scale.”
"Final resolution and separation of LY146032 from structurally similar compounds is impeded by the presence of impurities which are not identifiable by ultraviolet analysis of the fermentation broth. These so-called "non-uv" impurities are primarily saponins and other fragments. These compounds have solubility characteristics similar to LY146032 and are difficult to separate from LY146032. The presence of these compounds causes foaming during concentration procedures and poor resolution during subsequent chromatographic separation steps. Attempts to remove these impurities by various chromatographic methods, including reverse-phase chromatography on silica gel/C18 (Quantum LP-1), normal phase chromatography over silica gel, and ion-exchange chromatography, failed to significantly improve the purity of LY146032 over the use of HP-20 as described above. All of these methods are plagued by low, capacity, poor resolution and low recovery of LY146032."
“No, I do not think hindsight has anything to do with it. If you had asked me in 2000, when I was much more closely being at the bench, or pre-2000 at the bench doing chromatography and you had asked me the same question or the same sorts of questions, is doing hydrophobic interaction chromatography again and again and again a good idea, I would have said no. I would have said that it would be better to include a different sort of chromatography, and ion-exchange chromatography to try and effect a better purification.”
“A. I see. If they were starting with this process I would agree you would look for another method of separation to improve the purity rather than continuing with HIC. I would agree with that. Q. One routine choice would be ion-exchange chromatography? A. It would be one of a number of potential choices of chromatographic and non-chromatographic separation techniques.”
“158. Fourthly, allegations of obviousness in the light of common general knowledge alone need to be treated with a certain amount of care. They can be favoured by parties attacking the patent because the starting point is not obviously encumbered with inconvenient details of the kind found in documentary disclosures, such as misleading directions or distracting context. It is vitally important to make sure that the whole picture presented by the common general knowledge is considered, and not a partial one.”
“In one embodiment of the instant invention, commercially feasible methods are disclosed that result in daptomycin at a purity level of 95 to 97%. In another embodiment of the instant invention, a commercially feasible method is disclosed that almost completely eliminates the major impurities anhydro- daptomycin and β isomer as well as other impurities in preparations of daptomycin.”
“Another embodiment of the instant invention is drawn to a chromatography method that produces a highly purified lipopeptide not achievable by prior art chromatography methods. The chromatography method comprises the use of modified buffer enhanced anion exchange chromatography to purify a preparation containing a lipopeptide. In a preferred embodiment, the method is used to produce highly purified daptomycin or a daptomycin related lipopeptide. This method, when used with partially purified daptomycin, produces daptomycin that is at least 98% pure. The method also produces daptomycin that is free or essentially free of anhydro-daptomycin.”
“A. I think the very simple model, which I will call the tennis bat model, with the ring being, or the head of the tennis bat being, the hydrophilic parts and the handle being the hydrophobic parts -- is the diagram that appears in the specification as well about how micelles are formed. That at the time was the generally accepted way of how surfactin was arranged. All the diagrams show the hydrophobic tail pointing down and the hydrophilic head pointing up. I agree that when you look at the actual arrangement of the amino acids, it is perhaps counterintuitive. However, we know that it is a biosurfactant. If you look at the daptomycin, there is actually a bit of a clearer distinction between the hydrophilic head and the hydrophobic tail -- just by looking at the primary sequence….”
“There is nothing particularly special, is there, professor, about using the pH to control the CMC? It is just one of a number of different ways you could control the CMC if you wanted to control the CMC? Right, but the nice thing about the pH swing is that you do minimal alteration to the solution to form and disassociate the micelles. In a separation process the ideal thing is not to add much, if anything, to the solution that you’re going to have to get out again so pH swing is a good method from that basis.”
“The present invention relates to a process for preparing the highly purified form of the lipopeptide daptomycin. The present disclosure further relates to micelles of lipopeptides. The present disclosure also relates to pharmaceutical compositions of the lipopeptide micelles and methods of using these compositions. The present invention also relates to methods of making daptomycin micelles from non-associated monomers of daptomycin, and for converting daptomycin micelles to non-associated monomers. The present invention also relates to a process for preparing daptomycin using micelles that is easily scaled for commercial production.”
“1. A method for purifying daptomycin comprising: (a) subjecting the daptomycin to conditions in which a daptomycin micellar solution is formed by altering the pH; (b) separating the daptomycin micelles in the daptomycin micellar solution from low molecular weight contaminants by a size separation technique; (c) subjecting the daptomycin to conditions in which a daptomycin monomeric solution is formed by altering the pH; and (d) separating the monomeric daptomycin molecules in the daptomycin monomeric solution from high molecular weight molecules or aggregates by a size separation technique.”
"This process can be further modified and employed for the recovery and purification of most surfactants from aqueous solutions at concentrations above the critical micelle concentration."
“A. Yes. I mean, what you are suggesting is that it is almost as though you are going to use this method alone for the purification of surfactin or daptomycin and I think in both cases, I know surfactin is not an injectable, but I think this method alone is not sufficiently safe to guarantee the removal of pyrogens in either case, just because the formation of micelles can always carry along – you would need another one of the normal methods for reducing pyrogens to ensure that there was no pyrogen contamination.”
“Q. Right, for reasons we have been discussing, it might be important to the biological activity. A. I do not think that is true. They have isolated a natural product that they know is essentially a single compound. They know that it has a certain set of biological activities which are useful to them. They know that they can reproduce the production of this compound. It is going to be a useful thing whether they know the structure or not. If it is there, they might go and have a look. Q. I think you are saying that they would go and have a look and that is to do with the stereochemistry and I am trying to explore with you why they would be interested in the stereochemistry. A. Well, I hoped they are chemists who were interested in all forms of stereochemistry. It does not mean it affects their compound or the way it is made or the way it is isolated. Or the way it can be used.”