Genentech, Inc v Grandis Deutschland GmbH ( Minor Correction) - [2005] APO 20

ABSTRACTS OF DECISIONS

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Application : No. 686567 in the name of Genentech, Inc.

Title: Human Growth Hormone Aqueous Formulation

Action: Opposition under section 59 of the Patents Act 1990 by Grandis Deutschland GmbH

Decision: Issued 21 April 2005.
Abstract

The invention relates to a storage stable, pharmaceutically acceptable, aqueous formulation of growth hormone comprising human growth hormone, a buffer at pH 5.5 to 7, a non-ionic surfactant present in the range of 0.1% (w/v) to 1% (w/v) and a neutral salt. The formulation optionally contains a preservative.

The opposition was unsuccessful on all grounds.

Costs were awarded against Grandis.

PATENTS ACT 1990

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Re:Patent Application No. 686567 by Genentech, Inc. and opposition under section 59 of the Patents Act 1990 by Grandis Deutschland GmbH.

BACKGROUND

Patent application 686567 (47927/93) in the name of Genentech, Inc (hereafter referred to as Genentech) was filed as PCT application PCT/US93/07149 on 29 July 1993 claiming priority from US 07/923,401 which was filed on 31 July 1992. The application was advertised as accepted on 12 February 1998. Grandis Deutschland GmbH (hereafter referred to as Grandis) filed a notice of opposition on 12 May 1998 and served their statement of grounds and particulars on 12 August 1998. Service of evidence in support was completed on 24 August 1999.
Evidence in answer was completed on 28 June 2000 and evidence in reply was completed on 25 July 2001.
Genentech sought leave to file further evidence and completed service of this evidence on 30 July 2004.
The statement of grounds and particulars was amended on 6 December 2004 to include the ground that the invention does not comply with paragraph 18(1)(b)(iii) of the Patents Act 1990 (the Act), and is not useful.
Although Genentech filed proposed amendments on the 18 January 2005, immediately prior to the hearing, these amendments were not considered at hearing and they were subsequently withdrawn on 11 March 2005.
The specification that was the subject of the hearing was the specification as accepted including a further amendment to the description filed 9 August 2001 and allowed 1 July 2002.
The matter was heard in Melbourne on Wednesday 16 February 2005. Grandis was represented by Mr Adrian Ryan of Counsel, assisted by Mr John Slattery, Patent Attorney for Davies Collison Cave, Melbourne and Dr Thomas Lehmeyer. Genentech was represented by Mr Barry Hess of Counsel, assisted by Ms Amanda Stark and Dr Vivien Santer, Patent Attorneys of Griffith Hack, Melbourne.

THE EVIDENCE

The evidence in support consists of:
· Statutory Declaration of John Michael Slattery, made 10 November 1998, together with exhibits D1-D12.
· Statutory Declaration of William Neil Charman, made 18 August 1997, together with exhibits WNC 1-7
The evidence in answer consists of:
·      Statutory Declaration of James Q Oeswein, inventor of 686567, made 9 February 2000, together with exhibit JQO-1.
·      Statutory Declaration of James Q Oeswein, made 26 June 2000.
·      Statutory Declaration of Desmond Berry Williams, made 27 June 2000, together with exhibits DBW 1-5.
·      Statutory Declaration of Vivien Bedford Santer, made 23 June 2000, together with exhibits VBS 1-3.
·      Statutory Declaration of Vivien Bedford Santer, made 4 May 2000, together with exhibits VBS 1-4
The evidence in reply consists of:
· Statutory Declaration of William Neil Charman, made 18 July 2001, together with exhibits WNC 8-11.
The further evidence consists of:
· Statutory Declaration of Dr Hans-Joachim Zeisel, made 27 July 2004.
· Statutory Declaration of John Michael Slattery, made 30 July 2004, together with JMS 1-4.

