The Children's Medical Center Corporation

[2011] APO 80

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

The Children’s Medical Center Corporation [2011] APO 80

Patent:2005202596

Title:Methods and compositions for inhibition of angiogenesis

Patentee:  The Children’s Medical Center Corporation

Delegate:  Dr L. F.  McCaffery

Decision Date:  7 October 2011

Hearing Date:  3 May 2011 in Canberra

Catchwords:  PATENTS – application for extension of term of patent– whether “goods” in section 70(3) includes the indication of the product in the ARTG – whether a combination of drugs presented as separate unit dosage forms of the individual drugs is a pharmaceutical substance per se– the requirements of sections 70(2)(a) and 70(3)(a) are not satisfied by the request – application refused.

Representation:  Patentee: Spruson & Ferguson

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent:2005202596

Title:Methods and compositions for inhibition of angiogenesis

Patentee:  The Children’s Medical Center Corporation

Date of Decision:  7 October 2011

DECISION

The requirements of 70(3)(a) are not satisfied by the request for an extension of term based on the inclusion of the goods Thalomid in the ARTG.

The requirements of Section 70(2)(a) are not satisfied by the request for an extension of term since a “combination” of thalidomide and a steroid provided as separate unit dosages of the individual drugs is not a “pharmaceutical substance per se”.

I refuse the request for an extension of term.

REASONS FOR DECISION

1. This matter concerns a request filed on 17 June 2010 for an extension of the term of a pharmaceutical patent.  The patent in question (2005202596) is a divisional of Patent 780296, which in turn is a divisional of Patent 746713.  The date of the patent is 4 November 1997, so the maximum 20-year term will expire on 4 November 2017.  If the request for an extension of term is granted the maximum term of the patent will be extended to 4 November 2022 (that is, an extension of 5 years). 

1. Subsequent to the request, the examiner reported that an extension of term could not be granted based on the material provided in support.  In particular the delegate considered that the goods included in the ARTG did not contain or consist of a pharmaceutical substance falling within the scope of the claims as required under Section 70. The delegate maintained this objection despite submissions to the contrary by the patentee, and the matter was set for hearing in Canberra on 3 May 2011.  The patentee was represented at hearing by Ms Shahnaz Irani, patent attorney of Spruson & Ferguson.  Ms Yeah Sil Moon of Jones Day and Mr Richard Girards of Celgene Corporation were also in attendance.  The patentee was represented in matters following the hearing by Ms Carmel Hancock of Jones Day.

RELEVANT LAW

1. The interplay between the Patents Act and the Therapeutic Goods Act lies at the heart of the present matter, but the key considerations relate to Section 70 of the Patents Act. Section 70 sets out the conditions that must be met in order to obtain an extension of term of a pharmaceutical patent. Most relevant to the present case are that:

·    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 [Section 70(2)(a)].

·    goods containing, or consisting of, the pharmaceutical substance must be included in the Australian Register of Therapeutic Goods (ARTG) [Section 70(3)(a)].

1. The latter point was the focus of the present proceedings and I will deal with this first.  The issue of whether the specification met the requirements in relation to a “pharmaceutical substance per se” had not been disputed during the proceedings, but in view of submissions made at the hearing I sought further submissions from the patentee on this issue.  These were filed on 1 August 2011.  For sake of completeness I have also considered this issue below. 

THE PATENT

1. The invention relates to the treatment of angiogenesis.  Angiogenesis is the generation of new blood vessels in a tissue or organ.  Under normal physiological conditions angiogenesis only occurs in restricted situations such as wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta.  The control of angiogenesis may be altered in certain disease states, and in many cases the pathological damage associated with these diseases is related to uncontrolled angiogenesis.  Such uncontrolled angiogenesis has been implicated in disease states such as ocular neovascular diseases, rheumatoid arthritis, osteoarthritis, chronic inflammation, solid tumour growth and metastasis.

1. The invention relates to combinations comprising anti-angiogenic compounds with anti-inflammatory compounds (incuding steroids).  Thalidomide is a preferred anti-angiogenic agent and a wide range of anti-inflammatory steroids may be used.  Combinations of thalidomide with prednisone, dexamethasone, and prednisone together with melphalan are specifically named.

