University of Georgia Research Foundation, Inc and Emory University v Biochem Pharma, Inc

OFFICIAL NOTICE

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Application : No. 670637 in the name of University of Georgia Research Foundation, Inc. and Emory University

Title: Enantiomerically pure b-D-dioxolane-nucleosides

Action: Opposition to the grant of a patent by BioChem Pharma, Inc.

Decision: Issued
Abstract

Opposition succeeds on the grounds of novelty and inventive step.

Novelty:The citation disclosed the compounds as a mixture of enantiomers There is an enabling disclosure because a skilled reader would have known how to separate the enantiomers and would have been able to do so as a matter of routine. The application is a second selection for the same property and was not able to satisfy the I.G. Farbenindustrie test.
Inventive step: The citation provided a complete solution to the problem, so there was no inventive step.

PATENTS ACT 1990

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Re:Patent Application No. 670637 by University of Georgia Research Foundation, Inc. and Emory University, and an opposition to the grant of a patent by BioChem Pharma, Inc.

BACKGROUND

Patent application number 50933/93 was filed as an international application designating Australia (number PCT/US93/08044) on 25 August 1993 by the University of Georgia Research Foundation, Inc. and Emory University (hereafter referred to as the Universities). The application claims priority from US 935515 (which was filed on 25 August 1992). The application was examined by the Commissioner, and advertised accepted under the serial number 670637 on 25 July 1996.

BioChem Pharma, Inc. (hereafter referred to as BioChem) filed a notice of opposition on 25 October 1996. A statement of grounds and particulars was served on 28 January 1997, and amended on 13 February 1998. The evidence stages were completed on 7 September 1999.

The matter was heard in Sydney on 14 and 15 August 2000. The Universities were represented by Mr David Catterns QC, instructed by Dr Bill Pickering and Dr Jenny Petering of F.B.Rice & Co. Ms Sherry Knowles, the Universities' US attorney of King & Spalding, Atlanta, USA, was also present. BioChem was represented by Dr Annabelle Bennett SC and Katrina Howard of counsel, instructed by Mr Ken Finney of Cullen & Co. Ms Daniele Ethier and Mr Brion Heaney were also present.

GROUNDS OF OPPOSITION

The statement of grounds and particulars specifies the following grounds of opposition:

*         section 40 matters
*         novelty
*         inventive step
*         manner of manufacture

I note that in order to find that the grounds of opposition are made out, I must be clearly satisfied that the patent, if granted, would not be valid (see F.Hoffmann-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [67]).

Dr Bennett noted at the outset that there was no notice of entitlement from Emory University. There was no opposition on the ground of entitlement, so this matter was not argued.

EVIDENCE

The evidence in support of the opposition consists of declarations by Professor Jackson, Dr Marcuccio, Dr Evans, Ms Bernier, Mr Dugas, Dr Dixit, Dr Hooper, Professor Kitching, Mr O'Keefe, Ms Petit-Young, Ms Priddey and Ms Larsen.

The evidence in answer consists of declarations by Professor Schinazi, Professor Mander and Professor Hearn.

Evidence in reply consists of further declarations by Dr Evans, Professor Jackson and Dr Marcuccio.

The Universities filed further evidence in the form of additional declarations by Professor Hearn and Professor Schinazi. Evidence in response consists of a third declaration by Dr Marcuccio.

Copies of a large number of documents are attached as exhibits to the declarations. I will refer to these declarations and the exhibits where relevant in my decision.

THE SPECIFICATION

The specification was amended twice following acceptance of the application. A further amendment to the specification has been examined by the Commissioner. Leave to amend has been granted, and a notice of that fact was published in the Official Journal on 10 August 2000. These latest amendments have not yet been allowed (as the opposition period has not yet expired). Consequently the specification does not yet incorporate the latest amendments.

The description

The patent application relates to compounds for treatment of humans infected with HIV. The specific compounds are b-D-dioxolanyl purine nucleosides. These compounds have two substituents on the dioxolane ring, so exist in four isomeric forms. When the substituents are on the same side of the dioxolane ring, the conformation is known as b (or cis). The b-isomer can itself exist as two different isomers which are mirror images of each other. One is the D-enantiomer, and the other is the L-enantiomer. These individual enantiomers are identified as b-D and b-L.

Some of these compounds can be identified by abbreviations rather than the use of their full names. A list of abbreviations as used in this decision are given in Annex 1. It is important to note that I will use the abbreviations (such as ACPD) to refer to racemic mixtures, and prefixes such as b- and b-D- to refer to specific isomers and enantiomers.

Due to the series of amendments to the specification, the compounds described do not strictly correlate with the compounds presently claimed. The broadest aspect of the invention is given in the summary of the invention (page 4 to 5):

"A method for the treatment of humans infected with HIV that includes administering an HIV treatment amount of an enantiomerically pure b-D-dioxolanyl purine nucleoside of the formula:
wherein R is OH, Cl, NH₂, or H, or a pharmaceutically acceptable salt or derivative of the compound, optionally in a pharmaceutically acceptable carrier or diluent."

The compound in which R is hydroxyl is not the subject of any of the claims.

It is significant to note that the compounds are restricted to the b-D-enantiomers, which is one of the four possible stereoisomers.

The claims

The claims of the specification are directed to three different types of 1,3-dioxolanes (claims 5 and 6), pharmaceutical compositions containing them (claims 3 and 4) and treatment of HIV using them (claims 1 and 2). The claims are reproduced in full in Annex 2. The structures of the compounds that are the subject of the claims can be summarised as:

where R = H, Cl, NH₂ and
X = H, acyl, monophosphate, diphosphate, triphosphate.

These compounds are b-D-ACPD, b-D-APD and b-D-DAPD, and their acyl and phosphate derivatives.

Relationship of the invention to the prior art

Patent number 631786 is an originating patent in this area, disclosing a broad class of dioxolanyl nucleosides. Application number 91475/91 was filed two years later, and is directed to a small group of compounds selected from the '786 patent. The present application is directed to another group of similar compounds.

The present application is closely related to application number 91475/91 by the same applicants. In fact, the text of the present specification contains a large amount of text that is the same as that appearing in 91475/91 (by eye, over 50% of the text is the same). It is almost certain that the relevant text was copied directly from 91475/91. This is not objectionable, and the relationship of the present application to 91475/91 does not have to be acknowledged. Significantly, there are large portions of text that do not appear in 91475/91. This new text is the key information, providing (inter alia) a broad statement of the invention, and the preparation of b-D-ACPD and b-D-DAPD. This is consistent with the assertion that I will discuss later that the present application is further work down the pathway of the 91475/91 application.

It is apparent from the evidence and submissions that the compounds b-D-ACPD, b-D-APD and b-D-DAPD are prodrug forms of b-D-DXG. This means that they are converted to b-D-DXG in vivo, and will produce the same biological activity as b-D-DXG. It is suggested that the prodrugs are more soluble than b-D-DXG, making them better pharmaceuticals.

It does not appear from the specification that it was recognised that these compounds are prodrug forms of b-D-DXG, or that they operate by conversion to b-D-DXG. The specification refers to prodrugs, but the prodrugs are of a quite different type:

"In another embodiment, the invention includes a method for the treatment of humans infected with HIV that includes administering an HIV treatment amount of a prodrug of the specifically disclosed enantiomerically pure b-D-dioxolanyl purine nucleosides. A prodrug, as used herein, refers to a pharmaceutically acceptable derivative of the specifically disclosed nucleoside, that is converted into the nucleoside on administration in vivo. Nonlimiting examples are pharmaceutically acceptable salts (alternatively referred to as 'physiologically acceptable salts'), and the 5' and N⁶ acylated or alkylated derivatives of the active compound (alternatively referred to as 'physiologically or pharmaceutically acceptable derivatives')."
[pages 5-6]

It is unclear what persons skilled in the art would have understood about prodrugs of b-D-DXG. Dr Marcuccio thought that the b-D-ACPD, b-D-APD and b-D-DAPD were a routine prodrug modification of b-D-DXG, and the conversion of the prodrugs to b-D-DXG could have been predicted at the priority date (paragraph 5.4 of his second declaration). Professor Schinazi thought that it could not have been predicted that b-D-ACPD, b-D-APD and b-D-DAPD would be converted effectively to b-D-DXG (paragraph 31 of his second declaration). It seems that it is now clear that b-D-ACPD, b-D-APD and b-D-DAPD are prodrugs of b-D-DXG. It is unclear whether this would have been recognised at the priority date. It appears that the inventors thought this was a likely explanation for the observed activity of b-D-ACPD and b-D-DAPD in 1992 when they wrote an article published in the Journal of Medicinal Chemistry in 1993 (Exhibit RFS-3). The inventors were sure of the prodrug action in 1996, when they wrote an article published in Antimicrobial Agents and Chemotherapy (Exhibit RFS-6) acknowledging that b-D-APD and b-D-ACPD were being developed as prodrugs for b-D-DXG.

