The complete specification
249 The 807 patent is directed to a hypothetical skilled team which would include, as the primary judge explained (at [321]), a pharmaceutical scientist with expertise in particle engineering and a research pharmacist with expertise in pharmacology equipped with the common general knowledge in those fields as at 24 May 2002, being the priority date.
250 The specification describes the field of the invention at p 1 lines 5 to 7 in the following terms:
The present invention relates to a nanoparticulate composition comprising a fibrate, preferably fenofibrate or a salt thereof. The nanoparticulate fibrate, preferably fenofibrate, particles have an effective average particle size of less than about 2000 nm.
251 Nanoparticulate compositions and prior art methods of making them are then discussed in the section headed "Background Regarding Nanoparticulate Compositions". The specification states at p 1 lines 10 to 19:
Nanoparticulate compositions, first described in U.S. Patent No. 5,145,684 ("the '684 patent"), are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto the surface thereof a non-crosslinked surface stabilizer. The '684 patent does not describe nanoparticulate compositions of a fibrate.
Methods of making nanoparticulate compositions are described in, for example, U.S. Patent Nos. 5,518,187 and 5,862,999, both for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5, 718,388, for "Continuous Method of Grinding Pharmaceutical Substances;" and U.S. Patent No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles."
252 Fenofibrate is described in the section headed "Background Regarding Fenofibrate" at p 4 lines 17 to 19 as follows:
The compositions of the invention comprise a fibrate, preferably fenofibrate. Fenofibrate, also known as 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, is a lipid regulating agent. The compound is insoluble in water …
253 This is followed by a discussion of other US patents in which fenofibrate is described. Such patents include US patents nos. 6,074,670 and 6,277,405 both for a "Fenofibrate Pharmaceutical Composition Having High Bioavailability and Method for Preparing It", US patent no. 6,074,670 which refers to "immediate-release fenofibrate compositions comprising micronized fenofibrate and at least one inert hydrosoluble carrier", US patent no. 4,739,101 describing a process for making fenofibrate, and US patent no. 6,277,405 directed to micronized fenofibrate compositions having a specified dissolution profile.
254 The specification also refers to two international applications, WO 01/80828 for "Improved Water-Insoluble Drug Particle Process" and WO 02/24193 for "Stabilised Fibrate Microparticles". Both of these publications are said to describe a process for making small particle compositions of poorly water soluble drugs. We note that the primary judge found (at [326]) that both documents were specifically incorporated by reference into the 807 patent.
255 After referring to the processes described in those patents, the specification then states at p 5 lines 12 to 21:
The process requires preparing an admixture of a drug and one or more surface active agents, followed by heating the drug admixture to at or above the melting point of the poorly water soluble drug. The heated suspension is then homogenized. The use of such a heating process is undesirable, as heating a drug to its melting point destroys the crystalline structure of the drug. Upon cooling, a drug may be amorphous or recrystallize in a different isoform, thereby producing a composition which is physically and structurally different from that desired. Such a "different" composition may have different pharmacological properties. This is significant as U.S. Food and Drug Administration (USFDA) approval of a drug substance requires that the drug substance be stable and produced in a repeatable process.
256 This is followed by a reference to another prior art publication describing compositions of fibrate and vitamin E TGPS, a water soluble derivative of vitamin E, comprising particles the diameters of which are within defined ranges in which the mean diameter is about 100 nm to about 900 nm, with 50% of the particles of each composition below the range 350 nm to 750 nm (D50) and 99% below the range 500 nm to 900 nm (D99). The specification then states at p 6 lines 1 and 2 that that publication "… does not teach that the described compositions show minimal or no variability when administered in fed as compared to fasted conditions."
257 Further, as the primary judge explained (at [329]), the specification includes a description of a number of advantages that are said to arise using formulations of the fibrate composition to the invention. Compositions of the invention are said to significantly increase the bioavailability of fenofibrate which can enable the use of a smaller solid dosage size. Compositions of the invention are also said to have an improved pharmacokinetic profile that is not substantially affected by the fed or fasted state of a human to whom such a composition is administered.
258 We pause here to say something about drug absorption. For this purpose it is useful to set out some of the evidence given by Professor Roberts.
