Wyeth LLC
[2019] APO 1
•7 January 2019
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Wyeth LLC [2019] APO 1
Patent:2015264861
Title:Sodium ibuprofen tablets and methods of manufacturing pharmaceutical compositions including sodium ibuprofen
Patentee: Wyeth LLC
Delegate: Dr S. J. Smith
Decision Date: 7 January 2019
Hearing Date: 7 November 2018, in Canberra
Catchwords: PATENTS – application for extension of term of patent –composition defined in part by maximum sodium content relative to ibuprofen – pharmaceutical substance per se identified – contained in the goods Advil Rapid Release – application for extension of term accepted
Representation: Patent attorney for the patentee: Linda Govenlock and Claire Gregg of Allens Patent & Trade Mark Attorneys
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent:2015264861
Title:Sodium ibuprofen tablets and methods of manufacturing pharmaceutical compositions including sodium ibuprofen
Patentee: Wyeth LLC
Date of Decision: 7 January 2019
DECISION
I accept the application for an extension of term.
For the purposes of section 74(2)(a) this decision constitutes notification in writing of the acceptance. The acceptance will be advertised in the Official Journal.
REASONS FOR DECISION
Background
This matter concerns a request for an extension of the term of patent number 2015264861 in the name of Wyeth LLC (the patentee). The date of the patent is 21 June 2010 and accordingly the term of the patent (subject to the payment of renewal fees) will expire on 21 June 2030. An application for extension of the term of the patent under section 70 of the Patents Act 1990 (the Act) was filed on 3 November 2017.
The basis for the request for an extension of term is the inclusion in the Australian Register of Therapeutic Goods (ARTG) of ADVIL RAPID RELEASE®. The request identifies two relevant products as subject to ARTG registration commencing on 9 May 2017 (AUST R 288707, AUST R 288708). It follows from this information and the formula set out in section 77 of the Act that if an extension of term is granted the patent would expire on 9 May 2032.
A delegate of the Commissioner issued three deficiency notices explaining that she considered that the application did not meet the requirements of the Act and the patentee requested to be heard on 13 June 2018.
Specification
The specification relates to sodium ibuprofen cores and coated table/caplet compositions which have a low sodium content relative to other commercially available sodium ibuprofen dosage forms, and methods of manufacturing such cores. The specification indicates that such cores and coated core compositions are advantageous since they allow for the formation of tablet/caplet cores having a maximum daily sodium content for a patient of less than 140 mg/day (in the context of a maximum recommended daily intake of 1200 mg of ibuprofen). The specification further describes the cores and coated cores as having improved physical stability, high hardness and core strength, and excellent dissolution and bioavailability characteristics. This is set against a background of tablets having sufficient but not optimal hardness, and large total sodium content.[1]
[1] Page 1, [002]-[003].
The specification goes on to describe the invention, in a first aspect, as:
“a pharmaceutical composition comprising a core, said core comprising sodium ibuprofen dihydrate and an excipient mixture comprising (a) at least one binder selected from saccharose, glucose, fructose, lactose, mannitol, xylitol, maltitol, and sorbitol, (b) at least one disintegrant, and (c) at least one lubricant selected from stearic acid, microcrystalline cellulose and combinations thereof; wherein each ingredient in said excipient mixture is present in a functionally effective amount; wherein the excipient mixture comprises 10%-50% by weight of said core; and wherein the sodium content of said pharmaceutical composition is below 140 mg per 1200 mg of free ibuprofen.”[2]
[2] Page 4, [007a].
It is explained in the specification that 21 CFR 201.64 “Labeling Requirements for Over-the-Counter Drugs” requires that a warning must appear if the maximum daily dose of an over the counter drug includes more than 140 mg of sodium. Specifically:
“The labeling of OTC drug products intended for oral ingestion shall contain the following statement under the heading ‘Warning’ … if the amount of sodium present in the labeled maximum daily dose of the product is more than 140 milligrams: ‘Ask a doctor before use if you have … a sodium-restricted diet’.”
Accordingly, it is an advantage of the invention that such a warning is not required.[3]
[3] Pages 7-8, [019].
The specification further indicates the invention relates to sodium ibuprofen cores and corresponding coated tablets and caplets formed by compression. It is important that an adequately strong tablet is achieved to avoid breakage during handling, film-coating and shipping.[4]
[4] Page 6, [011].