THE SPECIFICATION

The specification relates to the preparation of storage stable, pharmaceutically acceptable, aqueous formulations of human growth hormone (hGH).
In the summary of the invention the specification states that the invention resides in an aqueous pharmaceutically acceptable, storage stable aqueous hGH formulation comprising hGH, a buffer and a non-ionic surfactant. The preferred concentration range for the non-ionic surfactant is between 0.1 to 1% w/v and the preferred pH range is between 5.5 and 7. When the surfactant and pH are within these ranges the hGH can withstand shear and surface stresses (see page 5, lines 30 to 36) and deamidation, aggregation and precipitation is reduced (see page 6, lines 15 to 19). As such, the specification makes it clear the stability of the hGH in solution is a consequence of the presence of at least a non-ionic surfactant at a concentration of 0.1% to 1% w/v and a buffer within a pH range of 5.5 to 7.
The specification also lists a range of other components that may be used in aqueous hGH formulations, in particular the specification discloses a neutral salt as a possible further component. However the specification is not as clear with respect to the role that the neutral salt plays in contributing to the stability of hGH in solution, with the neutral salt first introduced as an optional component in the summary of the invention but later defined as an essential component in the claims.
Although there is no explicit resolution of this ambiguity in the specification the issue can be resolved by reference to example IV, which describes the neutral salt as a replacement for mannitol in hGH formulations. Mannitol is a stabilising agent that is routinely used to enhance the stability of proteins in aqueous and lyophilised preparations. Example IV makes it clear that the combination of a neutral salt and a surfactant provides unexpected stability that is at least of the order of the stability provided by mannitol.

“These results demonstrate the unexpected stability of hGH in a formulation in which mannitol has been substituted with a neutral salt in the presence of a surfactant”.
Example IV thus teaches that it is not simply the combination of a non-ionic surfactant at a concentration of 0.1% to 1% and a pH of 5.5 to 7 that confers stability on hGH in solution, there is also the requirement for a neutral salt in combination with the surfactant and the buffer.
The specification also discloses a preservative as an optional component of the formulation. However, in contrast to the neutral salt the preservative does not contribute to the hGH stability and is simply present to reduce the likelihood of microbial contamination in multi-use preparations (page 6, lines 6 to 8). As such, the specification discloses the preservative as an optional, rather than an essential feature of the invention.
On the basis of this information I believe that the invention described in the specification relates to the discovery that the combination of a non-ionic surfactant at 0.1% to 1% w/v, a neutral salt and a pH of 5.5 to 7 can confer stability on hGH in solution.

THE CLAIMS

There are 3 independent claims in the specification. Claim 1 recites

A storage stable, pharmaceutically acceptable aqueous formulation of human growth hormone, comprising:
·    hGH
·    buffer to pH 5.5-7
·    non-ionic surfactant present in the range of 0.1% (w/v) to 1% (w/v)
·    neutral salt and
·    optionally, a preservative.
Claims 2-11 and 26 are dependent on claim 1 and relate to specific embodiments of the individual components and the formulation.
The second independent claim, claim 13 recites:

An aqueous hGH formulation comprising 5 mg/ml hGH, 8.8 mg/ml sodium chloride, 2.0 mg/ml polysorbate 20, 2.5 mg/ml sodium citrate, and 2.5 mg/ml phenol, at pH 6.0.
The third independent claim, claim 14 recites:
A method of preventing denaturation of human growth hormone aqueous formulations, comprising the step of mixing human growth hormone, a buffer of pH 5.5-7, neutral salt, and non-ionic surfactant in the range of 0.1-1% (w/v), whereby said mixed human growth hormone can be stored for six to eighteen months at 2-8⁰C.
Claims 15-25 are dependent on claims 14-24 and relate to specific embodiments of the individual components and the formulation.