It seems more likely that prodrug action was a rationalisation of observation rather than an expectation. It is more likely than not that even had prodrug activity been expected, it would still have been uncertain how effectively the prodrugs would be converted to b-D-DXG.

Understanding that the compounds are prodrugs is not essential to understanding that the compounds have anti-HIV activity. It merely provides insight into how the compounds produce this result.

SECTION 40 ISSUES

A number of section 40 matters were argued at the hearing. Many of these matters are interconnected, or are alternative ways of looking at a single issue. Not all of these matters were included in the particulars. As they were fully argued at the hearing I will deal with all of the issues. I will attempt to fully reflect the range of issues raised.

Clarity

The particulars indicate that the claims are not clear as it is not certain what is meant by 97% purity. The exact term as used in the claims as they are presently drafted is "at least 97% free of the corresponding b-L enantiomer". The plain meaning of this expression is that there is a maximum of 3% of the other enantiomer. The alternative construction, that the b-D enantiomer predominates by 97% and therefore the maximum amount of the other enantiomer is 1.5%, is actually the enantiomeric excess. If it had been intended to refer to the enantiomeric excess, then the claim would have used this term. Consequently the plain meaning is clearly appropriate.

Fair basis

The test for fair basis is to ask whether there is a "real and reasonably clear disclosure" of the matter that is claimed (Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 at 95, Patent Gesellschaft AG v Saudi Livestock Transport and Trading Co (1997) 37 IPR 523 at 530). This test is explained in the Rehm case as:

"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"
[page 95]

Dr Bennett asserted that there is no basis for claims that include b-D-APD, since the specification is silent on the preparation and activity of this compound. Mr Catterns stated that the efficacy of this compound was later proved (in an article by Chen in Antimicrobial Agents and Chemotherapy in 1996; Exhibit RFS-6).

There is no requirement for a description to exemplify every compound that is claimed. The question is whether what is described provides sufficient information to amount to a real and reasonably clear disclosure. One way of looking at this would be to ask whether it is a reasonable extrapolation to go from the exemplified compounds to the compounds that are claimed. The fact that it is subsequently shown that it has the activity predicted does not of itself make that extrapolation reasonable. The description refers to b-D-APD, and its structure is sufficiently similar to that of b-D-ACPD and b-D-DAPD that it is reasonable to extrapolate the method of synthesis and activity.

I am satisfied that claims including b-D-APD are fairly based.

Dr Bennett also asserted that there is no basis for the derivatives for the prodrugs (as that term is used in the description: compounds in which X is other than hydrogen). No acyl or phosphate derivatives are prepared. A general method of preparing phosphates is discussed at page 33-34, and there is no reason to believe that this method would not be effective. I consider that there is fair basis for this aspect of the invention.

The particulars specify that there is no support for a 97% purity of the enantiomers. There is no reference to the figure of 97% in the description. The examples appear to be 100% pure. The examples are thus at least 97% free of the other enantiomer. Although the choice of the specific value of 97% is not foreshadowed, it is a reasonable definition of a pure enantiomer. I am satisfied that the claims are fairly based in this regard.

Full description

The requirement for full description is a requirement to disclose the invention to a technical person.

"The specification contains a full description if it makes the nature of the invention plain to persons having reasonably competent knowledge of the subject and also makes it plain, to persons having reasonable skill, how to perform the invention"
[Patent Gesellschaft case at 530]

Dr Bennett argued that the specification does not disclose the best method of performance. The stated object of the invention is to produce enantiomerically pure dioxolane nucleosides with significant anti-HIV activity. However, the most active compound according to Table 1 of the specification (see Annex 3 of this decision) is b-D-DXG, which is not within the scope of the claims. It was argued that the best compound as described is not part of the invention, so there is no best method of performing the invention.

I think that the question that needs to be asked is best approached in two steps: (1) what is the invention that is claimed; (2) is there a best method of performing that invention. The specification may contain information about other compounds, that does not directly impinge on the question of best method of performance (but may go to other issues). The invention is the compounds of claims 5 and 6, and the specification discloses a best method in relation to these compounds (for instance, pages 14 to 24 provide experimental details).

Dr Bennett argued that the specification does not adequately distinguish the invention from the prior art. This was alleged to follow from the fact that the present specification is based substantially on the specification of 91475/91. The description asserts that the invention lies in four compounds (the three that are presently claimed and b-D-DXG). Those compounds are asserted to be the invention. A property that makes the compounds an invention (anti-HIV activity) is discussed in the specification. I consider that there is a description of an invention. It may be that the invention as described and claimed is not novel.

PRIORITY DATES

Dr Bennett questioned the priority date that should apply to the claims. This is a matter that must be determined before turning to assess any matters of anticipation.

The priority date of a claim is determined according to sections 43 and 114, and regulations 3.12, 3.13 and 3.14. Section 114(1) and regulation 3.14 are the most relevant provisions in the present case.

Priority date of certain amended claims
114 (1) Where a claim of a complete specification claims matter that was in substance disclosed as a result of amending the specification, the priority date of the claim must be determined under the regulations.
Priority dates: certain amended claims
3.14 If subsection 114(1) of the Act ("priority date of certain amended claims") applies to a claim of a specification, the priority date of the claim is:
(a)in the case of an amendment to which subsection 89(4) or (5) of the Act ("modified application of Act") applies - the date on which the amendment is taken to have been made under that subsection; and
(b)in any other case - the date of filing of the statement of proposed amendments that resulted in the disclosure referred to in subsection 114(1) of the Act.

The basic principle is that the priority date of a claim is the date that the subject matter of the claim was first disclosed, either by filing the priority document, by filing the patent specification or by filing amendments to the specification.

Priority dates of 670637

There are two questions that must be addressed. First, do any of the claims in question claim matter that was in substance disclosed as a result of amending the specification. Second, if the first question is answered in the positive, what was the date of the amendment that disclosed that amendment. While section 114 does not use the language "fairly based", it is established that "this requirement of 'fairly based' is virtually the same as the requirement that the amendment must be 'in substance disclosed'" (Ethyl Corporation's Patent [1972] RPC 169 at 195). It follows that section 114 comes into operation when newly claimed subject matter is not fairly based on the specification as filed.

The essence of the argument is that as a result of amendment the present specification became a selection, which is a change in the nature of the invention. I note that this same approach is used to assess the allowability of amendments, see Enichem Synthesis SpA v Ciba-Geigy AG (1996) AIPC 91-276 and Lumenyte International Corp v Light Transmission Cables Pty Ltd [1998] APO 20. I need to examine whether the present claims are fairly based on the specification as filed.

I have found that the present claims are fairly based on the description as it is presently drafted. The description as presently drafted differs from the specification as originally filed in only one way - pages 8 and 8/1 are substitute sheets provided under Rule 26 of the Patent Cooperation Treaty.

Thus the text of the description as filed is the same as the description before me. This leads to the question of whether the invention has become a selection, even though the text of the specification has remained unchanged. In my discussion of the subject of selection later in this decision, I have come to the conclusion that the claimed invention is not a proper selection. It follows that the nature of the invention has not changed, so there is no reason to defer the priority date. There was no suggestion that the claims should not take priority from the basic document, so I consider that the claims can take a priority date of 25 August 1992.

NOVELTY

It was alleged that the claimed invention is not novel in the light of two patent specifications:

Australian patent number 631,786
Australian patent application number 91475/91

The question of novelty raises three key questions:

(i)        what is disclosed by each of the citations?
(ii)       do the citations provide an enabling disclosure?
(iii)      is the present application a valid selection?

It was argued that the claims are not novel in the light of each of the citations. If a prima facie case of lack of novelty is established, it was argued that there is a valid selection from the '786 patent. The 91475/91 application is a selection from '786, and the present application is a second selection.

I will discuss the law in relation to this area before dealing with the facts of the citations.

It is well established that the test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228, at page 235:

"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"

This test is satisfied if the alleged anticipation discloses all the essential features of the invention as claimed (see Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 at page 517; 16 IPR 545 at page 549). A citation is part of the prior art base for the purposes of novelty if it was published before the priority date of the claim (see definition of "prior art base" in Schedule 1 of the Act).