Advantageous properties associated with particular excipients are described. For example, the specification indicates that binders of the invention include microcrystalline cellulose (MCC), which has unique compressibility and carrying capacity. MCC “compacts well under a wide range of compression pressures, has high binding capability, and creates tablets that are extremely hard, stable, yet disintegrate rapidly.” MCC is particularly valuable as a filler and binder for formulations prepared by roller compaction, direct compression and wet granulation. Mannitol is also noted as an excellent diluent-binder.[5]
[5] Pages 6-7, [013].
The specification notes that silicone dioxide may be used as a glidant in the invention and also indicates that MCC and sodium lauryl sulfate are contemplated for use as lubricants, although sodium ibuprofen is itself a good lubricant.[6] The specification states that in some embodiments the disintegrant component comprises MCC and one or more of, inter alia, crospovidone, alginic acid, carboxymethylcellulose, calcium silicate, a metal carbonate.[7]
[6] Page 7, [014]-[015].
[7] Page 7, [016].
Ten examples are provided. Examples 1-4 describe formulations of sodium ibuprofen tablets according to the invention. Table 1, describing the composition of one such tablet, is reproduced below. Example 5 describes various coating systems for tablet and caplet cores. Examples 6 and 7 describe the manufacturing process for sodium ibuprofen tablets. Examples 8 and 9 report friability data. Example 10 compares prototype tables with a marketed reference standard, concluding that the prototype tablets were bioequivalent to the reference standard with respect to extent and rate of ibuprofen absorption, and demonstrated peak plasma concentration within 40 minutes of dosing, which was faster than the reference standard.
The specification ends with 12 claims and the entire claim set is reproduced at Annex A. Claim 1 reads as follows:
A pharmaceutical composition comprising a core, said core comprising sodium ibuprofen dihydrate and an excipient mixture comprising (a) at least one binder selected from saccharose, glucose, fructose, lactose, mannitol, xylitol, maltitol, and sorbitol, (b) at least one disintegrant, and (c) at least one lubricant selected from stearic acid, microcrystalline cellulose and combinations thereof; wherein each ingredient in said excipient mixture is present in a functionally effective amount; wherein the excipient mixture comprises
10%-50% by weight of said core; and wherein the sodium content of said pharmaceutical composition is below 140 mg per 1200 mg of free ibuprofen.That is, the claim is directed to a pharmaceutical composition containing sodium ibuprofen dihydrate, particular excipients and having an upper limit on the amount of sodium present in the composition relative to the amount of free ibuprofen. The ingredients in the excipient mixture are present in “a functionally effective amount”, but there is no limitation on the actual amount of ibuprofen or sodium present beyond the defined relationship between them.
Claims 2-5 are appended to claim 1 and provide further limitations to the pharmaceutical composition with regard to its form, sodium content, hardness, and release profile. Only claims 1-5 are relevant for the present purposes.
The statutory framework
Part 3 of Chapter 6 of the Act 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.
(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) 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.”
The expression “pharmaceutical substance” is defined in Schedule 1 of the Act, and is:
“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.”
The expression “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 person; or
(c) testing the susceptibility of persons to a disease or ailment.”
If an extension of term is granted section 77 provides:
“(1)If the Commissioner grants an extension of the term of a standard patent, the term of the extension is equal to:
(a) the period beginning on the date of the patent and ending on the earliest first regulatory approval date (as defined by section 70) in relation to any of the pharmaceutical substances referred to in subsection 70(2);
reduced (but not below zero) by:
(b) 5 years.
Note: Section 65 sets out the date of a patent.
(2)However, the term of the extension cannot be longer than 5 years.”
The deficiency notices
Each of the three deficiency notices indicates that the requirements of section 70(2)(a) were not satisfied. The delegate indicated that the “qualifying feature of the pharmaceutical composition comprising less than 140mg sodium per 1200mg of free ibuprofen imposes a limitation on the nature of the pharmaceutical composition”,[8] akin to a “for use” limitation or limitation to a particular quantum of a substance, which are claim types typically not considered to be directed to pharmaceutical substances per se.[9] The delegate noted that the sodium content does not alter the way the active pharmaceutical ingredient (API), sodium ibuprofen dihydrate, works, or provide any new pharmacokinetic profile.
[8] Deficiency Notice dated 21 December 2017.
[9] Boehringer Ingelheim International v Commissioner of Patents [2000] FCA 1918; (2001) AIPC 91-670 at [18]-[19].
