Eli Lilly and Company v Novo Nordisk A/S

[1995] APO 55

official notice

decision of a delegate of the commissioner of patents

Application        :    No. 617427 in the name of Eli Lilly and Company

Title:    Pharmaceutical Growth Hormone Formulations

Action:    Opposition by Novo Nordisk A/S under Section 59 of the Patents Act 1952.

Decision:    Issued            .

Abstract:    Opposition fails on all grounds

patents act 1990

decision of a delegate of the commissioner of patents

Re:Patent Application No. 617427 by Eli Lilly and Company and opposition thereto by Novo Nordisk A/S.

background

Patent application 617427 by Eli Lilly and Company (Lilly) was filed on 27 February 1989.  The application claimed priority from US 162769 which was filed on 1 March 1988.  The application was advertised accepted on 28 November 1991.  On 27 February 1992 Novo Nordisk A/S (Novo) filed a Notice of Opposition.  On 25 March 1993 the applicant filed a voluntary request to amend the complete specification.  These amendments were allowed on 13 September 1993.  The serving of evidence was completed on 24 December 1993. 

As the application was filed before, but accepted after, the commencement of the Patents Act 1990, section 59 of the Patents Act 1952 and Chapter 5 of the Patents Regulations 1991 apply in relation to the opposition.

A hearing to determine the opposition took place in Canberra on 17 July 1995.  Lilly was represented by Dr Annabelle Bennett and Mr Stephen Burley of Counsel, assisted by Mr John O'Connor and Dr Colin Bodkin, patent attorneys of Spruson & Ferguson. Mr Jim Leeds of Lilly was also present.  Novo was represented by
Dr Kevin Pullen, patent attorney of Grant Adams & Company. 

the specification

The patent specification is entitled "Pharmaceutical Growth Hormone Formulations".  The specification indicates that the invention relates to a parenteral formulation of human growth hormone (somatotropin, hGH) which is stabilized against aggregation and decomposition of the hormone upon storage.  The formulation comprises hGH in admixture with aggregation and decomposition stabilizing amounts of glycine and mannitol.  Also disclosed and claimed is a method of reducing growth hormone aggregation and decomposition in a parenteral formulation by admixing hGH with aggregation stabilizing amounts of glycine and mannitol.

The specification defines "aggregation and decomposition stabilizing amounts" as those amounts of glycine and mannitol which, when admixed with hGH, produce a formulation which is stabilized against aggregation and decomposition.  "Stabilized against aggregation and decomposition" is defined as meaning that less aggregation and decomposition of hGH occurs when said hormone is formulated with aggregation and decomposition stabilizing amounts of glycine and mannitol than when hGH is formulated in the absence of both glycine and mannitol.  A preferred formulation is one containing hGH, glycine and mannitol in a 1:1:5 weight ratio respectively.

Examples are described from which it can be seen that the formulation containing hGH, glycine and mannitol in a weight ratio of 1:1:5 exhibited less decomposition and aggregation at days 14 and 30 than the formulations lacking either or both of glycine and mannitol.

The specification ends with ten claims.  Claim 1 is the only independent composition claim:

"1.  A parenteral pharmaceutical formulation comprising human growth hormone stabilized against aggregation and decomposition by utilization of aggregation and decomposition stabilizing amounts of glycine and mannitol in the formulation."

Claim 6 defines a method:

"6.  A method of reducing aggregation and decomposition of human growth hormone in a parenteral formulation   by admixing said human growth hormone with aggregation and decomposition stabilizing amounts of glycine and mannitol."

Claims 9 and 10 are omnibus claims which refer to the examples.

the grounds of opposition

The grounds and particulars of the opposition were set out in the statement of grounds and particulars as follows:

(1)Opposition to the grant of the patent has been lodged because the invention, as defined in any of the Claims 1-14, was published in Australia before the priority date of each claim, was obvious and did not involve an inventive step, having regard to what was known or used in Australia on or before the priority date of each claim. Thus opposition is based on the grounds specified in Section 59(1)(e) and 59(1)(g) of the Patents Act 1952.

(2)The invention as defined in any of the claims 1 to 14 is not a patentable invention because the invention is disclosed in each of the following:

(i) "Molecular and Cellular Endocrinology", 42 (1985) 269-282.

(ii) "Biological Substances".  International Standards and Reference, Reagents (1986), Published by World Health Organization, Geneva, Switzerland.

(iii) "J. Endocr." (1980), 87, 303-312.

(iv) A 1978 brochure produced by Nordisk Insulinlaboratorium describing a preparation comprising human growth hormone, glycine and mannitol.

