Emory University v Biochem Pharma Inc.

[1999] APO 50

OFFICIAL NOTICE

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Application  :          No. 658136 in the name of Emory University

Title:          Method and compositions for the synthesis of BCH-189 and related compounds

Action:          Opposition to the grant of a patent by Biochem Pharma Inc

Decision:          Issued 5 August 1999

Abstract

The opposition succeeds on the grounds of section 40, novelty and obviousness.

1. The allowability of further evidence must take into account the significance of the evidence, not just its relevance (page 5 - 6).

   Ferocem Pty Ltd v Commissioner of Patents (1994) AIPC 91-057; 28 IPR 243 and A Goninan & Co Ltd v Commissioner of Patents (1997) AIPC 91-330; 38 IPR 213 applied.

1. The specification discloses three methods of preparing enantiomerically enriched compounds.  The first method does not work because the tin chloride causes racemisation of the thioketal carbon (page 11).  The second method does not work because the butyryl ester is converted to an acetyl ester by DIBAL-H (page 13).  The third method is a variation of the second method using borohydride as the reducing agent.  This method might work, but requires a heavy burden of experimentation in order to work the process because there is no explanation of how to successfully carry out two key steps (page 15 - 16).

1. Section 40 matters

   ØImprecise terminology in the claims is clear as its meaning would be understood by a person skilled in the art (page 17).
   Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253 at 274 and Leonardis v Sartas No 1 Pty Ltd (1996) 35 IPR 23 followed.

   ØClaims defining the compound by reference to a name and a different structural formula did not lead to a lack of clarity.  The structural formula was precisely drawn, and was a simple derivative of the named compound.  The subject of the claim was the compound represented by the structural formula (page 18).

   ØClaims found to be not fairly based as the specification contains little information in relation to the invention, and this information is hidden within other misleading information (page 19 - 20).
   Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd (1987) 15 FCR 382 followed.

   ØThe specification does not fully describe the invention because the lack of detail places a burden of undue experimentation on a person seeking to work the invention (or alternatively, there is no enabling disclosure of the invention claimed) (page 23 - 24).
   Sami S. Svendsen Inc v Independent Products Canada Ltd (1968) 119 CLR 156 distinguished.
   Biogen Inc v Medeva plc (1996) 36 IPR 438 considered.
   Vidal Dyes Syndicate Ltd v Levinstein Ltd (1912) 29 RPC 245 applied.

   ØThe claims are construed in the context of the specification as a whole.  Consequently claims to a specific enantiomer must be understood as directed to that enantiomer free of the other enantiomer (page 25).
   International Business Machines Corp v Commissioner of Patents (1991) 22 IPR 417 applied.

1. Prior claiming

   The claims to the enantiomer take a deferred priority (consistent with the lack of fair basis of the claims) (page 27 - 28).

   Consequently the prior claiming documents are more appropriately considered under the ground of novelty.

1. Novelty

   Claims 25, 28 - 31 and 37 are not novel as a consequence of deferred priority.

   Enabling disclosure is a part of traditional English patent law, and thus is relevant to Australian patent law.  Enabling disclosure is a legitimate approach to the question of whether there are "clear and unmistakable directions" in the anticipation (page 30 - 32).
   Genentech Inc's (Human Growth Hormone) Patent [1989] RPC 613 and Asahi Kasei Kogyo KK's Application [1991] RPC 485 considered.

1. Obviousness

   Claims 26 and 27 are obvious.

   Obviousness was assessed using the problem-solution approach (page 36 - 39).
   Rhone-Poulenc Rorer S.A.'s Application [1995] APO 50 applicable.

   The evidence of experts only establishes that resolution could have been a matter of routine.  The evidence does not establish that it was a matter of routine to carry out a search of trade literature, or alternatively, it does not establish which trade literature it was routine to consult (page 45 - 46).
   Aktiebolaget Hässle v Alphapharm Pty Ltd [1999] FCA 628 referred to.

   The evidence of workers attempting to solve the actual problem is especially relevant (page 46).
   ICI Chemicals & Polymers Ltd v Lubrizol Corp Inc [1999] FCA 345 followed.

   ØIt was a matter of routine to try chiral HPLC, but it was not a matter of routine to achieve success (page 46, 49).

   ØEnzymatic resolution with esterase was not routine (page 50 - 51).

   ØEnzymatic resolution with other enzymes would have been more difficult as it requires chemical modification of the starting compound or the final compound (page 51 - 52).

   ØDiastereomer formation does not yield a useful level of enantiomeric enrichment (page 52 - 53).

1. Manner of manufacture

   The invention is a manner of manufacture.  Manner of manufacture is assessed on the face of the specification, and caution must be exercised when using extrinsic evidence to assess manner of manufacture (page 54 - 55).
   Advanced Building Systems Pty Ltd v Ramset Fasteners (Aust) Pty Ltd (1998) 152 ALR 604 followed.

   The Commissioner does not have an inherent power to refuse to grant a patent (page 56).
   Sami S. Svendsen Inc v Independent Products Canada Ltd (1968) 119 CLR 156 considered.

The applicant is given the opportunity to propose amendments to overcome the deficiencies identified.

PATENTS ACT 1990

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Re:Patent Application No. 658136 by Emory University, and an opposition to the grant of a patent by Biochem Pharma Inc

BACKGROUND

Patent application number 73004/91 was filed as an international application designating Australia (number PCT/US91/00685) on 31 January 1991 by Emory University (hereafter referred to as Emory).  The application claims priority from US 473318, which was filed on 1 February 1990.  The application was examined by the Commissioner, and advertised accepted under the serial number 658136 on 6 April 1995.