259 Oral administration is one of the most common forms of drug delivery. Most drugs that are administered orally, that is, via the gastrointestinal (GI) tract, are given for a systemic effect. In other words, they are delivered to the bloodstream to exert an effect somewhere else in the body after being carried there by the blood.
260 The rate and extent of systemic absorption of a drug administered orally can be affected by inter alia:
(a) the rate and extent of release of the drug from the dosage form in the GI tract after the drug in the dosage form is administered orally;
(b) the drug molecule's behaviour in the GI tract as related to its solubility, potential binding, and stability in the GI tract fluids;
(c) physiological conditions in the GI tract, such as gastric emptying rate or altered pH in the stomach, which may be induced by either co - or prior administration of water or food before taking the oral dose form, and transit time through the intestinal tract;
(d) the drug molecule's ability to cross the epithelial lining of the GI tract into the bloodstream after leaving the stomach; this factor may be affected by the individual's level of blood flow through the GI tract.
261 As has been indicated, the environment in the stomach may have an impact on the rate and extent of absorption, in particular whether the individual has fasted or eaten food just prior to administration of the drug; the type of food may also have an impact. If the presence of food affects the rate or extent of absorption of a drug, then this is referred to as a "food effect".
262 For some drugs, the presence of food can have a substantial effect on the rate and extent of absorption. For instance, it is known that high viscosity food, high and low temperatures of administered water, various sugars and carbohydrates, and also certain fats can slow down gastric emptying. In other cases, the administration of food may lead to an increase in the gastric fluid pH. And the presence of a fatty meal may assist in the dissolution of the drug. In yet other cases, drugs may bind to food being digested in the stomach. For example, the drug griseofulvin is lipid soluble and has a significantly better rate and extent of absorption if taken with food. Contrastingly, tetracycline can bind with divalent cations such as calcium ions and accordingly should not be taken with milk. As a further example, if food is present, then this typically increases the viscosity of the stomach contents and reduces the gastric emptying rate. If no food is present, then the stomach will typically empty quickly which would usually lead to a faster rate of absorption. The effect of food on the rate of stomach emptying means that food slows down the absorption process.
263 The extent to which drug absorption is affected by food is dependent on the properties of the drug, the dosage form or both. For most orally administered drugs, food does not greatly affect the rate or extent of absorption. It is usually the poorly water soluble drugs in acidic media that have a food effect. In many cases, the food that is administered is fatty and this will facilitate the dissolution of a drug that is soluble in lipids. More generally, given that a drug's water and lipid solubility may influence the food effect, formulation strategies may need to be employed to facilitate an adequate rate and extent of absorption.
264 As his Honour explained (at [330]), the specification asserts that the invention encompasses a fibrate, preferably fenofibrate, composition in which administration of the composition to a subject in a fasted state is bioequivalent to the administration of the composition to a subject in a fed state. In this respect the specification adopts the following measure of bioequivalence at p 16 lines 26 to 30:
"Bioequivalency" is established by a 90% Confidence Interval (CI) of between 0.80 and 1.25 for both Cmax and AUC under USFDA regulatory guidelines, or a 90% CI for AUC of between 0.80 to 1.25 and a 90% CI for Cmax of between 0.70 to 1.43 under the European EMEA regulatory guidelines.
265 Further as to bioavailability, the specification states at p 6 lines 16 to 23:
Because fibrates, including fenofibrate, are so insoluble in water, significant bioavailability can be problematic. In addition, conventional fibrate, including fenofibrate, formulations exhibit dramatically different effects depending upon the fed or fasted state of the patient. Finally, conventional fibrate, including fenofibrate, formulations require relatively large doses to achieve the desired therapeutic effects. There is a need in the art for nanoparticulate fibrate formulations which overcome these and other problems associated with prior conventional microcrystalline fibrate formulations. The present invention satisfies these needs.