DECISION

Section 40

Grandis submitted that the specification fails to meet the requirements of paragraph 40(2)(a) because the specification does not fully describe hGH formulations or methods of preventing denaturation of hGH as claimed. Grandis submitted that the specification did not meet this requirement because the hGH neutral salt formulation disclosed in example IV was only shown to maintain stability over 3 to 4 months. Grandis argued that this time period is considerably shorter than the 6 to 18 month period described in the specification and acknowledged by the expert declarants for both parties as the period over which a storage stable pharmaceutical preparation should maintain stability.
However, there is no need for the specification to explicitly demonstrate that the neutral salt hGH formulation maintains stability after 6 to 18 months storage if there is other data in the specification that suggests that this is the case. Such data can be found in examples I and IV, which show that neutral salt and mannitol formulations have equivalent stability after 3 to 4 months storage at 2-8⁰ C and that the same mannitol formulations are still stable after 18 months storage at 2-8⁰ C.
Based on this information it is reasonable to conclude that mannitol and neutral salt formulations continue to behave in a similar manner during more extended storage and that neutral salt formulations will continue to exhibit the same stability as that seen for mannitol formulations after storage for 6 to 18 months at 2-8⁰ C.
Furthermore, Grandis did not challenge this expectation by providing any evidence that the neutral salt formulation will not remain stable over the extended period of 6 to 18 months. At the hearing Mr Ryan did draw my attention to the fact that example IV shows that the neutral salt does not show improved stability in comparison to mannitol. However, this observation would only relevant if the invention was in increased stability. This is not the case in the current application, with example IV simply describing a neutral salt as a substitute, or replacement for mannitol, rather than as a component that provides improved stability. Given this, there is no need for the specification to demonstrate improved performance for a neutral salt over mannitol, and it is sufficient that the specification simply supports the prediction that the neutral salt will provide equivalent stability to mannitol.
As such, I am satisfied that the specification meets the requirements of paragraph 40(2)(a).
Grandis also submitted that the claims lacked fair basis because the description of the invention in the specification was inconsistent with the invention as claimed.
The claims recite a storage stable aqueous hGH formulation comprising a buffer at pH 5.5 to 7, a non-ionic surfactant in the range of 0.1% to 1% w/v and a neutral salt. As such, and as agreed by both parties, the claims are in the form of a claim by result where the claimed formulations are produced by combining the components in a manner that maintains the stability of hGH over a period of 6 to 18 months. For a claim by result to be fairly based the specification must provide adequate directions for the skilled person to prepare the claimed material, which in the current case is stable hGH formulations comprising the buffer at pH 5.5 to 7, the non-ionic surfactant at 0.1% to 1% and the neutral salt without the need to exercise any inventive faculty.
I believe that the specification meets this requirement. The specification not only discusses the range of buffers surfactants and neutral salts that might be used in the invention and provides an explicit example of the preparation of a preferred embodiment, it also provides a range of procedures for testing the stability of formulations and selecting those that meet the requisite stability levels (see examples I to III). As such the specification provides adequate directions for the skilled person to both prepare and test formulations comprising the components listed in the claims and to select those formulations in which the combination of components produces the desired stability levels.
A further requirement for fair basis is disclosure in the specification that supports the premise that stability is the result of formulating hGH with the components listed in the claims. I believe that this requirement is also met, with pages 5 and 6 of the specification and example 4 explaining that the pH and surfactant are balanced to improve resistance to surface stresses and reduce deamidation, aggregation and precipitation and that it is the combination of surfactant and neutral salt that produces the unexpected stability in the formulations.
At the hearing Mr Ryan submitted that this premise is contradicted by the further evidence, which shows that when the preservatives cresol, benzyl alcohol, benzethonium chloride or benzalkonium chloride are added to aqueous hGH formulations comprising a buffer at pH 6, a non-ionic surfactant at 0.2% and a neutral salt, the resultant formulations lack stability. Mr Ryan suggested that this demonstrated that the components listed in the claims are not sufficient to confer stability on hGH formulations.
However, I do not believe that this conclusion is correct. In contrast to this I believe that the further evidence simply demonstrates that preservatives such as cresol and benzyl alcohol are capable of compromising the stability of hGH formulations. This conclusion is also supported by the specification which alerts the reader to the ability of further components to disrupt the stability of hGH formulations of the invention. Page 7 of the specification states:

“In general, the formulations of the subject invention may contain other components in amounts not detracting from the preparation of stable forms.”
Furthermore, when this issue was raised at the hearing both parties agreed that all of the evidence supported the understanding that the combination of a buffer at pH 5.5 to 7, a non-ionic surfactant in the concentration range of 0.1% to 1% w/v and a neutral salt alone is sufficient to confer stability on hGH in solution.
As such, Grandis has provide no evidence that the claims are inconsistent with the invention or that the specification does not provide a real and reasonably clear disclosure of the invention as claimed. As a consequence, I do not believe that the claims lack fair basis.
Grandis also submitted that the claims lack clarity because the scope of the term “storage stable” is not clearly defined. However, the specification deals with this term in the summary of the invention at page 3, where it describes a storage stable formulation as one in which there is acceptable control of degradation products, where the formulation is stable to agitation and where the formulation can be stored for 6 to 18 months at 2 to 8⁰C. Examples I and II also describe methods for testing the chemical and physical stability of an hGH formulation after storage at 2 to 8⁰C for 18 months and following vigorous agitation at room temperature. As such I believe that the specification clearly teaches that the parameters for storage stability are minimal degradation and aggregation of hGH after storage at 2 to 8⁰C for 6 to 18 months.
I am also satisfied that this definition is consistent with the term as it is understood in the art. Both parties’ agreed with the statement made by Dr Williams in his first declaration:

