GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No 2) Ltd v Apotex Pty Ltd
[2016] FCA 608
•31 May 2016
FEDERAL COURT OF AUSTRALIA
GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No. 2) Limited v Apotex Pty Ltd [2016] FCA 608
File numbers: VID 571 of 2014
VID 638 of 2014Judge: BEACH J Date of judgment: 31 May 2016 Catchwords: PATENTS – paracetamol – bilayer tablets – sustained release and immediate release layers – unique in vitro paracetamol dissolution profiles – dissolution testing apparatus – construction of the claims – common general knowledge – meaning of “the USP type III apparatus, reciprocating basket” – whether “reciprocating basket” a mistake or error in the claims and specification – whether claims to be construed as “reciprocating cylinder” – whether effect of construction is to re-write or amend the claims – meaning of “matrix forming polymer” – alleged infringement – whether respondents’ products within claimed dissolution profile – whether respondents’ products contained matrix forming polymer within the claims – infringement not made out – whether second applicant an exclusive licensee of the patent
PATENTS – cross-claims for invalidity – alleged lack of fair basis – paracetamol content range – ratio of immediate release to sustained release – in vitro dissolution ranges – matrix forming polymer – alleged lack of sufficiency – matrix forming polymer – in vitro dissolution profile – apparatus – alleged lack of clarity – alleged failure to define the invention – alleged failure to describe the best method – high viscosity HPMC – granulation end point – alleged lack of inventive step – common general knowledge – impermissible use of hindsight – validity of the patent upheld
Legislation: Evidence Act 1995 (Cth) ss 48, 56, 57, 58, 135, 136, 183
Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth)
Patents Act 1990 (Cth) ss 3, 7, 13(2), 18(1)(b)(ii), 40(2)(a), 40(2)(b), 40(3), Sch 1
Patents Amendment Act 2001 (Cth)
Cases cited: Adhesives Pty Ltd v Aktieselskabet Dansk Gaerings-Industri (1935) 55 CLR 523
Aktiebolaget Hässle v Alphapharm Pty Ltd (2002) 212 CLR 411
AMP Inc v Utilux Pty Ltd (1971) 45 ALJR 123
Artcraft Urban Group Pty Ltd v Streetworx Pty Ltd [2016] FCAFC 29
Asahi Kasei Kogyo Kabushiki Kaisha v W R Grace & Co (1991) 22 IPR 491
AstraZeneca AB v Apotex Pty Ltd (2014) 226 FCR 324
AstraZeneca AB v Apotex Pty Ltd (2015) 114 IPR 445
Beecham Group Limited’s (Amoxycillin) Application [1980] RPC 261
Bristol-Myers Squibb Co v Apotex Pty Ltd (2015) 228 FCR 1
British Acoustic Films Ld v Nettlefold Productions (1936) 53 RPC 221
Camco Inc v Whirlpool Corporation [2000] 2 SCR 1067
CCOM Pty Ltdv Jiejing Pty Ltd (1994) 51 FCR 260
Colgate-Palmolive Co v Cussons Pty Ltd (1993) 26 IPR 311
Conoco Specialty Products (Inc) v Merpro Montassa Ltd [1994] FSR 99
Electric & Musical Industries Ld v Lissen Ld (1939) 56 RPC 23
Farbwerke Hoechst Aktiengesellschaft v Intercontinental Pharmaceutical (Eire) Ltd [1968] FSR 187
Flexible Steel Lacing Company v Beltreco Ltd (2000) 49 IPR 331
General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd (1971) 1A IPR 121
GlaxoSmithKline Australia Pty Ltd v Pharmacor Pty Ltd [2014] FCA 1202
GlaxoSmithKline Australia Pty Ltd v Reckitt Benckiser Healthcare (UK) Ltd (2013) 305 ALR 363
GlaxoSmithKline Consumer Healthcare Investments (Ireland) (No 2) Ltd v Apotex Pty Ltd (2014) 109 IPR 492
H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151
ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc (1999) 45 IPR 577
ICI Chemicals & Polymers Ltd v The Lubrizol Corporation Inc (2000) 106 FCR 214
Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461
Jupiters Ltd v Neurizon Pty Ltd (2005) 65 IPR 86
Kauzal v Lee (1936) 58 CLR 670
Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1
Kimberly-Clark Australia Pty Ltd v Multigate Medical Products Pty Ltd (2011) 92 IPR 21
Kinabalu Investments Pty Ltd v Barron & Rawson Pty Ltd [2008] FCAFC 178
Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2005] RPC 169
Les Laboratoires Servier v Apotex Pty Ltd [2016] FCAFC 27
Lizzanno Partitions (UK) Ltd v Interiors Manufacturing Ltd [2013] EWPCC 12
LockwoodSecurity Products Pty Ltd v Doric Products Pty Ltd (2004) 217 CLR 274
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd(No 2) (2007) 235 CLR 173
Mainteck Services Pty Ltd v Stein Heurtey SA (2014) 89 NSWLR 633
Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228
Milliken Denmark AS v Walk Off Mats Ltd [1996] FSR 292
Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253
National Australia Bank Ltd v Clowes [2013] NSWCA 179
No-Fume Ltd v Frank Pitchford & Co Ltd (1935) 52 RPC 231
Norton and Gregory Ld v Jacobs (1937) 54 RPC 271
NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1992) 24 IPR 1
Olin Corporationv Super Cartridge Co Pty Ltd (1977) 180 CLR 236
Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157
Orion Corp v Actavis Pty Ltd (No 3) [2015] FCA 1373
Pfizer Overseas Pharmaceuticals v Eli Lilly & Co (2005) 68 IPR 1
Photocure ASA v Queen’s University at Kingston (2005) 216 ALR 41
Plimpton v Malcolmson (1876) 3 Ch D 531
Product Management Group Pty Ltd v Blue Gentian LLC (2015) 116 IPR 54
Rediffusion Simulation Ltd v Link-Miles Ltd [1993] FSR 369
Roach v Page (No 15) [2003] NSWSC 939
Sachtler GmbH & Co KG v RE Miller Pty Ltd (2005) 221 ALR 373
Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd (1994) 30 IPR 479
Simpson v Holliday (1866) L R 1 H L 315
