THE LIPOSOME COMPANY INC.

[1990] APO 2

In the Matter of the Patents Act 1952

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In the Matter of Application No. 49528/85 in the Name of THE LIPOSOME COMPANY INC.

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In the Matter of Examiner's Objections thereto.

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS:
Background
         Application No. 49528/85, which is entitled "Steroidal Liposomes" is an International Application which has a filing date of 10 October 1985.  The application was lodged in the name of THE LIPOSOME COMPANY INC. (LIPOSOME).
         The examiner has maintained objections to the specification even though the attorney representing LIPOSOME has proposed amendments to the specification.  Consequently the attorney requested a hearing on the matter which was set down in Canberra on 30 October 1989.  LIPOSOME was represented at the hearing by Mr P. Jones, patent attorney of Phillips, Ormonde & Fitzpatrick.  At the hearing Mr Jones foreshadowed further proposed amendments to the specification which were subsequently lodged on 2 November 1989.
The Specification
         The specification, as presently proposed to be amended, states under the heading "FIELD OF THE INVENTION" that the invention relates to methods and compositions for the entrapment of compounds in liposomes composed of salt forms of organic acid derivatives of

sterols that are capable of forming bilayers.  Sterols such as cholesterol or other lipids, to which a hydrophilic moiety such as a salt form of an organic acid is attached, can be used to prepare suspensions of multilamellar or small unilamellar vesicles.  The sterol liposomes of the present invention may be prepared with or without the use of organic solvents.  These vesicles may entrap water‑soluble compounds, partially water‑soluble compounds, and water insoluble compounds.
         The specification discusses the background of the invention in relation to liposomes and water‑soluble sterols.  Then under the heading "SUMMARY OF THE INVENTION" the specification states that the present invention involves methods and compositions for the entrapment of various compounds in liposomes, the bilayers of which comprise salt forms of organic acid derivatives of sterols.  The method of preparing the sterol vesicles involves adding to an aqueous phase, preferably an aqueous buffer, a salt form of an organic acid derivative of a sterol capable of forming closed bilayers in an amount sufficient to form completely closed bilayers which entrap an aqueous compartment.  A suspension of multilamellar vesicles is formed by shaking the mixture.
         Under the heading "DETAILED DESCRIPTION OF THE INVENTION" the specification states that any salt form of an organic acid derivative of a sterol which is capable of forming completely closed bilayers in aqueous solutions (i.e. liposomes) may be used in the practice of the invention.  The specification also states under this heading as follows:

"Generally any sterol which can be modified by the attachment of an organic acid may be used in the practice of the present invention.

.....

Organic acids which can be used to derivatize the sterols include but are not limited to the carboxylic acids, dicarboxylic acids, polycarboxylic acids, hydroxy acids, amino acids and polyamino acids.

.....

The organic acid can be linked to an hydroxyl group of the sterol via an ester or an ether bond using conventional methods ..."

The only salt forms of an organic acid derivative of a sterol which are exemplified and described in the specific embodiments are salt forms of cholesteryl hemisuccinate.
         The independent claims which are relevant for the purpose of this decision are claims 1, 35 and 58 which read as follows:

"1.A method for administering a compound in vivo comprising, administering to a host the compound entrapped in a liposome, the bilayers of which comprise a salt form of an organic acid derivative of a sterol.

35.A method for the preparation of sterol liposomes, comprising adding to an aqueous phase a salt form of an organic acid derivative of a sterol capable of forming closed bilayers in an amount sufficient for forming completely closed vesicles, and shaking the mixture until a milky suspension of multilamellar vesicles is formed.

58.Steroidal liposomes comprising completely closed bilayers comprising a salt form of an organic acid derivative of a sterol."

