FEDERAL COURT OF AUSTRALIA

GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No. 2) Limited v Apotex Pty Ltd [2016] FCA 608

ORDERS

THE COURT ORDERS THAT:

1.    The applicants’ proceeding be dismissed.

2.    The respondent’s cross-claim be dismissed.

3.    The applicants on or before 14 June 2016 file and serve short written submissions (no more than five pages) on costs and any consequential orders sought.

4.    The respondent on or before 28 June 2016 file and serve short written submissions (no more than five pages) on costs and any consequential orders sought.

5.    The time for the filing of any notice of appeal or cross-appeal be extended until 21 days after all final orders, including on costs and ancillary orders, have been made.

6.    Subject to further order, any undertakings and cross-undertakings given by a party on the applicants’ infringement case shall continue to have force and effect until 21 days after all final orders, including on costs and ancillary orders, have been made.

7.    Liberty to apply.

Note:    Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.

ORDERS

THE COURT ORDERS THAT:

1.    The applicants’ proceeding be dismissed.

2.    The respondent’s cross-claim be dismissed.

3.    The applicants on or before 14 June 2016 file and serve short written submissions (no more than five pages) on costs and any consequential orders sought.

4.    The respondent on or before 28 June 2016 file and serve short written submissions (no more than five pages) on costs and any consequential orders sought.

5.    The time for the filing of any notice of appeal or cross-appeal be extended until 21 days after all final orders, including on costs and ancillary orders, have been made.

6.    Subject to further order, any undertakings and cross-undertakings given by a party on the applicants’ infringement case shall continue to have force and effect until 21 days after all final orders, including on costs and ancillary orders, have been made.

7.    Liberty to apply.

Note:    Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.

REASONS FOR JUDGMENT

BEACH J:

1    The first applicant, GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No. 2) Ltd, is the patentee of Australian standard patent AU 2001260212B2 (the Patent). The invention claimed in the Patent is for a sustained release paracetamol bilayer tablet with a specified in vitro dissolution profile.

2    The second applicant, GlaxoSmithKline Australia Pty Ltd (GSK Australia) is, as I have found, the exclusive licensee of the Patent. Since 2000 it has marketed, sold and supplied two sustained release paracetamol products in Australia, each of which is registered on the Australian Register of Therapeutic Goods (ARTG). These products are Panadol Back & Neck Long Lasting (ARTG 78493) and Panadol Osteo (ARTG 116619). The GSK products are commercial embodiments of the invention claimed in the Patent. For the moment, and unless otherwise specified, it is convenient to refer to the applicants collectively as GSK.

3    Apotex Pty Ltd (Apotex) is the Australian subsidiary of a Canadian group of companies. It markets and supplies in Australia, inter alia, generic pharmaceutical products.

4    Generic Partners Pty Ltd (Generic Partners) is an Australian company that manufactures and supplies only on a wholesale basis generic pharmaceutical products; its manufacturing function is sometimes outsourced to independent contractors. Generic Partners is the sponsor of 20 registrations on the ARTG, each for bilayer sustained release paracetamol tablets containing 665mg of paracetamol (the GP ARTG registrations).

5    Generic Partners intends to supply bilayer sustained release paracetamol tablets containing 665mg of paracetamol the subject of the GP ARTG registrations to Apotex for on-supply and sale in Australia (the alleged infringing products).

6    GSK commenced a proceeding against Apotex on 3 October 2014 (VID 571 of 2014) and a separate proceeding against Generic Partners on 29 October 2014 (VID 638 of 2014) for anticipated infringement of the claims of the Patent. GSK has sought injunctive relief to restrain the supply by Apotex and Generic Partners of the alleged infringing products which it is alleged would infringe claims 1 to 6, 8 to 11, 13 and 14 of the Patent.

7    Apotex and Generic Partners have brought cross-claims against GSK filed on 30 October 2014 and 25 November 2014 respectively seeking orders revoking claims 1 to 6, 8 to 11, 13 and 14 of the Patent on the following grounds:

    lack of fair basis;

    lack of sufficiency;

    lack of clarity;

    failure to define the invention;

    failure to describe the best method;

    lack of an inventive step.

8    Apotex and Generic Partners had also asserted a lack of utility as a ground of invalidity, but on 4 February 2016 that ground was abandoned.

9    As is typical of patent litigation, this case has raised a plethora of issues concerning the construction of the claims of the Patent, infringement and invalidity.

10    In summary, I have rejected both GSK’s infringement case and Apotex’s and Generic Partners’ invalidity assertions.

11    This case has raised numerous but interesting questions of pharmaceutical science; the length of these reasons is a reflection of that reality. Contrastingly, for the most part, only the application of well accepted legal principles has been necessary to dispose of the legal questions. But there is one legal issue that has troubled me, which has principally arisen on the case advanced by Ms Sophie Goddard SC for Apotex in defence of the infringement case.

12    I have found that the hypothetical skilled addressee is likely to have perceived that a mistake was made in claim 1 in identifying the relevant dissolution apparatus; “basket” should have read “cylinder”. The body of the complete specification also embodied that mistake. Should I construe the claim so as to re-write it to fit with that perception? Now “basket” has a clear and unambiguous meaning; I will elaborate later on why I say that. Moreover, there is nothing in the body of the specification, in either text or context that, in contradistinction to the term used in the claim, justifies re-conceptualising “basket”; the same mistake was made in the body of the specification as well. Further, the invention works whatever construction is used. Ms Goddard SC, astutely perceiving the risk that I might take a more free-wheeling construction approach more apposite to commercial contracts, cautioned me against such liberality. Her position was that I was not free to re-write the claim. Her point, however, was not to extol the virtue of some form of sclerotic intellectualisation engaged in by medieval scholastic types when construing a text. Rather, her point was that the specification was a public instrument and that I was not free to, in effect, amend the specification under the pretext or pretence of some construction exercise. Amendment was dealt with under a separate statutory mechanism.

13    Contrastingly, Mr David Shavin QC for GSK submitted that if the skilled addressee would have identified the reference to “basket” in the claim as a mistake and would have reinterpreted it to mean “cylinder”, then that was the end of the matter. He contended that I was constrained to read and construe “basket” in the claim as “cylinder”. But in my view, no case binding upon me has distorted the skilled addressee lens to that extent. This is not a case where an essential integer of a claim is ambiguous or uncertain. This is not a case where there is incongruence between a term used in the body of the specification and a term used in a claim; the same term is used throughout. This is not a case where the claim refers to or embodies an incorrect scientific theory (as distinct from being an essential integer) which can be put to one side. This is not a case where for one construction of an integer the invention works and for another construction it does not. This is not a case where the relevance of the mistake is being assessed only in a lack of sufficiency context.

14    No case expressly binds me to accept the result contended for by GSK. The hypothetical construct of the skilled addressee cannot be taken so far as to re-write or amend a claim of the specification. That conceptual tool has its limits. After all, the boundary constraint is that I am obliged to construe the claim as it is, rather than what it should have been. I accept Apotex’s contention. Accordingly, GSK must fail on infringement as claim 1 is the only independent claim. But Apotex and Generic Partners fail on invalidity.

15    For convenience, these reasons address the issues in the following sequence:

(a)    Procedural history — [16] to [26];

(b)    The Patent — [27] to [70];

(c)    Arthritis and the use of paracetamol — [71] to [100];

(d)    Basic principles of pharmaceutical formulations — [101] to [165];

(e)    Dissolution testing — [166] to [200];

(f)    Approach to drug development as at April 2000 — [201] to [232];

(g)    The expert witnesses — [233] to [266];

(h)    Principles of construction — [267] to [280];

(i)    Construction of claims 1 to 3: USP type III apparatus — [281] to [401];

(j)    Construction of claims 8 to 11: matrix forming polymer — [402] to [494];

(k)    Infringement case — [495] to [588];

(l)    Exclusive licensee — [589] to [599];

(m)    Fair basis — [600] to [682];

(n)    Sufficiency — [683] to [720];

(o)    Lack of clarity — [721] to [741];

(p)    Failure to define the invention — [742] to [746];

(q)    Failure to describe best method — [747] to [863];

(r)    Lack of inventive step — [864] to [999];

(s)    Conclusion — [1000].

procedural history

16    Before addressing the substance of the case it is necessary to make some observations on the procedural history.

17    Upon the return of GSK’s interlocutory injunction application on 8 October 2014, Apotex gave an undertaking that it would not offer to sell or supply the alleged infringing products pending the determination of the proceedings or further order. But it was foreshadowed at that hearing that Apotex would make an application to be released from its undertaking if a relevant competitor entered into the market in the meantime. It was anticipated that Apotex would also withdraw any application for listing of the alleged infringing products on the Schedule of Pharmaceutical Benefits under the Pharmaceutical Benefits Scheme (PBS) if its undertaking was not discharged. On 5 November 2014, Generic Partners gave similar interlocutory undertakings. GSK also gave a cross-undertaking that GSK would not offer to sell or supply any generic form of the GSK products whilst Apotex and Generic Partners were relevantly bound by their undertakings.

18    On 17 November 2014, Apotex advised that it had withdrawn its application to list the alleged infringing products on the PBS from 1 December 2014 but that it had made an application to list those products on the PBS from 1 January 2015.

19    On 5 December 2014, Apotex and Generic Partners each applied to be released from their undertakings, alternatively to amend their undertakings as to withdrawal of any application concerning the PBS. The apparent basis for their applications was that Pharmacor Pty Ltd had entered the market on 1 December 2014 with a relevant new generic product. By way of background, in GlaxoSmithKline Australia Pty Ltd v Pharmacor Pty Ltd [2014] FCA 1202 I made orders on GSK’s application for preliminary discovery against Pharmacor in respect of the latter’s generic extended release paracetamol products. But no further action was taken by GSK against Pharmacor to prevent Pharmacor from entering the relevant market for the supply of such generic products.

20    On 12 December 2014 I heard the applications of Apotex and Generic Partners to be released from their undertakings and reserved my decision until 15 December 2014. But on the morning of 15 December 2014, Generic Partners applied to re-open its case to raise a further ground of arguable invalidity. I heard the parties that morning on this issue. I then delivered judgment on 16 December 2014 (GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No 2) Ltd v Apotex Pty Ltd (2014) 109 IPR 492) leaving the restraints on Apotex and Generic Partners in place; but the undertakings dealing with Apotex and Generic Partners withdrawing their applications concerning the PBS were modified. The regime that was set in place at this time concerning the undertakings and cross-undertakings remains in place.

21    On 7 April 2015, I set both proceedings down for trial on 12 October 2015 on an estimate of 10 days. I also ordered that the two proceedings be heard concurrently and that evidence filed in each proceeding be treated as evidence filed in the other. The trial was to deal with all issues of liability on infringement and invalidity questions.

22    On 4 June 2015 and 3 July 2015, Apotex and Generic Partners each filed applications seeking leave to file and serve amended defences in order to withdraw various admissions. In particular, they sought to withdraw the admissions that the alleged infringing products had each of the essential integers of claims 1 and 8 to 11 of the Patent. On 24 July 2015, I heard the applications and adjourned both over for further hearing on 21 August 2015 after indicating my tentative views on how I might resolve such applications. On 20 August 2015, I made orders by consent that Apotex and Generic Partners have leave to withdraw the relevant admissions.

23    The trial proceeded for two weeks from 12 October 2015. GSK called Professor Dressman and Professor Davies, Apotex called Professor Fassihi and Dr Mooney and Generic Partners called Professor Tucker. On 15 October 2015 I was informed that Professor Davies had a personal difficulty and that it was uncertain when he would be in a position to travel from London to Melbourne to give evidence; given the importance of his evidence, it was not appropriate to take it on a video link. Tentatively, it was then anticipated that he could give evidence on 9 and 10 November 2015. But on 4 November 2015 I heard the parties as to the unavailability of Professor Davies to give evidence on 9 and 10 November 2015. In the circumstances and to meet the parties’ convenience and that of Professor Davies, I fixed a further five days for the trial from 1 February 2016 for Professor Davies’ evidence and closing submissions.

24    On 10 November 2015, Professor Tucker was also further cross-examined via video link from Dunedin, New Zealand.

25    The trial resumed on 1 and 2 February 2016 for Professor Davies to be cross-examined. Closing submissions were heard on 3, 4 and 8 February 2016.

26    Before proceeding further, it is worth identifying the applicable legislative framework. The Patents Amendment Act 2001 (Cth) amended inter alia s 7 of the Patents Act 1990 (Cth). But the amendments only apply in relation to patents for which the complete application was made on or after the day on which the amendments commenced, namely, 1 April 2002 (see Sch 1, part 1, item 13 of the Patents Amendment Act). The complete application for the Patent was filed prior to 1 April 2002 (12 April 2001). Accordingly, issues of infringement and validity are to be determined under the Patents Act 1990 (Cth) in the form in which it existed prior to the Patents Amendment Act 2001 (Cth) and, of course, prior to the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth).

THE PATENT

27    The Patent has a priority date of 19 April 2000.

28    The Patent claims a pharmaceutical composition containing paracetamol. It comprises “a bilayer tablet having an immediate release phase of paracetamol and a sustained release phase of paracetamol”. The following is stated in the complete specification (p 1 lines 3 to 23):

The present invention relates to pharmaceutical compositions containing N-acetyl-p-aminophenol, known by the generic names paracetamol, acetaminophen and APAP (hereinafter referred to as paracetamol). In particular, the invention relates to a sustained release paracetamol formulation having an advantageous pharmacokinetic profile.

Paracetamol is an analgesic and antipyretic agent which is widely used in prescription and non-prescription medicines, often in combination with other biologically active compounds.

The elimination half-life of paracetamol is reported to be in the range of 1.9 – 2.5 hours. Its absorption following oral doses of conventional immediate release tablets is characterised by passive absorption with high bioavailability (80%) and rapidly occurring maximum plasma concentration (tmax 30–90 min). These characteristics determine the conventional dosage regimen of 1000mg every 4 to 6 hours for the drug. Although this regimen is acceptable in the short-term treatment of acute pain, it becomes inconvenient in the context of long-term treatment of sub-chronic or chronic pain. Therefore, extended release paracetamol may improve patient’s quality of life by reducing the number of doses to be taken and providing steadier levels of the drug in the blood as determined by plasma or serum drug concentrations.

29    The Patent refers at p 1 lines 25 to 28 to the desirability of a t.i.d oral dosing paracetamol product (two tablets of 600 – 667mg paracetamol per dose); t.i.d is a reference to three times per day.

30    At p 1 lines 29 to 32 to p 2 line 3 the Patent refers to the McNeil Inc European patent EP-A-305051 (the McNeil patent) (a form of the 522 Patent that I will discuss later) which is said to disclose a sustained release bilayer tablet containing 650 or 667mg of paracetamol which contains an equal amount of paracetamol in the immediate and sustained release layers. Such a tablet is said to be marketed by McNeil Inc as Tylenol® Extended Relief. It is said that the sustained release layer is provided by a matrix comprising a mixture of hydroxyethylcellulose and polyvinyl-pyrrolidone.

31    The invention is then discussed by reference to the existing McNeil sustained release bilayer paracetamol tablet and the advantages that the invention provides over that tablet.

32    The Patent then discusses at pages 2 to 3 the ideal pharmacokinetic properties for a sustained release paracetamol product. At p 2 lines 5 to 7 the Patent notes that a sustained release paracetamol oral dosage form designed for t.i.d dosing should also provide all the benefits of immediate release paracetamol plus a sustained action.

33    The Patent notes that one potential disadvantage of a formulation containing more than the standard dose of paracetamol (500mg) is accidental or intentional overdose.

One potential disadvantage concerning a formulation containing more than the standard dose of paracetamol (500mg) is accidental or intentional overdose. In such circumstances more paracetamol will be ingested from an extended release formulation compared to a conventional immediate release formulation for any given number of unit doses such as tablets. This could have serious consequences for an overdose patient, especially if a large amount of the dose is absorbed before rescue therapy could be initiated. It would therefore be preferable if the unit dose (such as a tablet) was designed to limit the amount of paracetamol absorbed in the first few hours following dosing. An advantageous sustained release formulation should therefore demonstrate a lower mean Cmax (preferably at least 20% lower) than a conventional immediate release formulation which would be indicative of a lower initial exposure. (Patent p 2 lines 11 to 22)

34    Further, one possible consequence of formulating an oral paracetamol product designed to have a lower Cmax and slower rate of absorption is said to be:

that the extent of absorption may also be decreased, this could then lead to sub-therapeutic systemic levels of drug 6–8 hours following dosing thus leading to premature onset of pain before administration of a further dose. (Patent p 2 lines 24 to 28)

35    However, a further advantage for a product designed to have a lower Cmax and slower rate of absorption where the extent of absorption is essentially complete, as demonstrated by an equivalent dose corrected AUC (area under the concentration-time curve, a concept that I will elaborate on later) compared to the immediate release tablets, is said to be:

that it should have the advantage of maintaining therapeutic levels of paracetamol in plasma for extended periods following dosing and hence provide analgesia for longer than a conventional immediate release tablet or capsule. Furthermore as a result of a reduced Cmax, systemic levels of paracetamol are likely to remain at more constant levels, thus benefiting the patient. (Patent p 3 lines 1 to 5)

36    The Patent notes that it is desirable for plasma levels associated with a sustained release formulation to be maintained at therapeutic levels (>3mcg/ml) for longer than a conventional immediate release formulation:

Whilst such a formulation should have a lower Cmax compared to a conventional immediate formulation, it is still desirable to have a fast onset of action, therefore initial levels of drug in plasma should be rapidly attained (preferably within 30 minutes) and maintained at therapeutic levels of >3mcg/ml for at least 1.3 hours and preferably 1.5 hours longer than a standard immediate release tablet or capsule. In addition the extent of absorption should be equivalent to a conventional immediate release formulation.

Furthermore, upon multiple dosing of a sustained release formulation the steady state plasma levels of paracetamol should be more constant than those achieved following multiple dosing of a conventional immediate release formulation. A convenient measure of the fluctuation in plasma concentrations is the fluctuation index (FI) which is defined as (Cmax – Cmin) / Caverage. A low FI number (ie <1) is considered to be advantageous as it suggests a reduction in the variability of plasma concentrations indicative of a safer product. (Patent p 3 lines 7 to 21)

37    At p 3 line 23 to p 4 line 10 the Patent summarises the desirable attributes for a sustained release paracetamol product for oral administration to possess. It states:

In summary, an advantageous sustained release paracetamol product for oral administration should possess the following pharmacokinetic attributes:

(1)    therapeutically active drug plasma concentrations should be attained rapidly.

(2)    the mean maximum plasma concentration (Cmax) should be at least 20% lower compared to standard immediate release formulation;

(3)    a mean plasma concentration of at least 3 mcg/ml should be maintained for at least 1.3 hours longer (preferably 1.5 hours longer) than a standard immediate release formulation;

(4)    the extent of absorption should be equivalent to a conventional immediate release paracetamol;

(5)    plasma levels of paracetamol following multiple dosing should be more constant compared to multiple dosing of an immediate release formulation as measured by a reduction in the fluctuation index.

38    At p 4 line 12 the specification states:

Surprisingly it has now been discovered that such an advantageous pharmacokinetic profile can be provided by a two phase (immediate release and sustained release) formulation of paracetamol which satisfied a unique in vitro dissolution profile.

