Sanofi-Aventis

Case •

[2007] APO 35

•

2 October 2007

ABSTRACT OF DECISIONS

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Application  :          No. 771902 in the name of Sanofi-Aventis (formerly Sanofi-Synthelabo)

Title:          Controlled-Release Dosage forms Comprising Zolpidem or a Salt Thereof

Action: Request under s70 of the Patents Act for an extension of term and objections of the Commissioner thereto

Decision:          Issued 2 October 2007.

Abstract

The patentee requested an extension of term of the patent on the basis of the inclusion of STILNOX CRTM on the Australian Register of Therapeutic Goods.  The patent relates to modified release formulations of the short acting hypnotic Zolpidem.  The dosage units are formulated to result in a bi-phasic profile of dissolution.  STILNOX CRTM is a bi-layered tablet comprising an immediate release layer and a prolonged release layer.

The extension was originally refused as not meeting the provisions of s70(2)(a). It was contended that a bi-layered tablet consists of a controlled spatial configuration and therefore does not meet the requirements of being a mixture of pharmaceutical substances as espoused in LTS Lohmann Therapie-Systeme GmbH & Co KG [2002] APO 12.

It was found that STILNOX CRTM is not a mixture in the Lohmann sense.

The extension was granted on the basis that STILNOX CRTM is a compound of pharmaceutical substances and therefore fulfils the requirements of s70(2)(a).

PATENTS ACT 1990

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Re:Patent Application No. 771902 by Sanofi-Aventis, a request under s 70 of the Patents Act for an extension of term and objections of the Commissioner thereto.

BACKGROUND

  1. This matter concerns a request by the patentee, Sanofi-Aventis (hereafter referred to as Sanofi), for an extension of term of patent number 771902 under section 70 of the Patents Act 1990.  The patent relates to “Controlled-Release Dosage Forms Comprising Zolpidem or a Salt Thereof”.  The application was filed on 1 December 1999 and sealed on 12 August 2004.  Accordingly its 20 year term will expire on 1 December 2019.  The application for extension was lodged on 13 December 2006, and if successful will extend the term of the patent until 6 July 2021.

  1. The basis of the request for the extension of term is the inclusion in the Australian Register of Therapeutic Goods (ARTG) of STILNOX CRTM (and STILNOXIUM CRTM), both modified release Zolpidem tartrate tablets comprising either 6.25mg or 12.5mg bi-layered dosage units. ARTG commencement was on 6 July 2006.  Following the filing of the application for extension, a delegate of the Commissioner reported that he considered the patent did not include any claim to a pharmaceutical substance per se. He also questioned whether there was any substance in the relevant goods listed in the ARTG that fell within the scope of the claims, and noted that the date of first inclusion of Zolpidem tartrate appeared to be 13 August 1997, precluding the present patent from an extension of term under s70. Despite further submissions and filing of a substitute extension of term request form, the delegate maintained his objection to an allowance of the extension, contending the patent did not include any claim to a pharmaceutical substance per se, and further, that the bi-layered goods listed in the ARTG are not pharmaceutical substances per se.

  1. The matter was subsequently heard in Canberra on 29 June 2007.  Sanofi was represented by Mr Michael Caine, patent attorney of Davies Collison Cave, Melbourne. 

    THE SPECIFICATION

  2. The present patent relates to controlled-release formulations of Zolpidem, and in particular to Zolpidem tartrate, a short acting hypnotic from the therapeutic class imidazopyridines.  The dosage units are formulated to result in a bi-phasic profile of dissolution.  The first phase provides immediate release, intended to induce the rapid onset of sleep.  The second phase provides prolonged release, enabling sleep to be sustained for a suitable period, while allowing for the timely elimination of the drug from the body. 

  3. Claim 1 is the sole independent claim and is recited as:

    1.  A pharmaceutical composition comprising zolpidem or a salt thereof wherein said composition consists of a controlled-release dosage form adapted to release zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution when measured in a type II dissolution apparatus according to U.S. Pharmacopoeia in 0.01 M hydrochloric acid buffer at 37°C, where the first phase is an immediate release phase having a maximum duration of 30 minutes and the second phase is a prolonged release phase, and wherein 40 to 70% of the total amount of zolpidem is released during the immediate release phase and the time for release of 90% of the total amount of zolpidem is between 2 and 6 hours.

