Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth
[2010] FCA 1211
•8 November 2010
FEDERAL COURT OF AUSTRALIA
Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2010] FCA 1211
Citation: Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2010] FCA 1211 Parties: SIGMA PHARMACEUTICALS (AUSTRALIA) PTY LTD v WYETH and WYETH AUSTRALIA PTY LIMITED
ALPHAPHARM PTY LIMITED v WYETH and WYETH AUSTRALIA PTY LIMITED
GENERIC HEALTH PTY LTD v WYETH and WYETH AUSTRALIA PTY LIMITED
File numbers: VID 195 of 2009
NSD 596 of 2009
NSD 1124 of 2009Judge: JAGOT J Date of judgment: 8 November 2010 Catchwords: PATENTS – validity – priority date – whether claims fairly based on matter disclosed in body of specification – whether invention sufficiently described – whether claims clear
PATENTS – validity – inventive step – obviousness – whether claims lacked an inventive step compared with prior art base – commercial success
PATENTS – revocation of patent – whether patent obtained by false suggestion or misrepresentation – entitlement – whether claimed invention is useful
PATENTS – infringement
Legislation: Patents Act 1990 (Cth) Cases cited: Aktiebolaget Hässle v Alphapharm Pty Limited (2002) 212 CLR 411; [2002] HCA 59
Alphapharm Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618; [2008] FCA 559
Alphapharm Pty Ltd v Wyeth (2009) 82 IPR 71; [2009] FCA 945
Apotex Pty Ltd (formerly GenRx Pty Ltd) v Sanofi-Aventis (2008) 78 IPR 485; [2008] FCA 1194
Apotex Pty Ltd v Sanofi-Aventis (2009) 82 IPR 416; [2009] FCAFC 134
Atlantis Corporation Pty Ltd v Schindler (1997) 39 IPR 29
BP Exploration Co (Libya) Ltd v Hunt [1980] 1 NSWLR 496
Commercial Union Assurance Company of Australia v Ferrcom Pty Ltd (1991) 22 NSWLR 389
EI Du Pont de Nemours and Company v ICI Chemicals & Polymers Ltd (2005) 66 IPR 462; [2005] FCA 892
Fresenius Medical Care Australia Pty Ltd v Gambro Pty Ltd (2005) 224 ALR 168; [2005] FCAFC 220
H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151; [2009] FCAFC 70
ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc (1999) 45 IPR 577; [1999] FCA 345
ITW AFC Pty Ltd v Loi & Tran Pty Ltd (2008) 76 IPR 129; [2008] FCA 552
JMVB Enterprises Pty Ltd (formerly known as A’Van Campers Pty Ltd) v Camoflag Pty Ltd (2005) 67 IPR 68; [2005] FCA 1474
Jones v Dunkel (1958) 101 CLR 298
Kimberly-Clark Australia Pty Limited v Arico Trading International Pty Limited (2001) 207 CLR 1; [2001] HCA 8
Leonardis v Sartas No 1 Pty Ltd (1996) 67 FCR 126
Lockwood Security Products Pty Limited v Doric Products Pty Limited (No 1) (2004) 217 CLR 274; [2004] HCA 58
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) (2007) 235 CLR 173; [2007] HCA 21
Martin v Scribal Pty Ltd (1954) 92 CLR 17
Merck & Co Inc v Arrow Pharmaceuticals Ltd (2006) 68 IPR 511; [2006] FCAFC 91
Microsoft Corporation v PC Club Australia Pty Ltd (2005) 148 FCR 310; [2005] FCA 1522
Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 16 IPR 545
Pfizer Overseas Pharmaceuticals v Eli Lilly & Company (2006) 68 IPR 1; [2005] FCAFC 224
R v Commissioner of Patents; Ex parte Martin (1953) 89 CLR 381
Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC (2008) 77 IPR 449; [2008] FCAFC 82
Regie Nationale des Usines Renault SA v Zhang (2002) 210 CLR 491; [2002] HCA 10
Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth (2009) 81 IPR 339; [2009] FCA 595
Speedy Gantry Hire Pty Ltd v Preston Erection Pty Ltd (1998) 40 IPR 543
Stack v Davies Shephard Pty Ltd (2001) 108 FCR 422; [2001] FCA 501
The Wellcome Foundation Limited v VR Laboratories (Aust.) Proprietary Limited (1981) 148 CLR 262
Trident General Insurance Co Limited v McNiece Bros Proprietary Ltd (1988) 165 CLR 107
University of British Columbia v Conor Medsystems Inc (2006) 155 FCR 391; [2006] FCAFC 154
University of Western Australia v Gray (No 20) (2008) 76 IPR 222; [2008] FCA 498
Welch Perrin and Company Proprietary Limited v Worrel (1961) 106 CLR 588
WM Wrigley Jr Company v Cadbury-Schweppes Pty Ltd (2005) 66 IPR 298; [2005] FCA 1035Date of hearing: 15-16, 19-23, 29-30 April 2010, 3-7, 25-28, 31 May 2010 Date of last submissions: 3 November 2010 Place: Sydney Division: GENERAL DIVISION Category: Catchwords Number of paragraphs: 632 Counsel for the Applicant / Cross-Respondent in VID 195 of 2009: Mr D Shavin QC and Ms HMJ Rofe Solicitor for the Applicant / Cross-Respondent in VID 195 of 2009: Griffith Hack Lawyers Counsel for the Applicant / Cross-Respondent in NSD 596 of 2009: Mr SCG Burley SC and Mr PW Flynn Solicitor for the Applicant / Cross-Respondent in NSD 596 of 2009: Mallesons Stephen Jaques Counsel for the Applicant / Cross-Respondent in NSD 1124 of 2009: Ms AH Bowne SC Solicitor for the Applicant / Cross-Respondent in NSD 1124 of 2009: Middletons Counsel for the Respondents / Cross-Claimants in VID 195 of 2009, NSD 596 of 2009 and NSD 1124 of 2009: Mr AJL Bannon SC and Mr C Dimitriadis Solicitor for the Respondents / Cross-Claimants in VID 195 of 2009, NSD 596 of 2009 and NSD 1124 of 2009: Jones Day Lawyers
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
VID 195 of 2009
BETWEEN: SIGMA PHARMACEUTICALS (AUSTRALIA) PTY LTD
Applicant / Cross-RespondentAND: WYETH
First Respondent / First Cross-ClaimantWYETH AUSTRALIA PTY LIMITED
Second Respondent / Second Cross-Claimant
JUDGE:
JAGOT J
DATE OF ORDER:
8 NOVEMBER 2010
WHERE MADE:
SYDNEY
THE COURT DECLARES THAT:
1.The Applicant / Cross-Respondent has threatened to infringe each of claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of Australian Patent No 2003259586 (the Patent) by importing, marketing, taking orders for, selling, supplying, and offering to supply products included in the Australian Register of Therapeutic Goods under the name “Evelexa XR” (the Evelexa XR Products) in Australia for use by persons in need of venlafaxine for treatment of depression or social anxiety disorder, and by authorising, procuring or inducing or joining in a common design with other persons to do such acts, without the licence or authority of First Respondent / First Cross-Claimant.
THE COURT ORDERS THAT:
2.The draft reasons for judgment provided to the parties on 23 September 2010 be published as the reasons for judgment, except for:
(a)the quote in [624]: 2nd paragraph last sentence, 4th paragraph after “excipients” to the end of the 4th paragraph, 5th paragraph last sentence;
(b)[628] 3rd to 6th sentences inclusive; and
(c)[629] 4th to 8th sentences inclusive
(together the confidential sentences).
3.The parties be provided with the reasons for judgment both as published and including the confidential sentences.
4.The confidential sentences be kept confidential by the parties (other than Alphapharm Pty Limited) and not be disclosed other than to their legal representatives and such other person as may be agreed to in writing by Alphapharm Pty Limited.
5.The Application be dismissed.
6.Order 1 made on 3 June 2009 be discharged and the Respondents / Cross-Claimants be released from the undertakings given by them to the Court in relation to those orders, being undertakings:
(a)to submit to such order (if any) as the Court may consider to be just for the payment of compensation, to be assessed by the Court or as it may direct, to any person, whether or not a party, adversely affected by any operation of those orders or any continuation (with or without variation) thereof; and
(b)to pay the compensation referred to in (a) to the person there referred to.
7.The Applicant / Cross-Respondent (whether by itself, its directors, servants, agents or otherwise) be restrained from infringing claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of the Patent, including, without limitation, by, in Australia, during the term of the Patent and without the licence or authority of the First Respondent / First Cross-Claimant:
(a)importing, marketing, taking orders for, selling, supplying or offering to supply the Evelexa XR Products (or any other product comprising the same generic extended release formulation of venlafaxine hydrochloride) for use by persons in need of venlafaxine;
(b)applying to list the Evelexa XR Products (or any other product comprising the same extended release formulation of venlafaxine hydrochloride) on the Schedule of Pharmaceutical Benefits;
(c)authorising any other person to do any act referred to in sub-paragraphs (a) or (b) above; or
(d)procuring or inducing or joining in a common design with any other person to do any act referred to in sub-paragraphs (a), (b) or (c) above.
8.Within 14 days of the date of these orders the Applicant / Cross-Respondent destroy any Evelexa XR Products (or any other product comprising the same generic modified release formulation of venlafaxine hydrochloride) in Australia in the possession, power or control of the Applicant / Cross-Respondent.
9.Within 14 days of the date of these orders the Applicant / Cross-Respondent file and serve an affidavit verifying compliance with order 8 of these orders.
10.The Applicant / Cross-Respondent pay the Respondents / Cross-Claimants’ costs of and incidental to the proceeding, as agreed or taxed.
THE COURT CERTIFIES THAT
11.For the purpose of section 19 of the Patents Act 1990 (Cth), the validity of claims 1 to 28 of the Patent was questioned unsuccessfully in this proceeding.
THE COURT FURTHER:
12.ORDERS that orders 8, 9 and 11 above be stayed:
(a)initially until the date which is 14 days after the making of these orders; and
(b)if a notice of appeal to the Full Court of the Federal Court is filed within that period, until the determination of that appeal.