It is relevant to have regard to the recent decision of the Federal Court in Bristol-Myers Squibb Co v F H Faulding & Co Ltd (2000) 46 IPR 553. The Court noted that in the case of a paper anticipation, the reverse infringement test cannot be applied literally. This is because the infringement arises because someone hypothetically does what is suggested by the document. After reviewing the traditional authorities, the majority concluded:

"What all those authorities contemplate, in our view, is that a prior publication, if it is to destroy novelty, must give a direction or make a recommendation or suggestion which will result, if the skilled reader follows it, in the claimed invention. A direction, recommendation or suggestion may often, of course, be implicit in what is described and commonly the only question may be whether the publication describes with sufficient clarity the claimed invention or, in the case of a combination, each integer of it."
[page 576]

It was acknowledged that not everything published in a document is an anticipation. For instance, information that is a speculation or a proposal for a trial would not be an anticipation. The judges drew a distinction between a teaching of useful things in relation to a subject matter, and a teaching of the invention as claimed.

When a citation has a disclosure in generic form (as is common in chemical patents), the question arises as to which compounds within the scope of the generic disclosure are taught to the reader. I have considered this question in a number of earlier decisions. (For instance, see Application by American Home Products Corporation (1994) APO 58, Pharmacia Aktiebolag v Ueno Fine Chemicals Industry Ltd (1995) 34 IPR 445) It is not enough to find that a specific compound is within the scope of the broadest disclosure of the citation (which can be considered as the intellectual content of the disclosure). It is necessary to find that a reader would have understood that the specific compound was part of the technical information of the specification, and there must be an enabling disclosure of that compound (for instance, see my analysis of the doctrine of enabling disclosure in Biochem Pharma Inc v Emory University [1999] APO 50).

A disclosure of a racemate does not necessarily amount to a disclosure of the individual enantiomers. For instance, in Imperial Chemical Industries (Howe's) Application [1977] RPC 121 there were citations that disclosed racemates without any indication of interest in either of the isomers. Obviousness was pursued rather than novelty. The same approach is evident in Application by Rhone-Poulenc Rorer S.A. [1995] APO 50. Clearly, the teaching of a compound requires something more than the fact that it is encompassed by a disclosure.

The relevant date for construing a citation was discussed by the parties. The traditional authorities indicate that the relevant date is the date of publication of the citation (see General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd [1972] RPC 457 at 485 and Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 at 523, 524)). At the hearing it was asserted that it was normal practice for the courts to construe citations at the priority date of the application under opposition. If there is a conflict between the law and normal practice, then the law should prevail. After the hearing I was informed of a recent decision of the Federal Court that is relevant to this question (ICI Chemicals & Polymers Ltd v Lubrizol Corp Inc [2000] FCA 1349 dated 20 September 2000; both parties provided written comments on this case). Lee, Heerey and Lehane JJ reviewed the traditional authorities and indicated their belief that the priority date of the application under opposition is the relevant date. The judges make it clear that this is merely obiter, albeit a very forceful obiter. I believe that the law is clear from the General Tire case, and that I must apply that law until such time as a court clearly changes the law. I will use the date of publication of the citation as the relevant date (but I note that the final result would be the same in either case).

Much of the evidence in this case refers to what was known at the priority date of the present application. Clearly, this date is later than the publication date of the potential citations. There was also some argument that the presumption of continuity was relevant in this situation. The presumption of continuity is explained as a presumption that facts may be proven by establishing their previous or subsequent existence. My understanding is that this presumption is based on the probability that the fact would have continued with passing time. I accept that the principle can operate retrospectively, for instance proof that a person was alive at a given date would be conclusive that they were alive shortly before. However, where the evidence relates to the state of the common general knowledge (for example), it may not be as certain that matters were also common general knowledge at an earlier time. I will deal with these matters where they arise, and I will evaluate the weight of evidence at subsequent dates according to the probability that the facts were the same at earlier times.

What is taught by 631786

Patent number 631786 in the name of Biochem Pharma Inc is entitled "2-Substituted-4-substituted-1,3-dioxolanes, Synthesis and Use Thereof". This document was published on 12 October 1989. The broadest aspect of the invention is given on pages 5 and 6 of the specification:

"More specifically, the novel 2-substituted-4-substituted-1,3-dioxolane derivatives of the present invention correspond to the following formula (L):

(L)

wherein R₁ is selected from H, an aliphatic acyl radical from 2 to 16 carbon atoms, a benzoyl which may be substituted in any position by a halogen (bromine, chlorine, fluorine or iodine); a lower alkyl, a lower alkoxy, nitro and trifluoromethyl groups and R₂ is a heterocyclic radical selected from:

wherein R₃ and R₄ are respectively selected from H and a lower alkyl radical having from 1 to 3 carbon atoms, R₄ is an alkenyl radical and R₅ is selected from a lower alkyl or alkenyl radical having from 1 to 3 carbon atoms or a halogen selected from fluoro and iodo.
Also within the scope of the present invention are the 2,4-disubstituted-1,3-dioxolanes of Formula (L) wherein R₂ could be any nucleoside base analog, those base analogues being known by those of skill in the art of nucleoside chemistry.
There are two asymmetric carbons (asterisks) in the disubstituted 1,3-dioxolane molecule which provide for two racemic forms (±) and therefore four optical isomers. These racemates differ in the relative configurations of the 2- and 4-substitutents which can either assume the cis- and trans-configurations. The use of a graphic representation of the 2,4-disubstituted-1,3-dioxolanes of Formula (L) is meant to include the dl racemic mixture as well as the separate d and l isomers thereof."

The structures of these compounds overlap with those of the present application. The description in the '786 patent indicates that the invention includes individual isomers. The examples in the '786 patent include three compounds that are the racemic forms of compounds claimed by the present application. These compounds are clearly prepared, and have spectroscopic data provided. The compounds (as exemplified in the '786 patent) are:

Example 15: cis-2-hydroxymethyl-4-(2'-amino-6'-chloro-purin-9'-yl)-1,3-dioxolane (b-D-ACPD)
Example 16: cis-2-hydroxymethyl-4-(2'-amino-purin-9'-yl)-1,3-dioxolane (b-D-APD)
Example 17: cis-2-hydroxymethyl-4-(2',6'-diamino-purin-9'-yl)-1,3-dioxolane (b-D-DAPD)

Mr Catterns contended that the citation only teaches one compound. This compound is referred to as "trans-XII". The structure of trans-XII is

Clearly trans-XII is not a compound of the type claimed in the present application as it does not have a purine base, and it is not a b-isomer. Mr Catterns' reason for believing that trans-XII is the only compound taught is based on his interpretation of what is taught by a citation. The '786 patent states that only some of the compounds that it discloses are valuable as non-toxic inhibitors of HIV (page 13). A table of activity data on page 14 shows that trans-XII is more active than AZT (a well known anti-HIV agent that is used as a control drug). In contrast, a compound identified as cis-XIV is not useful. Cis-XIV has a purine base:

It is true that the specification indicates that trans-XII is more useful than cis-XIV, and that a reader is taught this difference in activity.

I believe that the teaching that is needed to anticipate a claim of a patent application is a teaching of the invention as claimed. Claims 5 and 6 are directed to the compounds per se. The teaching that is needed to anticipate these claims is a teaching of the compounds. It is not necessary for the citation to also teach the activity of the compounds. On the other hand, claims 1 and 2 are directed to treatment of HIV. The teaching that is needed to anticipate these claims is a teaching of useful anti-HIV activity. Mr Catterns' submissions are pertinent to claims 1 and 2 (and also to the compositions of claims 3 and 4), but they are not relevant to the compounds of claims 5 and 6.

I accept that the '786 patent discloses the b-D-ACPD, b-D-APD and b-D-DAPD, and that these compounds are the racemic forms of compounds that are the subject of the present application. However, the present application is directed solely to the b-D-enantiomers of the compounds. The question is whether the '786 patent discloses, or teaches, the b-D-enantiomers, and whether there is an enabling disclosure of those enantiomers.

It was contended by Dr Bennett that a person reading the '786 patent would have been directed to individual enantiomers by the words of the specification. It is true that the patent mentions the fact that the compounds exist as isomers, and states that the invention extends to the separate isomers. Is this enough to teach the b-D-enantiomer?