“I consider that in practical terms, a reasonable shelf-life for a liquid aqueous formulation or for a lyophilised preparation would be at least 18 months, anything less would not be practicable in commercial terms. If a drug product has a high medical demand in a highly specialised area, a shelf-life of 12 months may sometimes be acceptable.”
I believe that this definition is broadly consistent with the term as used in the specification and as such I am satisfied that the scope of the term as used in the specification would have been clear to the skilled person.

Utility

Grandis also submitted that the claims did not meet the requirement of 18(1)(b)(iii) of the Act because the claimed invention was not useful.
Mr Ryan explained that the further evidence provides specific examples of hGH formulations that lack stability. In particular the further evidence shows that the preservatives cresol, benzyl alcohol, benzalkonium chloride and benzethonium chloride all compromise the stability of hGH formulations. All of these preservatives are described at page 6 of the specification as preservatives that may be included in the formulation to retard microbial growth and all are recited in claims 12 and 25 as optional components of the claimed formulations. In addition, claim 1 and thereby all of its dependent claims include a preservative as an optional component of the claimed formulation. Mr Ryan submitted that this creates a situation where the claims clearly recite formulations that are not useful in the context of the invention because they do not provide the requisite level of stability.
However, Mr Ryan has failed to take into account the fact that the preservatives are always defined as optional features and that, as such the claims never expressly define a formulation that has as an essential feature of the claim a preservative that compromises the stability of the formulation. In every case the claims simply recite a stable formulation wherein the formulation may optionally comprise a preservative. As such, although the claims are exceedingly clumsy and poorly drafted, they do not actually recite formulations that do not meet the stability requirements of the invention.
Given this, and in the absence of any further evidence from Grandis relating to the inability of a buffer, a surfactant and a neutral salt to confer stability on hGH in solution, I do not believe that the claimed invention fails to meet the requirement of 18(1)(b)(iii).

Priority date

Grandis’ Statement of Grounds and Particulars challenged the priority date of 686567 on the basis that the invention as claimed was disclosed in earlier US applications filed more than 12 months before the filing date of 686567.
However none of the earlier US applications filed by Genentech disclose the use of a neutral salt in place of mannitol. As such, 686567 and its priority document are the first applications to disclose this particular feature.
Grandis also submitted that the matter claimed in 686567 was not fairly based on the disclosure in the priority document.
However, there is substantial overlap between the text and examples in the priority document, particularly with respect to the example that describes hGH formulations as claimed in 686567. As such I am satisfied that the formulations and methods claimed in 686567 are in substance disclosed in the priority document.
Given this, I believe that 686567 is entitled to its priority date.

Novelty

The basic test for novelty is the “reverse infringement” test as stated in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd, (1972) RPC 457 at pages 485, 486.:

“If carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim”.
However, in applying this test regard must be given to whether the prior art publication has provided clear and unmistakable directions to do what patentee has claimed, as also stated in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd at page 486.

"To anticipate the patentees claim, the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented ... A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee."

Although the statement of grounds and particulars listed nine documents, Grandis chose to only pursue 4 of these documents at the hearing. These documents were WO 91 18621, WO 89 09614, EP 211601 and US 4637834. I will deal with each of these documents independently and then provide a brief discussion of the remaining citations.