  4. The remaining 24 dependent claims are directed to similar pharmaceutical compositions defined by their particular pharmacokinetic profiles, excipients and dosage forms.  As the decision at hand turns on whether certain compositions argued to fall within the scope of claim 1 are pharmaceutical substances per se, I do not consider it necessary to further elaborate on the details of the dependent claims.

  1. The resultant dissolution profile defined by claim 1 is described as being achievable by various means.  These include:

    • A capsule comprising one or more immediate release tablets and one or more prolonged release tablets
    • A capsule comprising one or more immediate release pellets and one or more prolonged release tablets
    • A tablet with prolonged release coated pellets embedded in a fast disintegrating matrix comprising the active principle
    • A multicoated tablet
    • A multilayer tablet

  2. Of most relevance is Example 6, which teaches bi-layer tablets comprising an immediate release layer and a prolonged release layer, containing a total of 12.5 mg of Zolpidem hemitartrate.  (These tablets are found in the ARTG as a STILNOX CRTM Zolpidem tartrate 12.5mg modified release tablet blister pack.)  I note with interest that the specification asserts the dissolution profile of the bi-layer tablet to be different to the profile observed when an immediate release tablet and prolonged release tablet of the same composition are administered simultaneously.  This is described in Comparative Example 2 and Figure 9 of the specification, and indeed appears to be evidence of a synergistic effect between the two layers. 

    THE RELEVANT PROVISIONS

  3. Part 3 of Chapter 6 of the Patents Act 1990 provides a statutory framework for the 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."

  1. The patent under consideration in these proceedings falls into the first category, s 70(2)(a). Section 70(2)(b) therefore does not require any further treatment here.

  1. The expression "pharmaceutical substance" is defined in Schedule 1 of the Act to mean:

"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. The term "therapeutic use" is also defined in Schedule 1.  It means:

"use for the purpose of:

(a) preventing, diagnosing, curing or alleviating a disease, ailment, defect or injury in persons; or
(b) influencing, inhibiting or modifying a physiological process in persons; or

(c)  testing the susceptibility of persons to a disease or ailment."

  1. Section 70(3) provides that the following conditions must be satisfied in relation to at least one of the pharmaceutical substances referred to in s 70(2):

"(a) goods containing, or consisting of, the substance must be included in the Australian Register of Therapeutic Goods;
(b) the period beginning on the date of the patent and ending on the first regulatory approval date for the substance must be at least 5 years."

  1. Section 70(4) requires that the patent must not have been previously extended under Part 3.

  2. It is asserted by the patentee that the first substance registered on the ARTG that falls within the scope of a claim in the present patent is the bi-layered modified release tablet, STILNOX CRTM. 

  1. Following a request by the delegate, the provision of further information on the dissolution properties of STILNOX CRTM, has removed any question that goods containing or consisting of at least one substance falling within the scope of a claim were included on 6 July 2006 in the ARTG.  Furthermore, the attorney has advised that the earlier monolayer formulations of Zolpidem tartrate (listed in the ARTG on 13 August 1997) show complete, total dissolution of the tablet in only 10 minutes. Accordingly these earlier formulations do not satisfy the requirements of claim 1.  It follows that this is the first ARTG registration of a good containing or consisting of STILNOX CRTM, and that the patent has not been previously extended under Part 3 of the Patents Act. I am satisfied that the patent meets the requirements set out in both s70(3) and s70(4).

  2. The question to be answered is whether the requirements set out in s70(2)(a) have been met. It is clear that STILNOX CRTM is in substance disclosed in the complete specification of the patent, and falls within the scope of claim 1.  The crucial issue is whether a bi-phasic, controlled-release dosage form comprising an immediate release layer and a prolonged release layer is a pharmaceutical substance per se within the meaning of the Act.