39    Pages 4 to 6 set out the various consistory clauses.

40    They begin with what is said at p 4 line 27 to p 4a line 8:

In one aspect, the present invention provides a pharmaceutical composition comprising a bilayer tablet having an immediate release phase of paracetamol and a sustained release phase of paracetamol,

the immediate release phase being in one layer and comprising from about 10 to 45% by weight of the total paracetamol; and

the sustained release phase being in the other layer and comprising from about 55% to 90% by weight of the total paracetamol in admixture with a matrix forming polymer or a mixture thereof;

said composition comprising from 600 to 700mg of paracetamol per unit dose and a pharmaceutically acceptable carrier, wherein said composition has an in vitro paracetamol dissolution profile (as determined by the USP type III apparatus, reciprocating basket, with 250ml of 0.1M HCl at 37C set at a cycle speed of 15 strokes/min) with the following constraints:

•    30 to 48% released after 15 minutes

•    56 to 75% released after 60 minutes

•    >85% released after 180 minutes.

41    At p 5 lines 15 to 32 it is said:

The immediate release phase and the sustained release phase both contain paracetamol and a pharmaceutically acceptable carrier and are suitably combined together into a unit dose form. For example the immediate release phase and the sustained release phase can be separate blends, granules or pellets which can be mixed together before being compressed into a tablet or being filled into a capsule. A preferred unit dose form is a bilayer tablet having an immediate release layer of paracetamol and a sustained release layer of paracetamol.

Suitably the sustained release phase comprises a matrix-forming polymer to provide a sustained release of paracetamol.

Examples of matrix-forming polymers include both water soluble and water insoluble polymers or mixtures thereof, with soluble polymers being preferred. Examples of water soluble polymers include hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methacrylate hydrogels, polyethylene glycols and xanthan gum. An example of a water insoluble polymer is ethylcellulose. A preferred matrix-forming polymer is hydroxypropylmethylcellulose.

42    At p 6 lines 2 to 9 it is said:

The amount of matrix-forming polymer in the sustained release phase and the relative amounts of paracetamol in the sustained release and immediate release phases are selected so as to provide the desired in vitro dissolution rate as herein before described.

Thus, the matrix-forming polymer is suitably present in an amount from 0.5 to 10%, preferably from 1 to 6%, and more preferably from 2 to 4% by weight of the sustained release phase.

43    At p 6 lines 20 to 28 it is said:

Compositions of the present invention will generally contain at least one pharmaceutically acceptable carrier conventionally used in the art of tablet and/or capsule formulation. Suitable carriers which may be incorporated include lubricants, for example magnesium stearate and stearic acid; disintegrants, for example cellulose derivatives and starches; binders, for example modified starches, cellulose derivatives and polyvinylpyrrolidone; glidants, for example colloidol [sic] silicas; compression aids, for example cellulose derivatives; as well as preservatives, suspending agents, wetting agents, flavouring agents, bulking agents, adhesives, colouring agents, sweetening agents appropriate to their form.

44    The discovery is then illustrated by way of four example formulations (Formulations A to D), two of which are said to have an in vitro dissolution profile outside the scope of the invention (Formulations A and B). These are the subject of example 1. The other two formulations are said to have an in vitro profile falling within the scope of the invention (Formulations C and D).

45    The ingredients of Formulations A and B are listed in the table on p 9 of the Patent.

46    The paracetamol used in the immediate release layer of Formulations A and B is identified as DC90. The Patent notes at p 9 lines 30 to 32 that this is a commercially available directly compressible paracetamol granulation containing about 90% by weight of paracetamol together with pregelatinised starch, croscarmellose sodium, polyvinylpyrrolidone and stearic acid.

47    The release profiles for Formulations A and B, characterised using the described apparatus (I will return later to contentious aspects as to the description of the apparatus) with 250ml 0.1M HCl at 37°C set at a cycle speed of 15 strokes/min, are set out in Table 1 on p 10. It is not necessary for present purposes to reproduce Table 1 at this point.

48    Formulations A and B were assessed in a pharmacokinetic study in healthy fasted volunteers using 500mg immediate release paracetamol tablets as a control (p 10 lines 10 to 14). The results are presented graphically in Figure 1 on p 11. Again, it is not necessary to reproduce Figure 1.

49    The Patent notes that neither Formulation A nor B met the criterion of achieving a mean paracetamol plasma concentration of 3mcg/ml for at least 1.5 hours longer than the immediate release tablet (p 11 lines 5 to 7).

50    Thus far I have referred to Formulations A and B and example 1. It is appropriate to now discuss Formulation C and example 2.

51    Example 2 compares the properties of a commercially available immediate release 500mg paracetamol tablet with a sustained release bilayer tablet having an in vitro dissolution profile falling within the scope of the invention (Formulation C). The ingredients of Formulation C are set out in the table on p 12 of the Patent.

Example 2

This Example compares the properties of a commercially available immediate release 500mg paracetamol tablet with a sustained release bilayer tablet (Formulation C) having an in vitro dissolution profile falling within the scope of the present invention.

This advantageous bilayer tablet containing a total of 666.6mg of paracetamol was prepared from the following ingredients:

The release profile of test formulation C was characterised using the USP type III apparatus (reciprocating basket) as hereinbefore described and was found to have the following dissolution rate as detailed in table 2.

Table 2: Dissolution Profile for Formulation C

Formulation C was assessed in a pharmacokinetic study. The study design was a four-way crossover, using a panel of 26 healthy volunteers which compared the pharmacokinetics of paracetamol in serum in both fed and fasted states following a two tablet dose of the formula C and a two tablet dose of a currently marketed standard immediate release paracetamol 500 mg tablet. The mean pharmacokinetic profiles are shown in Figure 2.

FIGURE 2

Formulation C met all of the pharmacokinetic criteria outlined above for an ideal sustained release paracetamol tablet. The pharmacokinetic analysis demonstrated that the Cmax was significantly lower for formulation C (mean value 10.1 mcg/ml) compared to the reference immediate release product (mean value 18.7 mcg/ml) (in the fasted state). In addition therapeutic serum concentrations were rapidly attained and mean serum levels of 3 mcg were maintained until 7.4 hours post dose compared to only 5.3 hours post dose for the 500mg immediate release tablet. The two formulae were bioequivalent with respect to AUC indicating that the extent of absorption was the same for formulation C as for conventional immediate release paracetamol.

These advantageous properties of formulation C are particularly surprising when compared with the plasma concentrations described in Example 1 of EP-A-305051 which suggests that the Cmax of the prior disclosed sustained release paracetamol formulation is as high as that observed for an immediate release formulation.

52    As stated in the specification, the release profile of Formulation C was characterised using the relevant apparatus and was found to have the dissolution profile as detailed in table 2. Formulation C was assessed in a pharmacokinetic study, using a panel of 26 healthy volunteers and a two tablet dose of a standard immediate release 500mg paracetamol tablet comparator. The results of the study were presented graphically as set out above. Formulation C was said to have met all of the pharmacokinetic criteria outlined above for an ideal sustained release paracetamol tablet. In particular, in comparison to the reference immediate release product, Formulation C was bioequivalent with respect to AUC, it had a significantly lower Cmax and mean plasma levels remained above the therapeutic level of 3mcg/ml for longer.

53    As indicated in the passages set out above, the Patent says (at p 15 lines 4 to 7) that the advantageous properties of Formulation C are particularly surprising when compared with the plasma concentrations described in example I of the McNeil patent which suggests that the Cmax of the prior disclosed sustained release paracetamol formulation is as high as that observed for an immediate release formulation. The Patent notes earlier at p 2 line 2 that McNeil markets a bilayer sustained release paracetamol tablet as Tylenol® Extended Relief. The Patent later highlights the advantages of Formulation D over the Tylenol® Extended Relief product at p 17. Let me turn to Formulation D and example 3.

54    Example 3 compares the properties of a commercially available immediate release 500mg paracetamol tablet with Formulation D, a sustained release bilayer tablet having an in vitro dissolution profile falling within the scope of the invention.

55    The bilayer tablet of Formulation D is said to be “essentially similar to Formulation C but contained a total of 665mg of paracetamol and had a slightly different ratio of sustained release to immediate release paracetamol (% w/w SR:IR APAP was 69:31)” (Patent p 15 lines 15 to 18).

56    The release profile of Formulation D characterised using the relevant apparatus was set out in Table 3 on p 15; it is unnecessary to reproduce this Table.

57    Formulation D was the subject of a further biostudy involving 27 subjects. There were two study sessions each consisting of two days’ dosing. The two study treatments were as follows:

(a)    two bilayer sustained release (SR) tablets of Formulation D each containing 665mg given three times per day (every 8 hours); and

(b)    two immediate release (IR) paracetamol 500mg tablets given four times per day (every 6 hours).

The study sessions were separated by 48 hours.

58    Pharmacokinetic analysis was conducted for the period of 24 hours — 48 hours following commencement of the dosing schedule. The results showed that the two treatments were bioequivalent with respect to AUC24–48 and Formulation D provided a lower Cmax, a higher Cmin and a substantially lower fluctuation index (FI) compared to the immediate release formulation. Mean plasma paracetamol concentrations versus time were shown in Figure 3. It is appropriate to reproduce Figure 3 at this point:

59    The Patent teaches that Tylenol Extended Relief does not have a lower FI than the immediate release tablet, stating at p 17 lines 7 to 13:

The substantially lower FI for the SR product is surprising considering previous reports for a steady state biostudy conducted with a 650mg bilayer tablet (Tylenol Extended Relief) which showed that the SR product had a numerically higher FI (of 1.49) compared to a reference 500mg IR tablet (of 1.44) as illustrated in Figure 4. Furthermore, Paracetamol plasma levels were maintained substantially above 3mcg/ml for the entire study period, which is in contrast to the steady state study reported for Tylenol® Extended relief.

60    The low FI number of <1 found for Formulation D is said to be “particularly advantageous” for a sustained release formulation as it indicates a reduction in the variability of plasma concentration suggesting a much safer and more reliable product (p 18 lines 5 to 7). In elaboration, there is a useful explanation of FI at p 3 lines 15 to 21:

Furthermore, upon multiple dosing of a sustained release formulation the steady state plasma levels of paracetamol should be more constant than those achieved following multiple dosing of a conventional immediate release formulation. A convenient measure of the fluctuation in plasma concentrations is the fluctuation index (FI) which is defined as (Cmax – Cmin) / Caverage. A low FI number (ie < 1) is considered to be advantageous as it suggests a reduction in the variability of plasma concentrations indicative of a safer product.

61    Figure 4 on p 18 compares the FI of Tylenol Extended Relief and an immediate release tablet based on a steady state biostudy of the two. It shows that the Tylenol Extended Relief had a numerically higher FI than the immediate release formulation. Figure 4 shows that sustained release formulations do not, as a matter of course, have a lower fluctuation index compared to a corresponding immediate release formulation. Figure 4 also illustrates that the plasma level of Tylenol Extended Relief drops below 3mcg/ml on a number of occasions. It is not necessary to reproduce Figure 4 for present purposes.

62    Example 4 compares the clinical properties of a commercially available paracetamol 500mg immediate release tablet with a sustained release bilayer tablet of Formulation D. The study was a multicentre, single dose, double-blind, double dummy, two armed parallel group efficacy study involving 510 patients with post-surgical dental pain following third molar extraction under general anaesthesia to compare the efficacy of a two tablet dose of either a sustained release tablet containing 665mg paracetamol per tablet (252 patients) or a two tablet dose of a commercially available tablet containing 500mg of immediate release paracetamol per tablet (258 patients). The Patent reports the results of the study at p 20 and says:

Based on the patient global assessment at 4 hours, the extended release product was shown to be equivalent or better than the immediate release product. A successful response was defined as a ‘very good’ or ‘excellent’ rating: 88 of 252 (35.1%) patients treated with the SR paracetamol formulation gave a successful response compared with 71 of 258 (27.7%) patients treated with standard IR paracetamol. Equivalence was concluded from the 90% confidence interval of the treatment difference (7.3% in favour of SR paracetamol) between the two formulations.

There was no significant difference between SR paracetamol and standard IR paracetamol in either development of analgesia (time to peak pain relief, time to peak pain intensity difference, total pain relief 1 hour after treatment) or peak analgesic effect (peak pain relief, peak pain intensity difference). However, the SR tablet was significantly more effective than standard IR paracetamol for the summed pain analogue intensity difference at 6 hours (p = 0.0344) and 8 hours (p = 0.0500). Furthermore, the median time to re-medication was longer for SR paracetamol (245 mins) compared with standard IR paracetamol (190 mins). Although this was not statistically significant, it was clear from the separation of the two curves on the Kaplan-Meier plot that a smaller proportion of patients treated with SR paracetamol re-medicated between approximately 3 and 6 hours compared with standard IR paracetamol.

63    The Patent concludes that the example 4 results indicate that the sustained release tablet gave rapid analgesia which was maintained for up to eight hours following dosing and the sustained release tablet had a longer duration of action than immediate release paracetamol (p 20 lines 27 to 30).

64    Let me now deal with the claims. The independent claim, claim 1, claims:

A pharmaceutical composition comprising

a bilayer tablet having an immediate release phase of paracetamol and a sustained release phase of paracetamol,

the immediate release phase being in one layer and comprising from about 10 to 45% by weight of the total paracetamol; and

the sustained release phase being in the other layer and comprising from about 55% to 90% by weight of the total paracetamol in admixture with a matrix forming polymer or a mixture thereof;

said composition comprising from 600 to 700mg of paracetamol per unit dose and a pharmaceutically acceptable carrier,

wherein said composition has an in vitro paracetamol dissolution profile (as determined by the USP type III apparatus, reciprocating basket, with 250ml of 0.1M HCl at 37C set at a cycle speed of 15 strokes/min) with the following constraints:

•    30 to 48% released after 15 minutes

•    56 to 75% released after 60 minutes

•    >85% released after 180 minutes.

65    Claims 2 and 3 claim narrower dissolution ranges.

66    Claims 4 and 5 claim compositions in which the paracetamol is present in an amount of 630 to 680 mg and 650 to 667 mg respectively.

67    Claims 6, 8, 9, 10 and 11 are dependent claims as to the matrix forming polymer. They are expressed as follows:

6.    A composition according to any one of claims 1 to 5 in which the matrix forming polymer is a water-soluble or a water-insoluble polymer or a mixture thereof.

7.    …

8.    A composition according to claim 6 in which the matrix forming water-soluble polymer is selected from hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellu-lose, methacrylate hydrogels, polyethylene glycols, xanthan gum or a mixture thereof.

9.    A composition according to claim 8 in which the water-soluble matrix forming polymer is hydroxypropylmethylcellulose.

10.    A composition according to any one of claims 1 to 9 in which the matrix forming polymer is present in an amount from 0.5 to 10% by weight of the sustained release phase.

11.    A composition according to claim 10 in which the matrix forming polymer is present in an amount from 1 to 6% by weight of the sustained release phase.

68    Claims 7 and 12 can be put to one side. Claims 13 and 14 are dependent claims as to the percentages of total paracetamol in the immediate and extended release layers.

69    The dissolution profile in claim 1 (and accordingly incorporated in the other dependent claims) is defined by reference to being determined by “the USP type III apparatus, reciprocating basket”. Contrastingly, the text of the United States Pharmacopeia then current as at the priority date described the inner vessel of the USP type III apparatus as a “reciprocating cylinder”. One of the principal debates between the parties has been as to how the expression “the USP type III apparatus, reciprocating basket” would be read by the skilled addressee and how it should be construed. Is a reference to a “basket” a mistake? Should it be construed and would it be read and understood by the skilled addressee as meaning “cylinder”? Or should it be construed as it states, namely, a “basket”? I will return to this issue later. Apotex has taken the lead on this issue, which has many dimensions both for GSK’s infringement case and the respondents’ invalidity arguments. I have set out a diagram of what could be described as the standard or “complying” USP type III apparatus with reciprocating cylinder later in these reasons.

70    Before proceeding further I should also note one other construction question that has arisen concerning “matrix”, “matrix forming” and “matrix forming polymer”. Mr Tom Cordiner, counsel for Generic Partners, has had the principal carriage of this question on behalf of the respondents. I will also return to this issue later.

ARTHRITIS AND THE USE OF PARACETAMOL

71    It is appropriate to set the scene in terms of paracetamol and its primary use. In this section I have largely drawn upon the uncontested evidence of Professor Peter Brooks, a consultant rheumatologist and a professorial fellow at the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne. From time to time in this section I have referred to April 2000; as I have said, the priority date of the Patent is 19 April 2000.

(a)    Arthritis

72    Arthritis is a term which describes inflammation in a joint. The term derives from the Greek “arthro” meaning joint, and “itis” meaning inflammation. There are at least 150 different types of arthritis which have been generally divided into the following categories:

(a)    the degenerative category;

(b)    the inflammatory category;

(c)    the gout category; and

(d)    the infectious category.

73    The most common of these categories is the degenerative category, with the most common form being osteoarthritis. Osteoarthritis affects most people at some stage in their lives. It is a “wear and tear” condition. Osteoarthritis does not usually primarily involve inflammation, but there is an inflammatory component. Osteoarthritis occurs due to a degradation of cartilage, the “soft” material that covers the ends of bones. This causes rough surfaces to rub together which leads to intermittent mild inflammation. This is a major cause of pain in osteoarthritis.

74    The inflammatory category is a less common category of arthritis which affects only about 1 to 2% of the general population; it includes rheumatoid arthritis. Rheumatoid arthritis is a severe disease with affected persons being typically positive for the rheumatoid factor (RhF) in serological (blood) tests.

75    Another group of arthritic diseases within the inflammatory category are the seronegative arthropathies. Seronegative arthropathies include ankylosing spondylitis (a chronic, painful, degenerative inflammatory arthritis primarily affecting spine and sacroiliac joints causing eventual fusion of the spine) and psoriatic arthritis (associated with psoriasis, a skin rash). While seronegative arthropathies are inflammatory like rheumatoid arthritis, patients with seronegative arthritis are typically negative for RhF in blood tests.

76    Inflammation is the result of the body’s immune response. It is the way the body fights infection effectively and heals after injuries or operations. Inflammation involves a sequence of complex, interrelated events that ultimately brings plasma proteins, phagocytes (white blood cells that consume microbes and other foreign material) and other cellular elements to the injured area for the purpose of initiating tissue repair. Without inflammation, the common cold, for example, could result in death. The problem with inflammatory arthropathies such as rheumatoid arthritis and associated seronegative arthropathies is that the immune response does not know when to stop and “invades” the joints.

77    The gout and infectious categories are less common and can be put to one side for present purposes.

(b)    Pain

78    Pain is the most common symptom of persons having arthritis, regardless of the type of arthritis. The pain experienced tends to be intermittent and not usually experienced at a constant level. With rheumatoid arthritis, the pain experienced is sometimes worse in the morning (morning stiffness) and then alleviates as the person is active during the day. With appropriate treatment, most pain associated with arthritis can be reasonably controlled within four to six weeks of treatment commencing.