266 The specification includes a number of definitions. According to the specification at p 6A lines 10 to 12, "comprise" and its variants do not exclude other additives, components, integers or steps. We also note that at p 12 lines 3 to 11 there is a definition of "stable":
As used herein with reference to stable fibrate, preferably fenofibrate, particles, "stable" includes, but is not limited to, one or more of the following parameters: (1) that the fibrate particles do not appreciably flocculate or agglomerate due to interparticle attractive forces, or otherwise significantly increase in particle size over time; (2) that the physical structure of the fibrate, preferably fenofibrate, particles is not altered over time, such as by conversion from an amorphous phase to crystalline phase; (3) that the fibrate, preferably fenofibrate, particles are chemically stable; and/or (4) where the fibrate has not been subject to a heating step at or above the melting point of the fibrate in the preparation of the nanopartic1es of the invention.
267 The specification sets out a summary of the invention and various embodiments at p 6A line 16 to p 7 line 22:
The present invention relates to nanoparticulate compositions comprising a fibrate, preferably fenofibrate. The compositions comprise a fibrate, preferably fenofibrate, and at least one surface stabilizer adsorbed on the surface of the fibrate particles. The nanoparticulate fibrate, preferably fenofibrate, particles have an effective average particle size of less than about 2000 nm.
A preferred dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be utilized.
Another aspect of the invention is directed to pharmaceutical compositions comprising a nanoparticulate fibrate, preferably fenofibrate, composition of the invention. The pharmaceutical compositions comprise a fibrate, preferably fenofibrate, at least one surface stabilizer, and a pharmaceutically acceptable carrier, as well as any desired excipients.
One embodiment of the invention encompasses a fibrate, preferably fenofibrate, composition, wherein the pharmacokinetic profile of the fibrate is not affected by the fed or fasted state of a subject ingesting the composition, in particular as defined by Cmax and AUC guidelines given by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA).
Another aspect of the invention is directed to a nanoparticulate fibrate, preferably fenofibrate, composition having improved pharmacokinetic profiles as compared to conventional microcrystalline fibrate formulations, such as Tmax, Cmax, and AUC.
In yet another embodiment, the invention encompasses a fibrate, preferably fenofibrate, composition, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, in particular as defined by Cmax and AUC guidelines given by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA).
268 A number of consistory clauses are then set out. The first consistory clause at p 8A lines 1 to 16 mirrors the language of claim 1. This is then followed by five more consistory clauses that mirror the language of claims 2, 3, 40, 41 and 42. The first three consistory clauses, which mirror claims 1, 2 and 3, refer to compositions. The second three consistory clauses, which mirror claims 40, 41 and 42, refer to methods of treatment.
269 The consistory clauses are followed by a detailed description of the invention including by reference to two graphs, being Figures 1 and 2, which are plots of fenofibric acid concentrations against time, with different time scales used on the x-axis for each graph. For present purposes it is not necessary for us to reproduce these graphs.
270 Then follows a detailed description of the invention. The specification states at p 10 line 16 to p 11 line 16:
The present invention is directed to nanoparticulate compositions comprising a fibrate, preferably fenofibrate. The compositions comprise a fibrate, preferably fenofibrate, and preferably at least one surface stabilizer adsorbed on the surface of the drug. The nanoparticulate fibrate, preferably fenofibrate, particles have an effective average particle size of less than about 2000 nm.
As taught in the '684 patent, and as exemplified in the examples below, not every combination of surface stabilizer and active agent will result in a stable nanoparticulate composition. It was surprisingly discovered that stable, nanoparticulate fibrate, preferably fenofibrate, formulations can be made.
Advantages of the nanoparticulate fibrate, preferably fenofibrate, formulations of the invention as compared to conventional non-nanoparticulate formulations of a fibrate, particularly a fenofibrate such as TRICOR® (tablet or capsule microcrystalline fenofibrate formulations), include, but are not limited to: (1) smaller tablet or other solid dosage form size; (2) smaller doses of drug required to obtain the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles of the nanoparticulate fibrate, preferably fenofibrate, compositions when administered in the fed versus the fasted state; (5) improved pharmacokinetic profiles; (6) bioequivalency of the nanoparticulate fibrate, preferably fenofibrate, compositions when administered in the fed versus the fasted state; (7) an increased rate of dissolution for the nanoparticulate fibrate, preferably fenofibrate, compositions; (8) bioadhesive fibrate, preferably fenofibrate, compositions; and (9) the nanoparticulate fibrate, preferably fenofibrate, compositions can be used in conjunction with other active agents useful in treating dyslipidemia, hyperlipidemia, hypercholesterolemia, cardiovascular disorders, or related conditions.