    THE APPLICANT’S SUBMISSIONS

  3. The applicant’s submissions are briefly summarised as follows. 

    • Any pharmaceutical tablet, bi-layer or otherwise, would generally be considered to represent a pharmaceutical substance per se.
    • In any case, the statement appearing in parentheses in the definition of pharmaceutical substance places the matter beyond doubt because mixtures of substances and compounds of substances can represent “a pharmaceutical substance”.
    • The spatial configuration of the bi-layered tablet STILNOX CRTM does not constitute a mixture of pharmaceutical substances.  Rather, STILNOX CRTM is a compound of pharmaceutical substances. 
    • The term compound is used in both the chemical arts and the pharmaceutical arts. 
    • In the chemical arts, a compound is a substance resulting from the formation of chemical bonds or associations between two or more atoms or molecules. In the context of the Patents Act the term compound cannot assume the meaning it takes in the chemical arts.  If it were to assume this meaning, the inclusion of the term in the definition of pharmaceutical substance in Schedule 1 would be redundant.  Any pharmaceutically active agent would be a discreet chemical compound, and would necessarily already be considered a pharmaceutical substance.
    • In the pharmaceutical arts, the term compound refers to a composition or preparation containing one or more pharmaceutically active substances.  The process of “compounding” is the bringing together of two or more components into a form suitable for administration.  The formulated product is often referred to as a compound and does not require any consideration of spatial configuration.  STILNOX CRTM is a compound of pharmaceutical substances in this sense.
    • A pharmaceutical substance, including a compound of pharmaceutical substances can also include non-therapeutic components including carriers, lubricants, disintegrants and the like. 
    • Patents directed to pharmaceutical compositions comprising mixtures of active and non-therapeutic components have previously been granted.  It follows that pharmaceutical compositions comprising compounds of active and non-therapeutic components are also entitled to an extension of term.

    PHARMACEUTICAL SUBSTANCE PER SE

  4. The applicant has submitted that “any pharmaceutical tablet, bi-layer or otherwise, would generally be considered to represent a pharmaceutical substance”. I agree that it would seem counter-intuitive that a simple tablet may be extendable under the Act, while a more complex or technologically advanced tablet may not be. On the face of the matter, it would appear that the micro-structure of a tablet should not be a consideration when considering the provisions of section 70. However, this is not the proper test. The proper test is prescribed by the legislation.

  5. Under the Patents Act, a pharmaceutical substance is limited to "a substance (including a mixture or compound of substances) for therapeutic use" [emphasis added].  There is no dispute that STILNOX CRTM is for therapeutic use.  As a controlled release hypnotic, it is clear that it’s purpose is in preventing, diagnosing, curing or alleviating a disease, ailment, defect or injury in persons; or influencing, inhibiting or modifying a physiological process in persons, as defined in Schedule 1.

  6. Each layer of the tablet is comprised of a mixture of the active agent Zolpidem tartrate and appropriate excipients which confer the desired pharmacokinetic profile of the individual layer. When used, the active agent undoubtedly involves a chemical interaction with a human physiological system.  Further, due to the release properties provided by the excipients, the composition of each layer involves a physico-chemical interaction with a human physiological system.  It follows that, in isolation, each layer is considered to be a pharmaceutical substance per se, as defined in the legislation.

  7. The question remaining is whether the combination of the two layers, when taken as a whole defines a pharmaceutical substance, or a mixture or compound of pharmaceutical substances.  

    MIXTURES AND COMPOUNDS

    Mixtures

  8. The phrase “mixtures and compounds” has been discussed in LTS Lohmann Therapie-Systeme GmbH & Co KG [2002] APO 12 (hereafter referred to as Lohmann). The patent in this case related to a transdermal patch which delivered a known drug, 17-[beta]-estradiol. Claim 1 was defined in the following terms:

    1.  Transdermal therapeutic system containing the active substance 17-[beta]- estradiol and optionally further active substances, with a laminated structure comprising a backing layer which is substantially impermeable to moisture and impermeable to active substance, one or more matrix layers and, where non-adhesive matrix layers are present, an adhesive layer, characterised in that the concentration of the dissolved estradiol in all matrix layers and, where an adhesive layer is present, in the adhesive layer, lies between its saturation concentration in dry condition and its saturation concentration in moist condition, whereby the term "dry condition" is understood to mean that the base material is in equilibrium with a gas phase with less than 10% relative humidity, and the term "moist condition" is understood to mean that the base material is in equilibrium with a gas phase with more than 90% relative humidity.