13.ORDERS the Applicant, during the currency of the stay in order 12 above, not to move, transfer, or otherwise deal in any Evelexa XR Products.
14.NOTES the undertaking of the Respondents / Cross-Claimants to the Court that, until further order, they will not make any application to de-list Efexor-XR from the Pharmaceutical Benefits Scheme.
15.ORDERS that the notice of motion filed 27 October 2010 be dismissed with costs.
Note:Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.
The text of entered orders can be located using Federal Law Search on the Court’s website.
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 596 of 2009
BETWEEN: ALPHAPHARM PTY LIMITED
Applicant / Cross-RespondentAND: WYETH
First Respondent / First Cross-ClaimantWYETH AUSTRALIA PTY LIMITED
Second Respondent / Second Cross-Claimant
JUDGE:
JAGOT J
DATE OF ORDER:
8 NOVEMBER 2010
WHERE MADE:
SYDNEY
THE COURT DECLARES THAT:
1.The Applicant / Cross-Respondent has threatened to infringe each of claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of Australian Patent No 2003259586 (the Patent) by importing, marketing, taking orders for, selling, supplying, and offering to supply products included in the Australian Register of Therapeutic Goods under the name “Enlafax-XR” (the Enlafax-XR Products) in Australia for use by persons in need of venlafaxine for treatment of depression or social anxiety disorder, and by authorising, procuring or inducing or joining in a common design with other persons to do such acts, without the licence or authority of First Respondent / First Cross-Claimant.
THE COURT ORDERS THAT:
2.The draft reasons for judgment provided to the parties on 23 September 2010 be published as the reasons for judgment, except for:
(a)the quote in [624]: 2nd paragraph last sentence, 4th paragraph after “excipients” to the end of the 4th paragraph, 5th paragraph last sentence;
(b)[628] 3rd to 6th sentences inclusive; and
(c)[629] 4th to 8th sentences inclusive
(together the confidential sentences).
3.The parties be provided with the reasons for judgment both as published and including the confidential sentences.
4.The confidential sentences be kept confidential by the parties (other than Alphapharm Pty Limited) and not be disclosed other than to their legal representatives and such other person as may be agreed to in writing by Alphapharm Pty Limited.
5.The Application be dismissed.
6.Orders 1 and 2 made on 25 August 2009 be discharged and the Respondents / Cross-Claimants be released from the undertakings given by them to the Court in relation to those orders, being undertakings:
(a)to submit to such order (if any) as the Court may consider to be just for the payment of compensation, to be assessed by the Court or as it may direct, to any person, whether or not a party, adversely affected by any operation of those orders or any continuation (with or without variation) thereof; and
(b)to pay the compensation referred to in (a) to the person there referred to; and
(c)until further order, not to make any application to de-list Efexor-XR from the Pharmaceuticals Benefits Scheme.
7.The Applicant / Cross-Respondent (whether by itself, its directors, servants, agents or otherwise) be restrained from infringing claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of the Patent, including, without limitation, by, in Australia, during the term of the Patent and without the licence or authority of the First Respondent / First Cross-Claimant:
(a)importing, marketing, taking orders for, selling, supplying or offering to supply the Enlafax-XR Products (or any other product comprising the same generic modified release formulation of venlafaxine hydrochloride) for use by persons in need of venlafaxine;
(b)importing, marketing, taking orders for, selling, supplying or offering to supply the Enlafax-XR Products (or any other product comprising the same generic modified release formulation of venlafaxine hydrochloride) together with the giving of, or the publication of advertisements containing, instructions or inducements for the use of the Enlafax-XR Products by persons in need of venlafaxine;
(c)applying to list the Enlafax-XR Products (or any other product comprising the same generic modified release formulation of venlafaxine hydrochloride) on the Schedule of Pharmaceutical Benefits;
(d)authorising any other person to do any act referred to in sub-paragraphs (a), (b), or (c) above; or
(e)procuring or inducing or joining in a common design with any other person to do any act referred to in sub-paragraphs (a), (b), (c) or (d) above.
8.Within 14 days of the date of this order the Applicant / Cross-Respondent destroy any Enlafax-XR Products (or any other product comprising the same generic modified release formulation of venlafaxine hydrochloride) in Australia in the possession, power or control of the Applicant / Cross-Respondent.
9.Within 14 days of the date of this order the Applicant / Cross-Respondent file and serve an affidavit verifying compliance with order 8 of these orders.
10.The Applicant / Cross-Respondent pay the Respondents / Cross-Claimants’ costs of and incidental to the proceeding, as agreed or taxed.
THE COURT CERTIFIES THAT:
11.For the purpose of section 19 of the Patents Act 1990 (Cth), the validity of claims 1 to 28 of the Patent was questioned unsuccessfully in this proceeding.
THE COURT FURTHER:
12.ORDERS that upon the undertaking noted in paragraph 13 below, orders 8, 9 and 11 above be stayed:
(a)initially until the date which is 14 days after the making of these orders; and
(b)if a notice of appeal to the Full Court of the Federal Court is filed within that period, until the determination of that appeal.
13.NOTES that the Applicant undertakes to the Court that, during the currency of the stay in order 12 above, it will not move, transfer, or otherwise deal in any Enlafax-XR Products.
14.NOTES the undertaking of the Respondents / Cross-Claimants to the Court that, until further order, they will not make any application to de-list Efexor-XR from the Pharmaceutical Benefits Scheme.
Note:Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.
The text of entered orders can be located using Federal Law Search on the Court’s website.
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 1124 of 2009
BETWEEN: GENERIC HEALTH PTY LTD
Applicant / Cross-RespondentAND: WYETH
First Respondent / First Cross-ClaimantWYETH AUSTRALIA PTY LIMITED
Second Respondent / Second Cross-Claimant
JUDGE:
JAGOT J
DATE OF ORDER:
8 NOVEMBER 2010
WHERE MADE:
SYDNEY
THE COURT DECLARES THAT:
1.The Applicant / Cross-Respondent has threatened to infringe each of claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of Australian Patent No 2003259586 (the Patent) by importing, marketing, taking orders for, selling, supplying, and offering to supply any products the subject of ARTG registration numbers 151874, 151875, 151876, 151877, 151878, 151880, 151884, 151885 (the GH Products) in Australia for use by persons in need of venlafaxine for the treatment of depression or social anxiety disorder.
THE COURT ORDERS THAT
2.The draft reasons for judgment provided to the parties on 23 September 2010 be published as the reasons for judgment, except for:
(a)the quote in [624]: 2nd paragraph last sentence, 4th paragraph after “excipients” to the end of the 4th paragraph, 5th paragraph last sentence;
(b)[628] 3rd to 6th sentences inclusive; and
(c)[629] 4th to 8th sentences inclusive
(together the confidential sentences).
3.The parties be provided with the reasons for judgment both as published and including the confidential sentences.
4.The confidential sentences be kept confidential by the parties (other than Alphapharm Pty Limited) and not be disclosed other than to their legal representatives and such other person as may be agreed to in writing by Alphapharm Pty Limited.
5.The Application be dismissed.
6.Order 1 made on 10 November 2009 be discharged and the Respondents / Cross-Claimants be released from the undertakings given by them to the Court in relation to those orders, being undertakings:
(a)to submit to such order (if any) as the Court may consider to be just for the payment of compensation, to be assessed by the Court or as it may direct, to any person, whether or not a party, adversely affected by any operation of those orders or any continuation (with or without variation) thereof; and
(b)to pay the compensation referred to in (a) to the person there referred to; and
(c)until further order, not to make any application to de-list Efexor-XR from the Pharmaceuticals Benefits Scheme.
7.The Applicant / Cross-Respondent (whether by itself, its directors, servants, agents or otherwise) be restrained from infringing claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of the Patent, including, without limitation, by, in Australia, during the term of the Patent and without the licence or authority of the First Respondent / First Cross-Claimant:
(a)importing, marketing, taking orders for, selling, supplying or offering to supply the GH Products (or any other product comprising the same generic extended release formulation of venlafaxine hydrochloride) for use by persons in need of venlafaxine;
(b)applying to list the GH Products (or any other product comprising the same extended release formulation of venlafaxine hydrochloride) on the Schedule of Pharmaceutical Benefits;
(c)authorising any other person to do any act referred to in sub-paragraphs (a) or (b) above; or
(d)procuring or inducing or joining in a common design with any other person to do any act referred to in sub-paragraphs (a), (b) or (c) above.
8.Within 14 days of the date of these orders the Applicant / Cross-Respondent destroy any GH Products (or any other product comprising the same generic modified release formulation of venlafaxine hydrochloride) in Australia in the possession, power or control of the Applicant / Cross-Respondent.
9.Within 14 days of the date of these orders the Applicant / Cross-Respondent file and serve an affidavit verifying compliance with order 8 of these orders.
10.The Applicant / Cross-Respondent pay the Respondents / Cross-Claimants’ costs of and incidental to the proceeding, as agreed or taxed.
THE COURT CERTIFIES THAT:
11.For the purpose of section 19 of the Patents Act 1990 (Cth), the validity of claims 1 to 28 of the Patent was questioned unsuccessfully in this proceeding.
THE COURT FURTHER:
12.ORDERS that orders 8, 9 and 11 above be stayed:
(a)initially until the date which is 14 days after the making of these orders; and
(b)if a notice of appeal to the Full Court of the Federal Court is filed within that period, until the determination of that appeal.
13.ORDERS the Applicant, during the currency of the stay in order 12 above, not to move, transfer, or otherwise deal in any GH Products.
14.NOTES the undertaking of the Respondents / Cross-Claimants to the Court that, until further order, they will not make any application to de-list Efexor-XR from the Pharmaceutical Benefits Scheme.
Note:Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.
The text of entered orders can be located using Federal Law Search on the Court’s website.
