Aventis Pharma S.A. - [2016] APO 34

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Aventis Pharma S.A. [2016] APO 34

Patent:2005311191

Title:Antitumor combinations containing a VEGF inhibitor and 5FU or one of its derivatives

Patentee:Aventis Pharma S.A.

Delegate:  Dr B. Akhurst
Decision Date:  10 June 2016
Hearing Date:  Written submissions were filed on 13 April 2016
Catchwords:  PATENTS – s 70 application for an extension of the term of a patent – s 70(3) - whether the product-specific indications for a registered goods, or similar information in documents associated with the registration process, identifies goods included in the ARTG – application refused
Representation:  Phillips Ormonde Fitzpatrick.

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent:2005311191

Title:Antitumor combinations containing a VEGF inhibitor and 5FU or one of its derivatives

Patentees:Aventis Pharma S.A.

Date of Decision: 10 June 2016
DECISION
I refuse the application for an extension of the term of patent 2005311191.
REASONS FOR DECISION
Background

This matter relates to an application on 30 September 2013 by Aventis Pharma S.A. (the patentee), for an extension of term of patent 2005311191 under section 70 of the Patents Act 1990. The application was based on the 2 April 2013 inclusion in the Australian Register of Therapeutic Goods (the ARTG) of the pharmaceutical substance ZALTRAP® (aflibercept).
The 2005311191 patent was granted on 22 March 2012. Re-examination of the granted patent prompted amendments to the claims, which were advertised as allowed on 30 April 2015. The date of the patent is 2 December 2005 and in the normal course of events its 20 year term would expire on 2 December 2025. If an extension is granted on the basis asserted by the patentee, the term of the patent would be extended until 2 April 2028.
On 27 May 2015, the examining delegate issued a deficiency notice, advising that the application does not comply with section 70 because the ARTG-listed goods ZALTRAP® does not in substance fall within the scope of the claims of the patent specification. The delegate maintained this objection despite submissions to the contrary by the patentee, who on 9 December 2015 requested an oral hearing.
This matter was heard by way of written submissions filed on 13 April 2016, which were accompanied by an amended extension request reflecting the amended claims. An extension request based on the goods ZALTRAP® for unrelated patent 2004261165 was heard at the same time, and I have issued a separate decision in respect of that application.
The ARTG registrations
The patentee relied on two ARTG registrations with the 2 April 2013 start date. The Therapeutic Goods Administration (TGA)’s Public Summary documents establish that ARTG Entries 195234 and 195974 cover the products ZALTRAP® aflibercept in doses of 100 mg/4mL or 200 mg/8mL, respectively, as concentrated injectable solutions.
The Law
Part 3 of Chapter 6 of the Patents Act 1990 (the Act) provides a statutory framework for an extension of the term of standard patents relating to pharmaceutical substances.
Section 70 relevantly provides:
(1)The patentee of a standard patent may apply to the Commissioner for an extension of the term of the patent if the requirements set out in subsections (2), (3) and (4) are satisfied.
(2)Either or both of the following conditions must be satisfied:
(a)   one or more pharmaceutical substances per se must in substance be disclosed in the complete specification of the patent and in substance fall within the scope of the claim or claims of that specification;
(b)   one or more pharmaceutical substances when produced by a process that involves the use of recombinant DNA technology, must in substance be disclosed in the complete specification of the patent and in substance fall within the scope of the claim or claims of that specification.
(3)Both of the following conditions must be satisfied in relation to at least one of those pharmaceutical substances:
(a)   goods containing, or consisting of, the substance must be included in the Australian Register of Therapeutic Goods;
(b)   … .
(4)… .
(5)… .
The term “pharmaceutical substance” is defined in Schedule 1 to the Act as follows:
pharmaceutical substance means a substance (including a mixture or compound of substances) for therapeutic use whose application (or one of whose applications) involves:
(a) a chemical interaction, or physico-chemical interaction, with a human physiological system; or
(b) action on an infectious agent, or on a toxin or other poison, in a human body;
but does not include a substance that is solely for use in in vitro diagnosis or in vitro testing.
This decision ultimately turns on whether a relevant goods is included in the ARTG. However, it is convenient to first identify the pharmaceutical substance for the purposes of s 70(2) and then consider whether the application complies with s 70(3).
Section 70(2) – the pharmaceutical substance