The present invention also includes nanoparticulate fibrate, preferably fenofibrate, compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. The compositions can be formulated for parenteral injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments or drops), buccal, intracisternal, intraperitoneal, or topical administration, and the like.
271 The specification states at p 24 lines 2 to 8:
The invention provides compositions comprising fibrate, preferably fenofibrate, particles and at least one surface stabilizer. The surface stabilizers preferably are adsorbed on, or associated with, the surface of the fibrate, preferably fenofibrate, particles. Surface stabilizers especially useful herein preferably physically adhere on, or associate with, the surface of the nanoparticulate fibrate particles but do not chemically react with the fibrate particles or itself. Individually adsorbed molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.
272 The specification then goes on to discuss the question of surface stabilizers in considerable detail (pp 26 to 31). We pause here to give some explanation of particle size reduction and surface stabilizers. The following summary is drawn from the evidence of Associate Professor Morton that was adduced before the primary judge and does not appear to have been contentious.
273 Drug particle size has important implications on the bioavailability of many drugs. "Bioavailability" refers to the rate and extent of absorption of a drug following administration.
274 As we have indicated earlier, when a drug is administered orally in solid form, the drug must first dissolve in the fluids present within the lumen of the GI tract and then be absorbed across the GI tract wall to enter the bloodstream, from where drug molecules may be transported to their site of action within the body.
275 As to dissolution, the fluids present in the lumen of the GI tract are aqueous, which means that water forms a significant component of the GI tract fluids. For this reason, one of the factors which influences the rate at which a drug administered orally in solid form dissolves in the GI tract fluid is the drug's aqueous solubility.
276 As to absorption, the wall of the GI tract is lined by cells whose membranes are predominantly composed of lipids, that is, fatty compounds. For many although not all drugs, the rate at which drug molecules traverse the GI tract wall to enter the bloodstream, which is generally referred to as the drug's permeability, depends upon their lipid solubility, that is, the solubility of the drug in a fatty environment.
277 In the case of a drug which has low aqueous solubility and accordingly dissolves slowly in the GI tract but has relatively good permeability, the rate at which drug particles dissolve in the GI tract fluids is likely to be the factor which limits the rate and extent of the drug's absorption into the bloodstream after oral administration.
278 For many such drugs, the rate and extent of drug absorption can be enhanced by reducing the size of drug particles to achieve an overall increase in the ratio of surface area to volume for the drug particles. All else being equal, smaller drug particles generally dissolve faster than larger particles due to the increased total surface area per unit volume of the drug.
279 But when drug particles are reduced in size, the resulting small particles will generally demonstrate an increased tendency to aggregate together to form larger units. Depending upon the circumstances, this process may be referred to by terms including agglomeration and flocculation.
280 In simple terms, small drug particles demonstrate an increased tendency to aggregate together compared to larger drug particles because reducing particle size, and thereby increasing total surface area of the drug particles, increases the free energy of the system. Generally speaking, a collection of drug particles will behave in such a way as to reduce the overall free energy of the system. And one way in which free energy can be reduced is for small drug particles to aggregate together into larger units. Further, this tendency for small drug particles to aggregate together can also be explained as a competition between forces of adhesion and gravity. As particles become smaller and smaller, the gravitational forces pulling the particles downward, on the one hand, become less and the adhesive interactions pulling the particles together, on the other hand, increase in number.
281 In pharmaceutical preparations involving the use of small drug particles, aggregation of those small particles into larger units is usually undesirable. For example, if drug particle size has been reduced to increase total surface area and thereby increase dissolution rate of a poorly soluble drug, particle aggregation is undesirable because it will reduce the total surface area of the drug particles, leading to reduced dissolution rate, with adverse impacts on the rate and extent of drug absorption.