At the hearing Dr Pullen stated that the opponent would not be pursuing the ground of obviousness.

the evidence and submissions

At the hearing Dr Bennett requested that portions of the opponent's evidence be struck out.  I did not make a ruling at the hearing but where the evidence asserts conclusions of law I have disregarded it.  The evidence comprises a number of declarations.  I have given details of the evidence and submissions where appropriate in my decision.

decision

The generally accepted test for anticipation is the "reverse infringement test" as set out in Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228 at 235 where Aickin J stated:

"The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement."

Infringement of a claim occurs when each and every one of the essential integers of the claim have been taken (Rodi and Wienenberger AG v Henry Showell Ltd [1969] RPC 367). There is no reason to assume anything other than that all the features of claim 1 are essential features.

It is clear that a composition that anticipates claim 1 must contain hGH, mannitol and glycine.  It may contain other components that are not inconsistent with the invention.  The composition must be at least suitable for parenteral use.

From the definitions given in the description the amount of mannitol and glycine present is such that "less aggregation and decomposition" of hGH occurs than when the hGH is formulated in the absence of both glycine and mannitol.  I construe this as meaning that both less aggregation and less decomposition must occur. 

If a formulation has a ratio of hGH to glycine to mannitol in the order of the range described as preferred in the opposed specification (1:1:3 to 1:1:5) then it must be concluded that the glycine and mannitol are present in aggregation and decomposition stabilizing amounts.  For amounts outside this range comparative data is required in which the amount of aggregation and decomposition is given relative to a similar formulation with no mannitol or glycine. 

Of course, if a formulation is demonstrated to show less aggregation and less decomposition than a formulation that is described as preferred in the opposed specification, then it can be assumed that such a formulation also exhibits less aggregation and decomposition than formulations without mannitol and glycine.

A declarant for the opponent, Dr Hoelgaard, stated that it was not the proportion glycine:mannitol that was the critical feature in stabilization against decomposition and aggregation but rather variation in pH.  Whilst this may in fact be true it is of little relevance when assessing novelty.  It is the invention as claimed that must be compared to the prior art and an essential feature of the claim is the utilization of "aggregation and decomposition stabilizing amounts" of glycine and mannitol. 

I will consider each prior art document in turn to determine whether it discloses all of the essential features of the claims of the opposed application:

1.  KMP-1

Exhibit KMP-1 is a copy of Molecular and Cellular Endocrinology, 42 (1985) 269-282 which reports on a study for the preparation of standards for human growth hormone.  The purpose of the study was to calibrate candidate materials and compare preparations with existing reference preparations.  The study also examined differences in growth hormone activity by various assay procedures, and assessed the stability of the candidate material. 

In the study hGH was dissolved in a sterile pyrogen-free solution containing 2% glycine, 0.2% mannitol, 0.75% NaHCO3 and lactose, at pH 7.3.   

In a declaration for the applicant Dr Pikal asserts that this document makes no mention of any beneficial effect on the stability of hGH against decomposition and aggregation being obtainable by formulating hGH with appropriate amounts of mannitol and glycine.  The purpose of the study reported in Exhibit KMP-1 is not to compare the stability of the formulations which contained both mannitol and glycine with the stability of formulations which did not, but to assess the stability of hGH  of human origin compared to bovine Growth Hormone.

The formulation of KMP-1 contains lactose which in the opinion of Dr Pikal is undesirable in a protein formulation if the stability of the formulation is a concern, since a person of ordinary skill in the relevant art would realise that there is a potential for adduct formation between lactose and the protein.

In a declaration for the opponent Dr Hoelgaard agrees that the presence of lactose is undesirable but points out that this was not established until 3 years after the priority date of the opposed application.  She also states that when establishing a standard it is always a prerequisite that the resulting standard is stable.

The ratio hGH:glycine:mannitol in the citation is approximately 1:11:1 which is outside of the preferred range in the opposed application thus comparative data is needed to establish a lack of novelty.

In the citation the stability of the material when stored at different temperatures was measured and reported but there is no comparison of the stability relative to compositions in the absence of mannitol and glycine in this publication.

In his declaration Dr Pikal (one of the inventors of the opposed application) describes an experiment in which he compared two hGH formulations within the scope of the claims of the opposed application (ratios of 1:1:5 and 1:1:3 hGH:glycine:mannitol) with the international standard for hGH for bioassay as described in KMP-1 and KMP-2.  Comparative tests showed that the international standard exhibited considerably more decomposition than the two formulations of the invention.  There was some difference in the interpretation of the results that were obtained in respect of the amount of aggregation but I do not believe that I have to resolve that conflict because of the greater amount of decomposition that occurred.