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
VID 195 of 2009
BETWEEN: SIGMA PHARMACEUTICALS (AUSTRALIA) PTY LTD
Applicant / Cross-RespondentAND: WYETH
First Respondent / First Cross-ClaimantWYETH AUSTRALIA PTY LIMITED
Second Respondent / Second Cross-Claimant
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 596 of 2009
BETWEEN: ALPHAPHARM PTY LIMITED
Applicant / Cross-RespondentAND: WYETH
First Respondent / First Cross-ClaimantWYETH AUSTRALIA PTY LIMITED
Second Respondent / Second Cross-Claimant
IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION
NSD 1124 of 2009
BETWEEN: GENERIC HEALTH PTY LTD
Applicant / Cross-RespondentAND: WYETH
First Respondent / First Cross-ClaimantWYETH AUSTRALIA PTY LIMITED
Second Respondent / Second Cross-Claimant
JUDGE:
JAGOT J
DATE:
8 NOVEMBER 2010
PLACE:
SYDNEY
REASONS FOR JUDGMENT
A INTRODUCTION
A1 The proceedings
These proceedings concern the validity and, if valid, alleged infringement of Australian Patent No 2003259586 entitled “extended release formulation” granted on 11 May 2007 (the patent). The patent relates to the compound venlafaxine hydrochloride.
The compound, venlafaxine hydrochloride, was the subject of Australian Patent No 567524 (the compound patent). The compound patent expired on 6 December 2008.
A2 The parties
The respondent/cross-claimant Wyeth, an innovator pharmaceutical company, is the patentee of the patent. Wyeth’s subsidiary, Wyeth Australia Pty Limited (together, Wyeth), sells an extended release dosage form of venlafaxine hydrochloride in Australia known as Efexor-XR. Efexor-XR is an anti-depressant. Wyeth released Efexor-XR for sale in Australia in February 1999. Earlier, in mid 1996, Wyeth released in Australia an immediate release dosage form of venlafaxine hydrochloride known as Efexor or Efexor-IR.
The applicants/cross-respondents, Sigma Pharmaceuticals (Australia) Pty Ltd (Sigma), Alphapharm Pty Limited (Alphapharm) and Generic Health Pty Ltd (Generic Health) are generic pharmaceutical companies which have obtained registration of extended release formulations of venlafaxine hydrochloride on the Australian Register of Therapeutic Goods. Sigma’s product is known as Evelexa XR, Alphapharm’s as Enlafax-XR and Generic Health’s as “generichealth XR”.
A3 Background
Wyeth contends that the use of Evelexa XR, Enlafax-XR and generichealth XR as the applicants intend for the treatment of depression will infringe the patent. Wyeth asserts infringement of claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of the patent. The applicants’ principal defence to infringement is invalidity of the patent. They also contend that, if the patent is valid, their products do not infringe the patent.
On 3 June, 25 August and 10 November 2009 interlocutory orders were made restraining each of the applicants from selling their products pending the final hearing and determination of these proceedings (see Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth (2009) 81 IPR 339; [2009] FCA 595 and Alphapharm Pty Ltd v Wyeth (2009) 82 IPR 71; [2009] FCA 945).
A4 Issues
Subject to variations, the applicants assert invalidity of the patent on the grounds of:
·lack of novelty by reason of a deferred priority date and anticipation by another patent known as the Alza or Edgren patent;
·lack of fair basis;
·insufficiency;
·lack of clarity/ambiguity;
·lack of inventive step;
·false suggestions or misrepresentations; and
·lack of entitlement.
Although there are differences between the applicants’ arguments, Sigma’s closing submissions provide a convenient summary of the “essence of the attack” on validity, namely:
(a)by amendments made to the Patent specification and claims on and subsequent to 20 December 2006, after filing of the complete specification and prior to acceptance, Wyeth has travelled beyond the disclosure in both the Priority Document and the Patent as filed and thus the claims asserted against [the applicants] are not entitled to claim a priority date prior to 20 December 2006;
(b)if the priority date issue is resolved in [the applicants’] favour, the claims are anticipated by Wyeth’s sale of its own form of EFEXOR XR (an extended release form of venlafaxine hydrochloride);
(c)in any event, the invention purportedly claimed in claims 1 to 17 (and 27 insofar as it is dependent upon those claims) of the Patent does not disclose a manner of manufacture and is not inventive;
(d)the amended form of the Patent was obtained upon the making of false representations to the Commissioner of Patents, which materially contributed to the grant;
(e)Wyeth was not entitled to the Patent. In each of Canada and the United States, Wyeth filed declarations with the respective Patent Offices disclosing that, in addition to Ms Sherman, there were three additional inventors (and evidence has been filed by legal experts in each of those two countries as to the meaning and effect of those declarations as a matter of law in Canada and the United States of America respectively), late evidence filed in the last week of the hearing of evidence seeks, but fails to overcome this issue. Indeed it highlights the nature of the misrepresentation to the Commissioner of Patents concerning the identity of the inventor;
(f)in critical respects the claims of the Patent lack clarity and therefore do not claim an invention; and
(g)the claims are not fairly based on the disclosure in the Priority Document (external fair basing) nor the body of the specification (internal fair basing) whether or not the priority date is deferred.
The “priority document” referred to in Sigma’s submissions is United States Patent Application No 60/14006 (the US priority document). Based on the US priority document Wyeth claims a priority date for the patent of 25 March 1996. Wyeth accepts that if the priority date is 20 December 2006, as the applicants contend, the invention claimed in the patent is not novel by reason of the sale in Australia of Efexor-XR from February 1999.
A5 Meaning of terms
In these reasons certain terms and abbreviations appear. Their meaning is as follows:
AUC means the area under the curve of the plasma profile of a drug.
BID (bid) means a twice daily dose of a drug.
Cmax means the maximum plasma concentration of a drug.
Cmin means the minimum plasma concentration of a drug.
ER means an extended release oral dose formulation of a drug where, after ingestion, the formulation prevents the complete and immediate release of the drug. The time over which the drug is released is thus extended compared to an immediate release form.
GI tract (GIT) means the gastrointestinal tract.
GITS formulation or ALZA formulation or OROS formulation means gastrointestinal therapeutic system formulation, being an alternative ER formulation of venlafaxine hydrochloride to that disclosed in the patent.
HPMC means hydroxypropylmethylcellulose, a compound used in drug formulation.
In vitro means “in the glass” (that is, a procedure performed in a controlled environment such as a test tube).
In vivo means “in life” (that is, a procedure performed in a living organism).
IR means an immediate release oral dose formulation of a drug where, after ingestion, the drug is completely and immediately released from the dose form (that is, there are no formulation-related factors which impede the complete and immediate release of the drug).
LogP means the partition coefficient or the distribution between water and oil phases, being a measure of the hydrophilicity or lipophilicity of a drug.
NDA means New Drug Application.
ODV means an active metabolite of venlafaxine, O-desmethyl venlafaxine.
PD profile means the pharmacodynamic profile of a drug or the desired biological response to the drug.
PK profile means the pharmacokinetic profile of a drug, being the concentration-time course profile of drug within the systemic blood, which is a composite of the processes of drug release from the formulation, and subsequent absorption, distribution, metabolism, and elimination, all of which may be occurring simultaneously after oral administration of the drug.
PK/PD means the relationship between the pharmacodynamic and pharmacokinetic profile of a drug.
Plasma profile is the measurement of the plasma concentration of a drug over an appropriate period. Plasma profile is characterised by the shape of the curve (or graph) determined from graphically plotting the plasma concentration of drug as a function over time.
SNRI means a selective serotonin and noradrenalin re-uptake inhibitor.
SSRI means a selective serotonin re-uptake inhibitor.
SR is often used as synonymous with ER and means an extended or sustained release oral dose formulation of a drug.
TID (tid) means a three time daily dose of a drug.
Tmax means the time at which the maximum plasma concentration of the drug (the Cmax) occurs.
The Alza (or Edgren) Patent means International Patent Publication No WO 94/27589 published on 8 December 1994.
The compound patent means Australian Patent No 567524.
The DeVane article means DeVane CL, “Pharmacokinetics of the Newer Antidepressants: Clinical Relevance” (1994) 97(6A) The American Journal of Medicine 13S-23S.
The First Troy article means Troy SM et al, “The Pharmacokinetics of Venlafaxine when given in a Twice Daily Regimen” (1995) 35 Journal of Clinical Pharmacology 404-409.
The grandparent means Australian Patent Application No 16400/97.
The Klamerus article means Klamerus KJ et al, “Introduction of a Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite” (1992) 32 Journal of Clinical Pharmacology 716-724.
The Martindale Monograph or article means Reynolds JEF (ed), Martindale, The Extra Pharmacopeia (31st ed, Royal Pharmaceutical Society, 1996).
The Merck Index means Budavari S et al (eds), The Merck Index (12th ed, Merck & Co Inc, 1996).
The MIMS Annual means 1997 MIMS Annual – Australian Edition (MIMS Australia, 1997).
The Morton article means Morton WA et al, “Venlafaxine: A Structurally Unique and Novel Antidepressant” (1995) 29 The Annals of Pharmacotherapy 387-395.
The Muth article means Muth EA et al, “Biochemical, Neurophysiological, and Behavioral Effects of Wy-45,233 and Other Identified Metabolites of the Antidepressant Venlafaxine” (1991) 23 Drug Development Research 191-199.
The parent means Australian Patent Application No 65442/00.
The patent means Australian Patent No 2003259586.
The Second Troy article means Troy SM et al, “Pharmacokinetic and Pharmacodynamic Evaluation of the Potential Drug Interaction between Venlafaxine and Diazepam” (1995) 35 Journal of Clinical Pharmacology 410-419.
US priority document means United States Patent Application No 60/14006.
A6 Table of contents
These reasons are divided into the following sections:
A........ INTRODUCTION........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[1]
A1...... The proceedings........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[1]
A2...... The parties........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[3]
A3...... Background........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[5]
A4...... Issues........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[7]
A5...... Meaning of terms........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[10]
A6...... Table of contents........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[11]
B........ THE PATENT AND ITS BACKGROUND........ ........ ........ ........ ........ ........ ........ ....
[12]
B1...... The patent........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....
[12]
B2...... The amendments of 20 December 2006........ ........ ........ ........ ........ ........ .......