79    Pain is usually categorised as either acute pain or chronic pain.

80    Acute pain appears suddenly and can be either mild or severe. Acute pain is usually associated with an event (e.g. childbirth) or an injury (e.g. a burn or broken limb) and tends to go away post-event or once the injury has healed or been treated. Acute pain can last for a short period of time, say an hour, or for weeks or months. However, acute pain does not usually last longer than six months. Examples of acute pain include the pain associated with a kidney stone or back pain say from collapsed vertebra caused by osteoporosis.

81    Contrastingly, chronic pain usually tends to endure for weeks, months or even for years. It is not usually experienced at a constant level but fluctuates over time, sometimes disappearing altogether for a few days. Examples of chronic pain include pain associated with arthritis, headaches and back pain say from a degenerative intervertebral disc.

82    Persons with pain associated with arthritis are usually (and were as at April 2000) under the care of their general practitioner. However, where the GP could not control the person’s pain, or the person needed specialist treatment or to be assessed for a joint replacement, they were generally referred to a rheumatologist.

83    The treatment of chronic pain associated with arthritis involved as at April 2000 (and indeed thereafter) a number of steps and considerations in addition to medication. For example, lifestyle changes to reduce weight and relaxation techniques could help to alleviate the pain or the perception of pain. The perception of pain is of course subjective. Back pain was prior to April 2000 (and still is) the most common pain.

(c)    Paracetamol

84    Paracetamol has been marketed and used as an analgesic since the 1950s. It is appropriate to make a number of observations concerning its use in the period up to and including April 2000.

85    According to Professor Brooks, for a patient with pain associated with osteoarthritis, one would start them on a relatively mild analgesic, which was usually paracetamol, and monitor their response. Between 80% to 90% of patients were taking an analgesic. The most common analgesic was paracetamol. If a patient with arthritis had a very severe inflammatory process they may have had an increase in temperature that could be reduced by taking an antipyretic like paracetamol.

86    The November 1995 American College of Rheumatology Guidelines recommended paracetamol as a first line treatment for patients with osteoarthritis of the knee and of the hip, being the most common forms of osteoarthritis. The October 1993 British Society for Rheumatology Guidelines recommended paracetamol as the first line treatment for patients with osteoarthritis of the hip and knee. More generally, paracetamol was the first line treatment for patients with osteoarthritis anywhere in the body.

87    The use of paracetamol as a first line treatment for arthritis was also consistent with the principle that a person should be started on the drug that was least likely to cause side effects in the long term.

88    Some people experienced a skin rash as a side effect from using paracetamol, however the side effects were not usually as unpleasant as those from a non-steroidal anti-inflammatory drug (NSAID) or codeine. A skin rash was a common side effect of many drugs.

89    Paracetamol could be prescribed to treat the pain associated with the inflammatory forms of arthritis, such as rheumatoid arthritis. Paracetamol could also be prescribed for patients that did not have arthritis, for example those with back pain caused by non-arthritic conditions. Many patients took paracetamol for the long term treatment of chronic pain.

90    The available oral dosage forms of paracetamol were relatively fast-acting to alleviate pain. This was an advantage for patients. However, paracetamol had and has a relatively short half-life. The half-life refers to the time it takes for the drug concentration in the blood plasma to drop from peak concentration to 50%. The relatively short half-life of paracetamol meant that it had to be taken frequently to maintain pain relief. Typically a patient would take paracetamol four times a day. Often a person determined their own frequency based on the level of their pain. The level of pain could vary during the course of a day. As at April 2000 the recommended adult dose in Australia for use of paracetamol was 500mg to 1g every four to six hours, but not exceeding 4g a day. I will return to the significance of this later. The most commonly prescribed form of paracetamol in April 2000 was oral, immediate-release paracetamol 500mg tablets and capsules. By simple arithmetic, a person ought not to have had more than eight 500mg tablets a day of paracetamol.

91    Most patients were started on a dose of 2 to 3g of paracetamol per day. But if this was not providing enough pain relief, the dose of paracetamol could be increased to 4g a day before moving to another, stronger analgesic such as a combination of dextropropoxyphene hydrochloride and paracetamol, or dextropropoxyphene napsylate, or adding an NSAID. Patients were advised to take less paracetamol during periods when their pain was low and more paracetamol during periods when they were experiencing more pain.

92    Prior to 2000 in Australia in addition to the oral dosage forms, paracetamol was also available in other dosage modes. I do not need to elaborate for the moment.

93    In addition to immediate release forms of paracetamol, in the late 1990s there were slow-release paracetamol forms available.

94    A recognised potential problem with paracetamol was overdosing resulting in liver necrosis. Acute overdose was a problem for persons of all ages because paracetamol was (and still is) readily available in the home. It was also not recognised as being a dangerous drug. It was difficult to know exactly when toxicity issues might arise for an individual patient as there was not a good correlation between long term toxicity and liver function tests in somebody who might be developing liver toxicity from continuous regular usage, as opposed to an acute overdose. If a person took paracetamol regularly, then the level of toxicity in the liver could build up. The potential for liver toxicity was significant as many of the drugs prescribed to treat the inflammatory types of arthritis had liver toxicity as a side effect.

95    Persons suffering arthritis who took paracetamol and found it to be an effective treatment of pain relief generally needed to take paracetamol for life unless they were able to have surgery (such as a joint replacement) which sufficiently reduced or removed the pain. Persons with osteoarthritis also learnt to manage their pain by managing their medication.

96    A common problem with the treatment of chronic diseases was patient compliance in taking their medication. It was commonly known by medical prescribers that patient compliance with their medication decreased if the medication had to be taken multiple times a day.

97    According to Professor Brooks, the most desirable properties of an analgesic to treat chronic pain from arthritis were:

(a)    simple dosage form, such as oral tablets or capsules;

(b)    rapid relief from pain after dosing;

(c)    the relief from pain to continue for as long as possible after dosing to reduce the number of doses required per day;

(d)    no side effects; and

(e)    low cost to the consumer.

98    Further, rapid relief from pain was desirable for any person in pain. A relatively long period before another dose was required was both advantageous and convenient for persons with chronic pain as it minimised the number of required doses per day of the analgesic. It also reduced the incidence of a person waking up during the night because of pain. For persons taking an analgesic for an extended period of time for chronic pain, the absence or minimisation of side effects and low cost were also important considerations.

99    Generally, in relation to the five properties set out above, the following observations can be made concerning paracetamol and its use as at April 2000:

(a)    First, paracetamol was typically formulated in oral tablets, which met the first criterion;

(b)    Second, paracetamol could be and usually was formulated to give rapid pain relief;

(c)    Third, if formulated as an immediate-release product, the half-life of paracetamol was relatively low; patients would typically take paracetamol four times per day;

(d)    Fourth, the side effects of paracetamol were well known and manageable; and

(e)    Fifth, paracetamol was a relatively inexpensive drug.

100    I will expand further on some aspects of the above discussion when I come to deal with one of the respondents’ invalidity arguments concerning a lack of inventive step. For the moment it is appropriate to simply note that the respondents have contended that the principal property of paracetamol formulations that existed prior to April 2000 that would then have benefited from improvement was the duration of the pain relief provided, such that fewer doses were needed per day. Such a contention is supported by the evidence.

BASIC PRINCIPLES OF PHARMACEUTICAL FORMULATIONs

101    In what follows in this section, I will discuss some general concepts that would have been part of common general knowledge as at the priority date. In the following sections I will focus in on the approach to drug development as at April 2000. These are necessary background matters to my later discussion of inventive step.

102    The US Pharmacopeia 24 National Formulary 19 (1999) (USP) and the British Pharmacopeia (1993, 1998) are compendial references that were readily available before April 2000. The adjective “compendial” is referring to standards or compliance with standards. The USP and the British Pharmacopeia are books of pharmacopeial standards, including monographs for medicines, dosage forms and excipients. They also specify the tests and apparatus to be used to determine compliance with drug-release requirements in general and as particularly specified in individual monographs. I will elaborate on this later.

103    Literature in the field prior to the priority date also included the International Journal of Pharmaceutics, the Journal of Pharmacy and Pharmacology, the Journal of Pharmaceutical Sciences, Pharmaceutical Research and the Journal of Controlled Release.

(a)    General

104    The parties have not put before me an agreed description of the basic chemistry and pharmacology. Accordingly, in what follows I have had to largely draw upon Professor Ian Tucker’s description of some of the background concepts that were not, as best as I can ascertain, in contention. But I have made some modifications in order to ensure that this section of my reasons does not trespass into contentious areas. Professor Tucker was called by Generic Partners. There were some specific aspects of his evidence that I have not been persuaded by as I discuss later, but his general discussion of the background theory was helpful. What is stated in this section are formulation concepts and practices as at the priority date.

105    Formulation is the process around converting a drug, the active ingredient, into the dosage form, which has certain properties. For example, aspirin is a drug and an aspirin tablet is a dosage form. A dosage form is required to be stable, aesthetically pleasing, and present the correct dose of drug in a convenient form for use. Types of dosage forms include tablets, capsules, solutions, linctuses, eye drops, nose drops, injections and so forth. About 80% of all medicines are taken orally, of which tablets are the most common dosage form. I will elaborate in more detail on dosage forms later.

106    The aim of drug delivery is to deliver the right drug, at the right dose, at the correct rate and to the correct site for the required time. For example, a simple immediate release dosage form such as an aspirin tablet releases all of its drug soon after it is swallowed. More sophisticated oral drug formulations might slow the release of the drug or attempt to target delivery to a particular region of the gastrointestinal tract.

107    The USP and the British Pharmacopeia divide solid dose formulations into immediate release (also referred to as conventional release and “IR”) and modified release. An immediate release formulation will deliver the drug dose immediately. Modified release means that the release of the drug is not immediate. I will elaborate in more detail on these aspects below, but it is useful to make some general observations at this point. There are two sub-categories of modified release:

(a)    First, there is the sub-category of delayed release formulations. Delayed release means that the release does not occur immediately when the dosage form is swallowed. For example, an enteric coated tablet has a polymer coat that is insoluble in stomach acid but is soluble in the intestinal fluid. The polymer coat delays release of the drug until the tablet leaves the stomach;

(b)    Second, there is the sub-category of extended release formulations. Extended release means that the drug is not released all at once, but is trickled out over a period of time, perhaps up to eight hours.

108    It is appropriate to elaborate further.

109    Delayed-release oral dosage forms may be used if irritation of the stomach is of concern, or to prevent the degradation of the drug substance in the acidic conditions of the stomach. Enteric coatings are pH-dependent and prevent the drug substance from being released in the acidic environment of the stomach. When the enteric coating is exposed to a higher pH (generally about pH 5.5 and above), the coating dissolves and the drug substance is released as an immediate-release dosage form. Before April 2000, enteric coatings typically involved the following types of excipients:

(a)    Polymers — polymers form a film that are insoluble at acidic pH levels;

(b)    Plasticizers — these are used in order for the coating to form a film. Examples include polyethylene glycols and diethyl phthalate;

(c)    Colourants — these are used to colour the coating for marketing, identification purposes, or to stop light permeation. Examples include titanium dioxide and ferric oxide; and

(d)    Anti-tacking agents — these are used to prevent the coating material from sticking together and causing imperfections in the coating that may compromise the delivery of the dosage.

110    In relation to extended release dosage forms, there were many on the market by April 2000. Apparently, they became popular in the 1950s. As a result, in the 1950–60s, drug companies tried to distinguish their extended release products by different branding, so that “extended release” became known as, for example, “slow release”, “prolonged release”, “sustained release” and “span release”. Generally speaking, one can refer to these formulations as extended release or “ER” or sustained release or “SR”. Concepts of extended release dosage forms were taught in pharmacy schools from the 1960s onwards. The Controlled Release Society was set up in the 1970s. The principles in relation to extended release dosage forms were well known before 2000.

111    There are a number of advantages of extended release formulations over immediate release formulations of the same drug.

112    Set out below is an example of plasma concentration time curves (shown in red) for three separate immediate release dosage forms. The graph also shows an “ideal” plasma concentration time curve (purple) for an extended release dosage form of the same drug. The minimum effective plasma concentration (MEC) of the drug and the minimum toxic plasma concentration (MTC) of the drug are shown by, respectively, the lower and upper broken lines; plasma is the liquid component of blood. Between those two lines is what is described as the “therapeutic window” for the drug.

113    The concentration of a drug in blood increases over time until a “steady” state is reached. The increase occurs because drug from the tablet just taken is added to drug remaining in the body from tablet(s) taken previously. A “steady” state is reached when the average drug intake rate equals the average rate at which drug is eliminated from the body.

114    The “ideal” plasma concentration time curve for the extended release dosage form shows:

(a)    less fluctuation in drug levels in the blood over time, which may be associated with less side effects; and

(b)    on the assumption that therapeutic effect is related to drug plasma concentration (which assumption holds good for many drugs), that a constant therapeutic effect is sustained for a longer period and there are no periods where the drug concentration is below the MEC.

115    There are, however, the following disadvantages associated with extended release formulations. First, there may be a longer onset time for therapeutic effect with an extended release dosage form. This is depicted above, where the purple curve exceeds the MEC at a time (“tlag”), which is later than the immediate release dosage form. Second, a single extended release dosage form (tablet) includes a quantum of drug equivalent to multiple doses. If the dosage form “dumps” all of those doses at once, the total drug concentration in the blood may be toxic (depending on the MTC for that drug). This may occur if the dosage form fails for some reason.

116    To address the problem of a slow onset time, a patient may be able to take an immediate release tablet and an extended release tablet at the same time. Some dosage forms include an immediate release component to give therapeutic effect quickly, and an extended release component to achieve a sustained therapeutic effect. An example of such a dosage form is a bilayer tablet, which consists of an immediate release layer and a second extended release layer. The immediate release layer disintegrates away releasing particles or granules (a particle or granule contains billions of drug molecules together with excipients). The drug then dissolves quickly from the particles or granules. Contrastingly, the extended release layer releases the drug slowly over time. Another example of such a dosage form is a capsule with both extended release and immediate release particles.

(b)    Dissolution rate

117    An “ideal” extended release dosage form is a dosage form where the rate of release (rate of dissolution) of the drug is independent of the environmental conditions under which it is placed. What is meant by ideal is that the release rate is predictable because the release of the drug is controlled by the formulation, not by what is being done to the formulation by its environment.

118    But in reality all formulations change their release rate depending on the conditions of the environment, including the pH of the dissolution medium, anything that affects the hydrodynamics (flow) of that medium (e.g. the stirring rate, type of agitation, the shape of the vessel or the volume of liquid), temperature and the ionic strength of that medium.

119    The environmental conditions including the hydrodynamics of the dissolution medium can affect both “disintegration” of the dosage form to particles and “dissolution” of drug molecules from the particles; in these reasons, “particles” and “granules” can be treated as synonyms.

120    The rate of dissolution of a drug from a drug particle is predicted to some extent by the Noyes Whitney equation. But this is only a mathematical idealisation. I have previously observed (“Scientific Evidence: a Need for Caution in Decision-Making” (2010) 42 Australian Journal of Forensic Sciences 49 to 77) that there are the following limitations on using mathematical formulae in scientific empirical work:

(a)    First, a formula is usually used to explain an apparent regularity between empirical observations. But a formula (and the underlying data) does not of itself demonstrate any necessary causal connection. From a correlation between the movement in two variables, sometimes such a link is inferred. But philosophically this is always contestable in a Humean sense. And practically may be contestable in many individual cases. The correlation may be due to a separate but common cause. Movement in one variable preceding movement in the other is only the starting point for any analysis.

(b)    Second, a formula may only reflect a regularity observed from present or past data. And its function may simply be to explain that data rather than as a predictive tool. But even as an explanation for past data, the formula may have its limitations. Past data upon which the formula is built may only be a limited sub-set of the available data. The complete data set (if available) may change the apparent pattern of that regularity.

(c)    Third, and relevantly to the predictive case, the formula may only be one of many ways to express the apparent regularity of the observed phenomena. So a formula may be a useful explanatory tool to explain observed phenomena, yet as a predictive tool it may be of little utility. For example, take 10 empirical observations which are plotted on a graph showing for each observation variables x and y measurements. Assume that this graphing shows that the 10 points can be connected by a straight line. You might conclude that there is a linear correlation between variables x and y and posit a formula for the straight line function (f(x) = ax + b), where f(x) = y. So you have a good explanation of the relationship between your 10 observations. But how good is the formula for predictions? Theoretically there are an infinite number of lines (including curved) that could have been drawn to join the 10 points, with correspondingly different formulae. And a further measurement (the 11th point) may show the function not to hold. For any set of empirical data, there are multiple potential theories/formulae to explain the same, hence what philosophers of science identify as the under-determination problem.

(d)    Fourth, a mathematical formula takes its subject matter and their measurement as idealized and precise. But empirical data may be imprecise in quality or measurement. Indeed, statistical evaluation of primary data using stochastic equations and assumptions may be necessary to derive values for the variables to be used as inputs into the principal equation.

(e)    Generally, mathematical equations should be seen in their limited context as imperfect tools. At most, any formula is only an idealized representation of the apparent regularity consistent with the model underpinning the theory. Their apparent elegance ought not to be taken as giving a greater air of verisimilitude to a scientific theory or its application than is warranted after considering all qualitative and quantitative assumptions and inputs.

121    According to the theory underpinning the Noyes Whitney equation, around each particle is an unstirred layer of liquid. The rate of diffusion of drug molecules across the unstirred layer controls the dissolution rate of drug. Molecules which diffuse across this unstirred (stagnant) layer are replaced “immediately” by molecules leaving the surface of the solid particle. Consequently, the solution which is in immediate contact with the particle surface is saturated with drug molecules and assumed to be at a constant concentration. The bulk solution in which the drug particle (and its unstirred layer) is suspended is assumed for the purpose of the equation to be uniformly mixed and of a uniform concentration. The rate of dissolution across the unstirred layer is determined by the concentration gradient across the unstirred layer. This is conveniently depicted below:

A = surface area of particle (or the sum of the surface areas of all particles).

D = diffusion coefficient for the drug molecules through the unstirred layer.

Cs = concentration of the drug at the particle surface (it is equal to the solubility of the drug in the medium).

CB = concentration of the drug in the bulk solution.

h = thickness of the unstirred layer (or the diffusional distance).

122    The effect of hydrodynamics on the rate of dissolution can be shown by reference to changes to the parameters in the Noyes Whitney equation. So, for example, the faster the solution is stirred, the smaller the thickness of the unstirred layer (“h”) becomes, so the rate of dissolution increases. Further, the stirring also increases the total surface area (“A”) of the particles. That is, by dispersing the particles through the medium, the total surface area is greater than if those particles were sitting at the bottom of the vessel. The greater “A”, the faster the dissolution rate.

123    Cs is determined by the solubility of the drug in the medium chosen. If a different medium is used, or a medium of a different pH is used, the Cs value may change. If a medium in which the drug is more soluble is selected, Cs becomes larger and the rate of dissolution faster.

124    The concentration of the drug in the bulk solution (CB) depends on the volume of the medium. As the drug is released from the particle over time, “CB” increases. The volume of solution is usually chosen so CB is in “sink conditions”. That is, CB is less than 10% of Cs. If a small volume of bulk solution is used, “CB” will increase over time at a faster rate. As a consequence, the rate of dissolution will slow because the difference between Cs and CB will decrease.