  9. In this decision, the Hearing Officer concluded that the qualification "including a mixture or compound of substances" to the definition of "a substance" in Schedule 1 makes clear that "substance" is not limited to single chemical entities, but extends to mixtures and compounds of chemical entities.  He went on to state that the definition of " pharmaceutical substance" is necessarily limited to chemical entities per se, compounds of chemical entities and mixtures of chemical entities.

  10. The hearing officer characterised a mixture as:

    • An aggregate of two or more substances which are not chemically united, and which exist in no fixed proportions to each other (Macquarie dictionary)
    • A concept , at least at the macroscopic level, of an uncontrolled spatial configuration of the entities in a substance
    • Not involving any chemical association

  11. It was concluded that "....if a claim to an alleged pharmaceutical substance includes features specifying spatial configuration of the entities in the substance, it is not a claim to a pharmaceutical substance per se but a claim to an arrangement of substances characterised by that spatial configuration."

  12. While it may be tempting to apply this principle to the present application for extension, there are two important points that need to be recognised.

  13. Firstly, the Lohmann decision concerns itself with layered transdermal delivery systems that include a backing layer or “patch”. As patches are not within the normal understanding of a pharmaceutical substance, it follows that claims containing such integers cannot serve as the basis for an extension under section 70. Similarly, claims containing other physical integers are not extendable. Examples may be found in the aerosol can containing a pharmaceutical substance described in Boehringer Ingelheim International GmbH v Commissioner of Patents [2001] FCA 647 and in the transdermal delivery system described in Euro-Celtique, S.A. [2007] APO 13 (26 March 2007). In contrast, STILNOX CRTM consists of substances that fall within the everyday meaning of a pharmaceutical substance and does not include any separate physical integers. The substances meet the requisite criteria for being pharmaceutical substances within the meaning of Schedule 1.

  14. Secondly, Lohmann predominantly explores the concept of a mixture of pharmaceutical substances.   As a bi-layered tablet, STILNOX CRTM does indeed have a spatial arrangement and therefore does not qualify as a mixture in the Lohmann sense.  However, it is not contended by the applicant that STILNOX CRTM is a mixture.  Instead, it is contended that it is a compound, and that a compound may indeed include combinations of integers that have a definite spatial relationship.  Lohmann does not provide any detailed consideration or guidance on what may constitute a compound of pharmaceutical substances.  The concept of a compound of pharmaceutical substances was not material to the decision in this case. 

  15. I believe these points sufficiently distinguish the present application from Lohmann.

Compounds

  1. I will now examine the applicant’s assertion that STILNOX CRTM is a compound of pharmaceutical substances.  To do this I need to determine the meaning of the term compound within the context of the Act, and whether two layers, each comprising a mixture of excipients and active components, form a compound when combined into a single bi-layered tablet.

  2. The term compound is a commonly used word in the fields of both chemistry and pharmacy.  In chemistry it is well accepted that a compound is the product of the chemical bonding of two or more elemental atoms.  In pharmacy, it is well accepted that a compound is the product of formulating one or more therapeutic substances into a form suitable for administration, generally in combination with non-therapeutic excipients.  It may be argued that the term could assume either meaning within Schedule 1.  However, as the applicant has submitted, were “compound” to be interpreted in the chemical sense, the inclusion of the term in Schedule 1 would appear to be redundant.  A chemical compound would necessarily already be considered a pharmaceutical substance, itself being a discreet molecule.  Commonwealth v Baume (1905) 2 CLR 405 provides that all words must be given some meaning and effect. Construing “compound” in the pharmaceutical sense shows the only way in which the language of the statute can be given a workable meaning.