[22]
C........ OVERVIEW OF EVIDENCE........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[26]
C1...... Professor Charman........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .......
[27]
C2...... Professor McLachlan........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[32]
C3...... Dr Marshall........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[42]
C4...... Dr Reece........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .......
[53]
C5...... Dr Rowe........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........
[62]
C6...... Professor Grabowski........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[69]
D........ THE DEVELOPMENT PROCESS........ ........ ........ ........ ........ ........ ........ ........ ........ .
[77]
E........ INCORPORATION BY REFERENCE GENERALLY........ ........ ........ ........ ........ ..
[146]
F........ . THE PRIORITY DATE........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[152]
F1....... The US priority document........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[153]
F2....... The Alza or Edgren patent........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[166]
G........ SECTION 40 ISSUES........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ......
[175]
G1...... Fair basis........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .......
[177]
G2...... Sufficiency........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[227]
G3...... Lack of clarity........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .......
[239]
H........ INVENTIVE STEP........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[242]
H1...... General principles........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .
[245]
H2...... Overview of the applicants’ case........ ........ ........ ........ ........ ........ ........ ........ ..
[258]
H3...... The essence of the debate........ ........ ........ ........ ........ ........ ........ ........ ........ .....
[264]
H4...... Issues relating to hindsight........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[265]
H5...... Problem-solution approach........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[333]
H6...... Issues facing the skilled addressee – Professor Charman’s evidence........ ..
[340]
H7...... Absorption........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[373]
H8...... Metabolism........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[393]
H9...... Side effects........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[407]
H10.... Therapeutic efficacy........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....
[417]
H11.... Approaches of experts called by applicants........ ........ ........ ........ ........ ........ .
[431]
H12.... Wyeth’s development work........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[453]
H13.... Professor McLachlan’s draft affidavit........ ........ ........ ........ ........ ........ ........ ..
[460]
H14.... Persuasiveness of experts........ ........ ........ ........ ........ ........ ........ ........ ........ .....
[464]
H15.... Other points........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[479]
H16.... Conclusions on inventive step........ ........ ........ ........ ........ ........ ........ ........ ......
[486]
H17.... Commercial success........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....
[491]
I........ . FALSE SUGGESTIONS OR MISREPRESENTATIONS........ ........ ........ ........ ......
[515]
I1........ Background........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[515]
I2........ The completely unexpected and impossible to achieve representations......
[518]
I3........ Alza representation........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .......
[534]
I4........ The sole inventor representation........ ........ ........ ........ ........ ........ ........ ........ ..
[541]
I5........ Reduction in side effects........ ........ ........ ........ ........ ........ ........ ........ ........ ......
[555]
J........ . ENTITLEMENT........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ......
[556]
J1........ Background........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[556]
J2........ Facts........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ......
[561]
J3........ Applicants’ case........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[572]
J4........ Wyeth’s response........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[580]
J5........ Conclusions on entitlement........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[587]
J6........ The pleading point........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........
[591]
J7........ Mr Smith and Mr Sheskey........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[594]
K........ UTILITY........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..
[601]
L........ REVOCATION OF THE PATENT........ ........ ........ ........ ........ ........ ........ ........ ........ .
[603]
M....... INFRINGEMENT........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....
[605]
M1...... The dispute........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...
[605]
M2...... Conclusions on infringement........ ........ ........ ........ ........ ........ ........ ........ ........
[620]
N........ CONCLUSIONS........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ......
[632]
B THE PATENT AND ITS BACKGROUND
B1 The patent
The patent application was filed on 30 October 2003. On 20 December 2006 an amended specification was lodged. The patent was granted on 11 May 2007. The patent is a divisional of Australian Patent Application No 65442/00 filed on 10 October 2000 (the parent) which is a divisional of Australian Patent Application No 16400/97 filed on 20 March 2007 (the grandparent). According to the patent:
…the entire disclosure of both of these earlier applications is incorporated herein by reference.
The patent claims a priority date of 25 March 1996 based on the US priority document.
According to that part of the patent entitled “background of the invention” venlafaxine is “an important drug in the neuropharmacological arsenal used for treatment of depression”. Further, that extended release drug formulations are “conventionally produced as compressed tablets by hydrogel tablet technology”. However, where “the production of tablets is not feasible, it is conventional in the drug industry to prepare encapsulated drug formulations which provide extended or sustained release properties”. This part of the patent also states:
Venlafaxine hydrochloride is presently administered to adults in compressed tablet form in doses ranging from 75 to 350 mg/day, in divided doses two or three times a day. In therapeutic dosing with venlafaxine hydrochloride tablets, rapid dissolution results in a rapid increase in blood plasma levels of the active compound shortly after administration followed by a decrease in blood plasma levels over several hours as the active compound is eliminated or metabolized, until sub-therapeutic plasma levels are approached after about twelve hours following administration, thus requiring additional dosing with the drug. With the plural daily dosing regimen, the most common side effect is nausea, experienced by about 45% of patients under treatment with venlafaxine hydrochloride. Vomiting also occurs in about 17% of the patients.
This part of the patent concludes with the statement:
The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims.
There follows in the patent a “brief description of the invention”. The opening paragraph to this part states:
In accordance with this invention, there is provided a method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.
In a further embodiment, there is provided a method for moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilization of multiple daily dosing with venlafaxine hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.
In a further embodiment, there is provided a method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine by administering orally to said patient, a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period and a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.
In a further embodiment, there is provided a method for treating depression in a patient in need of such treatment, said method including the steps of administering orally to said patient, a single daily dosing formulation of venlafaxine hydrochloride over a 24 hour period with a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.
In a further embodiment, there is provided a method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over the 24 hour period with a peak blood plasma concentration of no more than 150 ng/ml.
Other embodiments and examples of the invention are then identified.
This part of the patent also contains the following statements:
It was completely unexpected that a single daily dosing formulation containing venlafaxine hydrochloride for use in the methods of the invention could be obtained because the hydrochloride of venlafaxine proved to be extremely water soluble. Numerous attempts to produce single daily dosing, extended release or tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies. Typically, the tablets prepared as hydrogel sustained release formulations gave 40% to 50% dissolution at 2 hrs, 60% to 70% dissolution at 4 hrs and 85% to 100% dissolution at 8 hrs.
Numerous spheroid formulations were prepared using different grades of microcrystalline cellulose and hydroxypropylmethylcellulose, different ratios of venlafaxine hydrochloride and filler, different binders such as polyvinylpyrrolidone, methylcellulose, water, and polyethylene glycol of different molecular weight ranges in order to find a formulation which would provide a suitable granulation mix which could be extruded properly. In the extrusion process, heat buildup occurred which dried out the extrudate so much that it was difficult to convert the extruded cylinders into spheroids. Addition of hydroxypropylmethylcellulose 2208 to the venlafaxine hydrochloride-microcrystalline cellulose mix made production of spheroids practical which proved to be practical for a single daily dosing formulation useful in the methods of the invention.
The following examples are presented to illustrate applicant’s solution to the problem of preparation of the extended release drug containing formulations of this invention.
Four examples of venlafaxine hydrochloride extended release capsules are then given. Towards the end of this section another statement is made in these terms:
Thus, the desired dissolution rate of a sustained release dosage form of venlafaxine hydrochloride, impossible to achieve with hydrogel tablet technology, has been achieved with the film-coated spheroid compositions of this invention.
The patent then identifies the claims defining the invention. There are 28 claims. The claims include:
1.A method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.
…
4.A method for treating depression in a patient in need of such treatment, which comprises administering orally to said patient, a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.
5.A method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over the 24 hour period with a peak blood plasma level of no more than 150 ng/ml.
…
8.A method for treating depression in a patient in need of such treatment, said method including the steps of administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml.
9.A method according to any one of claims 1 to 4 wherein the formulation provides a peak blood plasma level of venlafaxine of no more than 150 ng/ml.
10.A method according to any one of claims 5 to 7 wherein the formulation provides peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.
…
15.A method according to any one of the preceding claims, wherein the formulation of venlafaxine hydrochloride is an extended release formulation that is administered as a single daily dosing formulation.
16.A method according to any one of the preceding claims wherein the formulation provides a peak blood plasma level of venlafaxine from 5-8 hours after administration.
…
27.A method according to any one of the preceding claims wherein the formulation is an encapsulated formulation.
As Alphapharm submitted, these claims essentially involve one or more of the following four integers:
·administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride;
·that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period;
·that provides a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration; and
·with a peak blood plasma level of no more than 150 ng/ml.
B2 The amendments of 20 December 2006
The amendments made to the specification for the patent on 20 December 2006 are relevant to the applicants’ arguments. Section 116 of the Patents Act 1990 (Cth) (the Act) provides that:
The Commissioner or a court may, in interpreting a complete specification as amended, refer to the specification without amendment.
The original specification, as filed, was also entitled “extended release formulation”. The part of the patent entitled “background of the invention” remained much the same before the amendments. The part entitled “brief description of the invention”, however, stated:
In accordance with this invention, there is provided an extended release (ER), encapsulated formulation containing venlafaxine hydrochloride as the active drug component, which provides in a single dose, a therapeutic blood serum level over a twenty four hour period.
Through administration of the venlafaxine formulation of this invention, there is provided a method for obtaining a flattened drug plasma concentration to time profile, thereby affording a tighter plasma therapeutic range control than can be obtained with multiple daily dosing. In other words, this invention provides a method for eliminating the sharp peaks and troughs (hills and valleys) in blood plasma drug levels induced by multiple daily dosing with conventional immediate release venlafaxine hydrochloride tablets. In essence, the plasma levels of venlafaxine hydrochloride rise, after administration of the extended release formulations of this invention, for between about five to about eight hours (optimally about six hours) and then begin to fall through a protracted, substantially linear decrease from the peak plasma level for the remainder of the twenty four hour period, maintaining at least a threshold therapeutic level of the drug during the entire twenty-four period. In contrast, the conventional immediate release venlafaxine hydrochloride tablets give peak blood plasma levels in 2 to 4 hours. Hence, in accordance with the use aspect of this invention, there is provided a method for moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilization of multiple daily tablet dosing with venlafaxine hydrochloride which comprises administering to a patient in need of treatment with venlafaxine hydrochloride, a one-a-day, extended release formulation of venlafaxine hydrochloride.