In vitro dissolution profile / in vivo dissolution profile

125    The in vitro dissolution profile of a formulation describes the dissolution of drug from the dosage form (e.g. a tablet) under specific prescribed conditions. The in vitro dissolution profile for a formulation shows the amount of a drug substance that is dissolved from a dosage form over time using an experimental apparatus. The drug concentration is measured in the dissolution medium at particular time intervals to produce the profile.

126    Obtaining an in vitro dissolution profile is simpler than obtaining an in vivo dissolution profile; patients are not required. It can provide information that may be useful for predicting the in vivo characteristics of a drug formulation, although in vivo measurements are usually required to confirm the performance of a formulation being studied or considered. But formulators make use of in vitro data to streamline formulations or identify formulations for further consideration or development. In vitro dissolution studies are used as a screening tool of candidate drug formulations. For example, based upon a number of formulations, one formulation may be identified as having a desirable in vitro release profile and, therefore, as having the best chance of working in vivo.

127    An in vitro dissolution profile can also be used as a quality control test to determine whether a particular batch of tablets was within the specification set down by the manufacturer or an official monograph in the USP or the British Pharmacopeia for that tablet.

128    Different apparatus can be used to measure dissolution profiles. Dissolution experiments must be carried out carefully in terms of technical work and the apparatus and the principal variables related to it defined. If any of these principal variables are substantially changed, it may significantly change the rate of release of drug from the formulation and therefore the in vitro dissolution profile of the dosage form.

129    The USP typically specifies the in vitro release profile under prescribed conditions using a prescribed apparatus for an extended release dosage form of a drug.

130    I will discuss dissolution testing in more detail in a separate section of my reasons.

131    In about the late 1970s, people started to think about whether in vitro dissolution profiles could be used to predict drug release in the body. Scientists working in this area developed computer models to attempt to predict in vivo behaviour from in vitro testing. But there is no guarantee that a dosage form with a particular in vitro dissolution profile will have the same in vivo dissolution profile (i.e. the same dissolution profile in the body). Drug release in the body is affected by many factors including differences in volume of fluid present in the in vivo environment, the degree of agitation and the pH the formulation is exposed to in the gut.

132    Some correlation work can, however, be undertaken. There are various possible levels of in vitro/in vivo correlation. The highest correlation is a point to point correlation between the in vitro and in vivo curves. If a high level of in vitro/in vivo correlation has been established for a specific formulation of a drug, it may be possible to predict that a specific formulation of that drug made in accordance with the relevant product specification or drug monograph with that same in vitro dissolution rate, will have that in vivo pharmacokinetic profile. Conversely, in theory it may also be possible to predict that a formulation of that drug made in accordance with the relevant product specification or drug monograph with the same in vivo pharmacokinetic profile, will have that in vitro dissolution profile. I will return to discuss these predictive and correlation questions later.

Dissolution rate from an extended release formulation

133    Matrices and reservoirs are two types of extended release dosage forms for controlling the rate of release of a drug from a solid oral dosage form (e.g. a tablet or pellet). For present purposes I do not need to discuss reservoirs further.

134    In one sense, a matrix can be thought of as a dispersion of a drug and excipient(s) through some other material(s). In that sense, a matrix system may be a tablet or a pellet in which drug particles and excipients are dispersed in a polymer or a lipid. Such a matrix (in that sense) will remain intact and extend the release of the drug from the matrix by eroding slowly or by controlling the release of the drug from a non-eroding matrix, or a combination of these processes. Polymers or lipids may be used for matrix materials. Polymers can be classified as water soluble, swellable in water or water insoluble. I will discuss the more contentious issues in a later section of these reasons concerning the different types of use of the concept or term “matrix” when I come to consider how the claims are to be construed and the meaning of the expression “matrix forming polymer”.

135    But just proceeding for the moment using “matrix” in this simplistic sense, it is appropriate to make the following observations. For such a “matrix”, release of drug generally occurs by the following steps: first, medium penetrates through the boundaries between the polymer granules; second, drug particles dissolve i.e. become drug molecules in the medium; third, these molecules diffuse out though the medium-filled channels or pathways. Such diffusion through channels is not straightforward as diffusion occurs through a complex pathway.

136    When a matrix is made from or formed by a gelling polymer (I do not need to discuss lipids further at this point given the issues that I need to address), the typical release process is as follows.

(a)    First, water penetrates the outer layer of the tablet (or pellet).

(b)    Second, the water reacts with the polymer causing it to swell, forming a gelatinous layer.

(c)    Third, water transfers in through the gelatinous layer.

(d)    Fourth, drug particles dissolve in the water and drug molecules diffuse out through the gelatinous layer. This gelatinous layer is a barrier to diffusion of the drug molecules and thereby slows and extends the period over which release occurs.

(e)    Fifth, water continues to transfer into the tablet.

(f)    Sixth, the above steps are repeated in a continuous process. At the same time erosion of the gelatinous layer is also occurring.

137    The rate at which drugs diffuse out of the tablet or pellet depends on the nature of the gelatinous layer. The nature of the gelatinous layer (including how quickly it is formed and its thickness, which is related to its ability to resist erosion) is determined by the type of polymer used in the formulation. Further, the hydrodynamic conditions and the type and concentration of excipients (I will explain excipients later) may also affect the thickness of the gelatinous layer and its ability to form a coherent gel layer.

138    Further, the choice of polymer can affect the size of the polymer granules which are compressed or formed into the matrix (used in the loose sense described earlier) and, therefore, the length of the pathway over which diffusion of drug molecules must occur. That then impacts on the diffusion rate. The size of the granules can also affect the rate at which the gelatinous membrane breaks off.

139    Further, the concentration of drug in the matrix can also affect the release rate from a matrix. For some matrices, if there is a low concentration of drug and no water-soluble excipients, the drug at the surface may release but the remaining drug may be trapped in the matrix. Contrastingly, if there is a high concentration of drug, the release profile may change because the water may follow the drug pathways into the matrix, resulting in faster drug release (and less drug being trapped in the matrix).

(c)    Pharmacokinetics — in vivo concepts

140    I have touched upon some of these concepts earlier, but it is appropriate to elaborate further. Pharmacokinetics is the study of the change in drug concentration over time in the blood (pharmakon is Greek for drug, kinetics a time process). Pharmacokinetics concerns itself with what is referred to as ADME: absorption, distribution, metabolism, elimination. Distribution, metabolism and elimination constitute the disposition of the drug. One can look at these variables on a system wide basis or at a local level, say, a particular organ.

141    Pharmacodynamics is the dynamics (change) at the site of action or variable of interest in response to a drug over time. It is concerned with what is happening at the site of action or variable of interest by reason of the drug being in the body. For example, if a drug is meant to lower glucose levels in the blood, it would be possible to measure the concentration of drug in the blood (pharmacokinetics) or to measure what happens to glucose levels (pharmacodynamics).

142    I have discussed in vitro concepts above. It is appropriate to say something further on in vivo concepts.

143    The in vivo profile for a particular formulation looks at the concentration of the drug in a person’s bloodstream over time; it can also be looked at as an averaged concentration over a number of persons. Terms used to describe such a profile include:

(a)    Cmax, the maximum concentration of drug that is measured in the blood;

(b)    tmax, the time that the maximum concentration is reached; and

(c)    AUC (area under the curve) which represents the total amount of drug that has been absorbed into the bloodstream over time; this can be compared with the quantity of drug administered to the person.

144    The following figure again shows the “therapeutic range” or the “therapeutic window” between the MEC and the MTC. Cmax, the maximum concentration of the drug in the blood, is estimated from a concentration time curve. A patient swallows the dose (e.g. a tablet) with a defined amount of water either in a fasting or non-fasting (“fed”) state. In a fasting experiment, a patient would typically be required to fast for eight to ten hours (since the night before). In a non-fasting experiment, a patient would typically eat a standard meal before the experiment. Blood is taken from the patient at specified times and analysed to determine the concentration of drug in the blood. This forms a profile for an individual. The following diagram is an “ideal” concentration/time curve for an immediate release dosage form.

145    But there are different approaches to determining that maximum. For example, in a bioequivalence study, the Cmax is the highest concentration datum, without interpolation. Other approaches involve interpolation between the two highest concentrations.

146    For some drugs, absorption is affected by whether the drug is taken with food or without food. Absorption of most drugs occurs in the intestine. If a non-disintegrating tablet is taken on a fasted stomach, the dosage form will most likely stay in the stomach until “house keeper” contractions occur (about every 90 minutes). If such a tablet is taken on a fed stomach (particularly after eating fatty foods), the tablet may stay in the stomach for a much long period. For this reason, the absorption rate of some drugs decreases if the drug is taken with food. The extent of absorption can also be affected by food for other reasons (e.g. binding of drug to food components). The fasted and fed states may have a different effect on the same drug in an immediate release dosage form as compared to an extended release dosage form.

147    Tmax is the time at which Cmax occurs. After Tmax, the rate of elimination exceeds the rate of absorption and so the blood concentration of drug falls. T1/2 is the elimination half-life. It is the time taken for the concentration of the drug in the blood to decrease by half, provided there is no drug still being absorbed. First order elimination means that the rate at which drug is eliminated is directly proportional to the plasma drug concentration (rate = constant x plasma concentration). Accordingly, the rate of drug elimination in first order elimination changes with concentration. Sometime after the Cmax it is assumed that absorption is complete and only elimination is occurring. The matter is represented diagrammatically below. The elimination rate constant (ke) represents the fraction of drug eliminated per unit of time. Elimination half-life t1/2 = 0.693/ke. However, this is more complex for extended release tablets because absorption may still be occurring during the time of the decay curve.

148    I have referred to AUC being the area underneath the concentration time curve. This is measured to tlast (time last) by the usual trapezoidal rule for approximating the region under the graph as a series of trapezoids. But the AUC can be calculated to t∞ (time infinity) by adding the area in the tail of the curve (after the last datum) to the AUC0-tlast. The AUC is related to the total amount of drug which the body receives as follows:

Dose x F (fraction of dose absorbed) = CL (clearance of drug) * AUC0-∞

149    If a drug is given intravenously, F necessarily = 1 (100% is “absorbed” by definition because the drug enters the bloodstream directly). This allows the clearance of the drug (CL) to be calculated. Assuming that CL is a constant (the same for a drug taken intravenously or orally), the fraction of the dose absorbed orally can then be back-solved from the AUC for the drug given orally, the dose and the clearance. One can then calculate the total amount of drug to which the body is exposed (the extent of absorption) when the dose is taken orally (dose x F).

(d)    Dosage forms

150    It is appropriate at this point to elaborate in more detail on dosage forms.

151    Dr Brett Mooney, an expert in pharmaceutical formulation and called by Apotex, gave uncontroversial evidence on some background matters, some of which it is convenient to set out at this point. The statements that follow relate to dosage forms at and prior to April 2000.

152    Tablets were made by the compression of powders or particulate matter such as pellets, granules or beads. Tablets could be coated, including for functional reasons, such as an enteric coat, or for cosmetic reasons, such as a colour coat. Tablets could also be multilayer, with different layers having different properties. Most multilayer tablets had two layers and were called “bilayer” tablets. Bilayer tablets could be made to be biphasic, which meant that each layer had different release characteristics; for example one layer could have an immediate-release formulation and the other layer could have a modified-release formulation.

153    Capsules available by April 2000 consisted of either hard gelatin or soft gelatin. Hard gelatin capsules have a gelatin-based casing with a body and a cap that is loaded with materials, including one or more drug substance and excipients. These capsule shells were commonly coloured and printed for identification and marketing purposes. The material loaded into the hard gelatin capsules could be in the form of powder, granules/blend, beads or multiparticulates. Soft gelatin capsules are formed by injecting a liquid solution/suspension into a gelatine shell which seals during the process and is then dried.

154    The dosage forms prior to April 2000 included forms that differed in their release characteristics. As I have said, an immediate release formulation is a dosage form that is formulated to make the drug substance available for immediate dissolution after administration. For an immediate release formulation the drug substance is readily dissolved within a relatively short amount of time, such as no less than about 75% in less than about 30–40 minutes in a selected medium. I have explained above modified release forms including extended release or sustained release type formulations.

155    By April 2000 there were several different methods that could be used to formulate an extended or sustained release product, including use of a matrix formulation (diffusion-controlled or erosion), biphasic tablets or a formulation containing beads, pellets or multiparticulates.

Diffusion controlled matrix formulations

156    As I have explained, a diffusion controlled matrix formulation (using matrix in its simplistic sense) combines a polymer together with selected excipients and the drug substance. Examples of polymers that could be used for preparation prior to April 2000 included HPMC, ethylcellulose, alginates, hydroxypropyl cellulose and Eudragit (polymethacrylate-based copolymer). HPMC was commercially available in different molecular weights before April 2000. The molecular weight influences the viscosity of the polymer which affects its ability to control the release of the drug substance. For a specific drug substance high-molecular weight HPMC will have a higher viscosity and will generally provide a slower release as compared with low-molecular weight HPMC which will have a lower viscosity and will generally provide a faster release of the drug substance, ceteris paribus; of course, using the relative terms “slower” or “faster” says nothing about the absolute values or the real significance of any relative change.

157    Before April 2000 one could use a single polymer or a combination of polymers from the same or different families of polymers to achieve a target dissolution profile. Although it was preferable to have the simplest formulation consisting of only a single polymer, a combination of polymers could be necessary to achieve the desired dissolution profile. If a combination of polymers was used, the different polymers could be added to the dosage form at the same or different stages of the manufacturing process.

Erosion-controlled matrix formulations

158    For erosion-controlled matrix formulations (again using matrix in its simplistic sense), the matrix slowly erodes away, exposing the drug substance which then dissolves and diffuses out into the gastro-intestinal (GI) tract.

Biphasic tablets

159    Another form of sustained-release formulation before April 2000 was a biphasic tablet. An example is a tablet having an immediate-release layer and a sustained-release matrix-type layer. Each layer could contain the same, or a different, drug substance. These formulations were useful, for example, if it was necessary for some of the drug substance to be released immediately but also for the levels of drug substance in the blood to be maintained over a longer period of time.

Bead formulations

160    Sustained release formulations containing beads involve the use of spherical inert carriers, the surface of which can be loaded with drug substance and other excipients. A functional coat can then be applied to the beads. A formulation containing beads is generally more appropriate for use with low dosages of a drug substance, for example a dose of about 20mg or less (depending on the characteristics of the drug substance such as the solubility). If a large dosage is required, if one uses a sustained-release formulation based on beads this may increase the variability of the size of the beads in the dosage form, potentially making it more difficult to control the release profile of the dosage form. It may also take longer to manufacture the dosage form with more expense.

Pellet or multi-particulate formulations

161    Sustained release formulations can also be formulated that contain pellets or multiparticulates. In such a formulation, the individual particles can be formulated to create pellets or multiparticulates which can be used as is in a tablet or capsule that may be functionally coated. Alternatively, the particles can be coated with a functional coating and then used in tablets or capsules which again can be coated with a functional coat. The coating will be typically made from a polymer of the same types as described above.

(e)    Manufacturing processes

162    The dosage forms available prior to April 2000 also differed by the way in which they were manufactured. Manufacturing in this context is the bringing together and combining as a dosage form, in a defined process, the drug substance and the excipients; I will provide a more detailed discussion later concerning excipients. Manufacturing techniques that were well-known and used before April 2000 for solid oral dosage forms included direct compression, dry granulation and wet granulation.

163    Direct compression involves blending the drug substance and excipients in a specific amount and order to create a blend. This blend is then compressed into tablets or encapsulated in capsules. The resulting tablet or capsule can be coated for cosmetic (if a tablet) or functional purposes. This is the simplest method of manufacture.

164    Dry granulation also involves dispensing the components of the drug product and then blending the drug substance with a selection of excipients in a specific order to form a powder blend. This blend is then consolidated by a process such as slugging or compaction, for example using roller compaction, which densifies the blend, which is then passed through a screen to produce small particles (this process is being “sized”), referred to as granules. This process of densification is referred to as dry granulation. The granules are then blended with any remaining excipients in a specific order to create a blend which is compressed to form the tablet or encapsulated into capsules, which can be coated for cosmetic (if a tablet) or functional purposes to produce the final product. This method is useful when handling poorly compressible or moisture-sensitive materials. The dry granulation process ensures the production of compressible material with homogenously distributed drug substance within the blend, which in turn ensures that there is consistency of the drug substance dose in individual tablets or capsules.

165    The process of wet granulation involves similar steps as for dry granulation. The tablet components are dispensed, select excipients are combined with or without the drug substance in a granulator and then a liquid solution is added to the powder blend. The liquid solution may consist of water or an organic solvent, with or without the drug substance and other excipients (for example a binder or surfactant). The granulation process can be performed using either a high shear mixer or fluid bed granulator. The wet granulated mass from the high shear mixer can be sized and dried or extruded, spheronised and dried, and if required sized and functionally coated. The wet mass from a fluid bed will be dried in situ and, if required, sized and functionally coated. In the case of functionally coated particles these can be blended with additional excipients as required and encapsulated or compressed into tablets and if required a functional coat applied. The resulting dried granules can be screened using a sieve and blended with any additional excipients in a specific order (for example fillers, disintegrants, glidants or a lubricant) before the mixture is compressed to form the tablet or encapsulated in a capsule, which can be coated for cosmetic (if a tablet) or functional purposes to form the final product.

DISSOLUTION TESTING

166    The rate at which a pharmaceutical formulation dissolves under certain conditions is identified by “dissolution testing”, usually in vitro testing. Dissolution testing is typically carried out in conditions which are designed to mimic the dissolution of the drug from the formulation in the body. Dissolution testing of pharmaceutical formulations is also typically carried out under standard conditions for purposes of quality control of formulations.

167    Dissolution testing is fundamental to the formulation development process. It is used to evaluate changes in formulation. It is also used to monitor and satisfy quality control and regulatory requirements, such as the US Department of Health and Human Services, Food and Drug Administration (FDA) requirements for a biowaiver. A biowaiver is where the efficacy and safety section of a drug application is approved by the FDA based on evidence of equivalence with an existing drug. A biowaiver also includes where a drug of a particular dosage strength is approved by the FDA based on the evidence of demonstrated bioequivalence or bioavailability data already provided for a higher dosage strength of that drug. Generally, comparative in vitro dissolution data is often required as part of an application for a biowaiver to support assertions as to equivalence.

168    One needs to evaluate dissolution testing parameters and the effect of these factors on dissolution, including:

(a)    the effect of buffers (e.g. phosphate) and electrolytes (e.g. chloride ions);

(b)    the hydrodynamics, i.e., the flow of the dissolution fluid within the dissolution vessel;

(c)    the pH of the dissolution medium, which is usually considered within or across the physiological pH range of 1.2 to 7.5;

(d)    the volume of the dissolution medium;

(e)    the media surface tension and media viscosity;

(f)    the dissolution medium (e.g. aqueous water or organic solvent with water);

(g)    the temperature, which is usually 37°C, but can also be room temperature;

(h)    the sink conditions; and

(i)    the choice of the dissolution testing apparatus and components.