SNF (Australia) Pty Ltd v Ciba Speciality Chemicals Water Treatments Ltd (2011) 92 IPR 46
Streetworx Pty Ltd v Artcraft Urban Group Pty Ltd (2014) 110 IPR 82
Technograph Printed Circuits Ltdv Mills & Rockley (Electronics) Ltd [1972] RPC 346
TheWellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262
Tramanco Pty Ltd v BPW Transpec Pty Ltd (2014) 105 IPR 18
Valensi v British Radio Corporation [1972] FSR 273
Vidal Dyes Syndicate Ld v Levinstein Ld (1912) 29 RPC 245
Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588
“Z” Electric Lamp Manufacturing Company Ld v Marples, Leach & Co Ld (1910) 27 RPC 737
Date of hearing: 12, 13, 14, 15, 16, 19, 20, 21 and 22 October 2015, 4 and 10 November 2015, 1, 2, 3, 4 and 8 February 2016 Registry: Victoria Division: General Division National Practice Area: Intellectual Property Sub-area: Patents and Associated Statutes Category: Catchwords Number of paragraphs: 1000 Counsel for the Applicants: Mr D Shavin QC with Ms H M J Rofe QC Solicitor for the Applicants: Davies Collison Cave Law Counsel for the First Respondent: Ms S J Goddard SC with Mr C H Smith Solicitor for the First Respondent: Herbert Smith Freehills Counsel for the Second Respondent: Mr T Cordiner with Ms K Beattie Solicitor for the Second Respondent: Maddocks ORDERS
VID 571 of 2014 BETWEEN: GLAXOSMITHKLINE CONSUMER HEALTHCARE INVESTMENTS (IRELAND) (NO. 2) LIMITED
First Applicant
GLAXOSMITHKLINE AUSTRALIA PTY LTD
(ACN 100 162 481)Second Applicant
AND: APOTEX PTY LTD (ACN 096 916 148)
Respondent
AND BETWEEN: APOTEX PTY LTD (ACN 096 916 148)
Cross-Claimant
AND: GLAXOSMITHKLINE CONSUMER HEALTHCARE INVESTMENTS (IRELAND) (NO. 2) LIMITED
First Cross-Respondent
GLAXOSMITHKLINE AUSTRALIA PTY LTD
(ACN 100 162 481)Second Cross-Respondent
JUDGE:
BEACH J
DATE OF ORDER:
31 may 2016
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
VID 638 of 2014 BETWEEN: GLAXOSMITHKLINE CONSUMER HEALTHCARE INVESTMENTS (IRELAND) (NO. 2) LIMITED
First Applicant
GLAXOSMITHKLINE AUSTRALIA PTY LTD
(ACN 100 162 481)Second Applicant
AND: GENERIC PARTNERS PTY LTD (ACN 132 833 777)
Respondent
AND BETWEEN: GENERIC PARTNERS PTY LTD (ACN 132 833 777)
Cross-Claimant
AND: GLAXOSMITHKLINE CONSUMER HEALTHCARE INVESTMENTS (IRELAND) (NO. 2) LIMITED
First Cross-Respondent
GLAXOSMITHKLINE AUSTRALIA PTY LTD
(ACN 100 162 481)Second Cross-Respondent
JUDGE:
BEACH J
DATE OF ORDER:
31 may 2016
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:
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.
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.
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.
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).
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).
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.
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.
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.
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.
In summary, I have rejected both GSK’s infringement case and Apotex’s and Generic Partners’ invalidity assertions.
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.
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.
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.
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.
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
Before addressing the substance of the case it is necessary to make some observations on the procedural history.
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.
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.
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.
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.
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.
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.
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.
On 10 November 2015, Professor Tucker was also further cross-examined via video link from Dunedin, New Zealand.
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.
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
The Patent has a priority date of 19 April 2000.
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.
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.
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.
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.
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.
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)
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)
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)
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)
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.
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.
Pages 4 to 6 set out the various consistory clauses.
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.
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.
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.
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.
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).
The ingredients of Formulations A and B are listed in the table on p 9 of the Patent.
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.
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.
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.
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).
Thus far I have referred to Formulations A and B and example 1. It is appropriate to now discuss Formulation C and example 2.