1. The specification ends with 35 claims.  Claims 1, 4 and 5 are of greatest relevance to the present matter and read as follows:

1.  An anti-cancer combination comprising a therapeutically effective amount of thalidomide and a therapeutically effective amount of a steroid.

4.  An anti-cancer combination comprising a therapeutically effective amount of thalidomide and a therapeutically effective amount of dexamethasone.

5.  An anti-cancer combination comprising a therapeutically effective amount of thalidomide and a therapeutically effective amount of prednisone and melphalan.

THE GOODS INCLUDED IN THE ARTG

1. The request is based on the inclusion in the ARTG of the following goods, which were said to contain or consist of a combination of thalidomide and at least one steroid:

·    THALOMID, thalidomide 50 mg hard capsule blister pack (AUST R 156729);

·    THALOMID, thalidomide 100 mg hard capsule blister pack (AUST R 156902);

·    THALOMID, thalidomide 150 mg hard capsule blister pack (AUST R 156903); and,

·    THALOMID, thalidomide 200 mg hard capsule blister pack (AUST R 156918).

1. The ARTG certificate for each of these products provides similar information.  Therefore for the sake of brevity I will refer only to the entry for AUST R 156729 throughout this decision.  However the same considerations apply to all of the products identified above.

1. The ARTG certificate for AUST R 156729 states that it is “issued to Celgene Pty Limited for approval to supply THALOMID thalidomide 50mg hard capsule blister pack”.

1. Under the heading “Products covered by this Entry” there is another reference to “THALOMID thalidomide 50mg hard capsule blister pack”, together with details of the container type and material, as well as consumer information such as the shelf life for the product. 

1. A section titled “Product Specific Indications” states the following:

   “MULTIPLE MYELOMA – Thalomid in combination with mephalan and prednisone is indicated for the treatment of patients with untreated multiple myeloma aged 65 years or over or ineligible for high dose chemotherapy.  Thalomid in combination with dexamethasone is indicated for induction therapy prior to high dose chemotherapy with autologous stem cell rescue, for the treatment of patients with untreated multiple myeloma.  Thalomid, as monotherapy, is indicated for the treatment of multiple myeloma after the failure of standard therapies.  ERYTHEMA NODOSUM LEPROSUM (ENL).  Thalomid is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL).  Thalomid is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis.  Thalomid is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.”

1. The patentee identified the pharmaceutical substance for the purposes of section 70(2) (a) as a combination of thalidomide and at least one steroid which is presented as separate oral dosage forms of the individual drugs in order to enable the clinician to control the side effects of the drug combination.  The product Thalomid itself consists only of thalidomide and does not contain any steroid component.  The gist of the patentee’s submissions in this regard is that the entire ARTG entry should be taken into account when determining the goods included on the ARTG.  They asserted that the “goods” included on the ARTG are not limited to the active pharmaceutical ingredient “captioned” in the ARTG but includes the reference in the Product Specific Indications to Thalomid being used in combination with mephalan and prednisone and with dexamethasone. 

1. This same issue was recently considered by the Delegate in Celgene Corporation [2011] APO 37 (see paragraphs 18 to 23). In particular, the Delegate concluded that:

“[t]he goods that are included in the ARTG are limited to therapeutic goods (section 9A of the Therapeutic Goods Act 1989), which are goods intended for therapeutic use (section 3 of the Therapeutic Goods Act). Goods included in the ARTG have an indication, which is defined as the therapeutic use of the goods (section 3 of the Therapeutic Goods Act). The Therapeutic Goods Act draws a clear distinction between the goods and their indications. This distinction is evident in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at [239], [2009] FCAFC 70; 81 IPR 228 at 276, where Bennett J stated:

‘The level of the inquiry 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.’”