There is evidence that the b-isomer would have been expected to be more interesting than the a-isomer, for instance see page 2 of the present specification. However, this is not a critical point, since the citation clearly teaches the b-isomers. However, it does not appear that there is a reason to think that the citation taught the b-D-enantiomer in preference to the b-L-enantiomer. The teaching of enantiomers in the citation seems to be a teaching of both the D- and the L-enantiomers without an indication of a preference. However, in terms of the teaching of the citation, it is only necessary for the citation to teach the b-D-enantiomer, and it is not necessary to teach the advantages of this enantiomer. In the present case the b-isomer is disclosed, and individual enantiomers are indicated. As there are only two enantiomers, this is a sufficient teaching of each of the enantiomers of the actually prepared isomers. Consequently I accept that a reader of the citation would have considered that they had been taught both of the isomers of the compounds that are actually prepared.

There are many similarities with the case of Beecham Group Ltd's (Amoxycillin) Application [1980] RPC 261. That case involved an opposition to British patent number 1,241,844. The subject of the patent was a penicillin known as Amoxycillin. Amoxycillin is a single enantiomer. It is significant that the form of the invention claimed was a pharmaceutical composition containing Amoxycillin. The prior art documents were a patent and two patents of addition. The patent (having the number 873,049) disclosed a broad class of penicillins prepared in their racemic form. The patent indicated that the invention extended to the individual enantiomers. The first patent of addition is number 902,703. This patent related to resolved isomers of one of the penicillins. The second patent of addition is number 978,178. This patent relates to a specific penicillin derivative in which an hydroxy group is attached to a benzene ring. The patent is directed to the ortho, meta and para isomers prepared in their racemic form, and there is a statement that the invention extends to the individual stereoisomers. Amoxycillin is the (-) stereoisomer of the para-hydroxy compound.

Buckley LJ found that the second patent of addition (978,178) did not disclose a pharmaceutical composition. While it was apparently common knowledge how to prepare a composition (page 287), the second patent of addition did not teach that Amoxycillin would necessarily prove suitable for treatment of humans (page 290). On this basis, there was no anticipation. However, it seems clear that the judge considered that Amoxycillin itself was disclosed in the second patent of addition (page 286-287). It is significant to note that the racemic form of Amoxycillin was prepared and there was an explicit reference to isomers in the second patent of addition.

Thus there is a disclosure of the compounds of claims 5 and 6 where the R group is NH₂, H and Cl, and the X group is hydrogen. There is also a disclosure of pharmaceutical compositions and use for the treatment of HIV. Consequently the method of claims 1 and 2, and the compositions of claims 3 and 4 are also disclosed.

Is there an enabling disclosure

This takes me to the second issue, whether the citation provides an enabling disclosure of the b-D-enantiomers.

The question of what amounts to an enabling disclosure in the context of a generic disclosure is a complex issue. Normally the focus of attention will be the details of the specification. In the Biochem v Emory decision I noted (at page 33)

"The lack of information on how to prepare the compound is prima facie a lack of an enabling disclosure."

That is equally true in the present case. Disclosure as a member of a class will not normally represent an enabling disclosure unless it is immediately clear to the person skilled in the art how the compounds may be prepared. There is evidence that it would have been routine to separate the enantiomers of the compounds disclosed in the citation using well established techniques. I will summarise this evidence.

Two declarants state that they have separated compounds similar to those of the present application using conventional techniques. Louise Bernier separated the b-D and b-L-enantiomers of the dioxolane known as BCH-344. This was achieved using chiral HPLC. The separation was carried out prior to 25 August 1992. The structure of BCH-344 is shown below:

Dr Dixit separated the b-D and b-L-enantiomers of the dioxolane known as BCH-204. This was achieved using enzymatic resolution. The separation was carried out prior to 25 August 1992. The structure of BCH-204 is shown below:

There are several declarants who have not separated dioxolane nucleosides, but declare that it would have been a straight forward task to have separated the enantiomers of the '786 patent by working carefully through the range of available techniques. Professor Evans declared that many methods of separation of enantiomers were known as at 25 August 1992, such as GLC and HPLC (paragraph 2.16 of the first Evans declaration). Dr Marcuccio referred to a number of published papers on the separation of enantiomers (paragraph 1.11 of the first Marcuccio declaration). Dr Marcuccio further stated:

"These references show that it was well known in the art in Australia prior to 25 August 1992 how to carry out the separation of enantiomers in general and, in particular, how to separate the dioxolane nucleosides of the opposed application from racemic mixtures containing them, like those exemplified in the BioChem '786 patent."
[paragraph 1.11 of the first Marcuccio declaration]

It should be made clear that none of these documents disclose the separation of the precise compounds that are the subject of the opposed patent application, and I do not think that Dr Marcuccio is suggesting that. Rather, I interpret Dr Marcuccio as stating that the separation of similar compounds is reported.

Professor Kitching also stated that it would have been routine to separate enantiomers of the type in the '786 patent:

"At the date of the BioChem '786 patent, which I have been informed, is 11 April 1989, and particularly at the priority date of the '637 application (25 August 1992), resolution of the enantiomers of a racemic dioxolanyl nucleoside would have been within the capabilities of a typical organic chemist working in Australia with several years experience in a laboratory such as mine."
[paragraph 11 of the Kitching declaration]

Dr Hooper also stated that it would have been routine to separate the enantiomers of the type in the '786 patent:

"I also believe that such a person working in Australia [i.e. a researcher working in a laboratory such as that of Dr Hooper] as at and prior to 25 August 1992 would have been able to resolve enantiomers of the dioxolanyl nucleosides described in the BioChem '786 patent with only an ordinary amount of experimentation, or at least would have been able to have the enantiomers resolved."
[paragraph 10 of the Hooper declaration]

Dr Hooper goes on to state that he was able to separate the enantiomers of methylphenobarbital using HPLC in 1986-1987 (paragraphs 12 to 26). In addition Dr Hooper used HPLC to separate the enantiomers of 1-hydroxytacrine in 1991 (paragraphs 28 to 31). Dr Hooper also states that he separated the enantiomers of ethotoin in 1990 and 1991 (paragraphs 32 to 33). Dr Hooper appears to have regarded all of this work as routine. I note that none of these compounds are a dioxolanyl nucleoside.

Dr O'Keefe has no experience in separating nucleosides (paragraph 20), but considers that separating the enantiomers would have been a matter of routine:

"In my opinion, as at 25 August 1992 separating the enantiomers present in a racemic mixture was a matter of routine for a chemist who worked with optically active compounds having biological activity."
[paragraph 35 of the O'Keefe declaration]

Professor Jackson has been a Professor of Chemistry since 1973. He also considers that separation would have been a matter of routine:

"Careful and skilled application of the methods listed in paragraph 2.3 by someone who, at or prior to 25 August 1992, has had two or three years of relevant laboratory experience after an honours degree in organic chemistry or a related field should lead to the establishment of a method of resolution within a reasonable period of time using no more than standard methods."
[paragraph 2.5 of the first Jackson declaration]
"To my mind, the task of resolving the enantiomers of a particular racemate described in the BioChem '786 patent was a trivial one."
[paragraph 3.5 of the first Jackson declaration]

Professor Jackson also comments on the way that he would have approached the task of separating the enantiomers:

"If I had been asked to resolve one of the dioxolanyl nucleosides of the BioChem '786 patent, as at 25 August 1992, it would have not mattered to me that I had not worked with a nucleoside before. The described compounds contain a hydroxymethyl group substituted on a saturated heterocycle which is also substituted by an amino aromatic heterocycle. Therefore, I, and I believe my graduate students, would have done a literature search to determine what protocols had been applied previously to compounds of this type of functionality and structure. Had such a search been done, various published reports where chiral chromatography had been used successfully to separate similar compounds would have been located. E.L.Eliel and S.H.Wilen in their book Stereochemistry of Organic Compounds (Wiley Interscience, New York, 1994) summarise several chromatographic separation procedures for enantiomers which were available before 1992 (see Exhibit WRJ-6). The reverse phase separation of the enantiomers of several drugs including propanolol (an aminoalcohol) and verapamil (an aminonitrile) using a reverse phase version of a cellulose ester column was described in 1989; see K.Ikeda et al., Chem. Lett. (1989) 1089 (Exhibit WRJ-7). I, and I believe any of my graduate students, would have used these protocols and chiral supports, modifying them as necessary, to resolve any of the dioxolanyl nucleosides described in the BioChem '786 patent."
[paragraph 3.6 of the Jackson declaration]

There is an element of caution in these declarations, since it seems that they cannot say that any particular separation techniques would be successful. However, it is clear that they all believe that a separation could be achieved by following standard techniques. Most of the declarants go further and assert that a separation would be achieved by one technique or another. The critical date used by most of these declarants is the priority date of the present application. When considering whether it is safe to presume that the same facts would have applied at the publication date of the '786 patent, I need to consider how fast the art was changing at that time. Dr Marcuccio declared:

"In the period between the priority date of the BioChem '786 patent and the earliest possible priority date of the opposed application, there was a proliferation of information relating to the role of nucleosides in the treatment of AIDS, and of publications relating to the preparation and separation of enantiomers from racemic mixtures containing them."
[paragraph 3.3 of the first Marcuccio declaration]

Clearly there was a growth in knowledge about nucleosides during the critical period. Knowledge about the use of HPLC to separate nucleosides is found in exhibit RFE-23 to the declaration of Professor Evans. This exhibit is a paper published in the Journal of Chromatography in 1991 by Thomas and Surber. The paper states:

"A thorough search of the literature on chiral chromatography failed to reveal any examples of nucleoside separations."
[page 265]

At page 269 the authors comment that their use of HPLC appears to be the first use of HPLC to resolve a nucleoside. However, the authors also note that the method was poor yielding. Professor Hearn also noted that he was not aware of any reports of the successful resolution of dioxolanyl nucleosides prior to 25 August 1992 (paragraph 4 of his second declaration). On the other hand, there is a 1984 article by Forsman in the Journal of Chromatography (Exhibit RFE-24) that describes the resolution of the guanine compound:

While this is not a dioxolanyl compound, it is a structure that has many similarities to that of DXG.