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:
Ingredient Tablet Formulation C Sustained Release Layer mg/tablet % w/w Paracetamol 473.57 64.39 High viscosity HPMC 15.43 2.10 Pregelatinised Starch 5.14 0.70 Polyvinylpyrrolidone 10.28 1.40 Low viscosity HPMC 8.23 1.12 Magnesium Stearate 1.54 0.21 Immediate Release Layer Directly compressible
paracetamol granulation
DC90214.92 29.22 (Paracetamol content in
DC90)(193.43) (26.30) Film and Wax Coating 6.305 0.86 Total 735.42 100.00 % w/w SR:IR APAP 71:29 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
Time (minutes) In-vitro release Results
(% paracetamol released)15
60
120
180
39.4%
64.4%
89.0%
101.8%
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.
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.
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.
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.
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).
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.
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.
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:
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.
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.
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.
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.
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).
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.
Claims 2 and 3 claim narrower dissolution ranges.
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.
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.
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.
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.
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
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
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.
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.
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.
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.
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.
The gout and infectious categories are less common and can be put to one side for present purposes.
(b) Pain
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.
Pain is usually categorised as either acute pain or chronic pain.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
In addition to immediate release forms of paracetamol, in the late 1990s there were slow-release paracetamol forms available.
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.
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.
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.
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.
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.
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.
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
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.
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.
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
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.
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.
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.
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.
It is appropriate to elaborate further.
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.
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.
There are a number of advantages of extended release formulations over immediate release formulations of the same drug.
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.
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.
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.
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.
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
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.
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.
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.
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.
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:
Noyes Whitney equation: rate of dissolution =
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).
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.
Fifth, Dr Mooney immediately selected a bilayer tablet, rather than for example a capsule using beads or pellets whose technology was more developed and which were more common than bilayer tablets, or a single-layer tablet. Professor Davies explained that, in his experience, such formulations significantly release drug in the early phase thus avoiding the need for an immediate release layer.
Sixth, as at the priority date, Dr Mooney had never worked on a bilayer dosage form. Neither his employer, Alphapharm, nor anyone else in Australia had the plant and equipment necessary to produce a bilayer tablet and the only bilayer tablet he had heard of was one comprising two different active pharmaceutical ingredients (one that was enterically coated) that had been released in Europe and the United States. Further, it is implausible that an addressee would as a matter of routine move from the prior art to a formulation requiring the purchase of new equipment. On the one hand Dr Mooney confined himself to the equipment available at Alphapharm in April 2000, yet still said that for the purpose of developing his hypothetical formulation, he would buy a bilayer compression machine. I must say that I found that suggestion implausible.
Seventh, the respondents’ case relied on formulating a sustained release matrix which was not a typical matrix.
Eighth and generally, in my view Dr Mooney is an inventive and clever formulator. Generally, it would seem that thinking as creatively as he could as to how to deal with the challenge put to him, he immediately selected a bilayer two phase tablet. In the JER, Dr Mooney sought to defend his selection as being “based on experience with development of tablets as an oral dosage form”. But his experience with bilayer tablets was largely non-existent. Dr Mooney also properly conceded that his formulation decisions were artificially constrained and that his formulation selection was also artificially confined with reference to the particular equipment and expertise available at Alphapharm. I agree with GSK’s submissions that his selection was also made despite:
(a)knowing that sustained release dosage forms at 2000 tended to be single phase;
(b)knowing that modifying a monolithic sustained release profile was an option;
(c)knowing that dosage forms with more than one phase were uncommon, both in Australia and around the world;
(d)not having any experience preparing a dosage form with more than one phase prior to 2000;
(e)his only experience in making a sustained release tablet being to make a generic product, that is, when there was a corresponding sustained release dosage form in the market somewhere, and there was no immediate release phase in the dosage form;
(f)not having any experience prior to 2000 in formulating multilayer tablets;
(g)being aware that bilayer tablets require special equipment and being unaware of any bilayer machines in Australia at 2000;
(h)being only aware of one actual bilayer product at 2000; the product was not an immediate release/sustained release tablet, instead it had a first portion with an enteric coat which coated an immediate release form of a first active pharmaceutical ingredient and a second portion which comprised a mantle which comprised a second active pharmaceutical ingredient;
(i)being unaware of any bilayer tablet with sustained release and immediate release phases on the market in Australia at 2000;
(j)being aware that there was nothing typical about a bilayer tablet with immediate release and sustained release phases;
(k)being aware of the manufacture of beads, and being aware of a sustained release product on the market at 2000 which was an extended release capsule product;
(l)having not considered the results of any relevant literature (which he said in his affidavit would be the first step in a development process).
In my view, in April 2000 it was not a routine step to those skilled in the art in Australia to create a bilayer tablet for a sustained release product.
Dr Mooney acknowledged that his common general knowledge alone approach, based on simply looking at some immediate release paracetamol products and noting a score line, and relying on the development brief, did not reflect commercial reality. Further, his approach did not demonstrate a series of routine steps taken by a skilled but unimaginative worker.
Dr Mooney further agreed that there was no way to know whether any of his proposed formulations or in vitro profiles would meet the in vivo clinical targets. If one was trying to create for the first time a sustained release formulation one did not know the anticipated profile. Further, there was not necessarily a correlation between an in vitro profile of a drug and an in vivo consequence. Further, assuming that one was taking three doses a day, one did not know what the dissolution profile should be at two and a half hours or three and a half hours. Further, if one had a formulation with a desired in vitro profile, one tested it with clinical trials. If it did not give the desired pharmacokinetic properties, one would consider the formulation and data one had come up with and a new formulation and a new in vitro profile and try again.