Section 70(2) requires that at least one pharmaceutical substance per se and/or pharmaceutical substance when produced by a process that involves the use of recombinant DNA technology, is in substance disclosed in the complete specification of the patent and in substance falls within the scope of the claim(s).
The patent specification
The specification of patent 2005311191 is titled “Antitumor combinations containing a VEGF-inhibiting agent and 5FU or a derivative thereof”. Consistent with this, page 1 of the specification discloses the invention as relating generally to combinations of a vascular endothelial growth factor (VEGF) inhibitor and a chemotoxic agent of the class of 5-fluorouracil (5-FU) or 5‑fluoropyrimidines that are useful in the treatment of neoplastic diseases, particularly colon cancer or stomach cancer. Suitable VEGF inhibitors are identified in the specification as including “biological products chosen from soluble receptors, antisenses, RNA aptamers and antibodies” (page 1). A preferred VEGF inhibitor is a “VEGF-Trap” chimeric fusion protein “comprising the VEGFR1 signal sequence fused to the Ig domain D2 of the VEGFR1 receptor, itself fused to the Ig domain D3 of the VEGFR2 receptor, in turn fused to the Fc domain of IgG1, also called VEGFR1R2-FcΔC1” (page 1). The 5-fluoropyrimidine derivatives are chosen from 5-FU, capecitabine or gemcitabine (page 1).
The amended specification contains 23 claims to compositions of VEGF-Trap and 5-FU or 5-FU derivatives, and their therapeutic use. In this regard, the specification distinguishes combinations of the active agents which may be administered together or at different times (see for example page 4, lines 21-24), from compositions containing the combination of active agents (page 4, lines 15-16). The patentee relied on claims 18-23 to gain an extension of term. Claims 18-19 are independent and are reproduced below:
18. A composition of VEGF-Trap and at least 5-fluorouracil or a 5‑fluoropyrimidine derivative, said composition exhibiting a synergistic effect in the treatment of neoplastic diseases.
19. A composition exhibiting a synergistic effect containing VEGF-Trap with 5‑fluorouracil or capecitabine or gemcitabine.
Claims 18 and 19 refer to a composition “exhibiting a synergistic effect”. Prima facie, synergy between the active agents will only be realised when the composition is in use, which raises the question of whether these claims are de facto method claims. Where the claims are ambiguous, it is permissible to resort to the body of the specification to define or clarify the meaning of words used in the claims (Interlego AG v Toltoys Pty Ltd [1973] HCA 1, (1973) 130 CLR 461 at 479). The specification is short (only 7 pages) and is essentially directed to the preparation of “antitumor combinations” of the active agents (page 1 title and para 1) and means for determining the effectiveness of such a combination on tumour cells in vitro or in vivo (page 2, last para to page 4, para 3). The single example describes administration of a composition to mice, but stops short of determining or evaluating any therapeutic effect. Consequently, it is not reasonable to construe claims 18 and 19 as methods of treatment; they define compositions that will exhibit a synergistic effect, if administered to the relevant subject.
The pharmaceutical substance
The goods ZALTRAP® contains the pharmaceutically active agent aflibercept (the TGA’s Public Summary), which acts as a VEGF-Trap or a VEGF antagonist.
Aflibercept’s inhibitory (antagonist) activity is due to this recombinant protein being a high affinity soluble decoy receptor that binds VEGF and related ligands with higher affinity than the native receptors (hence its designation as a VEGF “Trap”), preventing ligand-receptor binding and subsequent receptor-mediated signalling (pages 5 and 52 of the AusPAR). Through its effect on endothelial cell survival, migration and proliferation, aflibercept is an antiangiogenic agent that inhibits the growth of blood vessels which tumours need to grow and metastasise (page 5 of the AusPAR; page 3 of the TGA’s Product Information for ZALTRAP®; page 11 of the European Medicine Agency Assessment Report for ZALTRAP).
Regarding the additional agents in the claimed compositions, the amended extension request relevantly asserts that 5-FU, fluorouracil and gemcitabine are fluoropyrimidine-based chemotherapeutic agents, while capecitabine is a prodrug converted to 5-FU in the tumour. In its’ submissions for the hearing, the patentee described these fluoropyrimidines as pyrimidine analogues which, during DNA replication, incorporate into the copied DNA strand halting the DNA synthesis that is necessary for cell division.
Given the activities of aflibercept and the fluoropyrimidines, I am satisfied that the claimed compositions fall within the Schedule 1 definition of a pharmaceutical substance, since they are for therapeutic use and their application involves a physico-chemical interaction with a human physiological system, and they are not solely for use in in vitro diagnosis or testing.