How should I resolve the conflicting evidence as to whether it would have been routine to use HPLC to separate dioxolanyl nucleosides? I accept that HPLC was a known separation technique in 1989, and that its use was on the increase. Because the area was developing, it is not safe to assume that the art in 1989 was the same in 1992. The presumption of continuity is not applicable. Instead I need to consider the direct evidence of what was routine in 1989. It is regrettable that the declarant Bernier has not been full and frank with regard to the date on which the enantiomers of BCH-344 were separated. This evidence gives me no information about what was routine in 1989.

It seems that the use of HPLC to separate enantiomers (including compounds containing purine bases) was routine for some people in the late 1980's. However, it seems that the separation of dioxolanyl nucleosides had not been attempted by 1989. Once dioxolanyl nucleoside separations were attempted, it appears that they were successful. It seems more likely than not that it would have been considered worth trying HPLC in 1989.

An alternative method of separating the enantiomers was enzymatic resolution. Enzymatic resolution was a known technique in 1989. Professor Schinazi declared that as of 25 August 1992 there would not have been a reasonable expectation that b-DAPD or b-ACPD could be a substrate for enzymatic resolution using adenosine deaminase. Dr Marcuccio declared to the opposite effect, basing his view on articles reporting separation of related compounds. Dr Dixit had separated the enantiomers of BCH-204 by 1992. I am not satisfied that these articles or the information contained in them was a part of the common general knowledge. On the limited evidence before me I find that it has not been shown that it was routine to use enzymatic resolution in 1989.

The weight of the evidence is that it would have been routine to try HPLC to separate the isomers of the compounds in the '786 patent. Consequently there is an enabling disclosure, which is sufficient to render the invention not novel. The final question is whether the present application is a selection.

Selection

The test for whether an application is a valid selection is based on the decision in I.G. Farbenindustrie A.G.'s Patents (1930) 47 RPC 289. The well known test is found in the paragraph bridging pages 322 and 323 of the report:

"Three general propositions may, however, I think be asserted as true:- First, a selection patent to be valid must be based on some substantial advantage to be secured by the use of the selected members. (The phrase will be understood to include the case of a substantial disadvantage to be thereby avoided.) Secondly, the whole of the selected members must possess the advantage in question. Thirdly, the selection must be in respect of a quality of a special character which can fairly be said to be peculiar to the selected group."

The three propositions are then further explained as follows:

"The first proposition is plain. I will add that this condition must not be assimilated with the doctrine of utility as applied to an originating patent. In such a patent there may well be invention without utility. In a selection patent the condition that there must be a substantial advantage attributable to the use of the selected members is inherent in the so-called invention.
The second proposition is derived from the circumstances that, if the selection embraces selected members, which do not possess the alleged advantages, the selection is defective and the patent would be misleading and would also fail for insufficiency and non-utility. It is not, however, intended to suggest that a few exceptions here and there would be regarded as invalidating the patent.
The third proposition requires a little explanation. If there are five thousand possible members of a group, and a hundred have been selected as possessing some new and definite advantage, it is not intended to assert that such a selection patent would be bad if it were shown as the result of further research that there existed another hundred members possessing the same advantage. If, on the other hand, it were to be established that there were a thousand unselected members which possessed the same advantage, I doubt very much whether the patent could be sustained. The quality must be of a special character. It must not be one which those skilled in the art will expect to find in a large number of the members. It would be rash to attempt a closer definition; for the question is ultimately one of appreciation."
[page 323]

Mr Catterns submitted that a selection is not invalidated if it is later found that are some other compounds that also possess the advantage. I think this is clearly supported by the views of Maugham J in relation to the third proposition (as quoted above). However, it seems that there is a question of degree involved. Some additional compounds with the same advantage is acceptable, but a large number of compounds with the same advantage might not be acceptable. Mr Catterns also submitted that it was possible to select from the original patent even if some other compounds within the scope of the original patent had been previously identified as possessing the same or similar advantage. This can be looked upon as a second selection based on the same advantage.

It is true that if you look only at the earlier patent, then the second selection will be based on an advantage and would look like a selection. However, the problem lies in the third proposition: is the advantage peculiar to the selected group when it is shared with the first selection? I read Maugham J as saying provided there has been a reasonable attempt to find all the members having the advantage, the selection is not invalidated if the applicant misses a few members. That is an approach that recognises the difficulties of research. However, if it is known from the start that the selection is incomplete that logic would not be applicable. The question would depend on how similar the advantages of the first and second selection are.

Mr Catterns referred to Beecham's (Amoxycillin) Application as an example of a second selection. In that case selection was argued in relation to the issue of obviousness. It was accepted that the patent was a selection from the second patent of addition (page 293). However, there are no other selections from the second patent of addition discussed in the report. Even though the compounds in the second patent of addition are described as having particularly desirable properties in relation to the original patent, it is clear that there is no selection since it is a patent of addition. This case does not support Mr Catterns' argument.

The parties referred me to a range of standard texts on patent law. I have examined all of these sources and consider that there is no clear guidance on the subject of a second selection. I believe that the appropriate test is the same as for any selection. If the application satisfies the selection criteria, then it can proceed as a selection patent. However, serious consideration will need to be given to the third proposition, since prima facie the property is not unique to the selected members.

The advantage possessed by the selected members must be clearly disclosed in the specification:

"I must add a word on the subject of the drafting of the specification of such a patent. It should be obvious, after what I have said as to the essence of the inventive step, that it is necessary for the patentee to define in clear terms the nature of the characteristic which he alleges to be possessed by the selection for which he claims a monopoly. He has in truth disclosed no invention whatever if he merely says that the selected group possesses advantages. Apart altogether from the question of what is called sufficiency, he must disclose an invention; he fails to do this in the case of a selection for special characteristics, if he does not adequately define them. The cautions repeatedly expressed in the House of Lords as regards ambiguity have, I think, special weight in relation to selection patents."
[I.G. Farbenindustrie at 323]

The failure to disclose the advantage will mean that a selection cannot be argued on that basis. The advantage possessed by the compounds of the present application is that they are more active as anti-HIV agents. The evidence for this property is given in Table 1 of the specification (reproduced in Annex 3). This table shows that the b-D enantiomer is more effective than the b-L of ACPD. It seems reasonable to extrapolate that the b-D enantiomers of DAPD and DXG are similarly more effective. However, there is no data on whether these enantiomers would be superior to the compounds of the '786 patent.

There is a statement on page 28 of the specification, following Table 1, that indicates that enantiomerically pure b-D-DOT has a surprising advantage over the disclosure in the Norbeck article (referred to in the prior art discussed on page 2 of the specification):

"In contrast to the previous report that b-D-(±)-dioxolane-thymine has low efficacy against HIV in ATH8 cells, the enantiomerically pure b form 11 exhibited a potent anti-HIV activity (EC₅₀ = 0.3 mM). It was surprising to discover that enantiomerically pure b-D-(-)-dioxolane-T has significantly higher anti-HIV activity than the racemic mixture of the compound."

However, I can find nothing that is a comparison with the compounds of the '786 patent. I am not satisfied that the specification demonstrates any substantial advantage over the compounds in the '786 patent. Consequently, the present application is not a selection.

This is sufficient to dispose of the selection matter. However, I will deal with the other propositions of the selection test as I believe that there are further deficiencies. I will assume that the advantage is superior anti-HIV activity.

