The Regents of the University of California & Regeneron, Inc. - [2016] APO 33

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
The Regents of the University of California & Regeneron, Inc. [2016] APO 33

Patent:2004261165

Title:Composition of a VEGF antagonist and an anti-proliferative agent and its use for the treatment of cancer

Patentees:The Regents of the University of California & Regeneron, Inc.

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:2004261165

Title:Composition of a VEGF antagonist and an anti-proliferative agent and its use for the treatment of cancer

Patentees:The Regents of the University of California & Regeneron, Inc.

Date of Decision: 10 June 2016
DECISION
I refuse the application for an extension of the term of patent 2004261165.
REASONS FOR DECISION
Background

This matter relates to an application on 30 September 2013, by The Regents of the University of California & Regeneron, Inc. (collectively, the patentee), for an extension of term of patent 2004261165 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 2004261165 patent was granted on 10 December 2009. The date of the patent is 23 July 2004 and in the normal course of events its 20 year term would expire on 23 July 2024. 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 6 May 2014, 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 contain or consist of a pharmaceutical substance falling within the scope of the claims of the patent specification. The delegate maintained this objection in a second report despite submissions to the contrary by the patentee, who on 7 November 2014 requested an oral hearing.
The hearing was originally set for 11 February 2015, but was deferred pending re-examination of patent 2005311191 which was also sought to be extended based on the goods ZALTRAP®. The hearing into both extension requests was conducted by way of written submissions filed on 13 April 2016. This decision relates to the application to extend the term of patent 2004261165. I have issued a separate decision in respect of the extension request for patent 2005311191.
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 2004261165 is titled “Composition of a VEGF antagonist and an anti-proliferative agent and its use for the treatment of cancer”. Consistent with this, the field of the invention is described in para 1 of the specification as relating to methods of treating cancer in a mammal by administering a vascular endothelial growth factor (VEGF) antagonist in combination with an anti-proliferative agent, and pharmaceutical compositions comprising a VEGF antagonists and an anti-proliferative agent. In this regard, the specification distinguishes combinations of the active agents which may be administered together or at different times (paras 5B, 5D, 5F, 22 and 30-36), from pharmaceutical compositions which comprise the combination of active agents (paras 5E and 23-28).
Suitable VEGF antagonists and anti-proliferative agents are identified in the specification. Most relevantly, para 5 states:
“In a specific embodiment, the VEGF antagonist is a VEGF trap, capable of high affinity binding of VEGF. More specifically, the VEGF trap is … , or VEGFR1R2-FcΔC1(a) (SEQ ID NOs: 1-2). In a specific embodiment, the anti- proliferative agent is a microtubule stabilizing agent such as paclitaxel, or a derivative, analogue, such as docetaxel (Taxotere®), or mixture thereof; a platinum-based chemotherapeutic compound such as cisplatin, carboplain [sic], iproplatin, and related compounds; or other conventional cytotoxic compounds. One commercial available form of paclitaxel is Taxol^TM (Bristol-Myers Squibb).
The specification contains 20 claims to pharmaceutical compositions and their therapeutic use. In its extension request the patentee relied on claim 9 and dependent claims 10-11 to satisfy s 70(2). Claim 9 is the broadest claim and is as follows:
“9. A pharmaceutical composition comprising a vascular endothelial cell growth factor (VEGF) antagonist, an anti-proliferative agent, and a pharmaceutically acceptable carrier, wherein the VEGF antagonist is VEGFR1R2-FcΔC1(a).”
In summary, the patent specification discloses the VEGF antagonist using the descriptor VEGFR1R2-FcΔC1(a) and its amino acid sequence and encoding nucleic acid sequence (SEQ ID NOs: 2 and 1, respectively) (paras 5-5G, 8, 14 and claims). In contrast, the extension request and accompanying documents describe the aflibercept protein more broadly in terms of the origin of its various domains and uses the descriptor VEGFRGIR2-FcDC1(a), which may contain a typographical error. The examining delegate appears to have accepted that aflibercept has the amino acid sequence disclosed in the patent specification and can reasonably be characterised as VEGFR1R2-FcΔC1(a) and for the purposes of this decision, I will adopt the same approach.
The pharmaceutical substance
Claim 9 encompasses a pharmaceutical composition comprising aflibercept, an anti-proliferative agent and a pharmaceutically acceptable carrier. Aflibercept’s VEGF antagonist activity is due to it being a high affinity soluble decoy receptor that binds VEGF and related ligands with higher affinity than the native receptors (hence its alternative name VEGF “Trap”), preventing ligand-receptor binding and subsequently 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 anti-proliferative agent, the extension request states this is used to maintain immunosuppression and treatment of rejection. As indicated above, specific embodiments in the patent specification act as microtubule stabilizing agents or chemotherapeutic or cytotoxic agents. Taken together, the claim 9 composition falls within the Schedule 1 definition of a pharmaceutical substance, since it is for therapeutic use and its application involves a physico-chemical interaction with a human physiological system, and it is not solely for use in in vitro diagnosis or testing.
The composition comprising aflibercept, an anti-proliferative agent and a pharmaceutically acceptable carrier is itself the subject of claim 9 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, an anti-proliferative agent and a pharmaceutically acceptable carrier - must be included in the ARTG.
The Public Summary documents establish that the goods ZALTRAP® contains one active agent, the VEGF antagonist aflibercept. This was not disputed by the patentee. As a matter of logic, ZALTRAP® also contains a pharmaceutically acceptable carrier (this is evident from the Public Summaries which describe ZALTRAP® as in liquid form).
Regarding the combination of ZALTRAP® and an anti-proliferative agent, 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:
“The ARTG registration of ZALTRAP relates to aflibercept in combination with irinotecan-fluoropyrimidine-chemotherapy indicated in adults with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen. The European Medicines Assessment Report provides confirmation that the therapeutic indication is for ZALTRAP (aflibercept) in combination with irinotecan/5-fluorouracil/folinic acid, which three compounds are known as Folfiri.
The anti-proliferative agents claimed in claim 9 of patent 2004261165 include irinotecan and fluoropyrimidine chemotherapeutic agents. The combination of a VEGF antagonist (aflibercept) and an anti-proliferative agent is therefore contained in the ARTG registration of ZALTRAP.”
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 an anti-proliferative agent 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 an anti-proliferative agent in product information associated with ZALTRAP®, when the ZALTRAP® goods does not contain an anti-proliferative agent?
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 an anti-proliferative agent 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 the antiproliferative agent were essential components in achieving registration of ZALTRAP® and must be considered ingredients of the ARTG. It remains our position that this 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 present claim 9 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 aflibercept and a pharmaceutically acceptable carrier. As acknowledged by the patentee, ZALTRAP® does not contain an anti-proliferative agent. 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 2004261165. 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 2004261165 does not comply with s 70(3) and consequently it must be refused.
Barbara Akhurst
Delegate of the Commissioner of Patents