Professor Davies considered that a more logical approach in answer to the development brief would be to first understand the suite of physicochemical and pharmacokinetic data and try to discern an optimal in vivo release profile. Once he had a target profile in mind, Professor Davies would consider whether a single system sustained release formulation might result in the advantageous pharmacokinetic profile or whether a more complicated formulation might be more desirable.
The respondents contend that the common general knowledge documents in evidence such as MIMS and Martindale contain much information that a person skilled in the art would readily have to hand. In particular, with respect to paracetamol this included the following:
(a)dosage and administration;
(b)maximum daily dose of 4 g;
(c)the elimination half life of paracetamol of 1 to 3 hours;
(d)the solubility of paracetamol (as sparingly soluble);
(e)the presentation of paracetamol, including scored tablets;
(f)that paracetamol is readily absorbed in 10 to 60 minutes;
(g)toxicity and overdose.
But I do not think that this carries the day.
In summary, in my view the evidence did not establish that a person skilled in the art would, by a matter of routine steps, move from the prior art in terms of common general knowledge to the invention claimed in each of the claims. To do so in the present case, Dr Mooney used ingenuity and cleverness well beyond the person of ordinary skill taking merely routine steps.
(f) The 522 Patent — Apotex’s principal case
It has been accepted by the parties that the 522 Patent is s 7(3) information that can be aggregated with common general knowledge.
Dr Mooney read the 522 Patent after he had proposed the basic elements of his initial formulation as set out earlier. The 522 Patent described a bilayer biphasic tablet of acetaminophen with an immediate-release and a sustained-release layer. The 522 Patent reported on a small-scale study of 12 adult male subjects, half of whom were given two 500 mg immediate-release tablets and half of whom were given two 650 mg bilayer biphasic tablets made using the formulation disclosed in the 522 Patent. Their blood concentrations were taken over nine time intervals and the averaged results provided in a table. The conclusion stated that the bilayer formulation of Example I (acetaminophen sustained release bilayer tablet) could extend the dosing interval to at least eight hours. Surprisingly in my view, Dr Mooney asserted that he did not agree that this was achieved. At this point I should note that Dr Mooney sought to second guess the results reported in the 522 Patent in a manner that was not justified in relation to Example I. I will return to this later. Apotex contends that the 522 Patent provided Dr Mooney with at least the following information:
(a)A recipe or list of components in a method to make an oral sustained-release form of acetaminophen including a bilayer tablet with an immediate-release and a sustained-release layer;
(b)The formulation contained a sustained release matrix which included a polymer, being hydroxyethylcellulose in combination with PVP;
(c)That it was beneficial to provide an acetaminophen product that extended the dosing interval beyond six hours while maintaining therapeutically effective levels of acetaminophen in the blood;
(d)The therapeutically effective levels of plasma concentration of paracetamol were likely to be about 2.9 mcg/ml, equivalent to the average plasma concentration level of the immediate-release product at six hours as shown in Table 2b (which required re-dosing at six hours). I should say that I disagree with this assertion. Table 2a shows 2.6 mcg/ml for the sustained release formulation at 8 hours and the 522 Patent in effect represents this to be an effective therapeutic level at 8 hours;
(e)The formulation could be dosed as two tablets each containing 650 mg of acetaminophen in a composition containing an IR and an SR layer;
(f)That the dosing intervals could be extended to eight hours (referring to Column 1, lines 53 and 54);
(g)That the relevant proportions of hydroxyethylcellulose and PVP were in the order of about 4% or less of the amount of acetaminophen (referring to Column 4, lines 4 to 9). While the small proportion of matrix binding agents was asserted to be a novel feature of the invention (at its priority date of 27 July 1987) and the preferred embodiment of the invention used only about 3% of hydroxyethylcellulose (Column 4, lines 40 to 42), Dr Mooney and Professor Davies were aware by the priority date of the Patent in suit of the ability to form a sustained-release matrix using a small amount of polymer;
(h)That the sustained-release matrix used well-known excipients such as disintegrants and water absorption promotion ingredients;
(i)The components of the method to construct a compressible bilayer tablet containing 325 mg in each tablet layer of paracetamol using wet granulation; and
(j)That an in vivo trial of the sustained-release formulation of Example 1, 2 tablets containing 650 mg each of paracetamol in each tablet, compared with the immediate-release paracetamol, 2 tablets containing 500 mg each of paracetamol in each tablet, showed a comparable extent of absorption measured by the AUC.
Surprisingly in my view, Dr Mooney did not agree that Example 1 demonstrated that eight hour dosing had been achieved for the sustained release formulations.
As concerns the choice of polymer, the binder used in the 522 Patent was a combination of hydroxyethylcellulose and PVP. Dr Mooney had already expressed a preference to use a polymer such as HPMC. He explained that he was not familiar with hydroxyethylcellulose as an excipient and he would use a more commonly used excipient from the cellulose family of polymers for creating a sustained-release matrix, including HPMC. Dr Mooney explained that he would not have used PVP because it is soluble and would not contribute to extending the release of paracetamol.