WO 91 18621

WO 91 18621 (D1) discloses a method for enhancing growth comprising preparing and administering insulin-like growth factor I (IGF-1) and growth hormone formulations. In particular the method is directed at administering human IGF-1 and hGH to a human subject.
At pages 8 and 10 to 12 D1 discusses the preparation of IGF-1 and hGH formulations for parenteral, internasal or oral administrations.
When discussing parenteral administration D1 discloses that the IGF-1 and hGH are preferably formulated with an isotonic carrier such as water, saline (a neutral salt), Ringer’s solution and dextrose solution in a range of buffers. It also states that parenteral formulations may contain among other additives non-ionic surfactants such as polysorbates and poloxamers.
However, in the following paragraph D1 discloses that in parenteral formulations “IGF-1 and GH are each typically formulated individually” and that hGH is stable at a pH of 7.4 to 7.8. This teaches toward formulations where IGF-1 and hGH are formulated individually and where, although the hGH formulation comprises a non-ionic surfactant, a neutral salt and a buffer, the pH is outside the range claimed in 686567.
D1 then continues with a discussion of additional aqueous formulations for storage where IGF-1 and hGH are formulated together in a citrate buffer at a pH of about 6 with polysorbate 20 at 0.1%. However this formulation does not contain a neutral salt.
D1 also has a single specific example of an hGH formulation. However this relates to a reconstituted lyophilised hGH formulation prepared in mannitol and phosphate buffer at a pH of 7.8. Again this pH is outside the range of 5.5 to 7 claimed in 686567. In addition the formulation does not contain a surfactant.
As such, although all of the essential features of claim 1 can be found at one place or another within the pages of D1, there is no teaching to combine all of these features in a single formulation.
Given this, I do not believe that the general disclosure or any single formulation in D1 clearly discloses a formulation with all of the features of the formulations claimed in 686567. As a consequence I do not believe that D1 deprives any of the claims of 686567 of novelty.

WO 89 09614

WO 89 09614 (D2) is directed at providing a stable, pharmaceutically acceptable formulation of hGH. Although the citation is primarily directed at the preparation of lyophilised formulations it also discusses the preparation of aqueous formulations and discusses the stability of both lyophilised and aqueous formulations.
However, in contrast to the pH range of 5.5 to 7 claimed in 686567, the preferred embodiment disclosed in D2 has a pH of 7.4. D2 teaches that this pH is necessary to reduce aggregation.
In addition, although D2 disclose buffers and non-ionic surfactants at the concentrations defined in 686567, the only time that a neutral salt is mentioned is when D2 discusses solutions that can be used to reconstitute lyophilised hGH preparations.
As such, I can find no single formulation in D2 that provides all of the features of the formulations or the methods claimed in 686567, nor can I find any clear directions to prepare such a formulation or conduct such a method. As a consequence, I do not believe that D2 deprives any of the claims of 686567 of novelty.

EP 211601

EP 211601 (D3) relates to the preparation of stabilised growth hormone formulations. In particular it discloses aqueous formulations comprising growth hormone, phosphate buffered saline and the non-ionic surfactant pluronic.
Although the general discussion in D3 mentions a broad pH range of 5 to 11, D3 teaches toward a pH between 7 and 10 and exemplifies a formulation with a pH of 7.3. As such, I do not believe that there is a clear teaching to use the range of 5.5 to 7 claimed in 686567.
Similarly, D3 discloses a broad range of non-ionic surfactant concentrations, with a preferred range of 1 to 30%, and a concentration of 5% in the examples. As such I do not believe that there is a clear teaching to the range of 0.1 to 1% claimed in 686567.
Although I accept that broad ranges may be sufficient for novelty if there are no clear advantages to the specific narrower ranges of pH 5.5 to 7 and non-ionic surfactant concentrations between 0.1% and 1%, I do not believe that this is the case in the current situation. As stated in the specification, the specific pH and non-ionic surfactant concentration are intentionally formulated in such a way that the surfactant protects the hGH from sheer and surface stresses while the pH minimises deamidation, aggregation and precipitation.
Furthermore, as agreed by the expert declarants for both parties, non-ionic surfactants at concentrations of 5% have a viscous or gel-like consistency, which is regarded as unsuitable for administration to human subjects because of the large gauge needles that must be used for delivery. D3 teaches that this higher concentration of surfactant provides advantages in terms of graduated release of the active agent from the site of injection. Given this, D3 teaches toward a concentration that would have quite different properties to the properties of surfactants within the claimed range of 0.1% to 1%.
As such, I do not believe that D3 provides clear and unmistakeable directions to the formulations or methods claimed in 686567. As a consequence I am satisfied that based on the evidence before me D3 does not deprive the claims of 686567 of novelty.