169    When considering the conditions for a reproducible and discriminatory dissolution procedure, it is important that the dissolution test is conducted under “sink conditions”. This refers to using a sufficient volume of dissolution medium in order for the drug to be freely dissolved and released from the formulation under test. To ensure that the dissolution test is conducted under sink conditions, the concentration of the total drug dissolved must not reach more than about 10 to 15% of its maximum solubility at any time during the dissolution procedure. If the dissolution test is not conducted under sink conditions, the drug release rate will be hindered and the dissolution medium around the drug can reach saturation solubility. Saturation solubility is the maximum amount of the drug that can be dissolved in the volume of the dissolution medium. If a dissolution study is performed and the drug is dissolved to a level of more than about 15% of its maximum solubility, it will not be under “sink conditions” and the dissolution rate would be significantly impacted by the solubility of the drug itself. When testing is under “sink conditions” the dissolution rate is principally impacted by the properties of the dosage form and not the drug’s solubility. For example, in the case of a sustained-release formulation, when sink conditions prevail, the properties of the matrix composition alone will control the rate of drug release from the dosage form (i.e. rate of release is limited only by the matrix polymer), rather than the combined effects of matrix composition and drug solubility limitation due to the absence of sink conditions.

170    It is important that all of the said parameters are well defined as part of the procedure including the type of dissolution testing apparatus that is used, so as to validate that the dissolution method works and is discriminatory in identifying release differences. This is important for reproducibility. Reproducibility is the ability of the dissolution test to be reproduced. It is also necessary to ensure that the test is discriminatory. A discriminatory dissolution test is sensitive to minor changes in a given formulation.

171    During the design of dissolution studies, it is also important to observe how the dosage form is moving within the dissolution apparatus. For example, if one observed a dosage form floating on the surface of the dissolution medium, one might decide to use a sinker to keep the dosage form on the bottom of the vessel below the stirring paddle used in USP type II apparatus. Any modifications to standard dissolution testing apparatus are based on the experience of the scientist, who has the purpose of optimising the method, with the aim of achieving reproducibility of results.

172    Standardised pharmaceutical dissolution testing apparatuses are described in the USP.

173    The United States Pharmacopeial Convention Inc is a scientific non-profit organisation that sets standards for drugs and excipients (these are referred to as “monographs”) and specifications for testing methods to evaluate drugs. That entity’s drug standards are enforceable in the United States by the FDA. Such standards are also used in many non-US countries such as Australia.

174    Such standards are continuously reviewed and updated based on new evidence and public health considerations. For such reviews and updates, the standards rely on volunteer experts who serve as decision makers on expert committees.

175    As at April 2000, the USP (the United States Pharmacopeia, US Pharmacopeia Convention, 24th review, 19th edition of the National Formulary, 1999 (USP 24 NF 19)) was the applicable standard for dissolution testing from 1 January 2000 through to about the end of 2001. The USP specifies seven apparatus for testing drug dissolution from a formulation. Four of these apparatus are designed primarily for oral solid dosage forms, being USP type I, II, III and IV apparatus. The remaining three apparatus are designed primarily for drug release testing of transdermal delivery systems, suppositories and topical products. The FDA would accept, as part of its regulatory approval of products, a modified apparatus standard where there was appropriate justification.

176    Prior to April 2000, there also existed the European Pharmacopeia, Council of Europe, 3rd Edition, 1996 (EP). The EP contained six apparatus for testing drug dissolution from a formulation. Three of these apparatus were designed primarily for oral solid dosage forms, being the paddle, basket and flow-through apparatus. The remaining three apparatus, being disk assembly, cell method and rotating cylinder, were designed primarily for drug-release testing of transdermal delivery patches.

177    USP type I apparatus is generally referred to by pharmaceutical scientists as a “basket”, USP type II apparatus as a “paddle”, USP type III apparatus as a “reciprocating cylinder” and USP type IV apparatus as a “flow through cell”. For convenience, in these reasons I will use Roman rather than Arabic notations for consistency.

178    USP type I apparatus and USP type II apparatus were first adopted by the USP in the 1970s. USP type III apparatus was adopted in the early 1990s.

179    Each of the four dissolution methods described in USP type I, II, III and IV apparatus provides different hydrodynamics. The differences in hydrodynamics have an impact on the dissolution results obtained. For example, if the same tablet is tested, the dissolution results from a test using the rotation of the paddle in USP type II apparatus will not be the same as the results when the rotating basket in USP type I apparatus is used. This is because each system creates a different fluid flow environment.

180    There is no established correlation between dissolution results measured using the different USP apparatus. Sometimes small differences are measured, other times the measured differences are large. Differences in measured dissolution profiles as between each of USP type I, II and III apparatus may not be predictable.

181    In a repeated dissolution study using any one of USP type I, II or III apparatus, variability in the measured dissolution profile for each sample of up to ±10% is considered normal and to be expected due to inherent analytical variability, and apparatus and sampling variability, although variability of ±5% is more ideal. It may be necessary to test at least 6 or 12 dosage units in a study using a particular USP apparatus, with well-defined and consistent testing parameters, in order to determine reproducibility with statistical reliability. The USP specifies the number of dosage units to test, which ranges from an initial 6 dosage units up to 24 dosage units.

182    Prior to undertaking a dissolution study, each USP apparatus has to be calibrated. Calibration involves making sure that all parts of the apparatus are in alignment and the equipment is functional with no mechanical failures. Reference standards can be purchased from the USP for calibration of a dissolution apparatus. These reference standards include disintegrating tablets, non-disintegrating tablets, extended-release tablets and extended-release beads, each of which were available prior to April 2000. The USP calibration standard specifies all parameters for the dissolution test as well as specific dissolution ranges for each measured time point. If the results fall within the dissolution ranges specified for the calibrator reference dosage form provided by the USP, it will indicate that the dissolution apparatus has been appropriately calibrated.

(a)    USP type I apparatus

183    USP type I apparatus uses a basket. USP type I apparatus is used for immediate-release, delayed-release and sustained-release solid dosage forms. USP type I apparatus is comprised of a cylindrical mesh basket attached to a shaft that is placed inside a one litre round-bottom cylindrical vessel containing the dissolution medium. The dosage form being tested is placed inside the cylindrical basket which rotates inside the dissolution vessel. The speed at which the basket rotates (measured in rotations per minute) has an impact on the measured dissolution of the sample.

184    The USP specifies that the basket is made of stainless steel mesh. Prior to April 2000 and subsequently, different grades of mesh sizes were available. The USP specifies that 40 grade mesh be used unless otherwise specified in an applicable individual monograph.

185    The “grade” of mesh refers to the width of wire and of the openings. For example, a 40 grade mesh is specified in the USP to be a 40 x 40 mesh with 0.25mm wire diameter with wire openings of 0.40 ± 0.04mm. Where a 20 grade mesh is specified, a 20 x 20 mesh, 0.40mm wire diameter with wire openings of 0.90 ± 0.09mm is to be used.

186    The rotation speed (rpm) and grade of mesh used for the basket directly influences the hydrodynamics of the system and has a resulting impact on the rate of dissolution measured. The tighter the mesh, the more resistance there is to the dissolution medium passing through it. A 40 grade mesh is tighter than a 20 grade mesh and has a greater resistance to the passage of dissolution medium. The mesh grade used is important for reproducibility. Depending on the dosage form being tested, there may be a need to vary the mesh grade for a specific reason. For example, if the dosage form being tested included matrix-forming polymers that swell and gel (forming a gel layer around the tablet) in the dissolution medium, one would select a more open grade of mesh (e.g. 20 mesh) because the tablet is less likely to stick to a mesh with wider openings compared to a finer mesh, and so less variation should occur in the measured dissolution values. Pellet formulations might also require a larger opening in the mesh, as they may be comprised of gel and become sticky in the dissolution medium.

187    In assessing the parameters of the dissolution method to be used to create a set of reference data, it is sometimes necessary to modify the standard USP dissolution apparatus in order to achieve reproducible results. For biowaiver purposes, the FDA requires highly reliable, reproducible and discriminatory dissolution testing rather than mere adherence to the USP. The FDA provides guidance to guide pharmaceutical companies as to the dissolution testing required to obtain a biowaiver. Modifications to the apparatus to achieve the required reproducibility of results may be made, based on the experience of individual scientists and the facilities of the laboratory in which they work, but it is important that anyone seeking to determine whether a sample dosage form has the required dissolution profile uses the same apparatus and testing conditions.

(b)    USP type II apparatus

188    USP type II apparatus uses a paddle. USP type II apparatus is comprised of a one litre round-bottom vessel containing the dissolution medium and a paddle attached to a shaft. The sample dosage form under test is added to the vessel and allowed to sink to the bottom, below the paddle. The paddle then rotates and stirs the dissolution fluid in the vessel.

189    USP type II apparatus is used for immediate-release, delayed-release and sustained-release solid dosage forms.

(c)    USP type III apparatus

190    The USP type III apparatus was first included in the relevant standards in 1991, as an alternative to the basket (USP type I) and paddle (USP type II) apparatus for drug release testing. After increased interest in the apparatus in the 1980s, especially in light of the great interest in development of controlled release pharmaceutical formulations at that time, the apparatus was evaluated in 1990 and was then made official.

191    As at April 2000 the USP type III apparatus was attractive for the study of controlled release formulations, particularly since changing the media to simulate passage through the GI tract could be easily and reproducibly achieved if required. Borst, I, Ugwu, S and Beckett, AH “New and Extended Applications for USP Drug Release Apparatus 3” Dissolution Technologies (February 1997) 11 conclude at 15:

USP 3 should be considered the first line apparatus in product development of controlled release preparations, because of its usefulness and convenience in exposing products to mechanical as well as a variety of physicochemical conditions which may influence the release of products in the GI tract.

192    The USP type III apparatus assembly consists of:

(a)    a set of cylindrical flat-bottomed glass vessels;

(b)    a set of glass reciprocating cylinders;

(c)    stainless steel fittings, and screens (made of suitable nonsorbing and nonreactive material) designed to fit in the bottom or top of the reciprocating cylinders;

(d)    a motor and drive assembly to reciprocate or dip the cylinders vertically inside the vessels, and if desired, index the reciprocating cylinders horizontally to a different row of vessels; and

(e)    a water bath which can be heated to the desired temperature.

193    A single test apparatus of the USP type III apparatus is shown below. This image has been taken from the USP with annotations added by Professor Dressman (a GSK expert witness):

194    In general terms, a USP type III dissolution test is carried out in the following manner (for the moment just taking one of the set of vessels and cylinders):

(a)    First, the dissolution medium is added to the glass vessel.

(b)    Second, the sample is placed in the reciprocating cylinder and then the cylinder is screwed onto the dipping rod. In this “in use” position, the evaporation cap covers the cylinder.

(c)    Third, the glass vessel is immersed in a suitable water bath of any convenient size that permits holding the temperature at 37 ± 0.5ºC during the test.

(d)    Fourth, after about 15 minutes (the time needed for the medium temperature to reach 37 ± 0.5ºC) the apparatus is activated so that the dipping rod moves up and down at the prescribed rate to move the cylinder (containing the dosage form) up and down within the glass vessel containing the dissolution medium. During the “dipping” or reciprocation, the cylinder changes its position within the vessel, enabling the dosage form to interact with the dissolution medium. On the up stroke, the bottom mesh of the cylinder moves upwards to contact the dosage form and on the down stroke the dosage form leaves the mesh and floats freely within the cylinder. The interaction of the dissolution medium and the dosage form results in drug release.

(e)    Fifth, at each of the sampling time points, a sample of fluid from the cylindrical glass vessel is removed, and then analysed to determine the percentage of the relevant active ingredient dissolved from the dosage form into the dissolution medium at that time point.

195    In USP type III apparatus, the mesh is inserted into the caps of the reciprocating cylinder. The purpose of the mesh is to allow adequate distribution of medium (and dissolved sample) into and out of the reciprocating cylinder, whilst retaining undissolved particles/dosage form within the reciprocating cylinder. As I have indicated, a mesh with larger holes may (undesirably) allow more undissolved particles to pass through the mesh into the lower part of the glass vessel, while a mesh with smaller holes may become blocked by undissolved particles, restricting flow of the medium into and out of the reciprocating cylinder. It is trite to observe that if either of these phenomena were observed during testing, the mesh size could be adjusted to optimise testing of the test dosage form.

196    The appropriate mesh size to use to carry out the dissolution testing using the USP type III apparatus on a paracetamol tablet is not specified in the USP. The protocol is silent on the mesh size to be used for USP type III apparatus. Moreover, the USP 24 NF 19 Official Monographs for acetaminophen (paracetamol) reveal that the dissolution test indicated for acetaminophen tablets does not use the USP type III apparatus. There is no guidance for mesh size in using the USP type III apparatus.

197    But notwithstanding that the USP is silent on which mesh size to use, one would normally select an appropriate mesh size to use. Professor Dressman said that selecting the mesh size to carry out testing using USP type III apparatus was a matter of routine as at April 2000 for those who had a knowledge of dissolution testing including using USP type III apparatus.

198    The mesh screens are sized to fit on the top and on the bottom of the reciprocating cylinder, but the USP does not specify that the mesh needs to be inserted at the top of the cylinder as well as to the bottom. Professor Dressman said that having a mesh at the top of the cylinder is optional. Further, she said that whether there was also a mesh at the top of the cylinder should generally have minimal influence on the dissolution results.

199    Finally, it is stated in the USP that:

Within the time interval specified, or at each of the times stated, raise the reciprocating cylinders and withdraw a portion of the solution under test for a zone midway between the surface of the Dissolution Medium and the bottom of each vessel.

200    The use of the word “zone” in the USP indicates that the withdrawal place is not a specific point within the vessel, but rather is a region. Professor Dressman said that the usual interpretation of a midway zone in a dissolution tester as at April 2000 (and still today) was and is that it is a zone which allows an accepted quantum of latitude in both the upwards and downwards directions. She said that that is how one would have taken a sample from USP type III apparatus in April 2000.

APPROACH TO DRUG DEVELOPMENT AS AT APRIL 2000

(a)    General

201    At this point it is convenient to draw upon some of the uncontested evidence of Professor Martyn Davies, a professor of biomedical surface chemistry at the University of Nottingham (UK), an expert called by GSK.

202    The development of new drugs or new formulations of existing drugs within the pharmaceutical industry involves research and development (R&D). The R&D process is undertaken by an interdisciplinary team, typically made up of clinicians, marketing or business analysts, medicinal chemists, toxicologists, clinical pharmacologists and formulators. The various members of the R&D team become involved and undertake tasks at different stages of the R&D process. The R&D process typically starts by the identification of a clinical need by clinicians and marketing/business analysts within a pharmaceutical company. This need can either be a completely new therapy, a desire to improve existing therapies using new compounds, or a desire to improve existing therapies by providing an alternative formulation of an existing compound. The R&D team would also include analytical chemists, who were responsible for the testing of raw materials (that is, the drug substance and the excipients), testing of any reference drug formulation (for its dissolution characteristics and stability evaluation), in-process material testing (for example, testing the uniformity of the drug substance in a blend during tablet manufacture), finished product testing (that is, release and stability testing to evaluate the physical and chemical properties following manufacture and during storage), process validation, analytical method development and validation, cleaning validation testing and packaging material testing. The R&D team would also include regulatory affairs personnel, who were responsible for constructing the regulatory dossier or components of regulatory dossiers for local or overseas affiliates or regulators. There would also be a project manager to oversee the overall development process.

203    The process of pharmaceutical development endeavours to minimise risk. The R&D team, including the pharmaceutical formulator, would be highly aware that should any problem emerge with the drug or formulation during later stages of the development phase, such as during clinical trials, the R&D process would either have to be stopped or the drug reformulated, requiring all the work to be repeated. The R&D costs to bring a product to market are substantial and hence any delay or setback will cost time and money and significantly delay the launch of the product. At each stage of the drug development process, there will be a critical discussion between members of the R&D team to evaluate the risk and benefit for progression to the next phase.

204    The role of the formulator is to take the candidate compound and create a stable formulation which can be taken through the clinical trials and ultimately potentially into production and onto the market. The degree of responsibility of the formulator within the R&D team is high. A failure of a formulation during the clinical trials process can require a repeat of the clinical trials with very substantial cost and time consequences. The formulator is usually tasked with developing a drug formulation that:

(a)    provides an accurate and safe dose of an active pharmaceutical ingredient (API);

(b)    maintains the stability of the API within the formulation shelf-life and until it reaches the site of absorption in vivo;

(c)    meets the target therapeutic effect; and

(d)    delivers the drug in a suitable way such that it provides the best opportunity to be clinically effective.

205    In order for an orally administered drug to be effective, the drug must be “bioavailable”. That is, it must dissolve, but not degrade, in the GI tract so that it can be absorbed into the bloodstream and be available to act on the body and treat the patient. The amount of drug absorbed into the bloodstream is known as its bioavailability. The bioavailability of an API is influenced by its physicochemical properties, its route of administration and by the formulation used. Drug delivery and absorption of an oral dose is a complex biological process involving multiple biological systems and internal organs. In designing the optimal safe and effective dosage form, in addition to a host of other information and considerations, a formulator must be familiar with the physiology of the GI tract.

206    After a patient ingests an oral dosage form, it will rapidly travel down the food tract (oesophagus) and enter the stomach. The rate of dissolution of a drug into the stomach acid will depend in part on its formulation. As I have earlier indicated, an immediate release formulation will rapidly disintegrate into particles. On the other hand, certain oral dosage forms (e.g., those with enteric coatings) are specifically designed to resist the breakdown by gastric acid entirely and therefore to avoid dissolution in the stomach. The stomach contents empty into the upper part of the small intestine, which serves as the primary source of maximum absorption for food as well as orally administered drugs. Digested food and drugs are absorbed into the blood via the rich supply of blood vessels that line the walls of the intestine. Once in the bloodstream, a drug is transported to the liver where it may undergo some degree of metabolism. It is then distributed around the body to the tissues where it exerts its therapeutic effect. Eventually, the drug or its metabolite(s) will be excreted from the body.

207    As I have said, the study of the absorption, metabolism, distribution and excretion of a drug is known generally as the field of pharmacokinetics. The R&D team would also include pharmacokineticists. As earlier indicated, the study of the pharmacokinetics of a drug is undertaken by plotting the plasma concentration of the drug against time (see the diagram set out earlier). As I have earlier indicated, the values of Cmax, tmax and AUC are used in bioavailability studies to assess the rate and extent of absorption of a drug from a pharmaceutical formulation. The plasma concentration of the drug can be measured using several analytical methods. One common method is high performance liquid chromatography.

208    There are two commonly used measures of bioavailability. The term “relative bioavailability” is where the bioavailability of a test formulation using its AUC value is compared to another formulation of the same dose and route of administration of the drug using its AUC value. In contrast, the term “absolute bioavailability” is used to compare the bioavailability of a test formulation by a specific route of administration to that of the drug when administered intravenously, i.e. when there is no barrier to absorption. Absolute bioavailability therefore measures the amount of the drug that is absorbed into the systemic circulation and assesses the effect of a different route of administration on drug absorption.

(b)    Developing a modified formulation of an existing formulation

209    Dr Mooney has given similar evidence to Professor Davies on the general approach to the research and development of a formulation, but with more of an emphasis on the approach one would have taken in April 2000 to developing a modified formulation of an existing formulation in order to change its properties. I generally accept his evidence on such general matters, although I have a difficulty with his specific evidence on inventive step which I will discuss as the final topic in my reasons.