The use of the one-a-day venlafaxine hydrochloride formulations of this invention reduces by adaptation, the level of nausea and incidence of emesis that attend the administration of multiple daily dosing. In clinical trials of venlafaxine hydrochloride ER, the probability of developing nausea in the course of the trials was greatly reduced after the first week. Venlafaxine ER showed a statistically significant improvement over conventional venlafaxine hydrochloride tablets in two eight-week and one 12 week clinical studies. Thus, in accordance with this use aspect of the invention there is provided a method for reducing the level of nausea and incidence of emesis attending the administration of venlafaxine hydrochloride which comprises dosing a patient in need of treatment with venlafaxine hydrochloride with an extended release formulation of venlafaxine hydrochloride once a day in a therapeutically effective amount.
None of the paragraphs starting with the words “In a further embodiment” were contained in the original specification. Instead there followed a part entitled “detailed description of the invention” stating:
The extended release formulations of this invention are comprised of 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride in admixture with microcrystalline cellulose and hydroxypropylmethylcellulose.
Other amendments (both by deletion and addition) were made to the specification before that part of the document describing the four examples of venlafaxine hydrochloride extended release capsules and the claims (which were also amended).
C OVERVIEW OF EVIDENCE
The central witnesses in the proceeding and matters dealt with in their evidence are set out below.
C1 Professor Charman
Professor Neil Charman graduated with a Bachelor of Pharmacy from the Victorian College of Pharmacy in 1981. He became a Doctor of Philosophy (PhD) in pharmaceutical chemistry in 1985. Between 1983 and 1985 he was a graduate research assistant at the University of Kansas. From 1986 to 1987 he was employed at the Sterling-Winthrop Research Institute, as a senior research scientist in the Department of Pharmaceutical Sciences. He was promoted to Institute Group Leader in 1988. He returned to Australia in 1989 to take up the position of senior lecturer in Pharmaceutics in the Department of Pharmaceutics, Victorian College of Pharmacy, Monash University. From 1989 to 1995 he held the positions of senior lecturer, was then appointed Personal Chair as Professor of Pharmaceuticals (June 1995 to December 2006), and Associate Dean (Research) (March 1999 to March 2002). In January 2007 he was appointed Dean of the Victorian College of Pharmacy, Monash University and Director of the Monash Institute of Pharmaceutical Sciences, Monash University. He continues to hold both positions although the Victorian College of Pharmacy has been re-named as the Faculty of Pharmacy and Pharmaceutical Sciences. According to Professor Charman the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University is the “most successful, largest and most experienced pharmaceutical sciences research program in Australia”.
Professor Charman’s major research areas include:
(a)lead optimisation and absorption, distribution, metabolism and excretion (ADME) studies for new drug candidates including metabolic profiling, bioavailability and pharmacokinetic assessment, toxicokinetic assessment and preformulation assessment. These programs typically involve extensive collaborations between the disciplines of drug discovery, medicinal chemistry and biological scientists;
(b)a multidisciplinary and collaborative approach to address major issues in drug discovery, drug delivery and the pharmaceutical sciences, especially in the field of malaria and neglected diseases. These studies typically involve the lead optimisation and compound design using a variety of structural biology, in vitro activity and in vivo animal models, pharmacokinetic and metabolic studies and early stage exploratory toxicology studies;
(c)the use of lipids and lipidic excipients to enhance the oral bioavailability of poorly absorbed drugs. This includes formulation design, physiochemical approaches to enhanced absorption and the assessment of the effects of lipids and lipidic excipients on biological factors;
(d)lymphatic drug transport and the major factors that can be manipulated, or exploited, to increase intestinal drug transport. This work includes assessment of the effects of post-prandial plasma lipoproteins on drug metabolism and drug clearance; and
(e)the integration of interfacial and colloidal chemistry for the optimal design and evaluation of multiphase pharmaceutical formulations which include microemulsions, self-emulsifying lipid emulsions, interactive solids and a variety of colloidal-based formulations.
Professor Charman has published in excess of 330 scientific papers and communications and given over 150 invited national and international presentations and lectures.
In addition to holding the academic positions detailed above, Professor Charman has also held the following key external appointments:
(a)Deputy Chair of the Expert Scientific Advisory Committee of the Medicines for Malaria Venture, which is a leading Public Private Partnership with an annual research budget of $50M USD for drug discovery and development for the treatment of malaria, based in Geneva, Switzerland;
(b)since 2006, the Chair of the Wellcome Trust Seeding Drug Discovery Committee based in London, UK. This is a 5 year, £91M program that funds high quality drug discovery and development projects addressing areas of major unmet medical need;
(c)a previous advisor to the World Health Organisation and various Scientific Advisory Boards; and
(d)Member of the Board of Directors of Acrux Limited (April 1999 to April 2003), and the Board of Directors of Sigma Company Limited (November 1997 to December 2005).
Professor Charman was called as an expert witness by Wyeth. His evidence dealt primarily with the principles of pharmacokinetics and pharmacodynamics, the GI tract, IR and ER formulations, the process of development of an extended release formulation of a drug, the polypharmacology of venlafaxine hydrochloride, the pharmacokinetics/pharmacodynamics of venlafaxine, the development of an extended release formulation of venlafaxine and hydrogel tablet technology.
C2 Professor McLachlan
Professor Andrew McLachlan graduated with a Bachelor of Pharmacy degree from the University of Sydney (First Class Honours) and was awarded the University Medal.
In 1992 he obtained the degree of Doctor of Philosophy from the University of Sydney on the basis of original research which he performed in the field of clinical pharmacokinetics.
From 1992 to 1994 Professor McLachlan held the position of Postdoctoral Research Fellow in Pharmacy at the University of Manchester, UK. During this time he undertook a range of research projects in clinical and experimental pharmacokinetics and pharmacodynamics, including: the use of physiologically based pharmacokinetic models to describe the disposition of barbiturates, pharmacodynamic modelling of the response to the anticoagulant drug warfarin and the theory and application of drug targeting principles to optimise drug delivery. The research particularly involved medicines used in the therapeutic areas of cardiology as well as medicines used in the treatment of cancer.
From 1994 to 1996 Professor McLachlan took up a postdoctoral fellowship in Clinical Pharmacology and Toxicology at St Vincent’s Hospital, Sydney. This fellowship was competitively funded by the Commonwealth AIDS Research Postdoctoral Fellowship. In this role Professor McLachlan undertook research into the clinical pharmacology of medicines used in the treatment of patents with HIV.
From 1996 to the present, Professor McLachlan has worked in the Faculty of Pharmacy at the University of Sydney, where he has held the positions of: Lecturer (1996-1999), Senior Lecturer (2000-2001), Associate Professor (2005-2006) and Professor of Pharmacy (Aged Care) (2006-current). During this period Professor McLachlan has lectured extensively. His teaching responsibilities have included basic pharmaceutical sciences as well as pharmacokinetics and pharmacodynamics.
Since 1996, Professor McLachlan has consulted to a number of Australian pharmaceutical companies in relation to projects involving the design, analysis and interpretation of pharmacokinetic studies conducted as part of both new drug development and new drug formulation development. For a number of these projects, Professor McLachlan worked with a team on the design of clinical studies for investigating the pharmacokinetic characteristics of new drugs to understand their in vivo characteristics and additionally to inform the optimal dosing regimen for the medicine for evaluation in clinical trials with patients. For other projects he was involved in the design and analysis of bioequivalence studies which compare the pharmacokinetic characteristics of two brands of the same drug. He has also been engaged to provide pharmacokinetic advice and critical appraisal of clinical pharmacokinetic study reports as part of new drug development.
Since 1999, he has developed materials for and taught subjects for the Masters of Drug Development course at the University of New South Wales, covering topics such as, the dose-response relationship as a function of pharmacokinetic and pharmacodynamic properties, qualitative investigation of pharmacokinetics variables, use of pharmacokinetic variables in dosage optimisation, methods used in drug development to investigate the pharmacokinetic characteristics of new chemical entities in the pre-clinical and clinical phase, the role of pharmacokinetics in drug selection, critical appraisal of the pharmacokinetic literature, investigating drug interactions and drug population pharmacokinetics as a tool to inform drug development.
Over the last 15 years, Professor McLachlan has led and collaborated with teams conducting research into the pharmacokinetics and pharmacodynamics of drugs from a broad range of therapeutic areas including drugs that are anti-infectives, for musculoskeletal diseases, anticancer agents, immunosuppressants, for cardiovascular disease, muscle relaxants, sex hormones, antidepressants and anti-diabetic agents. Each of these research projects involved analytical chemistry, pharmacokinetic data analysis and application to the clinical setting.
Throughout Professor McLachlan’s career, he has authored more than 120 papers in peer reviewed journals. He has acquired expertise in the clinical and experimental aspects of pharmacokinetics and pharmacodynamics in special patient populations, such as the elderly. A particular research interest of Professor McLachlan is the causes and consequences of variability in patient response to medicines, and how this can be managed to optimise patient care. Another of his research interests is the use of mathematical modelling techniques to characterise pharmacokinetic variability across patient populations and to determine the factors which influence drug pharmacokinetics.
Professor McLachlan was called as an expert witness by Wyeth. His evidence covered a range of topics including: pharmaceutics (including dosage form, disintegration and dissolution), pharmacokinetics, (including absorption, distribution, elimination, drug metabolism, drug excretion and clearance), pharmacodynamics as well as pharmacokinetic modelling and its use to inform the development of modified release formulations.
C3 Dr Marshall
Dr Phillip Marshall graduated from the University of Adelaide, South Australia in 1973 with a Bachelor of Science majoring in biochemistry and organic chemistry, and in 1974 obtained Honours in organic chemistry. In 1974 he was awarded a Commonwealth Postgraduate Research Award to undertake postgraduate studies, including studies in the design and synthesis of therapeutically active molecules. In 1978 he was awarded a PhD from the University of Adelaide based on his thesis in the disciplines of physical-organic and synthetic organic chemistry.