The second proposition is that all of the selected members possess the advantage. The difficulty is that there is no evidence of the activity of the compound b-D-APD. Given that this is an unexpected property allegedly possessed by only a small number of compounds, why is it reasonable to extrapolate from the compounds b-D-ACPD and b-D-DAPD to b-D-APD? Without a theory as to why the compounds have their advantage, the extrapolation to b-D-APD appears to be simple speculation. Is it reasonable to answer this by noting that it does not invalidate a selection if some of the selected members do not actually possess the property? The I.G. Farbenindustrie case suggests I should adopt this view, but it is worrying if there is a doubt over 1 out of 3 compounds. However, as there is no evidence that any of the selected members do not possess the advantage, as against a lack of evidence that the selected members possess the advantage, I am prepared to accept that the second proposition would be satisfied.

The third proposition is that the advantage is unique to the selected members. Here there is clear evidence that the property is not unique. The I.G. Farbenindustrie case states that it is acceptable if some additional members possessing the advantage are later discovered, provided the advantage is not possessed by a substantial number of the original class. The presence of two more members having the advantage does not invalidate the selection. However, the real difficulty is that the additional members were known before the present application was made. If the relevant property of the known compounds was not known, then it would seem reasonable to regard the advantage as new if the applicant identified it for the first time. However, if the relevant property of the known compounds was also known, then there is nothing new in the advantage. It is conceded by the parties that b-D-DXG and b-D-DOT were known to have an improved anti-HIV activity. Consequently, the advantage is not unique to the selected members as it was already known in connection with other members of the class. The application also fails the third proposition.

Since I have reached the conclusion that there is not a proper selection, it is not necessary to consider the further question of what degree of disclosure is necessary to anticipate a selection patent. I have not reconsidered the comments I made in the American Home Products decision.

Thus the present application is not a valid selection. The claims 1-6 are not novel in the light of the patent number 631786.

What is taught by 91475/91

Patent application number 91475/91 in the name of the Universities is entitled "Enantiomerically pure b-D-(-)-dioxolane nucleosides". The broadest aspect of the invention is given on page 5 of the specification:

"The invention as disclosed is an asymmetric process for the preparation of enantiomerically pure b-D-(-)-dioxolane-nucleosides. The process involves the initial preparation of (2R,4R)- and (2R,4S)-4-acetoxy-2-(protected-oxymethyl)-dioxolane from 1,6-anhydromannose, a sugar that contains all of the necessary stereochemistry for the enantiomerically pure final product, including the correct diastereomeric configuration about the 1 position of the sugar (that becomes the 4'-position in the later formed nucleoside)."
[lines 8 to 17]

The synthesis disclosed involves a Lewis acid catalysed condensation of a dioxolane moiety with a heterocyclic base to give stereochemically pure b-dioxolane-nucleoside. The base can be a purine (and guanine is specifically mentioned), but a thymine is preferred. The preparation of b-D-DOT is exemplified.

Dr Bennett argued that it was possible to mosaic the contents of 91475/91 with the contents of US 5041449. Australian patent application 91475/91 originated as an international application. When the Australian patent application was published, it was published in the form that it was published by the International Bureau of the World Intellectual Property Organisation. This document has an international search report attached to the end of the specification. The international search report is a report of a search of the invention carried out by an international searching authority (in this case, the United States Patent Office). It is important to note that the search report is a part of the Australian application as published, but it is prepared by the International Bureau and not by the applicant. One of the documents listed in the search report is "US, A, 5,041,449". This document is the equivalent of Australian patent number 631786. This document is identified as a category A,P document. Category A means the document defines the general state of the art and is not of particular relevance. Category P means the document was published before the international filing date of the application but after the priority date claimed.

Section 7(1)(b) permits the mosaicing of information in 2 documents if a person skilled in the art would regard them as a single source of information. Some guidance on mosaicing under the former Act is given in Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 16 IPR 545 at 570-571:

"Plainly, the degree of connection which is stated to exist in the documents themselves will be important. It is difficult to see how mere identification of prior patents as related or prior art would bring them sufficiently closely together for the purpose under consideration here. Again, even where there is a further description of the prior publication, it may nevertheless be that the purpose of the reference is to direct the reader away from it, as disclosing something outmoded or defective."

The fact that the search report was not prepared by the applicant does not mean that information in it cannot be used when considering a mosaicing question. The question is whether a reading of the document as a whole suggests a close connection with the second document. In this case the US document is categorised as an A document, which is not of particular relevance. This seems to me to be very similar to the suggestion in Nicaro v Martin of a reference that would direct the reader away. I think that the context of the reference to the US document is not such as to suggest that they should be regarded as a single source of information. Consequently I shall deal with the disclosure of 91475/91 on its own.

In the present case, it is admitted that b-D-DOT and b-D-DXG are disclosed in 91475/91. The evidence is that these compounds possess similar properties to the compounds of the present application. It did not seem to be suggested that this document taught compounds other than b-D-DOT or b-D-DXG. I agree. The disclosure of the nucleosides is too brief to teach the nucleosides of the present invention. Consequently 91475/91 does not disclose the compounds of the present application. The invention as claimed is novel in the light of this document.

Conclusion on novelty

Claims 1-6 are not novel in the light of patent number 631786.

OBVIOUSNESS

The particulars state that the invention claimed in all claims is obvious in the light of the common general knowledge. At the hearing there was also discussion that seemed to suggest that the claims are also obvious in the light of the documents raised under novelty.

Section 7(2) provides a definition of inventive step for the purposes of the Patents Act.

"(2) For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with either of the kinds of information mentioned in subsection (3), each of which must be considered separately.
(3) For the purposes of subsection (2), the kinds of information are:
(a)prior art information made publicly available in a single document or through doing a single act; and
(b)prior art information made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art in the patent area would treat them as a single source of that information;

being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area."
[The prior art base is defined in Schedule 1 of the Act.]

It is clear that inventive step is a matter that is presumed, unless it is demonstrated that the invention is obvious. The assessment of obviousness can be made against the common general knowledge alone, or the common general knowledge together with a document (or act) of the type covered by section 7(3). Section 7(3) documents must satisfy several requirements: the document must be publicly available inside or outside Australia (see the definition of "prior art base"); and the document would have reasonably been expected to have been ascertained, understood and regarded as relevant.

The normal approach to obviousness is the problem-solution approach: for instance, see Rhone-Poulenc Rorer S.A.'s Application [1995] APO 50. I note in passing that the problem-solution concept is evident in judicial decisions such as Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253 (e.g. at 298: "this solution to the known problem") and Winner v Ammar Holdings Pty Ltd (1993) 113 ALR 63 (e.g. at 67: "The problem and the solution were readily apparent"). Once the problem has been formulated, and the common general knowledge or prior art base has been determined, the question of whether the claimed solution is obvious must be addressed. The test for obviousness is whether it would have been a matter of routine to proceed to the claimed invention.

"It is still correct to say that a valid patent may be obtained for something stumbled upon by accident, remembered from a dream or imported from abroad, if it otherwise satisfies the requirements of the legislation. What is important is that the patent itself should involve an inventive step, whether or not it was consciously taken by the patentee and whether or not it appeared obvious to the patentee himself. 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."
[Wellcome Foundation Ltd v V.R. Laboratories (Aust.) Pty Ltd (1981) 148 CLR 262 at 286]

The question of what would be routine can be considered using the "obvious to try" approach. This approach is well explained in Beecham Group Ltd's (Amoxycillin) Application [1980] RPC 261 (which has been approved in Coopers Animal Health Australia Ltd v Western Stock Distributors Ltd (1986) 67 ALR 390 at 410 and W R Grace & Co v Asahi Kasei Kogyo Kabushiki Kaisha (1993) 25 IPR 481 at 492 - 494) at 290 - 291:

"It is clearly established that, for a particular step or process to be obvious for the purpose of either section, it is not necessary to establish that its success is clearly predictable. It will suffice if it is shown that it would appear to anyone skilled in the art but lacking in inventive capacity that to try the step or process would be worthwhile. Worthwhile to what end? It must, in my opinion, be shown to be worth trying in order to solve some recognised problem or meet some recognised need."
[citations omitted]

This approach suggests that an invention is obvious if it would have been considered well worth trying, with the likelihood of success being sufficient to warrant the actual trial. However, it must always be remembered that there is an unclear line between normal trial and error and an inventive step:

"However, the test of whether something was 'worth trying' involves questions of degree … If the expectation of success is sufficiently predictable, and the effort involved is not going to be very great, it may well be that there is no inventive step. On the other hand, if the expectation of ultimate success is doubtful and the effort involved is great, the person undertaking the work should be entitled to a monopoly. A patent monopoly is awarded, not to reward genius but to encourage the disclosure of information which is of value to the public in that it takes the store of knowledge ahead by the requisite 'inventive step'."
[ICI Chemicals & Polymers Ltd v Lubrizol Corp Inc (1999) 45 IPR 577 at 600-601, citations omitted]

The problem

The identification of the problem is the key first step in the problem-solution approach to inventive step. In the Rhone-Poulenc decision I decided that the problem can be formulated from a reading of the specification in the light of surrounding facts (see also my earlier decision in Biochem v Emory). If the problem is wrongly identified, then the rest of the inventive step analysis is inevitably wrong. Mr Catterns cautioned me to be careful in using the specification as a basis for identifying the problem because of the risk of incorporating the solution in the formulation of the problem. However, Mr Catterns agreed that the specification is a legitimate source of information relating to the problem.