210    Dr Mooney said that the R&D team would be assisted by:

(a)    people from the patents group (who provided relevant information from patent searches and provided assistance with preparing the regulatory dossier);

(b)    purchasing personnel, who were responsible for sourcing raw materials; and

(c)    quality assurance personnel, who were responsible for certain material approvals, providing reports on excipients, packaging materials and various aspects concerning batch manufacturing documents.

211    He also explained that the role of a pharmaceutical formulator in a commercial setting was to develop a formulation for a particular drug substance that:

(a)    consistently and reproducibly met appropriate physical quality limits and chemical quality properties, for example potency, dissolution where appropriate, purity and microbial contamination, as required by pharmacopeia and the regulatory authorities within the jurisdiction; the product had to remain stable within these specified parameters throughout the product’s shelf life;

(b)    met regulatory requirements for marketing authorisation, (for example, if the formulation was a generic version of a reference formulation, the product had to be bioequivalent to the reference drug); and

(c)    could successfully be scaled-up from pilot scale to commercial production.

212    Dr Mooney said that the first priority was the quality of the finished dosage form, but the R&D team was also mindful of cost considerations in all steps of the development process. Where opportunities for cost benefits or cost containment arose, these would be considered, including in relation to labour, choice of materials and process.

213    Dr Mooney said that for any formulation task, the formulation process could be divided into two stages: pre-formulation and formulation. Pre-formulation would be preceded by patent and literature searches. These searches might identify opportunities and information in relation to drug substances and potential products.

214    The pre-formulation process in the formulation of a generic version of a reference product involved:

(a)    review of the development brief and Drug Master File (DMF) or technical package for the drug substance;

(b)    identifying the physical and chemical properties of the drug substance, which might include experiments on the drug substance to be used;

(c)    identifying excipients to use in the formulation; and

(d)    further patent and literature searches (if necessary).

215    The formulation process for a generic version of a reference product involved:

(a)    continued investigations of the physical and chemical properties of the drug substance;

(b)    selecting the method of manufacture;

(c)    excipient selection;

(d)    analytical testing of the reference product, trial and scale-up batches;

(e)    conducting stability testing and choosing appropriate packaging;

(f)    bioequivalence studies; and

(g)    completion of regulatory requirements for registration of the final product.

216    Dr Mooney said that prior to April 2000, there was certain information about the drug substance and reference product that the R&D team or the formulators would expect to receive before commencing the development of a generic version of a reference product. This information was usually provided in the form of a development brief. Such a brief typically included the name of the reference product, the target markets for the generic product and the name of the drug substance manufacturer.

217    After receiving a brief, he said that the team (or relevant member) would look up details of the reference product in the USP and British Pharmacopeia, Martindale: The Extra Pharmacopeia (Royal Pharmaceutical Society, 31st ed, 1996) (Martindale), The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (Merck & Co Inc, 12th ed, 1996), US Physicians’ Desk Reference (Medical Economics Company, 53rd ed, 1999) (PDR), MIMS Annual (MediMedia Australia, 23rd ed, 1999) (MIMS) and the product information leaflet for the reference drug to obtain the following information (to the extent it was publicly available):

(a)    chemical structure of the drug;

(b)    physical properties of the drug;

(c)    the route of administration (that is, the way the dosage form was administered to a patient, e.g. orally, by injection, by inhalation);

(d)    qualitative formula of the reference drug (that is, a component list for the reference drug);

(e)    the dose (that is, the amount of a drug substance in the dosage form);

(f)    the dosage form (for example, tablet or capsule, if there were to be multiple strengths and whether or not a break line was required);

(g)    Cmax and Tmax;

(h)    the dissolution profile over a specified time period;

(i)    for an oral formulation, whether the product was coated, and whether this was for functional or cosmetic purposes; and

(j)    the packaging presentation.

218    The generic product’s dosage, dosage form, route of administration and release profile (immediate-release or sustained-release) would be selected to match those of the reference product.

219    The R&D team or the formulators would obtain a quantity of the drug substance (with the assistance of purchasing personnel) and samples of the reference product from markets where the reference drug was sold (from colleagues in the team). Samples of the reference product were required so that necessary tests, including in vitro dissolution tests, could be conducted.

220    In addition to the brief, the R&D team or formulators would either have been provided with or requested the DMF or technical package relevant to the drug substance. The DMF is a document prepared by the pharmaceutical company that has intellectual property rights to the synthetic process for the manufacture of the drug substance for the purpose of submission to a regulatory authority. The drug substance DMF contains information on the drug substance including, for example, information on the solubility of the drug. A DMF exists in both an open and a closed form. The open form contains quality information about the drug substance and may be requested from the company that submitted the DMF to the regulatory authority. The closed form contains quality information about the drug substance, as well as confidential details on the manufacturing process.

221    A technical package is typically a document produced by a drug substance manufacturer before a full DMF. It is less detailed than a DMF but contains quality information about the drug substance. The supplier of the drug substance may make a technical package available to potential purchasers.

222    It is necessary to understand the physical and chemical properties of the drug substance which will be used in a formulation. Details of the relevant physical and chemical properties of the drug substance were usually obtained. Where this information was not available, that data was generated by conducting or co-ordinating analytical testing of samples of the drug substance.

223    The relevant physical properties of a drug substance included:

(a)    density — a numerical value of mass in a specific volume;

(b)    particle size — a measure of the average diameter of particles of the drug substance;

(c)    surface area — a measurement of the surface area of the particles of the drug substance in a specific weight;

(d)    drug substance structure and structural features — the physical structure of the drug substance at the molecular level;

(e)    crystallinity — whether the drug substance existed in a crystalline or amorphous state at relevant condition parameters;

(f)    melting point — the temperature at which the drug substance changed state from a solid to a liquid; and

(g)    optical rotation — the way the drug substance rotated light, being a reflection of its racemic purity if the drug substance existed as an isomer.

224    The relevant chemical properties, which encompassed both standard chemical properties and quality attributes, included:

(a)    pH — the extent of acidity of the drug substance;

(b)    stability — including both solid state stability (i.e. sensitivity to light, temperature, humidity) and solution stability (i.e. in an acid or alkali solution or under simulated oxidation conditions);

(c)    solubility — the tendency of the drug substance to go from a solid phase into solution in a specific aqueous and organic media;

(d)    potency — the amount of pure drug substance in a known weight of drug substance expressed as a percentage;

(e)    purity — the amount of drug and non-drug substance in a known weight;

(f)    isomeric purity — whether the drug substance existed as a cis- or trans- isomer or as a racemic mixture; and

(g)    impurities — the amount and identity of non-drug substance in a known weight of drug substance.

225    Let me now elaborate further on the question of excipients, which also relates to the “matrix forming polymer” question that I will dwell on at some length later in these reasons.

226    As part of pre-formulation work, the development team or its formulators would identify the excipients to use in a formulation. Put simply for present purposes, the excipients are everything in the tablet or capsule other than the API. The excipients used in a formulation are based on the chemical properties of the drug substance (which influences its compatibility with excipients), the method of manufacture chosen and the desired dosage form. Compatibility studies can be used to test whether the drug substance interacts with any of the excipients, or any of the excipients interact with each other, in an undesirable way. The extent of any compatibility studies will be tailored referable to the chemical stability of the drug substance. For a generic product, if excipients are selected that are the same as those in the reference product and the drug substance is very stable, compatibility studies may be superfluous.

227    Before April 2000, common types of excipients that a formulator could use and that were well-known and used prior to April 2000 for oral dosage forms, included the following:

(a)    Fillers — These fill the volume of the tablet not occupied by the drug substance and other excipients to provide a presentable, manageable dose. They can be used to form a tablet or capsule to give it sufficient bulk to enable it to be conveniently handled by a patient. Fillers also contribute to the flow of the blend and facilitate compression during manufacture of the dosage form. Fillers can also improve the solubilisation of the drug substance. Common examples of fillers were lactose, microcrystalline cellulose, maize starch, pregelatinised maize starch and dibasic calcium phosphate. Some fillers can also be used to perform other functions.

(b)    Binding agents — These act to bind the drug substance with the excipients. Examples of binding agents included gelatin, maize starch, pregelatinised maize starch, povidone (a water-soluble polymer), low-molecular weight HPMC, hydroxypropylcellulose and ethylcellulose (water-insoluble). Again, any one of these binding agents could perform other functions.

(c)    Glidants — These assist a blend of drug substance and excipients to flow through the compression/encapsulation process to facilitate consistent tablet or capsule weight. Examples of commonly used glidants included talc and colloidal anhydrous silica. Colloidal silicon dioxide has, of course, the empirical formula SiO2. Its small particle size and large specific surface area give it desirable flow characteristics.

(d)    Lubricants — These ensure that the drug substance and excipients do not adhere to the punches and dies during the manufacture process. Prior to April 2000 the lubricant which was most commonly used was magnesium stearate (a salt formed from one magnesium cation with two anions from stearic acid, a fatty (octadecanoic) acid).

(e)    Disintegrants — These assist in the rupture of the structure of the dosage form to release the drug substance to allow it to dissolve. Examples of commonly used disintegrants included maize starch, pregelatinised maize starch, sodium starch glycolate, sodium croscarmellose and povidone XL. As one can appreciate, a substance used as a disintegrant in one context can be used as a binding agent in another context or perhaps as a filler in yet another context.

(f)    Antioxidants — These stop the oxidation of the drug substance. A well-known example was ascorbic acid.

(g)    Colourants — These are used to give the final product colour. Colour may be added for identification, for example to identify different strengths of a product, or for marketing purposes. Commonly used examples included ferric oxide, aluminium lakes and titanium dioxide.

(h)    Flavours — These are used to add flavour to the final product. Commonly used examples included spearmint and peppermint.

(i)    Buffers — These assist in maintaining the pH of the dosage form in a range within which the drug substance is stable. An example of a commonly used buffer was citric acid.

228    In selecting between different excipients the R&D team or its formulators would initially ascertain what excipients were used in the reference product by referring to published information about the reference product, for example information contained in the PDR and MIMS. These documents would not usually include details of the quantitative formulation (that is, the amount of each excipient that had been used) or what manufacturing method was used to make the dosage form. However, one could usually identify from the documentation relating to the reference product the function of each excipient and one could generally infer the manufacturing method based on the excipients used. One generally assumed that because of the need to obtain regulatory approval, which included consideration of compatibility and stability data, the excipients used in the reference product were compatible with each other and the drug substance.

229    If the proposed generic formulation was a delayed-release formulation, a sustained-release formulation or a combination of both, then in addition to the excipients listed above, one would also consider the use of excipients such as matrix-forming polymers or enteric coating excipients that would be necessary to achieve the required release characteristics. But in choosing modified-release excipients, one would be guided by the excipients used for the reference product.

230    The final dosage form might also require a coating. As I have indicated earlier, a coating can have a number of purposes that may be functional or cosmetic. Functional coatings can be used to change the location or rate of the release of the drug substance within the body. They can also be used to protect the drug substance (for example from moisture penetration or to stop oxidation degradation), to reduce the odour of the drug substance or for ease of packaging (coated tablets can be packed into blister packs more readily). Cosmetic coatings can be used for identification or to increase patient compliance or patient acceptance (to make a dosage form look more appealing).

231    Further, as I have indicated, before the R&D team or its formulators were given a development brief, appropriate patent and literature searches would usually have been done on the drug substance, with formulations containing the drug substance and any relevant patents and literature highlighted for the team. This information would have been provided to and considered by the team in the formulation work.

232    Finally, the process steps undertaken to construct oral dosage forms varied depending on whether direct compression, dry granulation or wet granulation was used and whether the product was coated or uncoated. It was not expected to be known what manufacturing process was used to produce the reference product but to some extent this could be inferred from knowledge of the reference product’s excipients. The R&D team and the formulators would use their experience and manufacture trial formulations to establish the best process appropriate to the equipment available. The manufacturing technique adopted would depend upon factors such as quality (physical and chemical), ease of manufacturing and the suitability of the process to the particular formulation being developed.

THE expert WITNESSES

233    The expert witnesses each gave their evidence separately and were cross-examined in the classical style. In the circumstances of this case, I did not consider it desirable to have the experts give their evidence in the contemporary style of a concurrent evidence session, notwithstanding that, advantageously, prior expert conclaves had been convened culminating in a joint expert report (JER). As I have said, Professor Dressman and Professor Davies were called by GSK. Professor Fassihi and Dr Mooney were called by Apotex. Professor Tucker was called by Generic Partners. It is necessary to set out in a summary form at the outset some general observations on their background and my general perceptions of their evidence. This will inform the discussion which follows on the detailed technical issues.

(a)    Professor Dressman

234    Professor Jennifer B Dressman completed her PhD in pharmaceutical chemistry in 1981 from the University of Kansas. She is a Professor of Pharmaceutical Technology and Director of the Institute of Pharmaceutical Technology at Johann Wolfgang Goethe University in Frankfurt, Germany. Prior to joining the University in 1994, Professor Dressman had been Associate Professor of Pharmaceutics at the University of Michigan and had also held various industry positions as a research chemist. She has published extensively in the field of pharmaceutical science including peer-reviewed articles, monographs, books and patents.

235    Professor Dressman is a talented and experienced dissolution expert with an extensive academic and practical background. More particularly, Professor Dressman had extensive practical knowledge and experience (both pre and post priority date) in conducting dissolution testing generally and using the USP type III apparatus. She also had considerable knowledge of and experience in dealing with sustained release oral dosage forms containing HPMC.

236    Professor Dressman’s evidence was neither selective nor given as an advocate for the party calling her. Moreover, she was able to answer detailed questions about dissolution testing and scientific publications without the need to constantly refresh her memory. Plainly she had the relevant technical knowledge at her fingertips and her technical literacy and conceptual understanding were impressive.

(b)    Professor Davies

237    Professor Martyn Christopher Davies received his PhD for a thesis on aqueous film coatings in 1985 from what is now King’s College London. He was appointed in that year to a lectureship position at the University of Nottingham where he taught and still teaches pharmaceutical technologies. In 1996 he became Professor of Biomedical Surface Chemistry at that University. Professor Davies also co-founded a company in 1997 through which he provides pharmaceutical development and formulation characterisation services. He has also authored over 380 peer-reviewed papers and book chapters.

238    Professor Davies is a person skilled in the art of formulation. He is also a highly qualified academic with practical experience with HPMC and in formulating oral dosage forms containing HPMC.

(c)    Dr Mooney

239    Dr Brett Antony Mooney obtained his PhD in synthetic organic chemistry in 1980 from the University of Adelaide. He has held a number of positions as a research and development chemist including as director of research and development at Alphapharm. Throughout his career he has been involved in the formulation of 130 oral solid dosage forms involving 150 drug substances. He is currently a consultant and director at BM Pharma Consulting Pty Ltd, a company he founded in December 2012 to provide advice in respect of oral solid dosage formulation and development.

240    Dr Mooney is an experienced and clever formulator. For most of the last 30 years he has been a successful formulator of generic drugs for Alphapharm. Dr Mooney gave evidence primarily on the issue of inventive step but he also expressed views on the question of matrix forming polymers.

241    GSK contended that Dr Mooney’s inventive nature and cleverness was well apparent when he was looking at the 522 and 194 Patents in the context of solving the problem articulated in the development brief. I am inclined to agree and I will elaborate on this later.

242    Dr Mooney’s formulation experience was gained in the context of making generic versions of innovator products. Moreover, as at 2000 he had no personal experience in formulating capsules using beads or pellets or with bilayer tablets. Generally, his only experience in making a sustained release product was making a generic version of a corresponding sustained release dosage form already on the market. He had never sought to create a completely new sustained release dosage form where he did not have access to another one already on the market. These matters justify circumspection in the weight to be given to some of his evidence.

243    Further, although Dr Mooney was familiar with looking at the results produced from dissolution testing using USP I and II type apparatus, he did not personally carry out such dissolution testing. Dr Mooney had no experience with dissolution testing conducted using the USP type III apparatus prior to 2000. Moreover, his employer, Alphapharm, did not have a USP type III apparatus at that time.

(d)    Professor Fassihi

244    Professor Alireza Fassihi Dehkordi obtained his PhD in pharmaceutics in 1978 from Brighton University in England. Since 1986 he has been a consultant to pharmaceutical companies in South Africa, the United Kingdom and the USA on dissolution testing and manufacturing. In 1992 he became Professor of Biopharmaceutics and Industrial Pharmacy at Temple University in Philadelphia where he teaches pharmaceutical manufacturing and biopharmaceutics. Since 1994 he has also been a consultant to the United States Food and Drug Administration. He has published over 130 peer-reviewed papers. He uses Fassihi rather than Dehkordi for his surname.

245    Professor Fassihi’s area of expertise was in dissolution testing.

246    I must say at this point that it became apparent during the oral evidence that Professors Dressman and Fassihi were the only experts with any practical knowledge and experience of conducting dissolution testing particularly using the USP type III apparatus.

247    I agree with GSK that Professor Fassihi had a tendency to argue the case. A good example of such a tendency was his attempt to hold the patentee to a higher level of disclosure than he adopted in his own peer reviewed publications and in his own patent. In his written evidence, Professor Fassihi emphasised that without information as to inter alia the mesh material, the mesh size and the mesh placement, there was insufficient detail in the description of the dissolution test in the Patent for him to reproduce it. Contrastingly, in his own peer reviewed publications and patent, Professor Fassihi omitted parameters of the type for which he criticised the omission by the patentee. Each of Professor Fassihi’s papers (Pillay and Fassihi, “In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract” Journal of Controlled Release 59 (1999) 229; Pillay and Fassihi, “In situ electrolyte interactions in a disk-compressed configuration system for up-curving and constant drug delivery” Journal of Controlled Release 67 (2000) 55; and Missaghi and Fassihi, “Release characterization of dimenhydrinate from an eroding and swelling matrix: selection of appropriate dissolution apparatus” International Journal of Pharmaceutics 293 (2005) 35) omitted details of the mesh size, mesh material and mesh placement in the descriptions of the dissolution tests using USP type III apparatus carried out. Professor Fassihi sought to justify the absence of details of mesh size in a number of ways: first, by asserting that he had always used size 20; second, by suggesting that reference could be had to the USP type I apparatus prescribed mesh sizes (20 and 40); and third, by asserting that it was not necessary to specify mesh size because “the editors, the reviewers, they were all familiar with my work”. Professor Fassihi then sought to justify the discrepancy between the levels of parameter detail given in his own articles and what should have been provided in the Patent by saying that a patent was not a peer reviewed publication. But his attempt to argue that patents should be held to a higher degree of disclosure than peer reviewed publications was doubtful given that his own patent (United States patent number 6,090,411 for a monolithic tablet for controlled drug release), like his articles, did not include any details of mesh size, mesh material or mesh placement. Apotex has asserted that the context of these papers was different and that “the reader would understand that the dissolution tests had been conducted using identical equipment, such that ‘like’ was being compared with ‘like’ …”. I am not convinced that this is a sufficient answer. Persons reading this literature might want to try and duplicate the results. It is apparent to me that, anomalously, the disclosures he made in his own publications did not meet his asserted threshold for the disclosure of the equipment and the parameters that he now asserts ought to have been made in the Patent. Yet skilled readers of his papers would have also needed sufficient disclosure in order to duplicate the results published in his literature. I must say that I have been a little sceptical of Professor Fassihi’s evidence on this issue.