From 1978 to 1979, Dr Marshall was a Postdoctoral Research Fellow at University College London, United Kingdom, in the Department of Chemistry, where he conducted research in connection with the synthesis of novel heterocyclic compounds. From 1999 to 1980, he was a Postdoctoral Research Associate at the University of Adelaide, in the Physical & Inorganic and Organic divisions of the Department of Chemistry. In 1981 to 1982, he was a research chemist for Colgate Palmolive Pty Ltd in Sydney.
From 1982 to 1991, Dr Marshall was employed at Faulding Pharmaceuticals (now Hospira), initially as a research and development scientist, and later in management roles in research and development, process development, scale-up and validation, and manufacturing. There he worked on projects which included:
·pharmaceutics: research, formulation and process development of new and innovative therapeutic and non-therapeutic products including controlled/sustained/enteric release therapeutic products, solid-dose forms, tablets, topical and oral liquids, creams, antiseptics etc.;
·technology transfer, scale-up design, validation and improvement of pharmaceutical and cosmetic processes and products;
·formulation development, scale-up and validation of therapeutic products involving a variety of pharmaceutical processes; and
·discovery and investigation of novel oral drug delivery systems in various oral dosage forms.
The pharmaceutical technologies with which Dr Marshall was involved at Faulding included: solid does forms (using techniques such as: wet and dry granulation, fluid-bed drying, extrusion/spheronization/marumerization, film coating, compression, slugging and encapsulation), filtration, emulsification, mixing, materials transfer, spray drying, lyophylization (freeze-drying) and packaging.
In 1991, Dr Marshall founded, and remains a director of, Pharmchem Technical Services Pty Ltd, an independent company which provides technical consultancy services to the pharmaceutical and bioscience industry. Since 1991, Dr Marshall has provided consultancy in varying capacities to over 100 companies in the Asia-Pacific region, Europe and North and South America. This has included providing strategic and scientific advice on the development of a number of confidential controlled release formulations to various clients and companies.
From 1991 to 1992, Dr Marshall was the Quality Assurance Manager at Pfizer Consumer Health, where he was responsible for all Australian and New Zealand quality issues associated with the company’s pharmaceutical operations.
Between 1994 and 2001 Dr Marshall was the Technical and Operations Manager (General Deputy Manager) at Numico Research Australia. His role involved operating and management responsibility for: scientific, clinical research management, regulatory affairs and pharmacovigilance, research and development programme, technology platform (including vaccine discovery and development, infectious diseases, (passive) vaccines, isolation and purification of novel bioactive compounds using various separation technologies to product novel and innovative compositions), and operations.
From 2004 to 2006, Dr Marshall was the General Manager, Scientific Affairs at Sigma, a senior executive position in which he had responsibility’s for Sigma’s six Australian manufacturing sites.
Dr Marshall holds the following appointments and memberships: Fellow and Chartered Chemist, Royal Australian Chemical Institute (since 1981), Member, Australian Regulatory and Clinical Scientists Association (since 1993), Authorised GMP Auditor, Australian Pesticides and Veterinary Medicines Authority (since 1995), Member, Australian Therapeutic Goods Consultants Inc (since 2001), Member, Australian Pharmaceutical Science Association (since 2001), and Member, AusBiotech Ltd (2001-2004 and 2009 to present).
Dr Marshall has previously held the following appointments and memberships: Member, Technical and regulatory Affairs Committee, Australian Health Industry Inc (2002-2004), Member, Australian Society of Cosmetic Chemists (1984-2004) and Foundation Vice-President, Australasian Research Management Society (2000-2001).
Dr Marshall was called as an expert witness by Alphapharm. Dr Marshall’s evidence dealt with the general drug development process, extended release formulations, common rationales for developing an extended release dose form prior to 25 March 1996, developing an extended release formulation as at 25 March 1996, developing an extended release formulation of venlafaxine hydrochloride and hydrogel tablet technology (including a consideration of the Alphapharm Enlafax formulation).
C4 Dr Reece
Dr Phillip Reece graduated from the University of Adelaide, South Australia with a Bachelor of Science in 1971 and was awarded First Class Honours in organic chemistry in 1972. He was awarded a PhD in medical chemistry in 1976 from the Australian National University.
After completing his PhD, Dr Reece was employed as a Hospital Scientist in the Department of Clinical Pharmacology at The Queen Elizabeth Hospital in Adelaide where he had both service-related and research-related duties. His research activities included collaborative research with various physicians and centred primarily on anti-hypertension drugs, anti-convulsives, and later oncology. Dr Reece also initiated several clinical research projects with various groups within and outside the hospital, where he had a small team of researchers working on the different projects. In 1983 Dr Reece was awarded a Churchill Fellowship pursuant to which he studied the pharmacokinetics of anticancer drugs at the Mayo Clinic in Rochester, Minnesota (US). He was also awarded Anticancer Foundation and National Health & Medical Research Council grants to support his research projects. While employed at The Queen Elizabeth Hospital, Dr Reece obtained training in pharmacokinetics, including at the Medical Centre of the University of California, San Francisco (US). During this time, Dr Reece was also part of the Adelaide Pharmacology Group, which allowed him to keep up to date with local and international developments in the area. Dr Reece remained employed at The Queen Elizabeth Hospital in various roles until September 1987.
Between January 1986 and September 1987, Dr Reece was also an evaluator for the Australian Department of Health. In this capacity he evaluated the pharmacokinetic component of applications for the regulatory approval of drugs. Dr Reece estimates that he reviewed approximately six different applications over this period, the majority of which were generic applications demonstrating bioequivalence.
In September 1987 Dr Reece became the Clinical Trials Manager at Astra Pharmaceuticals in Sydney. In this role, Dr Reece was responsible for conducting human clinical trials of Astra’s new pharmaceuticals for the purpose of obtaining regulatory approval of these products. His group had responsibility for ensuring that the clinical trial data which was generated met international regulatory requirements suitable for submission in support of a new drug application.
In 1988, Dr Reece took up the position of Associate Regional Director of Clinical Research at Parke Davis Ltd. In this role he was responsible for the clinical trial research activities of the international group in the Asia Pacific Region. The trials were with new chemical entities such as gabapentin for epilepsy and quinapril for hypertension and cardiac failure.
In 1990 Dr Reece became the Director of Clinical Pharmacology of Parke Davis in Michigan (US), where he managed the transition of new pharmaceuticals for central nervous system diseases from pre-clinical (animal trials) to Phase I and Phase IIA clinical studies (human trials). This involved testing prototype drugs in healthy human volunteers and collecting and analysing all of the associate pharmacokinetic and toxicology data. He was also responsible for preparing the clinical pharmacology reports for investigational new drugs and new drug applications and reviewed pre-clinical data for suitability for investigational new drug applications and Phase I studies with CNS drugs.
In 1993, Dr Reece took up the position of Director of Research and Development at Biota Holdings in Melbourne. During his various roles at Biota, Dr Reece was responsible for the company’s research and development activities. He was involved in research projects and establishing and expanding Biota’s laboratories.
Dr Reece left Biota in 2002 to become CEO and Managing Director of Boron Molecular Ltd in Melbourne and in 2003 became an independent consultant to the biotechnology industry both in Australia and overseas. Dr Reece is also an Honorary Senior Fellow in the Department of Pharmacology at the University of Melbourne.
Dr Reece was called as an expert witness by Alphapharm. His evidence covered a range of topics, particularly pharmacokinetic modelling in the context of the development of extended release formulations of existing drugs.
C5 Dr Rowe
Dr James Rowe completed a Bachelor of Pharmacy degree at the University of Sydney in 1998 and a Master of Science degree at Chelsea College, London in 1976. He obtained a PhD from the University of London in 1980. His PhD thesis focused on the bioavailability of microencapsulated controlled release systems. After completing his PhD, Dr Rowe was involved in supervising a Masters of Science student at the University of Sydney in a project which involved the production of controlled release formulations for oral administration using pellet technology produced by the ‘Wurster Process’ (a process of coating a drug core with various polymers in a fluid bed system and evaluating the release rate of the drug from that coating).
Dr Rowe has over 30 years’ experience in the pharmaceutical industry and in academia working in the field of general pharmaceutics, particularly on dosage form design, biopharmaceutics and pharmacokinetics.
Between September 1986 and August 1990, he worked as the Technical Manager at Abbott Laboratories in Sydney, where he was responsible for the design, evaluation and testing of new pharmaceutical formulations, as well as conducting in-house bioavailability studies on new and re-formulated products. This work included the testing of a number of extended release products for oral administration, for example, iron products such as ferrogradumet tablets and forrograd-folic tablets. During this time Dr Rowe also performed contract research for third parties involving the development of controlled release dosage forms for oral administration including matrix and encapsulated devices (for example, diethylpropion tablets with a methocel matrix).
From 1990 to 2007, Dr Rowe was the Scientific Director of Technical Consultancy Services Pty Limited, a company he co-founded. His work there included the development of at least 100 pharmaceutical dosage forms.
Dr Rowe is presently a Director of CoPharm Pty Ltd and NxGen Pharmaceuticals Pty Ltd. He is currently involved in the development of controlled release formulation of naltrexone, which can be used as an implant to treat drug addiction, and of flumazenil, for detoxification, as well as the formulation of oral controlled release formulations for various drugs for use in compounding pharmacies.
Dr Rowe is a member of the Controlled Release Society, Pharmaceutical Society of Australia, the Royal Pharmaceutical Society of Great Britain, the Royal Australian Chemical Institute, the Australian Pharmaceutical Science Association, the Sydney University Chemical Society and the Australian Academy of Forensic Scientists. As part of his work, Dr Rowe has written a number of publications in peer-reviewed journals in his area of expertise and has been named as a co-inventor on 12 patents and patent applications.
Dr Rowe was called as an expert witness by Sigma. His evidence dealt with formulation chemistry and extended release formulations of drugs, including development of an extended release formulation of venlafaxine hydrochloride.