I agree that care must be taken to ensure that the solution is not embodied in the problem. However, some regard must be had to the solution as the claimed invention must solve the problem as it is formulated. Clearly care needs to be exercised in this task.

I believe that the problem can generally be read out of the specification. For example, the explanation of the prior art and the stated problems that existed provide a reasonable starting point for the problem. Sometimes it may be necessary to look beyond the specification at the general state of the art, and what the declarants state were recognised problems in the art. However, care must be taken not to define the problem too narrowly, otherwise the solution will inevitably be obvious.

In the present case, the specification contains some very precise statements about the objects of the invention:

"As of the priority date of this application, a method of synthesis of a nucleoside analog with an oxygen in the 3'-position that results in an enantiomerically pure dioxolane nucleoside that has the same stereochemistry as the nucleosides found in nature (the b stereoisomer) has not been reported. There is a need for such a synthesis as a research tool to provide more information on the effect of stereochemistry on the anti-viral activity of nucleoside derivatives, and to provide new anti-HIV agents.
It is therefore an object of the present invention to provide a method of synthesis of enantiomerically pure dioxolane nucleosides.
It is another object of the present invention to provide enantiomerically pure dioxolane nucleosides with significant anti-HIV activity."
[page 4]

Looking at the claims as they stand, they are directed to a group of enantiomerically pure compounds, compositions containing those compounds and a treatment of HIV using those compounds. Clearly the emphasis of the invention claimed is different to the objects of the invention. Dr Bennett made submissions relating to the way that the invention changed during the prosecution of the application. It is regrettable that the description is not fully consistent with the claims. However, I believe that I can formulate a reasonable problem by recognising that the claims must be seen a solution to the problem, and not formulating the problem too narrowly.

The invention claimed is directed to compounds that have anti-HIV activity. The description is also concerned with anti-HIV activity. The description is focussed on dioxolanyl nucleosides, and on enantiomerically pure compounds. However, I believe that it would be incorporating too much of the solution to include these aspects in the problem. Consequently I believe that the problem relates to anti-HIV compounds. The next question is whether the problem should specify that the compounds should have greater anti-HIV activity than prior art compounds, or merely have useful anti-HIV activity.

The specification provides a table of data which indicates that some of the compounds of the invention are "potent anti-HIV agents" (page 26). However, it seems that the b-D-enantiomer of DOT is the most potent compound, but this compound is not one of the compounds claimed. This suggests that the problem is not to find superior anti-HIV compounds, but rather to find useful anti-HIV compounds.

It seems to me to be fair to frame the problem in the following terms:

To find a compound having useful anti-HIV activity.

Common general knowledge

The particulars of this ground refer to the relevant common general knowledge as:

"The common general knowledge is the knowledge of a person of skill in Australia as of 25 August 1992, as to how to resolve enantiomers of racemic mixtures of nucleosides."

I have discussed at length my reasons for considering that resolution by HPLC was a matter of routine. Consequently, I accept that this information is common general knowledge.

Given the nature of the problem, knowledge of resolution does not provide a solution unless there is also knowledge of the compounds that need to be resolved. The relevant compounds would be those in the '786 patent, and there is no evidence by declarants to show that this document was part of the common general knowledge. It is not possible to categorise this document as common general knowledge using the approach in Bristol-Myers v Faulding (see my discussion under MANNER OF MANUFACTURE below). Consequently, the challenge to inventive step based on the common general knowledge alone fails.

631786

Mr Catterns rightly pointed out that the particulars do not refer to obviousness in relation to this document. Strictly, this matter cannot be a part of the opposition. However, it is so closely related to the novelty issue and the broad discussion of obviousness, that I believe that it should be included in my decision. The parties addressed the matter in their submissions, and I do not believe that there is any procedural unfairness to the Universities. Imperfections in the process of particularisation can be adequately addressed under the issue of costs in this case.

This document discloses 1,3-dioxolane derivatives that are useful as antiviral agents. The treatment of AIDS-infected persons is specifically mentioned. The approach to determining whether a document would have been ascertained, understood and regarded as relevant that I have previously used is explained in Nippon Kayaku Kabushiki Kaisha and Sankyo Co Ltd v Rohm and Haas Co [1997] APO 40:

"A document would be ascertained if it was published in such a manner or form that it could reasonably have been expected to be found by a person skilled in the art. A patent document dealing with the same technical issues would prima facie have been ascertained by a person skilled in the art. The requirements of understood and regarded as relevant are not likely to be an issue where a document relates to the same art as the problem."

I consider that this approach is still appropriate. In the present case the citation is in the same technical field as the problem: compounds with anti-HIV activity. I am satisfied that it is appropriate for me to have regard to this document.

As explained previously under the heading of NOVELTY, this citation discloses that the compounds of the present invention are useful as anti-HIV agents. This provides a complete solution to the problem. It might be argued that the document does not disclose that it is the D-enantiomer that possesses the anti-HIV activity. The identification of which of two enantiomers possesses the most desirable biological activity is not an invention (see my decision in Rhone-Poulenc). Consequently the claimed invention lacks an inventive step in the light of this document.

There is no evidence before me on whether X groups other than hydrogen would be a matter of routine.

91475/91

This document was also not particularised, but for similar reasons to those above I will consider it. The document discloses specifically b-D-DOT and b-D-DXG as anti-HIV agents. I am satisfied that this document would have been ascertained, understood and regarded as relevant (for the same reasons as in '786 above).

The document does not suggest the three compounds of the present invention. The present invention would be obvious in the light of this document if it would have been a matter of routine to wish to prepare prodrugs of b-D-DXG. I have already decided that the evidence does not support this conclusion. Consequently the claimed invention is inventive in the light of this document.

Conclusion

The invention as claimed in all claims lacks an inventive step in the light of '786.

MANNER OF MANUFACTURE

The law on manner of manufacture has been examined in a number of recent decisions by Australian courts: the High Court in NV PhilipsGloelampenfabriken v Mirabella International Pty Ltd (1995) 183 CLR 655 and Advanced Building Systems Pty Ltd v Ramset Fasteners (Aust) Pty Ltd (1998) 194 CLR 171, the Federal Court in Bristol-Myers Squibb Co v FH Faulding & Co Ltd (2000) 46 IPR 553.

In the Bristol-Myers case, the majority summarised the effect of the Philips case as:

"Philips stands for the proposition (as a matter of construction of the 1990 Act) that if, on the basis of what was known, as revealed on the face of the specification, the invention claimed was obvious or did not involve an inventive step - that is, would be obvious to the hypothetical non-inventive and unimaginative skilled worker in the field (Minnesota at CLR 260 per Barwick CJ) - then the threshold requirement of inventiveness is not met."
[page 564]

It is clear that I must consider whether there is an inventive step in the light of what the specification states is known. What is known is not everything that is stated in the specification:

"Some elaboration, however, is required in relation to what the specification reveals as 'known'. If a patent application, lodged in Australia, refers to information derived from a number of prior publications referred to in the specification or, generally, to matters which are known, in our view the court - or the commissioner - would ordinarily proceed upon the basis that the knowledge thus described is, in the language of s 7(2) of the 1990 Act, part of 'the common general knowledge as it existed in the patent area'."
[Bristol-Myers at paragraph 30]

The assessment is based on the common general knowledge as it is presented on the face of the specification. If information is stated to be common general knowledge or can reasonably be inferred to be common general knowledge, then the Commissioner can accept that conclusion without any further evidence. It is not correct to say that every piece of prior art referred to in the specification is part of the common general knowledge.