1. I see no reason to depart from the approach taken by the Delegate in Celgene.  It follows in the present case the therapeutic goods included by the ARTG entry is Thalomid thalidomide 50mg hard capsule.  The indication provided, namely that it may be used in combination with certain steroids to treat multiple myeloma, is not an element of that therapeutic good.  Accordingly the reference to Thalomid being used in combination with mephalan and prednisone and with dexamethasone does not constitute inclusion in the ARTG of such a combination.

1. In conclusion the request does not meet the requirements of section 70(3) in that there are no goods containing or consisting of such a combination included in the ARTG.

PHARMACEUTICAL SUBSTANCE

1. Even if I am wrong in relation to whether the goods included in the ARTG contain or consist of the combination identified in the request, Section 70(2)(a) requires that 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.  I do not consider that this requirement is met.

1. As noted above, the patentee identified the pharmaceutical substance for the purposes of section 70(2) (a) as a combination of thalidomide and at least one steroid which is presented as separate oral dosage forms of the individual drugs in order to enable the clinician to control the side effects of the drug combination.  This was a surprising submission, particularly since a combination of separate components is prima facie in the nature of a “kit” and current Patent Office practice is that such combinations are not patentable.  Indeed the view throughout the prosecution of the application has been that the invention is limited to the two drugs presented as an admixture in a single unit dosage form.  Interestingly the claims as originally filed did not use the term “combination” in relation to the invention – the claims originally defined “angiogenesis inhibitory compositions” and the term “combination” was first introduced into the claims by the amendments dated 11 September 2009.  The issue of manner of manufacture is not relevant to the present determination, but I consider it necessary to construe the specification in order to determine the meaning of the term “combination” and whether the specification provides an “in substance” disclosure of the matter relied upon by the Patentee in their request.

1. No explicit definition of the term “combination” is provided in the specification. Throughout the description the terms composition and combination are used separately, suggesting that they are intended to refer to different entities.  However, at page 29 the specification notes that “the compositions and methods of the present invention include the combination of angiogenesis inhibiting compounds, such as thalidomide… with anti-inflammatory compounds, such as steroids.” Thus the term combination may be considered to include “compositions” comprising the active ingredients in admixture.  No specific example of a composition or method using a steroid and thalidomide in combination is provided.  However, as noted by Bennett J in Pfizer Inc v Commissioner of Patents [2005] FCA 137 at 75, this is not a requirement of Section 70(2)(a).

1. Furthermore, reference is made at page 20 to the use of angiogenesis inhibitors in combination with epoxide hydrolase inhibitors, wherein the inhibitors are administered together or sequentially.  The latter sequential administration option would require separate presentation of the two drugs.  “Combinations” of angiogenesis inhibitors and epoxide hydrolase inhibitors are not claimed in the present patent, but the use of the term “combination” in this way indicates that throughout the specification it is intended to include separate unit dosage forms of the individual active ingredients.

1. Accordingly, I consider that the reference to “combination” includes combinations where the two drugs are presented as an admixture in a single unit dosage form as well as combinations where the two drugs are presented as separate unit dosage forms of the individual drugs.  I therefore consider that there is an “in substance” disclosure in the specification of the combination relied upon by the Patentee in their request.

1. The subsequent question is whether such a combination would constitute a “pharmaceutical substance per se” for the purposes of Section 70. The term “pharmaceutical substance” is defined in Schedule 1 as follows:

“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”. 

1. Notably, the definition of “pharmaceutical substance” is qualified in Section 70(2)(a) by the words “per se”.  The meaning of “pharmaceutical substance per se” has been considered by the Federal Court in a number of decisions (H.  Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70, Boehringer Ingelheim International GmbH v Commissioner of Patents [2001] FCA 647, Prejay Holdings Ltd v Commissioner of Patents [2003] FCAFC 77 and Pharmacia Italia SpA v Mayne Pharma Pty Ltd [2006] FCA 305).