As concerns the proportion of paracetamol in each layer, apparently the information in the 522 Patent did not dissuade Dr Mooney from his earlier approach. His reasons for maintaining this view were said to be based on his reading of the data from the in vivo trials disclosed in tables 2a and 2b in the 522 Patent, as follows:
(a)That the time to Cmax (the Tmax value) was too rapid because the 522 formulation reached a Cmax of 12.8 mcg/ml at 1.5 hours after dosing, while the immediate-release formulation reached a Cmax of 12.1 mcg/ml 1 hour after dosing. In Dr Mooney’s experience, he would have expected a greater shift in Tmax than 30 minutes;
(b)The concentration levels of paracetamol in the in vivo study from the 522 formulation (measured in mcg/ml) at 1, 1.5, 2 and 3 hours in Example 1 were well in excess of the concentration levels of corresponding time points in the immediate-release tablets. This showed Dr Mooney, so it was said, that there was potential to extend the duration of release further by reducing those early concentrations;
(c)The concentration of paracetamol at 8 hours for the bilayer tablet of 2.6 mcg/ml was lower than the concentration at 6 hours of 2.9 mcg/ml for the immediate-release tablet (when re-dosing occurs).
For these reasons, Dr Mooney doubted, apparently, that Example 1 provided the required therapeutic levels of paracetamol and that genuine eight hour dosing was achieved, and he reasoned that it would be desirable to increase the concentration at eight hours. So he said, he saw the potential to improve the formulation by shifting the release of some of the paracetamol from a time when it significantly exceeded the minimum therapeutic level, to a later time when there was the potential for it to fall below such levels.
After reading the 522 Patent, Dr Mooney explained that he would conduct dissolution testing routinely as part of drug development to ensure that the formulation was pH independent and would release (i.e., dissolve) over a reasonable time frame. He initially proposed that the drug should have released by about 3 to 4 hours after ingestion. He believed that this time frame reflected the requirement that paracetamol be maintained in the blood at a level which would be therapeutic (i.e., at least 2.9 mcg/ml) for eight hours.
Dr Mooney proposed a dissolution profile that he would aim to achieve for his proposed formulation as follows:
·30% to 60% at 30 minutes;
·50% to 75% at 60 to 120 minutes (1 to 2 hours);
·No less than 80% dissolved at 3 to 4 hours.
He explained that he would use USP type II apparatus, paddle at 50 rpm at 37C in 0.1 M HCL to test the dissolution profile. If the prototype floated (which the evidence revealed is a common problem with USP paddle apparatus) he would change to USP type I apparatus at 100 rpm in the same temperature and medium.
Dr Mooney’s evidence was that he would have tried to achieve a dissolution profile “similar to” the 522 Patent. His evidence was not that he was trying to match that profile precisely. He explained that similarity in this context means ±10%, which was in accordance with the FDA Guidelines.
Apotex contends that there was no inventiveness in the dissolution profiles proposed by Dr Mooney. As concerns the time points, the FDA recommended the use of three time points. The last time point should be at a point where 80% to 100% of the drug has dissolved. Given that Dr Mooney proposed that the paracetamol be dissolved preferably after three hours, this gives his final time point at 180 minutes. There should be an early time point when the paracetamol from the immediate-release layer and some from the sustained-release layer would have dissolved, namely, within 15 to 30 minutes. Finally there should be a time point somewhere in the middle. Thus Dr Mooney’s 60 minute time point simply reflects this middle point.
Apotex compared Dr Mooney’s proposed ranges with claims 1, 2 and 3 of the Patent. These showed the percentage of acetaminophen dissolved versus time. With respect to claim 1, Dr Mooney’s proposed ranges came within claim 1. With respect to the narrower claims, Dr Mooney’s ranges fell outside those ranges.
Further, Dr Mooney explained that his trial formulations would be revised depending on whether or not the in vivo studies showed that the formulations achieved the desired performance. In particular he would adjust the proportion of paracetamol used in the immediate-release and sustained-release phases of the tablet and he would adjust the excipients that affect the dissolution performance of the tablet, namely, the sustained-release polymer, including its amount and its molecular weight (which affects its viscosity) and other excipients that were related to dissolution rate, including disintegrant and wicking agents, by varying the excipient to polymer ratios. In so doing, Dr Mooney said that based on his experience as a formulator he would be confident of being able to make adjustments by “routine trial and error” so as to achieve a formulation that achieved the desired sustained-release performance for paracetamol, allowing 8-hourly dosing. Accordingly, Dr Mooney contemplated that his initial formulations would be revised, based on the in vivo pharmacokinetic data, following a trial in patients.
Further, while Dr Mooney considered his proposed formulations were good enough as a starting point, he also considered that something within his proposed range of trial formulations would be likely to achieve the in vivo profile he was aiming for. But if the formulation did not achieve the desired in vivo profile, he believed he would be able to revise the formulation to change the in vitro dissolution profile. For example, he could extend the time over which the acetaminophen was released from the dosage form by either increasing the amount of polymer, change to a polymer of higher molecular weight or vary the excipient to polymer ratio in relation to excipients that supported the sustained-release behaviour. Alternatively, he could do the opposite if he needed to speed up the release. His initial contemplated formulations also proposed to test different proportions in the immediate-release and sustained-release layer for 200/450 to 300/350.