C6 Professor Grabowski
Professor Henry Grabowski is a Professor Emeritus of Economics at Duke University (US). Professor Grabowski received his Bachelor of Science degree from Lehigh University (US) in 1962. In 1967 he obtained a PhD in Economics from Princeton University (US).
Professor Grabowski is the Director of the Program in Pharmaceuticals and Health Economics at Duke University. His academic and research specialities are the pharmaceutical industry, including “Health Economics, Economics of Innovation, Government Regulation of Business and Industrial Organisation”.
Over his career, Professor Grabowski has studied the economics of pharmaceuticals and the pharmaceutical industry, and has published numerous articles and books on this topic.
Professor Grabowski has been an advisor and consultant to the National Academy of Sciences, the Institute of Medicine, the Federal Trade Commission, the General Accounting Office, and the Office of Technology Assessment (all United States bodies). Professor Grabowski has also had visiting scholar appointments at the International Institute of Management in Berlin (Germany), the Health Care Financing Administration (Washington, DC), the office of Health Economics (London) and the Centre for Medicines Research (London). Each of these positions related to the economics of pharmaceuticals and the pharmaceutical industry.
Until 2003, Professor Grabowski was a member of the Board of Directors of Triangle Pharmaceuticals, Inc., a development stage company that specialised in antiviral drug therapies. In this role, Professor Grabowski assisted with marketing strategies for new products.
Professor Grabowski has also served as a consultant in relation to the research and development and marketing for several of the major pharmaceutical companies in the United States.
Professor Grabowski has conducted extensive research on the economics of competition in the drug industry, including the role of patents and the importance of research and development.
Professor Grabowski was called as an expert witness by Wyeth. His evidence analysed the sales performance and market position of Efexor-XR in Australia, relating sales performance and market position to the sales performance and market position of competitor drugs.
D THE DEVELOPMENT PROCESS
The parties provided different descriptions of the process of development of the invention. The relevance of this material was in issue, particularly in respect of inventive step. Be that as it may, the development story must be identified in order to resolve the disputed questions of principle and fact. The following summary is compiled from annexure 1 to Wyeth’s submissions with amendments and supplementary paragraphs from the applicants’ submissions where necessary.
On 29 April 1991, Mr Doug Smith circulated a memorandum to Dr Robin Enever, among others, in response to a “request concerning the development of a venlafaxine sustained release formulation”. The memorandum provides a description of an exercise undertaken by Mr Smith to simulate a dissolution profile and the plasma levels expected from a 75 mg and 375 mg hydrogel tablet, together with three figures demonstrating the profiles generated. Mr Smith’s work was based on pharmacokinetic data obtained from the immediate release formulation of venlafaxine.
Mr Smith simulated a “dissolution profile … that closely resembles that from the etodolac sustained release hydrogel tablet”. The trade name for etodolac is Lodine. Mr Smith said “[a]bsorption of venlafaxine from these tablets [being the sustained release tablets] would be dissolution-rate limited”. Mr Smith used a “one compartment” pharmacokinetic model. On the basis of pharmacokinetic parameters obtained from the “GTR data base” (the identity and contents of which remain unknown), Mr Smith simulated “plasma venlafaxine levels representing the minimum (37.5 mg bid) and the maximum (125 mg tid) dosage regimens from immediate release tablets” which were depicted in Figures 1 and 2 attached to the memorandum. Mr Smith said “[t]herefore, simulations of plasma venlafaxine levels from a 75 and a 375 mg tablet used the dissolution rate data directly as input into the pharmacokinetic model”. Mr Smith then said “[t]he rate of release from both tablets is sufficiently slow as to not saturate the O-desmethyl venlafaxine pathway; thus systemic availability is 70%”. Further, that “[b]oth strengths of the venlafaxine sustained release tablets would be bioequivalent with respect to AUC to their respective immediate release regimens; 100% for the 75 mg tablet and 88% for the 375 mg tablet”.
Generic Health (but not Sigma or Alphapharm) contended that the invention as claimed in claims 3, 7 and 13 (and dependent claims) is not useful as referred to in s 18(c) of the Act. The contention is that a method within the claims will not, of itself, meet the objective of reducing the level of nausea and the incidence of emesis (referring to an article by Cunningham L, “Once daily venlafaxine extended release (XR) and venlafaxine immediate release (IR) in outpatients with major depression” (1997) 9(3) Annals of Clinical Psychiatry 157.
As Wyeth noted, Generic Health did not call evidence or make submissions in support of this contention. To the extent it is pressed, the contention should be rejected. The claims are limited by result, the result being reducing the level of nausea and the incidence of emesis. By definition a method within the claims will have that result. That suffices to dispose of this issue.
L REVOCATION OF THE PATENT
603The applicants have not established any ground under s 138(3) of the Act to justify revocation of the patent in whole or part.
604Accordingly Wyeth’s case for infringement must be considered.
M INFRINGEMENT
M1 The dispute
Wyeth alleged that the applicants’ threatened activities will infringe claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of the patent.
Sigma acknowledged in opening that its defence to infringement was invalidity. In its written submissions Sigma also said, however, that Wyeth has not established infringement of claims 5, 8, 9 and 10 of the patent each of which includes the 150 ng/ml integer. This is the integer that the single daily dosing formulation provides a therapeutic blood plasma concentration of venlafaxine over the 24 hour period with a peak blood plasma level of no more than 150 ng/ml. This, said Sigma, related to the Cmax in an individual patient and not a mean.
Sigma’s product information for its product, Evelexa XR, contains the following statement:
After administration of modified release venlafaxine (150 mg daily), the peak plasma concentrations (C max) of venlafaxine (150 ng/ml) and ODV (260 ng/ml) are attained within 6.0 ± 1.5 and 8.8 ± 2.2 hours, respectively.
However, according to Sigma, because the peak plasma levels contained in the product information for Evelexa XR are mean figures and not figures for a particular patient, there will be a range of values higher and lower than that mean (consistent with Professor Charman’s evidence). Further, the evidence does not cover the peak plasma levels for patients taking Evelexa XR who have existing plasma levels in excess of 55 ng/ml or who take a 225 mg dose which is also contemplated by Sigma’s product information. Hence, submitted Sigma, Wyeth has not established that: - (i) every patient taking a single daily dose of 150 mg or more of Evelexa XR will infringe claims 5, 8, 9 and 10, (ii) there will be such an infringement by a patient taking a single daily dose of 150 mg or more of Evelexa XR who has an existing plasma level in excess of 55 ng/ml at the time of dosing, or (iii) there will be such an infringement by a patient taking a single daily dose of in excess of 150 mg per day.
Alphapharm made submissions to the same effect as Sigma about the peak blood plasma level having regard to the Enlafax-XR product information which contains the following statement:
After administration of venlafaxine 75mg at steady state, the peak plasma concentrations (Cmax) of venlafaxine... were attained within 5.38 ± 1.37 hours... After the administration of venlafaxine (150mg) under the fasting conditions, the peak plasma concentration (Cmax) of venlafaxine.... were attained within 5.32 ± 1.48 hours... After the administration of venlafaxine (150mg) under the fed condition, the peak plasma concentration (Cmax) of venlafaxine (103.0 ± 49.2 ng/ml)... were attained within 6.11± 1.66 hours respectively
Professor Charman reviewed the Enlafax-XR product information and said that:
I note that based on the Product Information Extract, the mean plasma concentrations of venlafaxine for the doses and conditions mentioned are well below the peak blood plasma level of 150ng/ml, provided by claim 9 of the Patent. Assuming a typical distribution of individual patient Cmax values around the mean plasma concentration values reported for the doses-mentioned in the Product Information Extract, I would expect a significant proportion of the individual patients to have a Cmax value of less than 150ng/ml. On this basis (and on the basis set out in paragraphs 42 to 54 of My July 28 Affidavit), it is my opinion that administration of Enlafax XR products to those patients achieves the method of claim 9 of the Patent.
According to Alphapharm, this opinion lacks an underlying factual basis in a number of respects. First, as the Enlafax-XR product information does not specify whether the 150 mg dose was administered to patients at steady state, there is no evidence capable of founding a conclusion as to what proportion of individual patients to whom the 150 mg dose of Enlafax-XR is administered on a chronic basis (i.e. at steady state) will be above 150 ng/ml. Second, the Enlafax-XR product information does not specify what the Cmax is for doses other than 75 mg or 150 mg forms, in circumstances where the Enlafax-XR product information allows for dosing up to 225 mg.
Otherwise, and insofar as its submissions on infringement can be separated from those on invalidity discussed and rejected above, Alphapharm submitted that if (contrary to Alphapharm’s arguments and its version of Professor Charman’s oral evidence, discussed and rejected above) “therapeutic blood plasma concentration” means any single daily dosing formulation of venlafaxine hydrochloride which has therapeutic effect then “there is no evidence as to the range of plasma concentrations over a 24 hour period achieved by individual patients to whom Enlafax-XR is administered, and no evidence even as to the therapeutic window of venlafaxine in the general sense, [so that] infringement is not proved on this definition”.
Alphapharm’s primary defence, however, was that the words “a single daily dosing formulation of venlafaxine hydrochloride” should be construed as meaning “a single daily dosing formulation (not utilising hydrogel tablet technology)”. Further, that any technology using a mechanism of diffusion of drug through a hydrated gel matrix as the method of delaying release of the drug is hydrogel tablet technology within the meaning of the patent.
Finally, Alphapharm submitted that because the specification discloses only that venlafaxine is used in the treatment of depression, Wyeth cannot obtain an injunction for infringement in respect of the use of Enlafax-XR to treat social anxiety disorder. Alphapharm thus seeks to make further submissions on the form of any order in relation to the sale of Enlafax-XR to treat social anxiety disorder.
Generic Health relied on Alphapharm’s submissions and the evidence of its own product information about which Professor Charman had said the composition was the same as Alphapharm’s product.
Wyeth agreed that, in the claims in the patent, the references to a Cmax of 150 ng/ml involve the level in an individual patient and not a mean value. According to Wyeth that is immaterial – unless the level will not be present at all on administration the injunction would be granted.