248    More generally, I am concerned with other aspects of his evidence. On several occasions he sought to maintain problematic positions in the face of contrary documentary evidence. First, he refused to concede that the appendices to the Gray article were compendial (Gray, V A “Drug Release Calibrators for Apparatus 3 — Collaborative Study Results” Pharmacopeial Forum 20(1) Jan. to Feb. 1994, 6934); in my view there was no good reason to consider them to be anything other than compendial. Second, he sought to read “a selected row of vessels” as meaning all six rows of the USP type III apparatus:

MS ROFE: I suggest to you that you read that as a selected row of vessels and you use one row of them? --- Each vessel of selected rows. That means, whatever number of rows that you like to select. Generally there are, I think, seven or eight rows but you have to — depending on what conditions you want to use. Here they are using water, so they can have one row, two row, three rows. They can select, yes.

HIS HONOUR: It does say, Professor, “a selected row”. It doesn’t say “selected rows”. It says “a selected row” which suggests it’s in the singular. And you’re not changing the pH, so why would you have multiple rows? --- That is correct, yes. That could be the case here, yes. It could be one row, yes.

Third, he sought to maintain his position that a top mesh was essential in the face of USP documents showing an absence of a top mesh. Fourth, he refused to accept Professor Dressman’s solubility figures (20 to 23.7 mg/ml), notwithstanding that they were sourced from the peer reviewed literature published over several decades, for the solubility of paracetamol. Indeed and contrary to the other experts and the peer-reviewed literature cited by Professor Dressman, he sought to suggest that the solubility figure would vary according to polymorphs and particle size. Relatedly, he sought to depart from his and Professor Tucker’s evidence in the JER as to the relevant solubility being equilibrium solubility. I also enquired:

HIS HONOUR: Except, though, that all of the literature seems to be arranged at most between 20 and 23.7 milligrams a millilitre. So there seems to be general consensus on that as being the figure for 37 degrees Celsius. Or is that not how I should read this material? --- Again, your Honour, this is equilibrium solubility.

Yes? --- This is a little bit — you know, with this one — that’s why I’m saying that as a scientist, dissolution rate — rate is a dynamic phenomenon. This solubility is a static value. So if you’re measuring dissolution rate, of course, you need to be more careful.

Apotex has said that this factual issue did not relate to any “live issue”. I am not so sure, except that equilibrium solubility appeared to be agreed. Professor Fassihi seemed to seek to confuse this question with dynamic concepts that added little to the debate and in a manner I found unhelpful. Fifth, he raised for the first time in the JER the “percolation theory” that related to the use of HPMC in dosage forms that release active pharmaceutical ingredients over a period of 10 to 24 hours. Again, this was hardly of assistance to the issues in the case.

249    Professor Fassihi also found it difficult to give responsive answers to questions.

250    Further, another noticeable matter was Professor Fassihi’s need to frequently refresh his memory as to the contents of his own papers and those discussed in his affidavit. As I perceived it, this was not simply a manifestation of the usual caution to be expected from an expert witness seeking to be precise and accurate. To use the language submitted by GSK, it suggested that the dissolution issues on which he gave evidence were “not part of the working furniture of his mind central to his accumulated expertise”. The following was a typical example:

HIS HONOUR: Well, let’s take your own articles? --- All of them, they had sink conditions definitely, yes.

Do you report separately on equilibrium solubility, or dynamics or rates of solubility, as being a relevant metric? --- I don’t recall, your Honour, what I have said in there, but we definitely have done the calculation of sink conditions.

251    Generally, I have exercised caution in placing significant weight on his evidence concerning the use of the USP type III apparatus. To the extent that Professor Fassihi’s evidence differs from that of either Professor Dressman or Professor Davies on this topic, I am inclined to prefer the evidence of Professors Dressman and Davies.

252    Of course I accept that I should exercise caution in expressing observations on the reliability of evidence concerning expert witnesses. Nevertheless, where conflicting expert opinions have been expressed, I am bound to resolve any conflict where it goes to an issue in the case and to explain my reasons for preferring one view over another. After all, that is one of the tasks of a working trial judge mining facts from the coal face of forensic inquiry.

(e)    Professor Tucker

253    Professor Ian Tucker obtained his PhD in pharmaceutical sciences in 1980 from the University of Queensland. In 1991, he was appointed Professor of Pharmaceutical Sciences at Otago University in New Zealand. He was the Dean of the School of Pharmacy at the University from 1999 to 2010. Since 2011, he has been the Associate Dean (Research Commercialisation) for the Division of Health Sciences at the University. Professor Tucker has also consulted to the pharmaceutical industry in relation to formulation development. He has published 161 peer-reviewed research articles.

254    Professor Tucker gave evidence on all issues in the proceeding including matters related to the conduct of dissolution tests. He gave particular evidence concerning the use of the USP type III apparatus and the choice of mesh size. He also gave evidence concerning oral dosage forms which included using HPMC. I must say at the outset, ceteris paribus, that given the breadth of the areas that he covered, the weight of his evidence in any one area was more difficult to justify as carrying the same (let alone greater) weight than the weight of evidence given by a more specialised expert in that area. For example, his evidence on dissolution testing and equipment carried less force with me than the evidence of Professor Dressman on that topic who had a more specialised focus.

255    Let me also say that, in my view, Professor Tucker in some aspects did not read the Patent in a practical and preferable fashion. In some aspects he read the Patent with a sceptical and critical eye and through a lens distorted such as to cast doubt upon the clarity and scope of the claimed invention. Further, he applied the same approach to articles relied upon by GSK and its experts. For example, when taken to Cao et al “Formulation, release characteristics and bioavailability of novel monolithic hydroxypropylmethylcellulose matrix tablets containing acetaminophen” Journal of Controlled Release 108 (2005) 351, the following exchange occurred during cross-examination:

MR SHAVIN: Yes. At the moment I’m asking you to take this paper simply as a peer review paper as if you were reading it as part of the literature that you’re reading.

HIS HONOUR: Well, putting it another way, take it at face value and assume that they’ve carried out properly conducted experiments and — do you follow what I mean? --- Yes.

In other words, you seem to be wanting to ---? --- Your Honour, I ---

--- find something missing or ---? --- I’m sorry, your Honour. I read scientific papers with a very critical and a very sceptical eye because there’s much in the literature which is not right and, therefore, I read it carefully. So I’m not trying to find holes here. If I’m going to be asked about water uptake, I need to know that that paper there, 13, has done it properly. That they’ve allowed for the loss of paracetamol from the tablet. I’ve done these water uptake studies myself.

256    Contrastingly, and as GSK has pointed out, Professor Tucker did not exercise the same critical approach to other evidence in support of the respondents’ case. For example, his hypothetical H2 “thought experiment” relied upon an uncritical reading of the unpublished paper T J Grattan et al “The use of in vitro – in vivo correlation to develop a sustained release formulation of paracetamol with a predefined plasma concentration-time profile: A report on a step-by-step progression” May 2000.

257    Professor Tucker’s approach to the Patent and its construction was typified by his extensive exploration of all the theoretical linguistic ways in which the word “after” in claim 1 could be construed. His construction was not constrained by practicality let alone by how a person skilled in the art would construe the specification.

258    Professor Tucker’s detailed exploration in his first affidavit of “after” included various figures that depicted sharp vertical jumps in release at various time points. But he neglected to explain that he never actually anticipated such sharp vertical jumps. Ultimately he agreed with the other experts in the JER that the releases he depicted were only achievable with systems consistent with dosage forms that were not contemplated in the Patent.

259    In the JER, Professor Tucker agreed with the other experts that “released after” meant “released at”:

… within the context of the patent we anticipate the profiles would be smooth curves which must fit within the boundaries specified in the patent. The reason we think this is that the patent does not mention pulsatile or coated systems which would be necessary for achieving the limits in Figure 10 of Tucker’s June affidavit.

260    Further, Professor Tucker sought to justify a greater level of disclosure from the patentee than in his own peer reviewed scientific articles. But in Krajacic and Tucker, “Matrix formation in sustained release tablets: possible mechanism of dose dumping” International Journal of Pharmaceutics 251 (2003) 67 there was no identification of sampling volume, sampling point or discussion of sample replacement. I refer to what I said earlier concerning Professor Fassihi’s evidence and a similar disconformity between his criticisms of the disclosures in the Patent and his own publications.

261    Further, some of Professor Tucker’s evidence was in the nature of a thought experiment; I do not mean by the use of that phrase the description given to the highly intellectual conceptualisations of a theoretical physicist. Further, some of his evidence was speculation based upon only his reading done in preparation for his evidence in this case rather than his existing knowledge or experience. Professor Tucker lacked hard-edged experience in the formulation of oral dosage forms containing HPMC and dissolution testing using the USP type III apparatus. Nevertheless, this did not constrain him from speculating broadly in these areas. Let me elaborate further on these aspects.

262    Professor Tucker expressed opinions on matters relating to HPMC and matrix forming polymers including HPMC and the formulation of HPMC containing oral dosage forms. As I say, he had little direct experience of such matters. He agreed that with respect to HPMC his opinions were principally derived from materials he had read for the purpose of this litigation. Prior to 2000 he had not published any research about the formulation of solid dosage forms. Moreover, his research had not concentrated on the application of HPMC in solid oral dosage forms; his work concerning analysing the release of sodium salicylate from HPMC matrices had little relevance. Further, he had not done any practical work on gel formed by HPMC and had not undertaken any research on the proportions of gel in relatively shorter acting extended release formulations as compared with longer acting extended release dosage forms with release over 24 hours.

263    Further, Professor Tucker expressed views on various matters relating to dissolution testing using USP type III apparatus. But Professor Tucker’s first affidavit referred only to his experience with USP type I and II apparatus. In his second affidavit, Professor Tucker suggested that he was familiar with how the USP type III apparatus worked because as he described it:

the School of Pharmacy at the University of Otago has a USP Type III apparatus and I supervised students using it before 2000.

264    But under cross-examination, it was apparent that as at the priority date, Professor Tucker had no direct experience using the USP type III apparatus in the course of his work. By reason of his position as Dean from 1999 to 2000, Professor Tucker’s teaching responsibilities during that time were very limited. Further, under cross-examination, his statement that he “supervised students” evolved into “supervision in the lab occasionally”. When pressed, this turned out to be one doctoral student who had used the USP type III apparatus in her work in Croatia before she came to the University of Otago. Moreover, that student did not go on to use the USP type III apparatus under his supervision at Otago. Further, and more generally, Professor Tucker agreed that a study of the USP type III apparatus and how it was described was not part of the skill set that he possessed as at 2000. He had not himself used the USP type III apparatus before or after the priority date. The set up of the USP type III apparatus in Professor Tucker’s department was done by other people. It also follows that he was not the person making decisions as to mesh size to be used in the USP type III apparatus as at the priority date or thereafter. Generally, he had no cause (prior to giving evidence in the present proceedings) to consider appropriate mesh size for use with the USP type III apparatus or to study its effect on the relevant hydrodynamics. Further, he was not familiar with the common literature on the USP type III apparatus as at the priority date.

265    GSK made the submission that in the areas that I have identified above, Professor Tucker was not qualified as a witness with “specialised knowledge” based on “training, study or experience” for the purposes of giving admissible opinion evidence under s 79(1) of the Evidence Act 1995 (Cth). It was said that his opinions on these issues were not based on his specialised knowledge. Accordingly, it was said that his evidence on these matters was inadmissible. But in my opinion Professor Tucker was at least formally qualified to express opinions on dissolution testing and dosage forms, notwithstanding that he lacked direct experience in the areas indicated. Accordingly his opinions are admissible under s 79 and I have treated them accordingly. Nevertheless, it is appropriate to observe that, in the circumstances, I have given his opinions on the following topics reduced weight:

(a)    HPMC and matrix forming polymers;

(b)    the formulation of oral dosage forms containing HPMC;

(c)    the practicalities of dissolution testing such as the selection of appropriate mesh size, material and mesh placement in dissolution testing using the USP type III apparatus; and

(d)    the terms used by persons skilled in the art to describe the USP type III apparatus and how they would understand the reference to “basket” in claim 1.

266    On such topics, the evidence of Professor Dressman and Professor Davies has carried greater weight and has been more persuasive because of their more targeted knowledge and expertise in these areas. Professor Fassihi’s evidence has been given diminished weight for the reasons that I have indicated.

principles of CONSTRUCTION

267    The principles of law governing the construction of patent specifications, including claims, are well established. I adopt the principles that I set out in Streetworx Pty Ltd v Artcraft Urban Group Pty Ltd (2014) 110 IPR 82 at [58] to [68]. For convenience I have reproduced them in what follows in this section. But I should say at the outset that the principles I have set out below are subject to the boundary constraint that they cannot be used to justify re-writing a claim or amending a mistake in an essential integer. After all, these principles have been developed to construe what is, rather than to construe what should have been. I will elaborate on this boundary constraint in a separate part of my reasons when discussing the construction of claim 1 and the dissolution testing apparatus description.

268    The proper construction of a claim is a question of law.

269    A claim is construed from the perspective of a person skilled in the relevant art as to how such a person would have understood the patentee to be using the words of the claim in the context in which they appear. Further, a claim is to be construed in the light of the common general knowledge including the art before the priority date.

270    A measure of common sense should be used. Further, ordinary words should be given their ordinary meaning unless a person skilled in the art would give them a technical meaning or the specification ascribes a special meaning (Kimberly-Clark Australia Pty Ltd v Multigate Medical Products Pty Ltd (2011) 92 IPR 21 at [39] per Greenwood and Nicholas JJ).

271    In terms of how the body of the specification may be used in construing a claim:

(a)    The claim should be construed in the context of the specification as a whole even if there is no apparent ambiguity in the claim (Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 at 616);

(b)    Nevertheless, it is not legitimate to narrow or expand the boundaries of the monopoly as fixed by the words of a claim by adding to these words glosses drawn from other parts of the specification (Jupiters Ltd v Neurizon Pty Ltd (2005) 65 IPR 86 at [67]; Kinabalu Investments Pty Ltd v Barron & Rawson Pty Ltd [2008] FCAFC 178 at [44]); and

(c)    More particularly, if a claim is clear and unambiguous, to say that it is to be read in the context of the specification as a whole does not justify it being varied or made obscure by statements found in other parts of the specification.

272    Now the specification may stipulate the problem in the art before the priority date and the objects of the invention that are designed to address or ameliorate this. The specified objects may be useful in construing a claim in context. Further, the specified objects may be useful in considering any lack of utility argument (now abandoned by the respondents in the present case). Nevertheless, the specified objects are not controlling in terms of construing a claim; glosses cannot be drawn from the objects.

273    A claim should be given a “purposive” construction. To elaborate, words should be read in their proper context. Further, a too technical or narrow construction should be avoided. Further, the integers of a claim should not be considered individually and in isolation. Further, a construction according to which the invention will work is to be preferred to one in which it may not (Pfizer Overseas Pharmaceuticals v Eli Lilly & Co (2005) 68 IPR 1 at [250]). But to give a claim a “purposive” construction “does not involve extending or going beyond the definition of the technical matter for which the patentee seeks protection in the claims” (Sachtler GmbH & Co KG v RE Miller Pty Ltd (2005) 221 ALR 373 at [42] per Bennett J). To apply a “purposive” construction does not justify extending the patentee’s monopoly to the “ideas” disclosed in the specification (GlaxoSmithKline Australia Pty Ltd v Reckitt Benckiser Healthcare (UK) Ltd (2013) 305 ALR 363 at [60]).

274    I also adopt what was said in Artcraft Urban Group Pty Ltd v Streetworx Pty Ltd [2016] FCAFC 29 at [72] to [78] per Greenwood J (agreed to by Rares J at [142], [145] and [146]):

As already mentioned, s 40 of the Act provides that a complete specification for an invention must describe the invention fully including the best method known to the applicant of performing the invention and, so far as an application for an innovation patent is concerned, it must end with at least one claim (and no more than five claims) defining the invention.

In order to ascertain the invention “described and claimed”, it is necessary to refer to the specification as a whole. That was the course Menzies J took in Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 at p 593 (“Welch Perrin v Worrel”). On appeal, Dixon CJ, Kitto and Windeyer JJ also observed at p 610 that the specification must be read as a whole and further observed that “[i]f it is impossible to ascertain what the invention is from a fair reading of the specification as a whole that, of course, is an end of the matter”.

The complete specification, which includes both the body and the claims (see Kimberley-Clark Australia Pty Limited v Arico Trading International Pty Limited and Others (2001) 207 CLR 1 at [14], per Gleeson CJ, McHugh, Gummow, Hayne and Callinan JJ), must be construed in the light of the common knowledge in the art before the priority date and must not be read in the abstract. The Court must place itself in the position of some person acquainted with the surrounding circumstances as to the state of the art and manufacture at the relevant time: Kimberley-Clark Australia Pty Limited v Arico Trading International Pty Limited and Others at [24], per Gleeson CJ, McHugh, Gummow, Hayne and Callinan JJ.

Because the patent instrument is not a document operating inter-parties, but rather a public instrument, it must define the monopoly in such a way that it is not reasonably capable of being misunderstood. Even though the specification must be read as a whole, it is necessarily made up of parts which have different functions. It is not legitimate to narrow or expand the boundaries of the monopoly, as defined by the claims, by adding to the language of the claims, glosses drawn from other parts of the specification. Further, if the language of a claim is clear, it is not to be rendered obscure simply because obscurities can be found in particular sentences in parts of the specification: Welch Perrin v Worrel at p 610, Dixon CJ, Kitto and Windeyer JJ.

A proper analysis of the specification may show that references to a particular embodiment are by way of “illustration and explanation of the invention” rather than a “definition of it”: Welch Perrin v Worrel at p 612, Dixon CJ, Kitto and Windeyer JJ.

In Interlego A.G. v Toltoys Pty Ltd (1973) 130 CLR 461 at p 477, Barwick CJ and Mason J approached the construction of the claims and identification of the invention by reading the specification as a whole. Their Honours observed at p 478, in the circumstances of the questions in issue in that case, that it would be unlikely that anyone would conclude on reading the specification as a whole that the invention “as described makes claim to a method of assembly” of a particular kind. Their Honours observed, however, adopting the propositions derived from Welch Perrin v Worrel (described at [75] of these reasons) that the settled rule is that in ascertaining the width of a particular claim (that is, the construction to be attributed to the words defining the monopoly), it is not permissible to vary or qualify the “plain and unambiguous meaning of the claim” by reference to the body of the specification.

However, the rational starting point is not to simply turn to the language of the claims and seek to attribute meaning to those words in the abstract. The body of the specification and the claims must be read together as a whole in an attempt to identify the invention and determine whether the meaning of the words used in the claim (that is, the construction of the claim in question) is truly “plain and unambiguous”. If, having examined the s 40(2)(a) description of the invention in the body of the specification and the s 40(2)(b) definition of the claims, an expression used in the claims is not clear, it is then permissible to return to the body of the specification to either “define or clarify” the meaning of words used in the claim (see Interlego A.G. v Toltoys Pty Ltd, p 479 per Barwick CJ and Mason J) without infringing the rule that clear and unambiguous words in the claim cannot be varied or qualified by reference to the body of the specification. See also, to the same effect, Kimberley-Clark Australia Pty Limited v Arico Trading International Pty Limited and Others at [15], per Gleeson CJ, McHugh, Gummow, Hayne and Callinan JJ.