Further, Dr Mooney said that in vivo clinical trials would need to be conducted to confirm whether or not any of his formulations achieved the desired in vivo targets. If the formulation did not do so, he said that he would use the results of the in vivo trials to guide modifications to his formulation within the ranges of his proposed formulation, for example by varying the grade of polymer.
Both Dr Mooney and Professor Davies agreed that clinical trials would conventionally be carried out. Apotex has submitted that the observations in AstraZeneca concerning the additional information as to dosages which was absent from the s 7(3) disclosure and the prior art, are applicable in this case (see at [44] per French CJ, [88] and [94] per Kiefel J and [116] per Gageler and Keane JJ). Further, Nettle J at [123] recognised that carrying out clinical trials was conventionally done and “fell within the concept of working towards an invention with an expectation of success and that was consistent with the conclusion that the invention was obvious”.
Finally, in response to GSK’s assertion that the 522 Patent solves the problem and that Dr Mooney should not have proceeded further, the respondents have advanced the following arguments.
It is said that GSK’s asserted requirement that the notional skilled person must stop all enquiries once any solution becomes apparent does not circumscribe what is, or is not, obvious within the meaning of s 7(2). It imposes a narrower limitation not found in the statutory language. The notional skilled addressee’s hypothetical response when equipped with the common general knowledge and then s 7(3) information is a matter of evidence. I agree with these submissions.
Further, it is said that GSK’s approach misstates the use which may be made of information in s 7(3) as explained by the High Court in AstraZeneca. Even if it were accepted that the 522 Patent solved the problem, it is impermissible to limit what use may be made of s 7(3) information in the way GSK suggests. I also agree with these contentions.
As Gageler and Keane JJ observed in AstraZeneca at [115]:
The question is not whether it would have been obvious to the skilled addressee to choose rosuvastatin over NK-104; rather, it is whether a person skilled in the art would, in light of the common general knowledge plus either the Watanabe article or the 471 patent, have been directly led as a matter of course to try rosuvastatin in the expectation that it might well produce a solution to the problem which existed in the common general knowledge. Section 7(2) does not contemplate that a choice between apparently effective solutions must be attributed to the notional skilled addressee, much less that the notional skilled addressee might be so befuddled by an embarrassment of choices as to cease pursuit of the solution.
I note that their Honours applied the reformulated Cripps question. Applying this to the present case, the question is whether the skilled person would, in light of the common general knowledge plus the information in the 522 Patent, have been directly led as a matter of course to try a formulation of paracetamol within the terms of claim 1 in the expectation that it might well produce a solution to the problem that existed in the common general knowledge. Section 7(3) information is not information that must directly lead to the invention. It is information that is relevant to addressing the problem. It is to be considered together with common general knowledge. In my view, to apply a test about whether or not there is motivation to improve upon a s 7(3) disclosure inappropriately confines the use of that information. The information in s 7(3) documents does not need to provide an alternative path directly leading to the invention.
(g) The 522 Patent — Analysis
In my view, Dr Mooney’s use of the 522 Patent does not support Apotex’s case on lack of inventive step.
First, Dr Mooney, as a highly skilled innovative formulator, looked at the 522 Patent not through the lens of the hypothetical non-inventive formulator in the field seeking to solve the problem in the development brief, but as someone bringing all of his creativity, innovation and lateral thinking experience to try to improve the 522 Patent to create a different product which gave a commercial opportunity or “the best” product.
Second, the 522 Patent did not provide any in vitro dissolution data for any formulations. It is difficult to see how Dr Mooney could in essence take Table 2a, in essence ignore its teaching for 8 hours, adjust the formulation to put more API in the sustained release layer and then speculate concerning both appropriate in vitro dissolution profiles and in vivo effects.
Third, Example I of the 522 Patent disclosed a bilayer tablet which contained 650 mg of paracetamol split equally between two layers (325 mg in an immediate release layer and 325 mg in a sustained release layer).
Dr Mooney agreed that the formulation of Example I of the 522 Patent disclosed an advantage, and that advantage was eight hour dosing (see col 8 lines 45 to 48). As Dr Mooney noted, “the formulation disclosed in the ‘522 Patent is stated to achieve the objective in the Development Brief of eight hourly dosing”.
Dr Mooney also agreed that the Cmax for Example I formulations was reached at a similar time to the immediate release formulation. Further, during cross-examination Professor Davies explained that the Cmax of Example I was comparable to or maybe slightly higher than the Cmax of the immediate release, and that it was not a general goal of a formulator to reduce the Cmax of an immediate release formulation when making a sustained release formulation. This was consistent with the disclosure in the 522 Patent itself which explained at col 8 lines 33 to 40:
The results show that two bi-layer tablets of Example I, when compared to two tablets of non-sustained release acetaminophen (1000 mg dose), achieve the following: comparable rate of absorption: comparable maximum plasma concentration; and comparable extent of absorption (AUC or area under the curve) when adjusted for dose.
Apotex’s assertion that the SR Cmax was “well in excess” of the Cmax of the IR is not supported by the evidence, especially at the early release times which would enable rapid pain relief.
Accordingly, the formulation of Example I of the 522 Patent provided the solution to the problems formulated by Apotex in the development brief. But I accept that Dr Mooney did not have to stop there.