282 Before the priority date, a primary means to prevent agglomeration of small drug particles was to add materials to the system which would accumulate at the interface of the particles and accordingly impede particle aggregation. Such materials were and still are referred to as surface stabilizers. Surface stabilizers reduce the adhesion between small drug particles and so provide an energy barrier to particle aggregation.
283 In simplified terms, the surface stabilizers which were used before the priority date and indeed after to reduce or prevent aggregation of small drug particles operated on two broad principles. First, one could use substances which accumulated at the surface of drug particles and impeded particle aggregation as a physical barrier. This is referred to as steric hindrance. Secondly, one could use surfactants and surface active agents which impeded particle aggregation by electrostatic or related repulsion forces. Indeed, some surface stabilizers could exert their effects by a combination of these mechanisms.
284 When one refers to surface stabilizers that prevent or reduce particle aggregation by steric hindrance, one is referring to compounds that coat the surface of drug particles (for example, relatively large polymeric molecules that occupy considerable space at the molecular level) to prevent those drug particles from coming into close contact with each other. Before the priority date a variety of polymeric compounds were capable of being used as surface stabilizers for small drug particles, including various derivatives of cellulose such as polyvinylpyrrolidone and, significantly for present purposes, HPMC.
285 When one refers to surfactants, one is referring to amphiphilic molecules which have both a hydrophobic part and a hydrophilic part. Before the priority date, many surfactants were useful for preventing or reducing aggregation of small particles of a hydrophobic drug. When adequately mixed with small particles of a hydrophobic drug, the hydrophobic part of surfactant molecules would orientate towards the surface of the drug particles, whilst the hydrophilic part of surfactant molecules would orientate towards surrounding water molecules and, in this way, reduce the tendency of the hydrophobic drug particles to aggregate together; this is all notwithstanding any potential repulsive forces between the hydrophobic parts of the surfactant molecules and the drug particles.
286 Before and since the priority date, one generally categorised surfactants as non-ionic, cationic or anionic, depending upon whether they carried a net electrical charge and, if so, the polarity of that charge. Non-ionic surfactants have no net positive or negative charge, although they have more polar and less polar regions. Ionic surfactants bear an overall net charge, with cationic surfactants having a net positive charge and anionic surfactants having a net negative charge.
287 Examples of anionic surfactants which were used before the priority date included those containing carboxylate, sulfonate and sulfate ions as functional groups at their head. Examples of cationic surfactants which were used included amine salts, quaternary ammonium salts and, significantly for present purposes, SLS.
288 Examples of non-ionic surfactants which were used included fatty alcohols such as lauryl and cetyl alcohols, and fatty acid esters of alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose and cholesterol.
289 Before and after the priority date, as Associate Professor Morton explained, the identification of surface stabilizers to be used in a pharmaceutical formulation was realised by trial and error; for present purposes we will put to one side for the moment whether this was routine. This was because absolute prediction of a surface stabilizer's performance in a given system was rarely achievable. Before the priority date, when selecting a surface stabilizer system for a pharmaceutical formulation, it was the practice to review the scientific literature to narrow the broad range of available surface stabilizers to those that had been successfully used in similar systems and with acceptable toxicological profiles. After identifying a range of potential candidates, one would then conduct a series of tests on those surface stabilizers involving different combinations and quantities for the purposes of identifying an effective combination and quantity that would provide acceptable stability to small drug particles; again, we will put to one side for the moment whether this could be characterised as routine.
290 At p 26 lines 1 to 10, the specification states:
The choice of a surface stabilizer for a fibrate is non-trivial and required extensive experimentation to realize a desirable formulation. Accordingly, the present invention is directed to the surprising discovery that nanoparticulate fibrate, preferably fenofibrate, compositions can be made.
Combinations of more than one surface stabilizer can be used in the invention. Useful surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Surface stabilizers include nonionic, anionic, cationic, ionic, and zwitterionic surfactants.
291 This passage is followed by a lengthy list of surface stabilizers that can be used to perform the invention, as the primary judge explained (at [339]). The surface stabilizers referred to include HPMC, SLS, gelatin and others.
292 In this context, it is appropriate to set out some extracts from p 26 line 11 to p 27 line 24:
Representative examples of surface stabilizers useful in the invention include, but are not limited to, hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctyl-sulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Speciality Chemicals))…PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and the like.