Objections and Submissions
         The objections maintained by the examiner are an objection that the claims lack clarity and an objection that the claims are not fairly based on matter described in the specification.  The examiner's reports with respect to the clarity objection argue that the phrase "a salt form of an organic acid derivative of a sterol" is indefinite and the reports refer to many kinds of compounds which fall within the scope of this phrase.  The written responses lodged by the attorney present detailed arguments why the phrase has a clear meaning to the person skilled in the art.  The examiner's reports with respect to the fair basis objection argue that the abovementioned phrase includes any organic acid whereas the specification only discloses carboxylic acids.  Also in respect of the fair basis objection the reports argue that the abovementioned phrase includes compounds other than sterols derivatised to contain an organic acid group in salt form, which are the only kind of compound disclosed in the specification.  The written responses lodged by the attorney submit that the 4th Edition of "Hackh's Chemical Dictionary" defines an organic acid as a compound containing one or more carboxyl radicals.  The responses also state that LIPOSOME was entitled to retain the scope of the claims because the invention was a major advance in the art and because there was no prior art which described liposomes, the bilayers of which comprise a salt form of an organic acid derivative of a sterol.
         Mr Jones, at the hearing, submitted that the phrase "a salt form of an acid derivative of a sterol" had a plain meaning because the only possible interpretation of the phrase was that the words "salt form" referred to the word "acid", the word "acid" referred to the word "derivative" and the word "derivative" referred to the word "sterol".  He argued that it was not correct to interpret this phrase in any other manner, for example so that the words "salt form" referred to the word "sterol", because this ignored the order of the words in the phrase.  Thus, in his view, the phrase meant a sterol having an organic acid in salt form attached to it.  Mr Jones submitted that the present claims satisfied the Mond Nickel Rules (Mond Nickel Co Ltd's Application 1956 RPC 189 at page 194) which the High Court approved as an appropriate test in respect of "fair basis" (Hoffman‑La Roche and Co AG v Commissioner of Patents 123 CLR 529 at page 538). He also argued that the invention defined in the present claims did not go beyond the matter disclosed in the description in the specification (Mullard Radio Valve Co Ltd v Philco Radio and Television Corp of Great Britain Ltd 53 RPC 323 at page 347).
Decision
         The law on the interpretation of claims is that it is not permissible to vary or qualify the plain and unambiguous meaning of the claim by reference to the body of the specification (Welch Perrin and Co Pty Ltd v Worrel 106 CLR 588 at page 610). If an expression is not clear it is then permissible to resort to the body of the specification to define or clarify the meaning of words used in the claim without infringing the rule that clear and unambiguous words in the claim cannot be varied or qualified by reference to the body of the specification (Interlego AG v Toltoys Pty Ltd 130 CLR 461 at page 479). However it must be made plain to the reader of the specification if a word or phrase is used with a particular meaning which is set out in the description in the specification (Minerals Separation North American Corporation v Noranda Mines Ltd 1952 RPC 81 at page 94).
         The phrase "a salt form of an organic acid derivative of a sterol" specifies three features of the molecule however the lack of punctuation in the phrase does not make it apparent how these features are to be related to one another.  According to Mr Jones the features should be related in the order in which they occur in the phrase.  I understand what Mr Jones is saying, in effect, is that the feature of "a salt form" refers to the feature of "an organic acid derivative", therefore these form a combined feature of "a salt form of an organic acid derivative" which is attached to the remaining feature of "a sterol".  I note that the 4th Edition of "Hackh's Chemical Dictionary" defines the word "derivative" as follows:

"(1) A compound, usually organic, obtained from another compound by a simple chemical process; eg., acetic acid is a derivative of alcohol.  (2) An organic compound containing a structural radical similar to that from which it is derived, eg., benzene derivatives containing the benzene ring."

However "Hackh's" does not state that the order in which alternate definitions for the same word are numbered is significant; for example it does not state that "(1)" indicates the most widely accepted definition of the word.  Thus it seems to me that the skilled person would understand that both definitions can be used for the word "derivative".  Therefore  I think the skilled person would interpret the combined feature of "a salt form of an organic acid derivative" as an organic acid derivative which is in salt form.  However this skilled person would also know from definition "(1)" in "Hackh" that the organic acid functional group is not necessarily present in an organic acid derivative.  For example only one of the carboxylic acid groups of succinic acid appears as a carboxylic acid group in cholesteryl hemisuccinic acid.  Consequently I think the skilled person would conclude that the combined feature of "a salt form of an organic acid derivative" does not necessarily mean that an organic acid functional group in salt form is attached to the sterol.  For example a mono carboxylic amino acid which is bonded to the sterol through the carboxylic acid group also contains an amine functional group which can exist in salt form.  In my view, such a salt form, which does not contain the carboxylic acid in salt form, lies within the scope of the phrase "a salt form of an organic acid derivative of a sterol".
         However I consider that the skilled person would also understand that the three features in the phrase "a salt form of an organic acid derivative of a sterol" can also be interpreted in another manner without disregarding the order of the words in the phrase.  Thus the features of "an organic acid derivative" and "a sterol" may form a combined feature of "an organic acid derivative of a sterol".  I think the skilled person would understand that in this case the remaining feature of the "salt form" may be part of the derivatising organic acid or may be part of the sterol.  For example the sterol to which the organic acid group is attached, may also contain other functional groups which can exist in salt form such as an amine group.  It seems to me that such a salt form, which does not contain the organic acid group in salt form, lies within the scope of the phrase "a salt form of an organic acid derivative of a sterol".  Consequently I disagree with Mr Jones that the phrase "a salt form of an organic acid derivative of a sterol" only means a sterol with an organic acid in salt form attached to it.  I consider that the skilled person would know that the phrase included the meaning suggested by Mr Jones.  However I think the skilled person would understand that in the claims the phrase plainly refers to a compound in salt form which is a sterol derivatised by an organic acid which may, or may not be in salt form.  Thus it may be permissible to vary or qualify this plain and unambiguous meaning of the phrase in the claims by reference to the body of the specification if this is made clear to the reader (Minerals Separation North American Corporation v Noranda Mines Ltd loc. cit.).
         Mr Jones supported his interpretation, by referring to a statement on page 1b of the specification under the heading "FIELD OF THE INVENTION" which reads as follows:

"Sterols such as cholesterol or other lipids, to which a hydrophilic moiety such as a salt form of an organic acid is attached, can be used to prepare suspensions of multilamellar or small unilamellar vesicles."