The composition comprising aflibercept and the specified chemotherapeutic agent(s) is itself the subject of claims 18 and 19 of the specification, satisfying the requirements of s 70(2)(a) that a pharmaceutical substance per se is in substance disclosed in, and in substance falls within the scope of a claim of the specification (Prejay Holdings Ltd v Commissioner of Patents [2003] FCAFC 77 at [24], 57 IPR 424 at 429 applied). Furthermore, this same composition comprises a recombinant protein (aflibercept), satisfying the requirements of s 70(2)(b) that a pharmaceutical substance when produced by a process that involves the use of recombinant DNA technology is in substance disclosed in, and in substance falls within the scope of a claim of the specification.
The application complies with s 70(2).
Compliance with section 70(3)(a)
The goods
Paragraph 70(3)(a) of the Act requires that goods containing, or consisting of, the pharmaceutical substance - in this case the combination of aflibercept and one or more additional active agent(s) specified by claims 18 or 19 - must be included in the ARTG.
The Public Summary documents establish that the goods ZALTRAP® contains one active agent, the VEGF Trap aflibercept. This was not disputed by the patentee. Regarding the combination of ZALTRAP® and the additional active agent(s), the patentee submitted that this combination is “included in the ARTG” by way of the therapeutic indications for ZALTRAP® or by references to the combination in the product information associated with ZALTRAP®, including:
·   information in the TGA’s Public Summaries for ZALTRAP®, in particular the product-specific indications;
·   information in documents associated with ZALTRAP® that can be found on the TGA’s website such as consumer medicine information, product information including product-specific indications, and
·   any additional documents that were part of the application process for registering ZALTRAP® such as the TGA’s AusPAR.
Under the heading “Specific Indications”, the Public Summary documents for the ZALTRAP® Entries state:
“Zaltrap in combination with irinotecan-fluoropyrimidine-based chemotherapy is indicated in adults with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen.,[See clinical trials tor results of Zaltrap in combination with FOLFIRI. Other combinations have not been evaluated]”
In this regard, the patentee’s application for an extension of term states:
“ZALTRAP® aflibercept is registered on the ARTG as having a specific indication in combination with irinotecan-fluoropyrimidine-based chemotherapy in adults with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen. This ARTG registration therefore relates to and contains the combination of aflibercept together with irinotecan and a fluoropyrimidine-based chemotherapeutic agent. The European Medicines Agency Assessment Report relating to ZALTRAP® (attached) provides confirmation that the therapeutic indication is for ZALTRAP® (aflibercept) in combination with irinotecan/5-fluorouracil/folinic acid (also known as leucovorin) which 3 compounds are referred to as FOLFIRI®.”
I accept that the Public Summaries and other product information relied on by the patentee confirms that ZALTRAP® (aflibercept) is indicated for use in combination with the fluorouracil 5-FU, to treat metastatic colorectal cancer. However, for the reasons that follow, I reject the patentee’s submission that the product-specific indications for a pharmaceutical substance registered in the ARTG, or similar information in other documents relevant to the registration process, identify goods included in the ARTG for the purposes of paragraph 70(3)(a).
… goods containing, or consisting of, the substance must be included in the ARTG
The question is whether the requirements of s 70(3) are satisfied by references to the combination of aflibercept and at least 5-FU in product information associated with ZALTRAP®, when the goods ZALTRAP® does not contain 5-FU or any other additional agent specified in the claims?
I accept the patentee’s submission that in assessing compliance with s 70(3), regard may be had to information beyond the Public Summary documents to establish that a relevant goods is included in the ARTG. However, the patentee went further, submitting that “a comparison is to be made between the acknowledged pharmaceutical substance per se and the documents of the ARTG”. Specifically, the patentee submitted:
“… there is clear evidence that the combination of aflibercept and 5-fluorouracil, being part of the FOLFIRI® regimen was heavily analysed and considered during the process of registering ZALTRAP® through the ARTG. Each of the documents that may be found on the ARTG is consistent, in that the combination of aflibercept and FOLFIRI® were essential components in achieving registration of ZALTRAP®. It remains our position that that pharmaceutical substance per se, being the combination, must be considered as being included in the ARTG”