275    How the stipulation of preferred embodiments interacts with questions of construction has also been analysed by Jessup J in Artcraft Urban Group at [181] to [186]. Further, I would also refer to Lord Hoffmann’s observations in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2005] RPC 169 at [27] to [34] concerning a purposive approach to construction.

276    A claim is to be construed from the perspective of how a person skilled in the art would have understood the patentee to be using the words, informed by the notional skilled addressee’s general knowledge and what has been disclosed in the specification. But to consider such a perspective does not entail that the Court necessarily requires expert evidence to assist on construction. If it is clear that the claims are to be read according to their ordinary meaning with no special meaning given to any word or phrase, if the science or technical issues are easily comprehensible and if, more generally, the Court does not require expert assistance in understanding the context of the claims, then expert evidence on construction may not only be unnecessary, but unhelpful and distracting. The nature and complexity of the patent in suit and the issues raised will determine the utility or necessity for expert evidence on construction. But to say that expert evidence may not be required on construction does not entail that expert evidence may not in any event still be required on other issues such as novelty or innovative step, even if not necessary on construction per se.

277    The Court is to place itself in the position of a person acquainted with the state of the art and manufacture prior to the priority date. In terms of the skilled addressee, one is using a hypothetical construct. The following principles are applicable:

(a)    First, to identify the characteristics of the skilled addressee, the field to which the invention relates must be identified.

(b)    Second, the skilled addressee is taken to be a person of ordinary skill (as opposed to a leading expert) in that field and equipped with the relevant common general knowledge including the art before the priority date (Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253 at 293; Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1 at [24]).

(c)    Third, the qualifications and experience of the skilled addressee will depend on the particular case, having regard to the nature of the invention and the relevant industry. Formal qualifications are not essential. Practical skill and experience in the field may suffice. A patent specification is addressed to those having a practical interest in the subject matter of the invention; such persons are those with practical knowledge and experience of the kind of work in which the invention is intended to be used.

(d)    Fourth, the hypothetical person skilled in the art may possess an amalgam of attributes drawn from a team of persons whose combined skills, even if disparate, would normally be employed in interpreting and carrying into effect instructions such as those contained in the specification.

(e)    Fifth, as the skilled addressee comes to a reading of the specification with the common general knowledge of persons skilled in the relevant art, they read it knowing that its purpose is to describe and demarcate an invention. But the person skilled in the art is not particularly imaginative or inventive.

(f)    Sixth, the skilled addressee does not come to reading the specification seeking failure.

278    Generally, the Court is to place itself in the position of such a skilled addressee, using such expert evidence that is of assistance to the construction task.

279    As I have said, the legal construct may not be a single person but may be a team of persons whose combined skills would normally be employed in that art in interpreting and carrying into effect instructions such as those contained in the Patent. Where the art is a highly developed technology such as pharmaceutical science and the development and use of formulations, the hypothetical skilled addressee may be a team whose combined skills would normally be employed in that art in interpreting and carrying into effect instructions such as those which are contained in the Patent.

280    In the present case, the Patent is addressed essentially to a pharmaceutical formulator being a member of the wider R&D team that includes people with expertise in medicinal chemistry, analytical chemistry and in the field of pharmacokinetics, together with experience in pharmaceutical formulation development. The formulator would normally be educated to PhD level and have two to three years’ post-doctoral expertise. Alternatively, the formulator may not have a doctorate but would have five or more years’ experience working within the pharmaceutical industry and either an undergraduate or masters degree. In this case, a formulator would work with and seek guidance from a scientist with particular expertise in the dissolution testing of extended release oral dosage forms using USP apparatus, in particular the USP type III, to carry out the claimed invention.

Construction of claims 1 to 3: usp type iii apparatus

281    Apotex has contended that there are two alternative constructions of the words in claim 1 “the USP type III apparatus, reciprocating basket” being that the words:

(a)    describe the USP type III apparatus modified to use a reciprocating basket instead of a reciprocating cylinder;

(b)    alternatively, describe the USP type III apparatus where the word “basket” is erroneous and should read “cylinder”.

282    It contends that the first construction gives the words used a sensible construction that is supported by Professors Fassihi and Tucker and by Dr Mooney. It contends that adopting the second construction would involve the Court concluding instead that GSK made an error, the contention of GSK. In summary, in my view a mistake was made and the skilled addressee would so construe the relevant integer of claim 1.

283    Let me make several points at the outset on the mistake alternative. First, I accept that the cause of any mistake on the part of GSK is irrelevant. That is not the correct focus. Second, as Apotex rightly points out, GSK could have sought to amend the Patent to correct the mistake. But it has not done so, no doubt for what it perceives to be good reason. Third, and relatedly, the fact that the skilled addressee would so construe the relevant reference in claim 1 does not justify me in re-writing or in essence amending claim 1.

284    As to whether a mistake was made, Apotex contends that a conclusion that there is a mistake in the Patent should not readily be drawn for the following reasons in substance:

(a)    First, it says that there are various factual considerations that mean that the use of a reciprocating basket makes practical sense. Modifications to USP apparatus were well known; indeed there had been a “proliferation” of such apparatus before the priority date. The word “basket” describes a known USP part (being a basket used with a USP type I apparatus). Further, attaching a USP basket to a USP type III apparatus was possible, and there would be practical reasons for doing so.

(b)    Second, it says that there is nothing in the Patent itself including its repeated references to “reciprocating basket” that provides any support for the existence of a mistake.

(c)    Third, it says that the language of the Patent being “words of the patentee’s own choosing” is to be construed more strictly than a document operating inter partes such as a contract. This means, so it is said, that I should be slow to construe a word in a claim as being erroneous, particularly when that word has been used by the patentee six times to describe the apparatus.

(d)    Fourth, Apotex contends that the evidence suggests that an error was not made. It has referred to the fact that GSK by its legal representatives in a 7 May 2015 letter said that the words “reciprocating basket” were “synonymous” with “reciprocating cylinder”. Apotex asserts that I should assume that this explanation was given on instructions from GSK. I think that the reference to this letter is a jury point and a distraction. I have put it to one side.

285    In summary, and notwithstanding Apotex’s submissions, I have concluded that an error was made and that the skilled addressee would so construe claim 1. But as I have said, this does not avail GSK for reasons that I will later explain.

(a)    The Patent and the USP

286    Before proceeding further it is appropriate to make some preliminary observations concerning the Patent and the USP. I should also say for completeness that although the specification has been amended in some aspects, I have taken the approach of reading the specification as if the amended language had been originally included in the specification.

The specification

287    Claim 1 uses the description “as determined by the USP type III apparatus, reciprocating basket”. Parameters are set for the dissolution medium (0.1M HCl), the temperature (37°C) and the cycle speed (15 strokes per minute).

288    As to the body of the specification, there is no express reference, apart from the word “basket”, to a non-compendial apparatus being used. At various points in the specification there is just repeated the phrase I have set out earlier, with no other elaboration; see for example p 4a (amended page, 4 September 2006) lines 3 and 4, lines 14 and 15, p 10 lines 1 and 2 (“the USP type III apparatus (reciprocating basket) …”), p 12 at foot (“the USP type III apparatus (reciprocating basket) …”), and p 15 lines 20 and 21 (“the USP type III apparatus (reciprocating basket) …”).

289    Indeed, the specification and claim 1 use the definite article “the USP type III apparatus”. One might have expected that if a non-compendial form was intended to be referred to that the indefinite article would have been used, so as to refer to “a USP type III apparatus”.

290    What also should be noted is that in some parts of the specification, the words “reciprocating basket” have been bracketed after the phrase “the USP type III apparatus”, perhaps suggesting that only an elaboration was being included rather than a non-compendial operation.

291    It is also to be noted that reference is made to a “reciprocating basket”. The word “reciprocating” is, of course, different to “rotating”. The latter refers to uniform circular motion about a centre or axis. The former refers, in this context, to an alternation or oscillation in movement or action; in the present case an up and down movement at a uniform speed. As at the priority date, and as I have found (as I will subsequently explain), part of common general knowledge was an understanding that when one was using a basket for compendial USP apparatus, one was contemplating a rotating basket (USP type I apparatus). The phrase “reciprocating basket” would either jar with the skilled addressee as being an incorrect reference or be taken as a reference to something non-compendial. I will return to this subject later.

292    It is also to be noted that there is no detail in the specification for the “basket” in terms of shape, size or material of manufacture (cf the detail given for a USP type I apparatus). The absence of such detail may possibly lead the skilled reader to the conclusion that the reference to “basket” was a mistake, although it may also be said that the reader, in the absence of any detail for “basket”, might simply conclude that what was intended was a “basket” with the parameters as set out for the USP type I apparatus.

The United States Pharmacopeia

293    Let me begin with USP 23 NF 18. This applied from 1 January 1995. It was superseded by USP 24 NF 19, which applied from 1 January 2000, and which I have referred to as the USP.

294    In both USP 23 NF 18 and the USP, the following may be noted:

(a)    In section 711, there is a discussion of dissolution. There is a description of type I apparatus and type II apparatus.

(b)    The description of type I apparatus refers to a cylindrical basket. The basket is to be fabricated of stainless steel to the specifications shown in figure 1. It is stated that unless otherwise specified in the individual monograph, use 40 mesh cloth. It is also said that a basket having a gold coating may be used. Further, there is a specification for the distance between the inside bottom of the vessel and the basket.

(c)    Figure 1 is shown as follows:

(d)    There is also in section 711 a reference to type II apparatus, being the paddle. I do not need to discuss this further for the moment.

295    In both USP 23 NF 18 and the USP there is a further section 724 headed “Drug Release”. It is to be noted that some aspects of the setting out in USP 23 NF 18 were then altered in the USP. For example:

(a)    In USP 23 NF 18, reference is made to types I and II apparatus before the heading “Extended-release Articles — General Drug Release Standard”. Type III apparatus is discussed under that heading. Contrastingly, in the USP, the heading appears before types I and II apparatus. There are also other textual differences concerning what is discussed under the heading type I apparatus and type II apparatus.

(b)    In USP 23 NF 18 and the USP the headings differ. In USP 23 NF 18, the heading is “Apparatus 3 — ”. In the USP, the heading is “Apparatus 3 (Reciprocating Cylinder)”. That heading accentuates the principal mechanism and difference as compared with types I and II apparatus, namely, a “Reciprocating Cylinder”.

296    It is appropriate to set out fully what is said concerning type III apparatus in the USP:

Apparatus 3 (Reciprocating Cylinder)

Apparatus — The assembly consists of a set of cylindrical, flat-bottomed glass vessels; a set of glass reciprocating cylinders; stainless steel fittings (type 316 or equivalent) and screens that are made of suitable nonsorbing and nonreactive material and that are designed to fit the tops and bottoms of the reciprocating cylinders; and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels and, if desired, index the reciprocating cylinders horizontally to a different row of vessels. The vessels are partially immersed in a suitable water bath of any convenient size that permits holding the temperature at 37 ± 0.5° during the test. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smooth, vertically reciprocating cylinder. A device is used that allows the reciprocation rate to be selected and maintained at the dip rate specified in the individual monograph, within ± 5%. An apparatus that permits observation of the specimens and reciprocating cylinders is preferable. The components conform to the dimensions shown in Figure 1 unless otherwise specified in the individual monograph.

Apparatus Suitability Test — Individually test 1 tablet of the USP Drug Release Calibrator Tablets (Single Unit) and a specified amount of beads of the USP Drug Release Calibrator Beads (Multiple Unit) according to the operation conditions specified. The apparatus is suitable if the results obtained are within the acceptable range stated in the certificate for that calibrator in the apparatus tested.

Dissolution Medium — Proceed as directed under Dissolution (711).

Procedure — Place the stated volume of the Dissolution Medium in each vessel of the apparatus, assemble the apparatus, equilibrate the Dissolution Medium to 37 ± 0.5°, and remove the thermometer. Place 1 dosage-form unit in each of the six reciprocating cylinders, taking care to exclude air bubbles from the surface of each dosage-form unit, and immediately operate the apparatus as specified in the individual monograph. During the upward and downward stroke, the reciprocating cylinder moves through a total distance of 9.9 to 10.1 cm. Within the time interval specified, or at each of the times stated, raise the reciprocating cylinders and withdraw a portion of the solution under test from a zone midway between the surface of the Dissolution Medium and the bottom of each vessel. Perform the analysis as directed in the individual monograph. If necessary, repeat the test with additional dosage-form units.

Where capsule shells interfere with the analysis, remove the contents of not less than 6 capsules as completely as possible, and dissolve the empty capsule shells in the specified volume of Dissolution Medium. Perform the analysis as directed in the individual monograph. Make any necessary correction. Correction factors greater than 25% of the labeled content are unacceptable.

Time and Interpretation — Proceed as directed under Apparatus 1 and 2.

297    I should note here a number of features. First, there is a reference to a top mesh and a bottom mesh. Second, there are only references to cylinders. There is no reference to baskets. Third, there is reference to withdrawing “a portion of the solution under test from a zone midway between the surface of the dissolution medium and the bottom of each vessel”. There is no specification for mesh size (cf the description for type I apparatus). Perhaps it might be inferred from its absence that, given the different mechanism (as compared with a rotating basket for type I apparatus), its specification was not as important.

(b)    Relevant common general knowledge

298    I accept that the following common general knowledge of a skilled addressee of the Patent provides relevant factual context for construing the claim 1 dissolution test. The following propositions in my view would have been common general knowledge at the priority date.

General principles of dissolution testing

299    Claim 1 specifies a dissolution test for the purpose of defining what falls within the statutory monopoly.

300    In developing an in vitro dissolution test, a person skilled in the art of dissolution profiling would seek to develop a test that was reproducible and had good discrimination such that results were sensitive to changes in the formulation.

301    For a sustained-release formulation, the dissolution levels would usually be tested at a number of specified time points to produce a dissolution profile. But the dissolution profile is not an absolute property of the formulation. It is measured differently depending on the equipment and testing parameters used.

USP apparatus

302    To assist with the issue of reproducibility, there was a range of standardised dissolution testing apparatus available for use. The USP stipulated standardised sets of apparatus.

303    Standardised equipment permitted a skilled person to measure the dissolution profile for a formulation using the same testing conditions as those used by the person who specified any applicable dissolution profile criteria for that formulation. This facilitated reproducibility.

304    In addition to deciding which of the USP apparatus to specify, there could be further specified:

(a)    the variables to use for the selected apparatus; and

(b)    whether any modifications to the apparatus were to be made.

305    The variables that one could specify for use with a selected USP type III apparatus included:

(a)    the type of dissolution medium (claim 1 of the Patent specified 0.1M HCl);

(b)    the volume of dissolution medium (claim 1 of the Patent specified 250ml); and

(c)    the speed of the moving component (in revolutions per minute for types I and II apparatus and strokes per minute for type III apparatus).

306    The skilled addressee would also have known that a change in any of these variables could have an impact upon the dissolution results that were measured.

Modifications to USP equipment

307    If one could not achieve a reproducible and discriminatory test method using standard USP apparatus, then one might explore using modifications to such equipment.

308    I accept that Professor Dressman, for example, was aware of the use prior to the priority date of modifications to USP equipment. She accepted that there had been use of such non-compendial apparatus before April 2000. She was familiar with the use of a “peak vessel” with the USP type II apparatus and a “stationary basket” with the USP type II apparatus. Moreover, Borst, I. et al “New and Extended Applications for USP Drug Release Apparatus 3” Dissolution Technologies (February 1997) 11 also revealed an early modification of the USP type III apparatus being a “specially designed and fabricated VanKel Type wider lower cap (Figure 6)”.

309    In relation to the question of a “basket” modification, I will deal with the VanKel documents and their relevance (if at all) separately.

The specification of the USP type III apparatus

310    As at April 2000, USP type I and USP type II apparatuses were more commonly used for conducting dissolution tests including for modified-release formulations.

311    The Guidance for Industry — Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations, U.S. Department of Health and Human Services, FDA, September 1997 indicated that USP type I and II apparatus were the preferred apparatus, particularly for tablets. USP type III apparatus was designed for use with dissolution media at different pH levels in order to simulate passage through the gastrointestinal tract. It was also recommended for use with beads. I interpolate here that Professor Dressman’s laboratory group only began using a USP type III apparatus in January 2000. I accept that the specification of a USP type III apparatus is an indication that a patentee had decided not to confine itself to the use of the more commonly used apparatus. Apotex has asserted that in those circumstances, the specification of a modification to the USP apparatus (as distinct from an error having been made) may be less surprising so far as the skilled addressee was concerned. But I consider Ms Goddard SC’s leveraged reasoning to push the envelope. That is a characterisation, not a criticism.

Use of a basket with the USP type III apparatus

312    Apotex has asserted that a basket as used with a USP type I apparatus would fit within a USP type III apparatus vessel and that this would have been known to the skilled addressee at the relevant time. I accept, as Apotex asserts, that the dimensions shown in the USP confirm that a USP type I apparatus basket would readily fit into a USP type III apparatus vessel and that this would have been known to the skilled addressee. This is because:

(a)    the outer diameter of the basket is 25.0mm ± 0.02mm;

(b)    the inner diameter of the USP type III apparatus vessel is 47 ± 1.4mm (and the outer diameter of a reciprocating cylinder is itself wider than a basket at 26mm);

(c)    the length of the basket is 37 ± 3mm; and

(d)    the length of the USP type III apparatus vessel is 180 ± 1mm (and the length of a reciprocating cylinder is longer than a basket at 100 ± 1mm).

313    Apotex asserts that the “basket adapter” product in the VanKel documents (I will deal with these in a moment) enabled a USP type I apparatus basket to be attached to the shaft of the USP type III apparatus. Apotex contends that the commercial availability of such a part, even if only available after the priority date, is evidence that supports the likelihood of a skilled addressee understanding such an arrangement to be practicable as at the priority date. Apotex also submits that the evidence shows that a suitable adapter was available at the priority date. For present purposes it is sufficient to say that I accept that it was part of common general knowledge as at the priority date that it may have been possible and potentially practicable to adapt USP type III apparatus to fit a basket (of the type used in USP type I apparatus) in substitute for a cylinder, but that as at the priority date it was not known that this had been done. I reject the assertion that it was common general knowledge that such an adapter was available at the priority date but I accept that it would have been known that one could have been made.

314    Apotex submits that a USP type III apparatus fitted with a basket instead of a cylinder would have had different hydrodynamics which were likely to be more aggressive. Apotex then asserts that one reason for the modification might have been to simulate the more aggressive conditions of the stomach. It is said that another reason might have been to prevent the tablet from adhering to the glass walls of the cylinder. I accept that these are all conjectured but realistic possibilities that would have been known by the skilled addressee. But I consider that the greater likelihood is that the skilled addressee would have perceived there to have been an error made.

The VanKel documents and their admissibility

315    Prior to seeing the VanKel documents, the evidence of both Professors Tucker and Fassihi was that they were unable to construe the dissolution test. But after seeing the documents, both came to the same construction as set out in [281(a)] above.