A deficiency that the requirements of section 70(3) were not satisfied was raised in the first two deficiency notices but overcome upon provision of further information by the patentee.
Does a pharmaceutical substance per se in substance fall within the scope of the claims?
The meaning of the expression “pharmaceutical substance per se” in section 70(2)(a) has been considered by the Federal Court on a number of occasions. The Full Court in Boehringer Ingelheim International GmbH v Commissioner of Patents[10] approved the trial judge’s conclusions in relation to the scope of section 70(2)(a), including the following statement:
“Broadly speaking, a claim in relation to a pharmaceutical substance can be made in three ways
(i) a new and inventive product alone;
(ii) an old or known product prepared by a new and inventive process;
(iii) an old or known product that is used in a new and inventive mode of treatment.What is clear in s 70 is that only the first type of claim to a pharmaceutical product is to be subject to extension rights.
……the relevance of the expression ‘per se’ becomes clear. Section 70(2)(a) is only to make extension rights available when the claim is for a pharmaceutical substance as such, as opposed to a substance forming part of a method or process.”[10] [2001] FCA 647; 52 IPR 529 at [17].
Subsequently in Pharmacia Italia SpA v Mayne Pharma Pty Ltd[11] (Pharmacia) the Federal Court considered the following claim:
A sterile, pyrogen-free, anthracycline glycoside solution which comprises a physiologically acceptable salt of an anthracycline glycoside dissolved in a physiologically acceptable aqueous solvent therefor at an anthracycline glycoside concentration of from 0.1 to 50 mg/ml, which has not been reconstituted from a lyophilizate and the pH of which has been adjusted [to] from 2.5 to 5.0 solely with a physiologically acceptable acid.
[11] [2006] FCA 305; 69 IPR 1.
The specification of the patent considered in Pharmacia indicates that the invention is a ready-to-use solution of an anthracycline glycoside drug, preparation and administration of which does not require lyophilisation or reconstitution. While the key questions considered in Pharmacia (relating to whether the claim is properly understood as directed to a product or is limited by the process of its production) are not apposite to the present matter, the claim in question in Pharmacia is directed to a composition characterised by a therapeutic agent and non-active components.
Notably, in Pharmacia an expert witness gave evidence as to their opinion that the relevant pharmaceutical substance in that case was the physiologically acceptable salt of an anthracycline glycoside, and not the mixture comprising the therapeutically active anthracycline glycoside, solvent and acid.[12] That evidence was rejected,[13] with Weinberg J stating that “[t]o restrict the capacity to extend a patent to those unlikely cases where every component of the compound is itself therapeutically useful would be to deprive the section of any real utility”.[14] Weinberg J concluded that the claim was itself directed to a pharmaceutical substance per se, defining a therapeutically significant substance together with the solvent which makes up the overall product, and wherein references to lyophilisation and pH adjustment simply mark out the basis on which the substance can be distinguished from the prior art.[15]
[12] Pharmacia at [66]-[68].
[13] Pharmacia at [104].
[14] Pharmacia at [107].
[15] Pharmacia at [99]-[100].
Whether a pharmaceutical substance per se may be a mixture of an active agent with excipients or the active agent only was more recently considered in Spirit Pharmaceuticals Pty Ltd v Mundipharma Pty Ltd[16] (Spirit). In Spirit the relevant claims were directed to controlled release formulations of oxycodone, characterised by dosage amounts, excipients and/or release profile – that is, none of the claims related to oxycodone per se and the claims were limited by the result achieved by the formulation:
“Each of claims 3-11 comprised a definition that included a dosage or range of dosages of oxycodone to be delivered orally contained in a matrix of excipients. Critically, that definition identified the invention as a formulation in which the matrix of excipients was intended to control the rate of release of oxycodone into the human GI tract.”[17]
[16] Spirit Pharmaceutical Pty Ltd v Mundipharma Pty Ltd [2013] FCA 658; 102 IPR 55.
[17] Spirit at [28].