US 4637834

US 4637834 (D4) is directed toward the preparation of stable aqueous solutions of proteins using non-ionic surfactants. In particular the examples of D4 describe the use of surfactants in the range of 0.1% to 0.2% (w/v) to improve the stability of aqueous formulations containing proteins. The examples have a pH of 7, which is on the upper limit but within the range of the pH range claimed in 686567.
However, the only reference to a neutral salt is in an introductory paragraph, which lists sodium chloride among a list of customary agents that can be added to adjust isotonicity, for preserving or to buffer the pH.
In addition, D4 does not provide any specific mention of hGH or growth hormones. Growth hormones are not specifically included among the proteins described as suitable for formulation according to the directions provided in the citation and none of the examples deal with growth hormone-related proteins. Although D4 does list growth and differentiation factors among the list of types of proteins that may be prepared in the manner described, this same list also states that proteins with molecular weights of greater than 30,000 daltons are preferred, a size that is in excess of the 22-23,000 dalton molecular weight of human growth hormone.
As such, I do not believe that D4 provides clear and unmistakeable directions to prepare the formulations or conduct the methods of the claims. As a consequence I am satisfied that based on the evidence before me D4 does not deprive the claims of 686567 of novelty.

The remaining citations

Grandis also cited a further five documents, none of which were pursued at the hearing.
·    WO 9312811 (D5) and WO 9319766 (D6), which are whole of contents citations, neither of which discloses non-ionic surfactants at the concentrations claimed in 6866567. Further, D6 does not disclose a neutral salt;
·    AU 617427 (D7), discloses pH ranges of greater than 7,
·    EP 303746 (D8), does not disclose a neutral salt, a surfactant, or a pH of 7 or less, and
·    US 4783441 (D9) discloses formulations comprising insulin, not a growth hormone;
Given this, I do not believe that any of these documents are relevant to the novelty of the claims.

Inventive Step

An appropriate test for inventive step is that given by Aicken J in Wellcome Foundation Limited vVR Laboratories (Aust) Pty Ltd (1981) 148 CLR at page 286, and restated by the High Court in Aktiebolaget Hassle v Alphapharm Pty Limited [2002] HCA 59 (12 December 2002) (Alphapharm):

“The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.”
In particular Alphapharm is relevant to the current application because Alphapharm also dealt with a situation where the invention was in the interaction between a number of integers rather than in the a collocation of independent integers. This is synonymous with the current application where the invention is in a formulation where the invention is achieved by balancing the three integral formulation components in such a fashion that they interact to maintain the stability of hGH in solution.
Grandis cited the same documents against both novelty and inventive step. As with novelty, WO 91 18621 (D1), WO 89 09614 (D2), EP 211601 (D3) and US 4637834 (D4) appear to be the most relevant prior art. Given this, I have focused my discussion on these four in particular, followed by an abbreviated discussion of the remaining documents.
When discussing inventive step at the hearing Mr Hess submitted that Professor Charman could not be regarded as a suitably qualified expert declarant because he did not have the requisite credentials or impartiality. However I do not believe that I need to resolve this issue to make my decision. Where I have had to rely on expert declarants submissions to resolve questions about common general knowledge in the art both parties’ declarants have been in general agreement. As such my conclusions on inventive step have not required that I ascribe differing weight to the declarations of either party.