Dr Mooney’s quest to revise the formulation beyond that of Example I to “potentially” provide lower early levels, whilst providing the same therapeutic efficacy, was undertaken by him not in response to the development brief and the problems set out therein, but in response to a perceived problem with the 522 Patent and involved, in my view, ingenuity and other than routine work.
Dr Mooney proceeded to revise the Example I formulation in a context where he did not know, and agreed that the development brief did not provide him with, information on:
(a)the therapeutic window of paracetamol or the therapeutic dose;
(b)the half life of paracetamol;
(c)the solubility of paracetamol;
(d)the Cmax of the immediate release;
(e)the maximum tolerated dose;
(f)any of the pre-formulation information and other matters identified in his affidavit.
Moreover, Dr Mooney’s approach was founded on the guess that 2.9 mcg/ml was the minimum therapeutic level for paracetamol and an unsupported assertion that the 522 Patent misrepresented that Example I would provide eight hourly dosing.
In my view, as I have already said, Dr Mooney ignored the express teaching of the 522 Patent of eight hourly pain relief to speculate that the 522 Patent formulation did not provide effective eight hourly dosing (i.e. 2.6 mcg/ml (at eight hours) was not therapeutically effective). The basis for Dr Mooney’s speculation (rejected by Professor Davies) was his assumption that the six hourly dose level of the immediate release product (2.9 mcg/ml) was close to the minimum therapeutic concentration. But in cross-examination, Dr Mooney conceded that at six hours the immediate release formulation could be above a minimum therapeutic effect but be below at eight hours (1.8 mcg/ml), meaning that the minimum therapeutic level may be in between 1.8 and 2.9 mcg/ml. Dr Mooney agreed that a tablet was not, in reality, going to be dosed at intervals longer than six hours but shorter than eight hours.
Generally, in this case, Dr Mooney had pharmacokinetic data for a suitable sustained release formulation (Example 1 of the 522 Patent) but chose to ignore or reject it (along with other statements made in the 522 Patent as to the efficacy of the Example 1 formulation), but at the same time to accept (and use as the foundation for his development project) pharmacokinetic information for an immediate release formulation provided in that patent. Dr Mooney’s approach was unrealistic. It could not reasonably be described as a series of steps taken as a “matter of routine”.
Fourth, Dr Mooney’s approach based on the 522 Patent was also founded on his assumption that a dose of 250 mg will give therapeutic efficacy. But this required him to assume that the 522 patentee’s statements at col 1 lines 34 and 35 and col 8 lines 45 to 48 were wrong. But this was contrary to the express teaching of the 522 Patent. It was also speculative.
Fifth, Dr Mooney said that in devising his proposed product, he would substitute the hydroxyethylcellulose specified in the 522 Patent for another matrix forming polymer (e.g. HPMC or ethylcellulose) simply on the basis of his peculiar lack of knowledge of hydroxyethylcellulose before the priority date. But hydroxyethylcellulose is said to be the preferred polymer matrix of the formulations disclosed in the 522 Patent. The use in the formulations of Example I of hydroxyethylcellulose did not routinely lead to the further work proposed by Dr Mooney. Hydroxyethylcellulose was at the priority date known to be suitable for use in a matrix for a sustained release formulation.
Sixth, and as I have said, the 522 Patent did not provide any in vitro dissolution data for any formulations. Dr Mooney acknowledged that because the 522 Patent only provided in vivo data, he had to intuitively work backwards to an in vitro profile. Dr Mooney conceded that his proposed formulation, having a predicted in vitro profile as set out in his affidavit, was only a prediction which was “something to investigate” and merely “a concept”. He was “not going to know about the in vivo performance until [he] test[ed] it”. His suggestion that the Tmax of a formulation might be extended by modifying the 522 Patent formulation was just a hypothesis to be explored with testing. Dr Mooney accepted in relation to his proposed formulation and its in vitro profile two qualifications. First, that there was no way to know whether his proposed profile would provide an effective formulation without carrying out in vivo testing of the subject formulation. Second, that he did not know if too much paracetamol might be released too early if 30 to 60 per cent of the paracetamol dissolved in vitro in the first 30 minutes, as he proposed.
I agree with GSK’s contention that given both the absence of foundation for the 250 mg dose therapeutic effect assumption and its centrality to the path of further work, and that Dr Mooney agreed that he could not predict the in vivo efficacy of his proposed in vitro profile, it is difficult to see how Dr Mooney or the hypothetical person skilled in the art could have sensibly embarked upon the further work with an expectation of success.
I accept Professor Davies’ evidence that:
Dr Mooney’s approach pre-supposes, without any basis in the data, that reducing the amount of active ingredient in the immediate release layer will provide a minimum therapeutically effective amount. It is improbable that a skilled formulator would make a guess of that nature. A formulator would not know whether reducing the amount of active ingredient in the immediate release layer might alter the part of the 522 patent formulation which enables that formulation both to give a high level of immediate pain relief in combination with longer lasting relief than is available from the immediate release tablet. Thus there could be no expectation that making the change Dr Mooney speculates upon would be successful in providing a formulation that would satisfy the requirements of the Development Brief.
Seventh, Dr Mooney’s approach was of course hypothetical. The respondents conducted no experiments, not even in vitro dissolution ones, notwithstanding that they assert that it is “inevitable” that Dr Mooney’s development work would have resulted in a formulation falling within claim 1 of the Patent.