Rares J stated that:
“the expression ‘pharmaceutical substance’ used in s 70(2)(a), read with its definition and that of ‘therapeutic use’, relevantly in the context of considering the nature of OxyContin, meant a substance, including a mixture, used for the purpose of alleviating an ailment (pain), one of whose applications involved a chemical interaction with a human physiological system”[18]
and concluded that the pharmaceutical substance relevant to the patent under consideration was a controlled release formulation of oxycodone.[19] That is, the pharmaceutical substance per se was a mixture of oxycodone and excipients giving rise to the pharmacokinetic parameters defined in the claims:
“The specification or (as Spirit characterised it) the nominated result in the pharmacokinetic parameters, simply had the function of defining the necessary characteristics of whatever excipients were selected as part of the mixture to embody the formulation that would achieve the controlled release of the particular dosage of oxycodone. However, the mixtures formulated with the relevant dosages and excipients to achieve the pharmacokinetic parameters for the controlled release, as specified in claims 3 and 4, were all embodiments of the pharmaceutical substance per se, OxyContin, that met the criteria in s 70(2)(a). The same applies for formulations made in accordance with claims 5 to 12.”[20]
[18] Spirit at [49].
[19] Spirit at [66]-[67].
[20] Spirit at [73].
Accordingly, it is clear that the inclusion of limitations to the scope of a composition claim does not necessarily mean that the claim cannot be properly understood as being directed to a pharmaceutical substance per se. In this regard, I note the sentiment of Deputy Commissioner Spann in N.V. Organon[21] echoed recently by Deputy Commissioner Barker in iCeutica Pty Ltd: [22]
“As Deputy Commissioner Spann noted, the concept of a pharmaceutical substance should be understood with common sense in a way that does not draw artificial distinctions:
‘It also appears that I should be cautious in interpreting “substance” in a way that would unnecessarily exclude innovations in the pharmaceutical sector for which the extension of term scheme appears to be intended.’”
[21] [2009] APO 8; [2009] AIPC 92-345 at [21].
[22] [2018] APO 76 at [26].
The present claim defines a composition characterised by the API – sodium ibuprofen dihydrate, excipients, and an upper limit to the ratio of sodium to ibuprofen in the composition. It is uncontroversial that such a composition has a therapeutic use in the treatment of pain. The deficiency notices issued during consideration of the application for extension of term focussed to an extent on the qualification on the quantity of sodium in the composition. Is this a limitation that means that what is claimed is not a pharmaceutical substance per se?
The patentee submitted that the ratio of sodium to free ibuprofen simply moderates the excipients which make up the pharmaceutical composition – that is, the excipients must be chosen such that the maximum amount of sodium defined in the claim is not exceeded. I agree that this must be so, and to my mind this is analogous to the situation in Spirit, where the limitation to the pharmacokinetic profile dictated the selection of appropriate excipients. I also accept the patentee’s submission that for the purpose of satisfying section 70(2)(a) it is not necessary for the patentee to demonstrate that the excipients give rise to a different therapeutic profile to previous formulations of the API. This would seem to go the merits of the invention rather than the relevant enquiry with respect to section 70(2)(a) as to the nature of the claimed invention.
I consider that the subject of claim 1 is a pharmaceutical composition per se containing sodium ibuprofen dihydrate and an excipient combination satisfying the requirements of the claim, including with regard to sodium content. The manner of defining the excipient combination does not, to my mind, change the nature of the claim from being a pharmaceutical composition per se. That is, the claim is not limited by a method of preparation or use, or to use in a particular environment – it is directed to a composition per se.
The pharmaceutical substance per se must “in substance fall within the scope of the claim or claims” of the specification. This has been interpreted to mean that “it must itself be the subject of a claim of the relevant patent”.[23] In this case the subject of claim 1 is a pharmaceutical composition and I am satisfied that that composition is a pharmaceutical substance per se.
[23] Prejay Holdings v Commissioner [2003] FCAFC 77; 57 IPR 424 at [24].
Is the pharmaceutical substance per se in substance disclosed in the specification?
The meaning of “in substance be disclosed” was considered by Bennett J in Pfizer Inc v Commissioner of Patents:[24]
“There is, in my view, much to be said for the proposition that ‘in substance disclosure’ imports a ‘real and reasonably clear disclosure’. If there is a difference, to my mind the requirement for ‘in substance’ disclosure is a less requirement than for a ‘real and reasonably clear disclosure’ or description. Section 70(2)(a) does not require express disclosure. If it did, there would be no need for the words ‘in substance’. It seems to me that the additional words cannot import a higher test than ‘real and reasonably clear disclosure’.”
[24] [2005] FCA 137; 64 IPR 547 at [75].
I have discussed above the disclosure of the specification, including the examples, and I am satisfied that there is in substance a disclosure of the pharmaceutical substance.
Does the ARTG include goods containing or consisting of the pharmaceutical substance?