It is unfortunate that no data is available for a comparison against formulations containing no mannitol and glycine.  The opponent submitted that when establishing a standard it is always a prerequisite that the resulting standard is stable. The applicant submitted that the formulation of the prior art could be stable for a standard without being stable as a parenteral composition and that the formulation of KMP-1 could be stable as a standard for assay purposes but not suitable for clinical use. In the absence of relevant comparative data the opponent has failed to demonstrate that the amounts of mannitol and glycine disclosed in the citation are "aggregation and decomposition stabilizing amounts".

1. KMP-2

Exhibit KMP-2 is a copy of an extract from "Biological Substances", International Standards and Reference Reagents (1986), Published by World Health Organization, Geneva, Switzerland.  In this publication there is a disclosure of a standard for "Growth hormone, human, for bioassay".  This assay for human growth hormone utilises glycine and mannitol.   

This document discloses substantially the same standard as KMP-1.  The ratio of hGH:glycine:mannitol is approximately 1:11:1.  In the absence of comparative data there is no evidence that claim 1 lacks novelty in the light of this citation.

1. KMP-3

Exhibit KMP-3 is a copy of J.Endocr. (1980), 87, 303-312.  In the study hGH in a glycine buffer and in a gelatin solution were compared with regard to their effectiveness in promoting growth.  This document discloses a hGH formulation for injection comprising the hormone, glycine and mannitol.  The dose solutions were stored at 37oC and it is stated that there was no significant loss in potency of hGH under the conditions tested.

The hGH had a biological activity of 2.5 i.u. per mg and 3.5 i.u. was in vials with 5 mg mannitol.  Diluents for injection were in O.1M glycine buffer.  The dose solution contained 250 mi.u. hGH per ml.  Thus 1 ml of solution would contain 0.1 mg hGH and 7.5 mg of glycine.   This gives a ratio of hGH:glycine:mannitol of approximately 1:75:3.5.  This ratio is clearly outside the preferred range of the opposed application. 

Dr Pikal states that although this study may teach something about the impact of gelatin in drug delivery it teaches nothing about the stability.  In the absence of comparative data this disclosure does not provide "aggregation and decomposition stabilizing amounts" of glycine and mannitol.

1. KMP-4

Exhibit KMP-4 is a copy of a 1978 brochure produced by Nordisk Insulinlaboratorium describing a preparation comprising human growth hormone and glycine and mannitol.

In respect of KMP-4 Dr Pullen states:

"I have been advised that (a) this brochure was available in Australia when preparations commenced to launch the said composition onto the Australian market;  (b)  a Dr Bob Vines of Wade House Specialist Centre, Royal Alexandria Hospital for Children, Camperdown (New South Wales), Commonwealth of Australia was associated with the launch and received a copy of the said brochure; and (c) Dr Vines died in 1986."

In a second declaration Dr Pullen provided various exhibits relating to orders for the supply of Nanormon to Protea Pharmaceuticals of New South Wales as well as copies of statements indicating the amounts of growth hormone approved and used for individual patients in Australia.

At the hearing counsel for the applicant submitted that there was no clear evidence that this information was published in Australia before the priority date of the opposed application.  

This document discloses a preparation comprising hGH, glycine, sodium bicarbonate and mannitol.  The relative amounts of these components are not disclosed.  It is stated that additives used for stabilization and adjustment of pH are amino acetic acid and sodium bicarbonate.  No stability data are given and since the formulation is not fully specified it would be impossible to test stability.

The ratio of hGH:glycine:mannitol is not disclosed and there is no evidence relating to the stability of this formulation relative either to a similar preparation in the absence of mannitol and glycine, or relative to a formulation of the invention.  As the document does not disclose the invention I do not have to decide the question of publication to find that the claims do not lack novelty in the light of this citation. 

1. AHOE-3

Exhibit AHOE-3 is a data sheet on a preparation allegedly marketed by Eli Lilly in the U.S.A in 1987.  The data sheet discloses a preparation of 5 mg somatropin, 25 mg mannitol, 5 mg glycine and 1.13 mg dibasic sodium phosphate.  This corresponds to a ratio of hGH:glycine:mannitol of 1:1:5.  It appears that the claims would lack novelty in the light of this disclosure if the document had been published in Australia before the priority date of the opposed application.  There is, however, no evidence of publication in Australia and hence no lack of novelty.

conclusion

I have found that the opponent has failed to demonstrate that the claims are not novel.

costs

The normal practice of the Commissioner is for costs to follow the event.  In the present case amendment of the specification occurred which had the effect of removing the novelty objection.  I think it appropriate that costs be awarded against the applicant, Lilly, up to and including the date of advertisement of allowance of the amendment (30 September 1993) and against the opponent, Novo, thereafter. 

Vivienne Thom
Delegate of the Commissioner of Patents

Patent attorneys for the applicant  :  Spruson & Ferguson

Patent attorneys for the opponent   :  Grant Adams & Company