If desirable, the nanoparticulate fibrate, preferable fenofibrate, compositions of the invention can be formulated to be phospholipid-free.
Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
Other useful cationic stabilizers include …
293 The specification later states at p 30 line 22 to p 31 line 13:
In one embodiment of the invention, the preferred one or more surface stabilizers of the invention is any suitable surface stabilizer as described below, with the exclusion of PEG-derivatized vitamin E, which is a non-ionic compound. In another embodiment of the invention, the preferred one or more surface stabilizers of the invention is any suitable surface stabilizer as described below, with the exclusion of phospholipids. Finally, in another embodiment of the invention, the preferred one or more surface stabilizers of the invention is any substance which is categorized by the USFDA as GRAS ("Generally Recognized As Safe").
Preferred surface stabilizers of the invention include, but are not limited to, hypromellose, docusate sodium (DOSS), Plasdone® S630 (random copolymer of vinyl pyrrolidone and vinyl acetate in a 60:40 ratio), hydroxypropyl cellulose SL (HPC-SL), sodium lauryl sulfate (SLS), and combinations thereof. Particularly preferred combinations of surface stabilizers include, but are not limited to, hypromellose and DOSS; Plasdone® S630 and DOSS; HPC-SL and DOSS; and hypromellose, DOSS, and SLS.
The surface stabilizers are commercially available and/or can be prepared by techniques known in the art. Most of these surface stabilizers are known pharmaceutical excipients…
294 The specification also includes a description of other pharmaceutical excipients that may be used as binders, fillers, lubricants, sweeteners and flavourings. The description of excipients is followed by a description of the "nanoparticulate fibrate particle size". Page 32 line 24 to p 33 line 4 states:
The compositions of the invention contain nanoparticulate fibrate particles, preferably nanoparticulate fenofibrate particles, which have an effective average particle size of less than about 2000 nm (i.e., 2 microns), less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 run, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods.
295 It is not necessary to set out any further detail on this aspect at this point.
296 The specification then proceeds to describe what are said to be several "exemplary nanoparticulate fenofibrate tablet formulations" and "exemplary embodiments of the invention". As the primary judge explained (at [343]), the exemplary embodiments include descriptions of the invention in which it is said that the fenofibrate particles have an effective average particle size of less than about 2000 nm associated with a surface stabilizer that is not a phospholipid. Earlier as we have set out, at p 27 lines 15 and 16, it was stated that if desirable, fenofibrate compositions of the invention could be formulated to be phospholipid-free, although it was also stated (at p 27 lines 17 and 18) that phospholipids could be useful cationic surface stabilizers.
297 The description of the exemplary embodiments is followed by a section that describes methods for making the nanofibrate compositions. The specification states at p 36D lines 2 to 4 that "[t]he nanoparticulate fibrate, preferably fenofibrate, compositions can be made using, for example, milling, homogenization, or precipitation techniques. Exemplary methods of making nanoparticulate compositions are described in [US patent no. 5,145,684]". This statement is followed by numerous references to prior art describing methods of making nanoparticulate compositions.
298 The specification also includes a description of milling, microprecipitation and homogenization methods used to prepare the nanoparticulate fibrate compositions. These three methods are described at p 37 line 20 to p 39 line 5 although it is not necessary for us to set these out.
299 Further, the specification at p 42B to p 58 sets out and discusses eight examples which are said to illustrate the invention. The information presented includes a description of various formulations including details of particle sizes, redispersibility and a study of the food effect. The results presented are said at p 52 lines 11 to 14 to show that in one of the examples tested (example 5) the pharmacokinetic profile of the fibrate was not affected by the fed or fasted state of a subject ingesting the composition, that is, there was no food effect. At p 58 lines 8 to 18 it is also asserted that when compared to the conventional microcrystalline form of fenofibrate 160 mg dosage form, "the nanoparticulate fenofibrate dosage forms of the invention exhibit dramatically improved rates of dissolution".
300 For present purposes it is not necessary to further discuss these eight examples.
301 At p 6A lines 2 to 8, the specification sets out a boiler-plate provision:
The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.