The claims define the pharmaceutical substance in terms of the API (sodium ibuprofen dihydrate); a binder, disintegrant and lubricant in functionally effective amounts; the amount of excipient mixture in the core; and the sodium content. Together with the application for an extension of term the patentee provided a declaration by Jeffrey Gold, Assistant General Counsel and Lead Patent and R&D Counsel for Pfizer Consumer Healthcare, and familiar with the composition of ADVIL RAPID RELEASE®, stating that ADVIL RAPID RELEASE® 256 mg tablets contain less than 140 mg sodium per 1200 mg of ibuprofen, the excipient mixture comprises between 10% and 50% by weight of the core of the tablet, and the excipients present are colloidal silicon dioxide, mannitol, microcrystalline cellulose and sodium lauryl sulfate.
Subsequently, in response to a deficiency notice, a further declaration by Jeffrey Gold was provided stating that mannitol is present in a functionally effective amount as a binder and that microcrystalline cellulose is present in an amount effective to function as both a disintegrant and a binder. The declaration states that both these excipients are present in ADVIL RAPID RELEASE® tablets in an amount equivalent to the amount specified in Example 1 of the patent. On the basis of this information the delegate was satisfied that ADVIL RAPID RELEASE® tablets satisfy the requirements of section 70(3) and I agree with that conclusion.
Conclusion
Pursuant to section 74(1), the Commissioner must accept an application for extension of term if she is satisfied that the requirements of section 70 and 71 have been met. I am so satisfied and therefore I must accept the application for extension of term.
Dr S. J. Smith
Delegate of the Commissioner of PatentsAnnex A
1. A pharmaceutical composition comprising a core, said core comprising sodium ibuprofen dihydrate and an excipient mixture comprising (a) at least one binder selected from saccharose, glucose, fructose, lactose, mannitol, xylitol, maltitol, and sorbitol, (b) at least one disintegrant, and (c) at least one lubricant selected from stearic acid, microcrystalline cellulose and combinations thereof; wherein each ingredient in said excipient mixture is present in a functionally effective amount; wherein the excipient mixture comprises 10%-50% by weight of said core; and wherein the sodium content of said pharmaceutical composition is below 140 mg per 1200 mg of free ibuprofen.
2. The pharmaceutical composition according to claim 1, in the form of a tablet or caplet further comprising at least one coating.
3. The pharmaceutical composition according to claim 2 comprising a coated core, said core containing sodium ibuprofen, said coated core having a sodium content of less than 23 mg/dosage unit.
4. The pharmaceutical composition according to any one of claims 1-3, having a hardness of greater than 80 N.
5. The pharmaceutical composition according to any one of claims 1-4, wherein the Tmax of ibuprofen obtained by a human taking two such cores is about 40 minutes or less.
6. A process of manufacturing a pharmaceutical composition comprising a core, said core comprising sodium ibuprofen dihydrate and an excipient mixture comprising (a) at least one binder selected from saccharose, glucose, fructose, lactose, mannitol, xylitol, maltitol,
and sorbitol, (b) at least one disintegrant, and (c) at least one lubricant selected from stearic acid, microcrystalline cellulose and combinations thereof; wherein each ingredient in said excipient mixture is present in a functionally effective amount; wherein the excipient mixture comprises 10%-50% by weight of said core; and wherein the sodium content of said pharmaceutical composition is below 140 mg per 1200 mg of free ibuprofen;
wherein said pharmaceutical composition is manufactured using a process comprising (1) blending all of the sodium ibuprofen dihydrate with at least a portion of one or more excipients into a granulation mix; (2) milling said granulation mix; (3) blending in an additional portion of excipients, some of which may optionally have also been part of the granulation mix, to form a compression mix; (4) compressing said compression mix into said core; and (5) coating said core.7. The process according to claim 6, in the form of a tablet or caplet.
8. The process according to claim 7, wherein said coated core has a sodium content of less than 23 mg/dosage unit.
9. The process according to any one of claims 6-8, having a hardness of greater than 80 N.
10. The process according to any one of claims 6-9, wherein the Tmax of ibuprofen obtained by a human taking two of said cores is about 40 minutes or less.
11. A method for providing ibuprofen to a human, the method comprising administering to said human a composition according to any one of claims 1 to 5.
12. Use of a composition according to any one of claims 1 to 5, in the manufacture of a medicament for providing ibuprofen to a human.