To support this submission, the patentee relied on Merck & Co v Arrow Pharmaceuticals Ltd (Merck) [2003] FCA 1344 and H Lundbeck A/S v Alphapharm Pty Ltd (Lundbeck) [2009] FCAFC 70. However, for the reasons that follow neither Merck nor Lundbeck support a conclusion that product-specific indications in a Public Summary, or similar information in other documents relevant to the registration process, would form part of “goods … included in the ARTG” within the meaning in s 70(3).
Consistent with the patentee’s submissions, Merck confirms that a decision-maker may look beyond the TGA’s Public Summary when determining as a factual matter the nature and composition of goods included in the ARTG. In Merck at [26]-[28], Wilcox J found that a claimed pharmaceutical substance was present in a registered goods in minute quantities, which was sufficient to satisfy s 70(3)(a) that goods containing a relevant substance is included in the ARTG. However, it is clear from his reasoning in those paragraphs that Justice Wilcox was not departing from goods that were in fact included in the ARTG.
In Lundbeck, the Full Court confirmed that s 70(2) operates to identify a candidate patent for extension and “once that patent and the substance are identified, the inquiry turns to s 70(3) and whether that pharmaceutical substance is contained in goods on the ARTG” (Bennett J at [232], Middleton J agreeing at [250]). Consistent with the approach in Merck, in Lundbeck at [239], the majority judgement clearly indicates that what is being considered are the ingredients of goods that are registered in, i.e. included in, the ARTG:
“The level of enquiry required by s 70(3) does not look to the therapeutic effect of the pharmaceutical substance. Rather, it is a simple comparison of the pharmaceutical substance with the “ingredients” of the goods on the ARTG.” (Bennett J, Middleton J agreeing at [250])
Merck and Lundbeck do not support the patentee’s submission that documents that make reference to the pharmaceutical substance specified in its claims need to be viewed as being included on the ARTG. Nor do they support a conclusion that any combination of ingredients referred to in such documents, are necessarily included in the ARTG for the purposes of s 70(3).
While there is no direct judicial guidance on whether product-specific indications or similar information forms part of goods included in the ARTG, in Celgene Corporation (Celgene) [2011] APO 37 at [18]-[24] the Delegate considered the requirements in ss 70 and 71 of the Act for goods to be included in the ARTG. Relevant to the present circumstances, he considered whether the phrase “goods … included in the ARTG” identifies the product the subject of the ARTG registration, or alternatively, whether the product-specific indications should be taken into account when identifying the relevant goods. At [22], the Delegate found that statements in the ARTG Certificate and the provisions of the Therapeutic Goods Act 1989, drew a clear distinction between therapeutic goods (i.e. goods intended for therapeutic use) and their indication (the therapeutic use of the goods), leading to his conclusion at [23]:
“… in identifying the goods that are included in the ARTG I should not import elements of the indications of the goods. The “goods” for the purposes of the Patents Act is equivalent to the product that appears in the ARTG certificate, and does not extend to the indications.”
Subsequently, in The Children’s Medical Centre Corporation [2011] APO 80 at [10]-[12] the ARTG Certificate identified the registered goods as containing a single active agent, while the product-specific indications included the use of that agent in combination with another. The submissions evident at [13] of that decision, mirrored those advanced by the present patentee, that the entire ARTG entry should be taken into account when determining what goods are included in the ARTG. On this basis, The Children’s Medical Centre Corporation argued that the combination of the two agents were goods included in the ARTG. The Delegate at [15] rejected that argument, and saw no reason to depart from the approach taken in Celgene. I see no reason to do otherwise, particularly since the circumstances in The Children’s Medical Centre Corporation are directly analogous to the matter before me. I conclude that the product-specific indications for ZALTRAP® do not identify goods included in the ARTG for the purposes of s 70(3).
ZALTRAP® contains the active agent aflibercept. As acknowledged by the patentee, ZALTRAP® does not contain 5-FU or any other additional agent specified in claims 18 or 19. Thus, the patentee has not established that any goods are included in the ARTG that contain or consist of a pharmaceutical substance that in substance falls within the scope of the claim(s) of patent 2005311191. It follows that the application does not satisfy the requirements of s 70(3).
Conclusion

The patentee’s application to extend the term of patent 2005311191 does not comply with s 70(3) and consequently it must be refused.
Barbara Akhurst
Delegate of the Commissioner of Patents