1. It is clear from these decisions that the term “pharmaceutical substance per se” is intended to be a pharmaceutical that is presented as a single entity, and not in the form of a kit or as separate dosage forms.  As noted in Boehringer, the per se qualification was introduced by the 1998 amendments to the Patents Act, in order to limit the operation of this section to patents disclosing and claiming a pharmaceutical substance “by or in itself, intrinsically, essentially”, or “taken alone; essentially; without reference to anything else” (Boehringer at 34). In this regard the Full Bench noted that:

“The second reading speech speaks about the ‘development of a new drug’ and the research and testing required before ‘the product’ can enter the market.  This is plainly a reference to the drug itself; not to the drug in combination with other elements.

Similarly, the Explanatory Memorandum says that claims to ‘pharmaceutical substances per se, would usually be restricted to new and inventive substances’.  The Explanatory Memorandum excludes the application of the new provisions to ‘new processes of making pharmaceutical substances or new methods of using pharmaceutical substances, where the substances themselves are known”.

1. A combination of separate known dosage forms does not constitute a “new and inventive substance” as contemplated by the Explanatory Memorandum.  Nevertheless the patentee sought to rely on the approach taken by the Deputy Commissioner in LTS Lohmann Therapie- Systeme GmbH & Co. KG [2002] APO 12, arguing that the present combination is consistent with the meaning of “mixture” as it comprises an aggregate of two or more substances that are not chemically united and exist in no fixed proportion to each other.

1. I do not find this submission persuasive.  In particular, the reference to a “mixture” by the Deputy Commissioner was in the context of the components of a mixture being presented as a single entity having an “uncontrolled spatial configuration” (see paragraph 15).  Notably the Deputy Commissioner concluded that a pharmaceutical substance “is a chemical entity, or a mixture or compound of chemical entities; it is not a reference to whatever the ‘substance’ is made up of”.  A combination of separate components does not constitute any of these entities.

1. The patentee argued further that according to Schedule 1 a pharmaceutical substance is a substance for therapeutic use whose application involves a chemical interaction or physicochemical interaction with a human physiological system.  A pharmaceutical substance is therefore defined by its action in the body after administration - the present combination of two separate pharmaceutical substances being consistent with this interpretation since the application of the two active agents results in a therapeutic outcome (treatment of cancer).

1. I note that similar arguments were addressed by Allsop J in Prejay (supra). In Prejay the invention claimed a method of treatment, and the patentee argued that based on the definition provided in Schedule 1 there was a pharmaceutical substance that fell within the scope of the claim because the substance was for therapeutic use.  Allsop J interpreted the definition in Schedule 1 as follows:

“I do not see the definition so widely.  The definition refers to a substance, which must have a purpose or use- therapeutic use, and whose application involves the other matters identified in the definition.  The definition is of a particular kind of substance, but it is of a substance, and only a substance.”

1. Thus in order to meet the requirements of a pharmaceutical substance according to Schedule 1, a substance must have a therapeutic use that involves direct interaction with a human physiological system or with a toxin or agent within the human body.  However, the use does not characterise or change the nature of the substance in any way – the substance is the substance per se.  It follows in the present case that the separate components cannot be considered a single pharmaceutical substance per se because of the interaction they have in the human body following their separate administration to the patient.

1. Finally, it could be argued that the use of the two drugs in combination would provide a single pharmaceutical substance at the point of administration, the argument being that a single “substance” exists after administration of the separate drugs to the patient.  However, such a substance would not meet the requirement of it being a pharmaceutical substance per se that is a substance “by or in itself, intrinsically, essentially”, or “taken alone; essentially; without reference to anything else”.

1. I therefore conclude that the request does meet the requirements of section 70(2)(a) in that the combination of thalidomide and at least one steroid as set out by the Patentee does not constitute a “pharmaceutical substances per se”. 

CONCLUSION

1. The requirements of Section 70(2) and 70(3) are not satisfied by the request for an extension of term based on the inclusion of the goods Thalomid in the ARTG and the pharmaceutical substance identified by the patentee in their request.

1. Section 74(3) says that the Commissioner must refuse to accept an application for an extension of term if the requirements of Section 70 are not satisfied.  I have found that the present application does not satisfy these requirements, and accordingly I must refuse the application for an extension of term.

L.  F.  McCaffery
Delegate of the Commissioner of Patents