WO 9118621

The most important question to ask when considering D1 as an inventive step citation is would it have been a matter of routine to prepare a formulation as claimed in 686567 if your goal was to provide a stable, aqueous hGH formulation?
Although stability is part of the focus in D1, the stable formulations that it discloses are not limited to aqueous formulations comprising hGH alone and also include lyophilised hGH compositions, lyophilised IGF-1 formulations, stable aqueous IGF-1 formulation and hGH formulations for immediate use.
D1 provides only one example of an aqueous hGH formulation suitable for storage. This formulation contains hGH, a citrate buffer at pH 6 and a non-ionic surfactant at 0.1%. There is no discussion of further components that may be added to the formulation. In particular there is no suggestion that a neutral salt may be added. Although there is some discussion of neutral salts elsewhere in D1, this discussion relates to the use of saline as one of a range of carriers used to establish isotonicity in formulations for immediate parenteral administration.
Although this disclosure advocates adding a neutral salt to establish isotonicity, it would only be obvious to apply this approach to a storage stable solution if there was the expectation that a neutral salt would not adversely affect the stability of the formulation.
Based on the submissions of both parties, in particular the submissions of their respective expert declarants, I do not believe that the skilled person would have been able to make this prediction. At the priority date of the application, although it was routine to use excipients such as non-ionic surfactants, buffers at pH 5.5 to 7 and neutral salts in aqueous protein solutions it was well understood in the art that protein stability was unpredictable and that combinations of excipients could have profound and unexpected effects on protein stability.
Both parties expert declarants explained that proteins can be difficult to formulate, primarily because their three dimensional structure, which is essential for activity, can be easily degraded and denatured. As a consequence of recognition of this problem it is generally accepted in the art that much of the work in protein formulation revolves around testing a range of excipients to determine which combinations and concentrations will work for the specific protein under study.
In his declaration Professor Charman states that:

“A semi-empirical approach to pharmaceutical protein formulation began in the mid to late 1980s due to the increased emergence of protein- and peptide-based drugs and a growing appreciation of the complexity and nature of their degradation mechanisms.” and,
“Physical instability (aggregation) was also know to be a significant obstacle to the development of protein formulations.”
Although there was a known range or library of preferred excipients available to formulators at the priority date of 686567 there was no standard formula or approach that could be applied to predict how components might be selected and combined to achieve storage stability for any particular protein. As stated in one of the review articles referenced by both declarants (see WNC-4):

“Consequently the stability of any proposed therapeutic protein to various excipients in varying conditions of temperature, pH, ionic strength etc. must be thoroughly examined.”
Given this I believe that the skilled person would have been wary of adding new excipients, particularly those that would alter conditions such as ionic strength, and would only have been led to try a specific excipient if they had reason to believe that the excipient was unlikely to alter the stability of the protein in question. In the current situation there is nothing in D1 or in any of the submissions provided by Grandis that suggests that it was routine practice to add neutral salts to protein formulations intended for long term storage or that the skilled person would have regarded a neutral salt as an excipient that was unlikely to affect protein stability.
As such, I do not believe that the skilled person would have been led as a matter of routine to add a neutral salt to the hGH formulation disclosed in D1 or that D1 deprives the claims of an inventive step.

WO 8909614

D2 is primarily directed to lyophilised hGH formulations and all of the examples in D2 relate to the preparation and reconstitution of lyophilised hGH formulations. As such I do not believe that the skilled worker would consider that the teachings in D2 could be used as a matter of routine to predict the behaviour of hGH in aqueous formulations.
In addition, as explained in respect of novelty the primary difference between D2 and 686567 is that the preferred embodiments and examples in D2 all relate to formulations with a pH of greater than 7.
At the hearing Mr Ryan suggested that although the examples and preferred embodiments in D2 relate to a pH of greater than 7, figure 1 teaches toward the advantages of formulating hGH at a pH of less than 7.
Figure 1 relates to an example where hGH was formulated at different pHs and then tested for deamidation. The example and figure demonstrate that there is a minimum of deamidation at pH 6, a pH that is within the range claimed in 686567. Deamidation is one of the primary degradation reactions in protein formulations and consequently it is a significant contributor to protein degradation and instability.
However, when assessing the effect that this disclosure would have on the approach taken by the skilled person when formulating hGH figure 2 must be taken into account. Figure 2 plots aggregation against pH and shows that as the pH falls from 8 to 6 aggregation increases, with significant aggregation at pHs of 7 and below. D2 explains that these results demonstrate that there are two competing factors associated with pH and that a pH of 7.4 is optimal for achieving a balance between aggregation at low pH and deamidation at high pH.
Given this, I believe that contrary to Mr Ryan’s submissions D2 actually teaches away from the invention and as a consequence does not deprive the claims of an inventive step.