The face of the specification admits certain information on pages 1-4. The US equivalent of Australian patent number 631786 (i.e. US 5041449) is mentioned in this discussion. I will quote in full the reference to this document:

"European Patent Application Publication No. 0 337 713 and U.S. Patent No. 5,041,449, assigned to IAF BioChem International, Inc., disclose that a generic formula of 2-substituted-4-substituted-1,3-dioxolanes exhibit antiviral activity."
[page 3]

The information on the face of the specification is extremely limited. There does not appear to be an assertion that this document is common knowledge. There is also a reference to the compound b-DOT:

"There has been recent interest in the synthesis of nucleoside derivatives in which the 3'-carbon of the nucleoside has been replaced with a heteroatom. Norbeck, D.W., et al., in Tet. Lett., 1989, 30, 6263, reported the synthesis of (±)-1-[(2b,4b)-2-(hydroxymethyl)-4-dioxolanyl]thymine (referred to below as (±)-dioxolane-T, see Figure 1), that results in a racemic mixture of diastereomers about the C4' atom. The product is a derivative of 3'-deoxythymidine in which the C3' atom has been replaced with an O3' atom. The product was synthesised in five steps from benzyloxyaldehyde demethylacetal and (±)-methyl glycerate to produce a 79% yield of the 1:1 diastereomeric mixture. The X-ray crystallographic analysis of the product revealed that the dioxolane ring adopts the ³T₄ conformation commonly observed in ribonucleosides, with the O3' atom in the endo position. Norbeck reported that the racemic mixture of dioxolane-T exhibits an anti-HIV activity of 20 mM in ATH8 cells, and attributed the low efficacy against the virus to an effect of the endo conformation of the O3' atom. Tetrahedron Letters 30 (46), 6246, (1989)."
[page 2-3]

The description of the Norbeck article suggests that this information is not part of the common knowledge. b-DOT is the compound that is closest to the compounds that are claimed. Since b-DOT is not disclosed as common knowledge, there is no indication of the type of compounds that are claimed. Even if I were wrong in this view, the description is actually stating that b-DOT has low efficacy against HIV, which would seem to run contrary to a lack of invention on the face of the specification.

An alternative argument was that the present invention is merely a new use (more effective HIV treatment) of known enantiomers of known racemates. This argument is based on the well known case of Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232. Microcell stands for the proposition that

"We have in truth nothing but a claim for the use of a known material in the manufacture of known articles for the purpose of which its known properties make that material suitable. A claim for nothing more than that cannot be subject matter for a patent, and the proposition cannot be affected either by the fact that nobody thought of doing the thing before, or by the fact that, when somebody did think of doing it, it was found to be a good thing to do."
[page 251]

I found that the individual enantiomers are known in the sense that they are not novel. The issue is whether this sufficient to make the enantiomers "known" in the sense that that term is used in the Microcell decision. I note that Microcell refers to the substances as "well-known" and the properties as "known generally". This seems to be suggesting something more than the public knowledge that is sufficient to establish lack of novelty. I note that a similar conclusion was reached in Warner-Lambert Co v WM Wrigley Jr Co [1996] APO 4. Consequently, I consider that the enantiomers in the present case are not known in the Microcell sense, so the challenge to the specification on this ground also fails.

CONCLUSION

The opposition is successful on the grounds of lack of novelty and lack of inventive step.

All claims are anticipated. I allow the Universities 60 days from the date of this decision to propose amendments to overcome the problems that I have identified.

I noted that there was no Notice of Entitlement from Emory University. During the preparation of this decision the Notice of Entitlement was amended to list the names of both of the applicants. This amendment was allowed by the Commissioner on 31 August 2000.

COSTS

The power of the Commissioner to award costs is based on section 210 and regulation 22.8. This power is discretionary, so I must take into account all relevant considerations.

The opposition succeeded on the major grounds of novelty and inventive step. It is appropriate to award costs against the Universities. I note that the success on the ground of inventive step was based on the patent document 631786, which was not included in the particulars, rather than on the ground as particularised. It is appropriate to discount the award of costs to take account of this deficiency by BioChem. Since only one of the two major, successful, grounds was properly particularised, costs should be reduced to half the normal entitlement.

I award half of the costs according to Schedule 8 against the University of Georgia Research Foundation, Inc and Emory University.

Dr S.D.Barker
Delegate of the Commissioner of Patents

Patent attorneys for the applicant : F.B. Rice & Co
Patent attorneys for the opponent : Cullen & Co

ANNEX 1: ABBREVIATIONS FOR DIOXOLANYL NUCLEOSIDES

Abbreviation	Name	Structure
ACPD	2-hydroxymethyl-4-(2'-amino-6'-chloro-purin-9'-yl)-1,3-dioxolane
b-ACPD	cis-2-hydroxymethyl-4-(2'-amino-6'-chloro-purin-9'-yl)-1,3-dioxolane
APD	2-hydroxymethyl-4-(2'-amino-purin-9'-yl)-1,3-dioxolane
b-APD	cis-2-hydroxymethyl-4-(2'-amino-purin-9'-yl)-1,3-dioxolane
DAPD	2-hydroxymethyl-4-(2',6'-diamino-purin-9'-yl)-1,3-dioxolane
b-DAPD	cis-2-hydroxymethyl-4-(2',6'-diamino-purin-9'-yl)-1,3-dioxolane
DOT or Dioxolane T	(2-hydroxymethyl-4-dioxolanyl)thymine
b-DOT	(cis-2-hydroxymethyl-4-dioxolanyl)thymine
DXG	2-hydroxymethyl-4-(guanin-9'-yl)-1,3-dioxolane
b-DXG	cis-2-hydroxymethyl-4-(guanin-9'-yl)-1,3-dioxolane

ANNEX 2: THE CLAIMS OF 670637

A method of treatment of HIV infection in humans, comprising administering an HIV treatment amount of an enantiomerically pure b-D-dioxolanyl nucleoside of the structure:

wherein R is NH₂ and X is selected from the group consisting of hydrogen, acyl, monophosphate, diphosphate, and triphosphate, or its pharmaceutically acceptable salt, and wherein the compound is at least 97% free of the corresponding b-L enantiomer.

A method for the treatment of HIV infection in humans, comprising administering an HIV treatment amount of an enantiomerically pure b-D-dioxolanyl nucleoside of the structure:

wherein R is H or Cl, and X is selected from the group consisting of hydrogen, acyl, monophosphate, diphosphate, and triphosphate, or its pharmaceutically acceptable salt, and wherein the compound is at least 97% free of the corresponding b-L enantiomer.

A pharmaceutical composition comprising an effective amount of an enantiomerically pure b-D-dioxolanyl nucleoside of the structure:

wherein R is NH₂ and X is selected from the group consisting of hydrogen, acyl, monophosphate, diphosphate, and triphosphate, or its pharmaceutically acceptable salt, and wherein the compound is at least 97% free of the corresponding b-L enantiomer, in a pharmaceutically acceptable carrier or diluent.

A pharmaceutical composition comprising an effective amount of an enantiomerically pure b-D-dioxolanyl nucleoside of the structure:

wherein R is H or Cl, and X is selected from the group consisting of hydrogen, acyl, monophosphate, diphosphate, and triphosphate, or its pharmaceutically acceptable salt, and wherein the compound is at least 97% free of the corresponding b-L enantiomer.

An enantiomerically pure b-D-dioxolanyl nucleoside of the structure:

wherein R is NH₂ and X is selected from the group consisting of hydrogen, acyl, monophosphate, diphosphate, and triphosphate, or its pharmaceutically acceptable salt, and wherein the compound is at least 97% free of the corresponding b-L enantiomer, in a pharmaceutically acceptable carrier or diluent.

An enantiomerically pure b-D-dioxolanyl nucleoside of the structure:

wherein R is H or Cl, and X is selected from the group consisting of hydrogen, acyl, monophosphate, diphosphate, and triphosphate, or its pharmaceutically acceptable salt, and wherein the compound is at least 97% free of the corresponding b-L enantiomer.

ANNEX 3: TABLE 1 OF THE SPECIFICATION

Table 1

R	Anomer	EC₅₀*
Cl	b-D	0.9
Cl	b-L	13.4
NH₂	b-D	0.7
OH	b-D	0.03

* Mean of at least 2 assays, using different donor cells. Standard error estimated at plus or minus 10%

NOTES:

1. "The EC50 is the concentration of compound at which there is a 50% inhibition of viral growth." (page 26 of the specification)

2. An amendment item dated 7 January 2000 proposes amending the EC₅₀ value for the first compound to 0.067.

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Citations

University of Georgia Research Foundation, Inc and Emory University v Biochem Pharma, Inc [2000] APO 68

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[2000] APO 68

8 November 2000