  1. The applicant has also provided an assortment of publications summarised as follows.

    • US Patent 1 414 815 describes a medicinal compound for external use as a plaster or ointment.  The compound consists of a mixture of belladonna and lard and is applied to the skin. 
    • The patient information sheet provided by S.A.D. SELF MEDICATION [PTY] LIMITED for a liquid antitussive/expectorant provides the proprietary name as “Theophen Compound Elixir”
    • The British Pharmaceutical Codex describes an “Elixir Taraxaci Compositum” as being a “Compound Elixir of Taraxacum”, and further describes one of the components as a “Compound Tincture of Cardamoms”.  The composition appears to be a simple mixture of the various components.
    • An abstract of a Doctoral Thesis by Sofia Mattsson titled “Pharmaceutical binders and their function in directly compressed tablets: Mechanistic studies on the effect of dry binders on mechanical strength, pore structure and disintegration of tablets” refers to “compound tablets”.
    • The internet encyclopedia “Wikipedia” describes Lydia Pinkham’s patent medicine as a “Vegetable Compound” consisting of various botanical ingredients combined with alcohol.  It further recites two folk songs relating to her compound.

  2. Whilst somewhat obscure, these publications provide evidence of the term compound being used in the pharmaceutical arts, and support the contention that a compound within the meaning of the Act is a pharmaceutical compound and not a chemical compound.  However, they appear to describe mixtures, and do not demonstrate any compounds having a layered structure or particular spatial arrangement such as that found in STILNOX CRTM.

  3. While I am satisfied that the term compound as used in the Act is to be read in the pharmaceutical sense, I must still determine whether a bi-layered tablet is a compound.  The applicant has further provided dictionary definitions of compound from Princeton University’s wordnet.  They are extracted as follows.

    • a whole formed by a union of two of more elements or parts
    • create by mixing or combining
    • combine so as to form a whole; mix “compound the ingredients”
    • put or add together “combine resources”

  4. These definitions qualify a compound as being a true mixture (in the Lohmann sense), but also contemplate a compound that is formed by combining elements or parts, or creating a union of parts.  In this sense a compound is not necessarily limited to any particular spatial arrangement of components.   It would seem reasonable to infer that a tablet formed by the combination or union of two layers falls within the meaning of compound. 

  5. Further, the explanatory memorandum to the Intellectual Property Laws Bill of 1997 noted that, with the exception of substances produced by processes involving the use of recombinant DNA technology, claims to pharmaceutical substances per se would be usually restricted to new and inventive substances.  Indeed, it is actually the bi-layered spatial arrangement of STILNOX CRTM that imparts the unique pharmacokinetic profile asserted to provide an improved night’s sleep.  It is the synergistic combination of the layers which provides the essence of the invention.  I think it reasonable to infer that granting an extension to the new and inventive pharmaceutical substance, STILNOX CRTM is consistent with the intent of the legislative provisions.

    CONCLUSION

  6. I am satisfied that the bi-layered Zolpidem tartrate tablet STILNOX CRTM is a compound of pharmaceutical substances.  Each of the layers consists of a mixture of a therapeutically active substance and non-therapeutic pharmaceutical excipients that fall within the everyday understanding of the term “pharmaceutical substances”.  The union of the two layers brings the two mixtures into a form suitable for administration and is considered to result in a “compound of pharmaceutical substances” within the meaning of the legislation. 

  7. I am further satisfied that as a compound of pharmaceutical substances, STILNOX CRTM is a pharmaceutical substance per se.  It does not contain any purely physical integers, rather, it consists solely of integers that are in themselves well understood to be pharmaceutical substances.

  1. The requirements of section 70(2) have been fulfilled and accordingly I allow the request to extend the term of patent 771902.

    Gillian Jenkins
    Deputy Commissioner of Patents

    Patent attorneys for the patentee: Davies Collision Cave,  Melbourne

Actions
Download as PDF Download as Word Document
Most Recent Citation
N. v Organon [2009] APO 8
Cases Citing This Decision

5

iCeutica Pty Ltd [2018] APO 76
iCeutica Pty Ltd [2018] APO 78
iCeutica Pty Ltd [2018] APO 77
Cases Cited

4

Statutory Material Cited

0

LTS Lohmann Therapie-Systeme GmbH & Co KG [2002] APO 12
Boehringer Ingelheim International GmbH v Commissioner of Patents [2001] FCA 647
Euro-Celtique, S.A. [2007] APO 13