I consider the skilled reader of this statement as well as the statements under the heading "DETAILED DESCRIPTION OF THE INVENTION", which I have quoted earlier in this decision, would conclude that the phrase "a salt form of an organic acid derivative of a sterol" has a similar meaning in the description to the meaning suggested by Mr Jones.  However I think the specification does not make it plain to the skilled reader that the phrase has this meaning throughout the description and claims.  Therefore, in my view, the skilled reader would realise that the scope of the phrase in the claims is wider than the scope of the phrase in the description in relation to the kinds of salt forms included in the phrase.  Consequently it seems to me that this conflict means that the relevant claims lack clarity.
         Gummow, J in a recent judgement (Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd 11 IPR 289 at pages 303 to 305) referred to the Mond Nickel Rules suggested by Mr Jones but stated that the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification.
         I think it is clear from a perusal of the description that, apart from the repeated use of the phrase "a salt form of an organic acid derivative of a sterol" with respect to the liposome bilayers, the only steroidal liposomes disclosed, are those the bilayers of which comprise a sterol derivatised with the salt form of a carboxylic acid or a substituted carboxylic acid.   The written responses from the attorney quote the definition from "Hackh" which defines an organic acid as a carboxylic acid.  However I note that the present specification is inconsistent in this regard as on page 20, lines 20, 23 and 27 the description refers to "organic carboxylic acids".
         I consider that the skilled reader would adopt a purposive construction (Catnic Components Ltd v Hill and Smith Ltd 1982 RPC 183 at page 242) of the term "organic acid" rather than the narrow definition from "Hackh" which the attorney relies on in the written responses. In my view the purposive construction of the term which the skilled reader would adopt is that an organic acid is a compound containing any acid group bonded to any organic group, for example a pyridine sulphonic acid. Thus I consider that there is no real and reasonably clear disclosure in the body of the specification of the claimed steroidal liposomes, the bilayers of which comprise a sterol derivatised with any organic acid (Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd loc cit).  Alternately, on applying the modified Mond Nickel Rules (Hoffman‑La Roche and Co AG v Commissioner of Patents loc cit), as suggested by Mr Jones, I consider that the body of the specification is wholly silent with respect to steroidal liposomes, the bilayers of which comprise a sterol derivatised with any organic acid as claimed in the present claims.  Earlier in this decision I found that the scope of the phrase "a salt form of an organic acid derivative of a sterol" was wider in the claims than in the description in relation to the kinds of salt forms included in the phrase.  Thus a similar analysis of the fair basis of the claims with respect to these salt forms, produces similar results to the analysis with respect to organic acid.
         In my view the present scope of the independent claims would tend to discourage research and development in the field of steroidal liposomes, for example research into steroidal liposomes whose bilayers comprise a sterol in salt form derivatised by an organic acid which is not in salt form.  Moreover I do not think that LIPOSOME has conceived of and brought into existence an entirely new or revolutionary product which stands so far in advance of and, apart from, previous developments that it works a radical transformation in the field in which it is introduced (Olin Corporation v Super Cartridge Co Pty Ltd 14 ALR 149 at page 172). Thus page 5 of the present specification admits that steroidal liposomes can be constructed which consist "entirely of cholesterol, provided a stabilising hydrophilic anchor is supplied". The specification goes on to state that cholesterol liposomes were prepared from cholesterol derivatives including cholesterol‑SO4, which appears to be a salt form of an inorganic acid derivative of cholesterol, and cholesterol‑phosphocholine which appears to be an internal salt form of an organic acid derivative of cholesterol.
         Therefore I am satisfied that the independent claims 1, 35 and 58 which I have quoted earlier in this decision, as well as the other independent claims 55 and 56, are not fairly based on matter described in the body of the specification.  I am also satisfied that these claims lack clarity.
         Prior to issuing this decision I telephoned Mr Jones and informed him of several minor matters which were not raised by the examiner but which I considered should be amended before application No. 49528/85 was ready for acceptance.  These matters were:

1.Paragraphs 1 and 2 on page 9 of the specification use the phrase "present invention" with respect to matter, which was deleted by the proposed amendments lodged on 2 November 1989;

2.Claim 35 lacks clarity because line 4 of the claim refers to the amount of sterol as sufficient for forming completely closed vesicles rather than bilayers.  The specification on page 3, lines 9 to 13 states that the term "vesicles" includes monolayers;

3.Claim 67, which is appended to claim 66, lacks clarity because there is no antecedent for the term "the cation" in claim 66.

Therefore I am satisfied that there are still lawful grounds of objection to application No 49528/85 and I afford the applicant an opportunity to lodge a statement of proposed amendments to my satisfaction within the time remaining for acceptance.

(M. KENDALL)