EP 211601

Although D3 is also directed at directed at the preparation of aqueous, stable growth hormone formulations, the formulation that solves the problem in D3 contains non-ionic surfactant at 5% w/v and a buffer at pH of 7.3.
In their submissions Grandis stated that the skilled worker would have been led to reduce the concentration of surfactant from 5% to a concentration within the range claimed in 686567 to reduce the viscosity of the formulation. If the formulation is too viscous a wide guage needle must be used for injection and wide gauge needles are not recommended with human subjects because they cause too much discomfort. Grandis also submitted that the skilled person would expect that reducing the surfactant concentration to between 0.1 and 1% would not adversely affect stability of the hGH because the range of 0.1 and 1% is a range routinely used to stabilise a wide range of proteins in formulations.
Although I accept this submission and agree that the skilled worker might have predicted that reducing the surfactant concentration would not adversely affect hGH stability, I do not agree that the same can be said for altering the pH.
As discussed previously, at the priority date of the application it was generally accepted that variables such as pH played a significant role in protein stability. In particular, as discussed in WNC-4 and WNC-2, pH has a major influence on deamidation, one of the major causes of chemical instability in proteins.
Given this, I believe that the skilled person would have been wary of reducing the pH disclosed in D3 because they would have been concerned that this would adversely affect the stability of the hGH solution. As a consequence I do not believe that D3 deprives the claims of an inventive step.

US 4637834

In contrast to 686567, D4 is directed at the broader problem of formulating proteins in general and it does not focus on the problem of formulating hGH in solution. In particular, as discussed in relation to novelty, growth hormone is not among the specific proteins listed in D4 nor is it similar to any of the specific proteins exemplified in D4. In addition, at 22 kda it is considerably smaller than the 30 kda discloses as the preferred minimum size for proteins formulated in the manner described in D4.
As such, I do not believe that the skilled worker would apply the teaching of D4 to the problem of formulating stable hGH as a matter of routine and thus I do not believe that D4 deprives the claims of an inventive step.

The remaining citations

Of the five remaining documents cited by Grandis, two are published after the priority date of 686567 and are not relevant to inventive step, two teach that a pH of greater than 7 is necessary for hGH stability and the fifth is specifically directed at insulin formulations, a peptide that has quite different characteristics to those of hGH.
With respect to the two citations that disclose pHs of greater than 7, as discussed previously it is well understood in the art that pH has a significant effect on stability of proteins in solution. Given this, I believe that a pH of greater than 7 teaches away from the formulations claimed in 686567.
With respect to the remaining citation that discloses formulation of insulin, as also discussed previously the behaviour for one protein cannot necessarily be extrapolated to predict the behaviour for another. As such, I do not believe that the citation discloses information that the skilled worker would regard as predictive of stability for hGH in the same solution.
Therefore, I do not believe that any of the remaining citations deprive the claims of an inventive step.

Manner of Manufacture

The statement of Grounds and Particulars submitted that the invention was not a manner of manufacture because the invention was a mere collocation of integers where each integers is balanced to ensure that each of integer contributes to the stability of the formulation without adversely affecting the function or contribution of the other integers. For example, in the general methods it is repeatedly stated that the quantities and selections of each of the components is dependent on the other ingredients present (see page 6) and example 4 clearly states that there is unexpected stability when there is a neutral salt in the presence of a surfactant (see page 14).

Interaction between formulation components is also supported by Professor Charman’s and Dr William’s discussion of the practical difficulties associated with protein formulation. Both expert declarants acknowledge that different components within protein formulations will interact with each other and that the unpredictability of these interactions makes it difficult to make predictions about the stability of any particular protein formulation.
Based on the disclosure in the specification and the submissions of both parties I believe that there are various components in the claimed formulation do interact with one another and that as a consequence the claimed invention represents a manner of manufacture.

Conclusion

I find that the opposition is unsuccessful on all grounds.
Based on this finding, I direct that the application proceed to sealing after thirty days from the date of this decision. If the Commissioner of Patents is served with a notice of appeal from this decision before that time, I direct that sealing not occur until the appeal has been decided or discontinued.

Costs

Genentech submitted that costs should follow the event. Whereas Grandis submitted that regardless of the outcome of the opposition, costs up to the date of filing of Genentech’s proposed amendments on 18 January 2005, should be awarded against Genentech. However, these amendments were not the subject of the hearing and they have subsequently been withdrawn.
Given this I see no reason to depart from the principle that costs should follow the event and I therefore award costs against Grandis.

Terry Moore
Delegate of the Commissioner of Patents

Patent attorneys for the applicant : Griffith Hack, Melbourne
Patent attorneys for the opponent : Davies Collison Cave, Melbourne