In summary, I do not accept that Apotex has made out its case on lack of inventive step on the foundation of common general knowledge taken together with the 522 Patent.
(h) Combining the 522 Patent and the 194 Patent
An alternative basis that the respondents rely on is common general knowledge combined with Australian Patent No 751194 (the 194 Patent), which is accepted to be s 7(3) information, considered alone or with the 522 Patent. The 194 Patent cross-references the 522 Patent at p 3 line 4. It can be taken to incorporate the 522 Patent to that extent.
The 194 Patent was a further document that Dr Mooney identified as being relevant to making a formulation to meet the requirements of the development brief. The 194 Patent was published some ten years after the 522 Patent (1989) and shortly before the priority date.
Dr Mooney explained that in reading the 194 Patent he would have wanted to consider it together with the cross-referenced 522 Patent, in particular because he read in the 194 Patent that the 522 Patent involved use of a bilayer tablet, which was Dr Mooney’s first choice of a formulation method to address the development brief.
Dr Mooney explained that the 194 Patent provided additional useful information in developing a formulation in that it included a dissolution profile for Tylenol extended release paracetamol caplets, which would provide an initial in vitro dissolution profile to aim for (whether combined with the teaching in the 522 Patent or combined with Dr Mooney’s selection of a bilayer tablet using common general knowledge).
Professor Davies’ evidence about the disclosure in the 194 Patent was that:
I see no reason why a person skilled in the art in April 2000, having read the 194 patent, would want to make any change, let alone change the proportions of acetaminophen between the immediate release and the sustained release layers, based solely on the fact that one of the commercial immediate release tablets is scored (which appears to be the sole basis for Dr Mooney’s unequal split hypothesis in paragraphs 134, 135 and 187). In the absence of clinical trials demonstrating inadequate pain relief in the first hour, I would not have a basis in the data provided in the 194 patent to know whether a change in the proportions of paracetamol in the immediate release and sustained release layer would have an appropriate response and I note that there is no suggestion in the Development Brief that the conventional immediate release form fails to give adequate pain relief in the first hour.
The 194 Patent disclosed a sustained release paracetamol formulation made up of a blend of beads or particles of immediate release and sustained release paracetamol, which was delivered in a capsule or blister. Two example compositions were provided. The first appeared to comprise an equal amount of paracetamol in the immediate and sustained release bead material. The second comprised only extended release beads, with no immediate release paracetamol. The 194 Patent used ER Tylenol, known to be clinically effective at that time, as the bench mark for assessment of the 194 Patent formulations.
In vivo studies, reported in Figures 2 to 4, showed that the 194 Patent composition initially reduced fever at the same rate as immediate release paracetamol but continued to achieve temperature reduction for longer. A pain study reported that the 194 Patent composition provided equally effective pain relief over an eight hour period as ER Tylenol.
The formulation described in the 194 Patent was therapeutically effective in terms of providing rapid relief in the temperature study, matched the sustained release efficacy of ER Tylenol over eight hours in a pain study and had the same bioavailability as the Tylenol Immediate Release Elixir formulation.
But there was absolutely nothing in the 522 or 194 Patents which suggested that an equal amount of paracetamol in each of the two layers had failed to achieve an acceptable result. Quite the converse in each case. Dr Mooney had to concede that when he first read the 194 Patent he did not consider that it suggested an unequal split of paracetamol might be appropriate. Dr Mooney agreed in cross-examination that there was nothing in the 194 Patent claims which suggested an unequal split of paracetamol.
In my view, there was nothing in the combination of the 522 and 194 Patents which provided motivation for Dr Mooney to move beyond the solutions provided in both to undertake the further work proposed by Dr Mooney. And to the extent that he did so, the work was not routine, but rather involved ingenuity and cleverness on his part. Moreover, even if I were not to apply a reformulated Cripps question, but rather Apotex’s test taken from Lockwood (No 2), Apotex still fails on this ground.
(i) General
Further, there was no basis for saying that Dr Mooney’s proposed formulation would have a dissolution profile within the limits specified in claims 1, 2 or 3 of the Patent when tested under the conditions specified in those claims.
Further, having arrived at a prototype formulation and defined its theoretical dissolution profile, Dr Mooney explained that “the product would be evaluated in vivo to establish the pharmacokinetic behaviour and refinements to the formulation be made as required”. But even having devised a prototype formulation, there was no cogent evidence upon which to draw an inference that the prototype formulation would produce a therapeutic effect, let alone that such a formulation would have the particular advantageous attributes identified in the Patent.
Further, Dr Mooney did not provide any details of his prototype formulation, beyond possible ranges of paracetamol in each of the IR and SR layers.
In my view, the respondents’ case on lack of inventive step has not been made out. It has failed on the various permutations of the application of ss 7(2) and 7(3).
Conclusion
None of the respondents’ arguments on invalidity have been made good. Accordingly, their cross-claims will be dismissed. But as I have said earlier, GSK has failed on its infringement case as “basket” in claim 1 means basket. Each of the parties has had a measure of success. My tentative view is to make no order for costs in favour of any party, but I will give the parties an opportunity to make submissions thereon including on any consequential orders.
I certify that the preceding one thousand (1000) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Beach. Associate:
Dated: 31 May 2016
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