Wyeth otherwise relied on Professor Charman’s evidence based on reviews of the product information for the applicants’ products. This evidence establishes that:
… for each of the Evelexa-XR, Enlafax-XR and Generic Health XR products:
(a) the active ingredient of the product is venlafaxine hydrochloride;
(b) the product is a capsule;
(c) the product is an extended release formulation;
(d) the product is indicated for the treatment of (at least) depression;
(e) the product is to be administered chronically and orally in a single daily dose;
(f) the product has been shown to be effective in treating depression;(g)after administration of the product, the mean peak plasma concentration of venlafaxine is attained within the range of 4 to 8 hours (and, more particularly, within the range of 5 to 8 hours); and
(h)the mean peak plasma concentration of venlafaxine following administration is no more than 150ng/ml, or the peak plasma concentration will be below that level for at least a significant proportion of patients.
While it is true that, as Alphapharm noted, Professor Charman did not use the words “at least” to describe the proportion of patients who would have a peak plasma concentration below 150 ng/ml, his evidence did identify his expectation that “a significant proportion of the individual patients [administered the applicants’ products] to have a Cmax of less than 150 ng/ml”.
According to Wyeth this evidence (subject to the hydrogel argument) is sufficient to establish infringement of claims 1, 4, 5, 8, 9, 10, 15, 16 and 27 of the patent in that:
Such infringement arises:
(a)pursuant to s 117 of the Act, on the basis that the products are capable of only one reasonable use (s 117(2)(a)); there is reason to believe that the products, not being staple commercial products, will be used in the manner referred to (s 117(2)(b)); and because such use will be use in accordance with instructions or inducements given for the use of the products (s 117(2)(c));
(b) by authorisation pursuant to s 13(1) of the Act; and
(c) at common law, under the principles of joint tortfeasorship.M2 Conclusions on infringement
Insofar as the applicants relied on arguments essentially of construction (150 ng/ml and therapeutic blood plasma concentration) Wyeth’s submissions must be accepted. It is clear from Professor Charman’s evidence read with the applicants’ product information that the use of the applicants’ products would infringe the claims of the patent on which Wyeth relies. The evidence supports an inference that the applicants themselves have reason to believe that a significant proportion of patients will have a Cmax of less than 150 ng/ml after administration of their product and that a therapeutic (that is, clinically effective) blood plasma concentration of venlafaxine will be achieved.
In other words, and consistent with Wyeth’s case, the only defence of substance is the hydrogel argument. The difficulty for Alphapharm and Generic Health is that, assuming their products to use hydrogel tablet technology within the meaning of the patent, there is no sound basis to construe the words “a single daily dosing formulation of venlafaxine hydrochloride” as meaning “a single daily dosing formulation (not utilising hydrogel tablet technology)”. Those words of limitation cannot be read into the claims by reference to the specification. The reference in the claims to “a single daily dosing formulation of venlafaxine hydrochloride” is not unclear. The scope of those words cannot be read down by reference to the specification (Welch Perrin and Company Proprietary Limited v Worrel (1961) 106 CLR 588 at 610).
In contrast to the observation in H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151; [2009] FCAFC 70 at [120] on which Alphapharm and Generic Health relied, this is not a case where the words in question have no positive meaning thereby enabling recourse to the text of the specification to ascertain the nature of the invention. If such recourse may be had, the specification construed as a whole also does not support the construction for which Alphapharm and Generic Health contend. The specification discloses that the invention is the method. The particular formulation is one embodiment of the method of the invention which, in contrast to the inventor’s attempts to use hydrogel tablet technology, proved practical for use in the method of the invention. In this context, the words “a single daily dosing formulation of venlafaxine hydrochloride” cannot be construed to mean “a single daily dosing formulation (not utilising hydrogel tablet technology)”.
The parts of the specification called in aid by Alphapharm and Generic Health do not provide a sufficient basis for a contrary construction. The words “extended release or tablets by hydrogel technology” on p 4C of the patent must be read in context. In context, they mean only that the inventors attempt to achieve the method by a formulation using hydrogel technology failed for the reasons given. Otherwise the impossibility representations have been discussed above. These conclusions on construction are sufficient to dispose of the case in defence to infringement put forward by Alphapharm and Generic Health.
As noted, Wyeth also claimed that, if the construction of Alphapharm and Generic Health were accepted, the evidence established that the relevant formulations were not within the scope of the exclusion of hydrogel tablet technology. In this regard, Alphapharm relied upon the evidence of Dr Marshall to show that “each of the Enlafax Formulations… are hydrogel technology and fall within the description of hydrogel technology in the Hydrogel Passage”, (the “Hydrogel Passage” being the description in the “Background of the Invention” section of the patent which refers to extended release drug formulations being conventionally produced as drug formulations by hydrogel tablet technology). Dr Marshall’s evidence in this regard was as follows:
It is clear to me from the manufacturing process and process controls that the Enlafax Formulations are tablet(s) contained in a hard gelatin capsule shell…
The excipients in the Enlafax Formulations are predominantly hypromellose (Methocel K100M which is a particular grade of HPMC) i.e. a cellulose ether. This component performs the primary ‘hydrogel’ function described in the Hydrogel Passage. That is to say, it is the water soluble polymer that swells to form a matrix through which water must diffuse… The function of the other excipients is… to modify the rate of release of the drug. #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### .
Further, although each of the tablets within the capsule of the Enlafax Formulations are coated tablets, this does not impact on the characterisation of the formulations as hydrogel tablets. The particular coating agent used (Eudragit E100) is a well known material, used for film coating purposes only, and does not affect the release rate.
Aside from the active ingredient and the coating, there are three other excipients in the Enlafax Formulations: ammonio methacrylate copolymer, sodium lauryl sulphate and magnesium stearate. Sodium lauryl sulphate and magnesium stearate are common tablet excipients, #### #### #### #### #### #### #### #### ### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### ###.
I do not consider that the presence of any or all of these three additional excipients changes the characterisation of the Enlafax Formulations as hydrogel table technology, or takes those formulations outside the description of hydrogel tablets in the Hydrogel Passage… [T]he Hydrogel Passage anticipates the presence of other excipients in addition to the cellulose ether, as is the case with the Enlafax Formulations. The cellulose ether (hypromellose) will still, when exposed to moisture in the digestive system, swell upon hydration to form a gel, limiting exposure of the venlafaxine hydrochloride to moisture; water will progressively penetrate the gel matrix and the venlafaxine hydrochloride will dissolve and diffuse out through the gel, becoming available for absorption in the body. #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### ##.
The coating of the Enlafax Formulations does not materially contribute to the mechanism of release of the formulation and therefore does not, in this instance, influence the characterisation of the Enlafax Formulations as hydrogel tablet technology.
For the detailed reasons outlined above, and for the key reason that the principal and predominant mechanism of drug release is provided by limitations imposed by the matrix system, in my opinion, each of the Enlafax Formulations as shown to me are hydrogel tablet technology and fall within the description of hydrogel technology in the Hydrogel Passage.
Although it is not necessary to deal with this argument, my conclusions are as follows.
First, and contrary to Wyeth’s submissions (and consistent with the position above on onus), Alphapharm carried no onus to prove that the Enlafax-XR formulation is within the scope of the assumed exclusion.
Second, it is true that the references to “hydrogel tablet technology” and “hydrogel technology” in the specification are to be construed in the context of the specification as a whole including the passage under the heading “background of the invention” referring to the way in which hydrogel tablets are conventionally produced. That is, if the applicants’ approach to construction is permissible then the words of exclusion “(not utilising hydrogel tablet technology)” also have to be construed in light of the specification as a whole. Read in context, they mean the attempts to produce sustained release tablets using the conventional technology described under the heading “background of the invention”. Thus, if “a single daily dosing formulation of venlafaxine hydrochloride” should be construed as to mean “a single daily dosing formulation (not utilising hydrogel tablet technology)”, hydrogel tablet technology must itself mean sustained release tablets using the conventional technology described under the heading “background of the invention”.
Third, the evidence discloses that, whatever else it might be, the Enlafax-XR formulation is not a sustained release tablet using the conventional technology described under the heading “background of the invention”. The Enlafax-XR formulation is a gelatine capsule containing two or three film coated tablets. #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### ###. This evidence is sufficient to enable the conclusion that Wyeth has proved that the Enlafax-XR formulation is not a sustained release tablet using the conventional technology described under the heading “background of the invention”.
The Enlafax-XR formulation, as Professor Charman concluded, does not involve a tablet in which the cellulose ethers swell upon hydration and gradually leach away by moisture with the active ingredient slowly dissolving and diffusing through the gel. It involves a gelatine capsule in which there are a number of film coated tablets. While one aspect of the formulation involves the swelling of cellulose ethers the other aspects are different from and outside the scope of hydrogel tablet technology as used in the specification. #### #### #### #### #### #### #### #### #### #### #### #### # #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### #### . This too is different from and outside the scope of the description of hydrogel tablet technology in the specification given the limits therein on the mechanism to delay the release rate (that is, the swelling of the cellulose ethers).
For these reasons it is unnecessary to consider Wyeth’s additional submission that the Enlafax-XR formulation is itself protected by European Patent No 1502587B which, in any event, does not add to the force of the submissions already noted. If Alphapharm’s approach to construction is permissible then the approach must be applied not only to the meaning of “a single daily dosing formulation of venlafaxine hydrochloride” but also “hydrogel tablet technology” in the purported exclusion. Once that is done it is apparent from the evidence that the Enlafax-XR formulation is not “hydrogel tablet technology” in the sense that term is used in the specification. The same conclusion must apply to the Generic Health formulation given Generic Health’s position that its formulation is the same as the Enlafax-XR formulation.
It follows that the limited bases on which the applicants defended Wyeth’s infringement claims have not been sustained.
N CONCLUSIONS
For the reasons given above the applications for revocation of the patent under s 138(3) of the Act must be dismissed. Wyeth’s cross-claims for relief against infringement under s 122 should be granted, subject to any further submissions on the extent and form of the appropriate injunctions. Directions need to be made to this end.
I certify that the preceding six hundred and thirty two (632) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Jagot. Associate:
Dated: 8 November 2010
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