Biochem Pharma Inc (hereafter referred to as Biochem) lodged a notice of opposition on 19 May 1995, and served a statement of grounds and particulars on 21 August 1995.  A delegate of the Commissioner subsequently allowed several amendments to the statement (see Emory University v Biochem Pharma Inc (1996) AIPC 91-242; 33 IPR 466).

The present matter was heard in Canberra from 17 to 20 May 1999.  Emory was represented by Mr David Catterns QC instructed by Dr Bill Pickering and Dr Jenny Petering, patent attorneys of FB Rice & Co, Melbourne.  Mr Robert Baechtold of Fitzpatrick, Cella, Harper & Scinto, New York, USA, and Ms Sherry Knowles of King & Spalding, Atlanta, USA also made submissions.  Biochem was represented by Dr Annabelle Bennett SC and Ms Katrina Howard of counsel, instructed by Mr Ron Haliday and Dr Ken Finney, patent attorneys of Cullen & Co, Brisbane.  Mr Robert Krupka of Kirkland & Ellis, Chicago, USA and Mr Anthony Zelano of Millen, White, Zelano & Branigan, Arlington, USA also made submissions.  Dr Shona McDiarmid from Biochem, Dr Helen Quillin from Glaxo Wellcome plc, Mr Tony Muratore of Freehill, Hollingdale & Page, Dr Sebastian Marcuccio from CSIRO and Ms Kim O'Connell of Anderson Legal were also present.

THE RELEVANT LAW

The present action before the Commissioner is part of a global series of actions relating to family members of the present application.  Actions are also proceeding in the United States, Europe and Japan.  This reflects the global nature of the pharmaceutical industry.  However, the present action is brought under the provisions of the Australian patents legislation, and is determined solely by reference to the law applying in Australia.

Patent application number 658136 was lodged on 31 January 1991, advertised accepted on 6 April 1995 and a notice of opposition was lodged on 19 May 1995.  By virtue of subsections 234(2) and 234(3) the present opposition is governed by the Patents Act 1990 (Cth), except that Part V of the Patents Act 1952 (Cth) replaces Chapter 5 of the Patents Act 1990 (Cth). Consequently the grounds of opposition are those specified in the Patents Act 1952 (Cth).

The Commissioner should only refuse to accept an application when it is clear that a patent would be invalid.  This follows from cases such as McGlashan v Rabett (1909) 9 CLR 223, Stamp v WJ Powell Pty Ltd (1918) 24 CLR 339, Henry Berry & Co Pty Ltd v Potter (1924) 35 CLR 132 at 138, Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232 at 244 - 245 and Farbwerke Hoechst Aktiengesellschaft Vormals Meister Lucius & Bruning v Commissioner of Patents (1971) 45 ALJR 235 at 239. Consequently, the opponent has the responsibility of bringing forward evidence to satisfy the Commissioner that a valid patent would not issue.

GROUNDS OF OPPOSITION

The statement of grounds and particulars specifies five grounds of opposition:

Øsection 40 matters

Øprior claiming

Ønot novel

Øobviousness

Ømanner of manufacture

EVIDENCE

Extensive evidence has been produced by both parties, and I will refer to the relevant parts of the evidence where appropriate to my decision.

Biochem completed its evidence in support on 21 November 1995.  Emory completed its evidence in answer on 17 June 1996.  Biochem completed its evidence in reply on 24 January 1997.

Further evidence

On 4 March 1997 Emory applied to serve further evidence.  A Deputy Commissioner allowed the application (see Emory University v Biochem Pharma Inc (1997) 39 IPR 603), and the further evidence was completed on 29 January 1998. Biochem completed evidence responding to the further evidence on 10 August 1998.

On 28 January 1999 Emory filed a copy of the European patent corresponding to the present application (EP 0513200).  The Patent Office regarded this document as (second) further evidence.

On 7 May 1999 Emory applied to serve additional (third) further evidence.  The Assistant Opposition Officer advised the parties on 10 May 1999:

"Given that the substantive hearing is scheduled for 17-21 May 1999, there is insufficient time for the Commissioner to formally process the further evidence application before the hearing.  Therefore, the application will be dealt with at the substantive hearing by the hearing officer.  If the opponent has any objection to the application for leave to serve further evidence, they can raise them at that stage.

If the hearing officer considers that the application for leave to serve further evidence should be allowed, he may impose terms for granting leave.  For example, if leave was granted, it may be subject to the terms that the opponent will have one month to provide evidence in response.  Such terms will be discussed with the parties at the hearing.

At the hearing, the hearing officer will also determine how the parties provide submissions on the further evidence, if this further evidence is allowed.  It may be appropriate, for example, to provide the parties with an opportunity after the hearing to provide submissions based on further evidence and any evidence in response."

At the opening of the hearing, there was no objection to the third further evidence, and I allowed Biochem to serve responding evidence, which they provided at that time.  Objection was taken that some of the response evidence was not actually in response to matters in the further evidence.  Dr Bennett agreed that the "Invention Disclosure" of Dr Liotta and an article from the Journal of Medicinal Chemistry were not strictly responsive.  Since these pieces of evidence were not responsive, I directed that they were not part of the evidence for the opposition.

On the second day of the hearing, Biochem applied to serve further (fourth) further evidence.  This evidence consisted solely of the Invention Disclosure document mentioned above.  After studying the evidence I indicated (on the third day) that it was not apparent on the face of the document that it was sufficiently significant to justify admitting the document.  Dr Bennett made submissions on the admissibility of the evidence.  Mr Catterns chose not to make any submissions.  On the fourth day I refused the application for further evidence, and stated that full reasons would be given in my decision of the substantive matter.  My reasons are as follows.

Further evidence is governed by regulation 5.10.  The relevant subregulations state:

(4)  The Commissioner may:
  (a)  on the application of a party;  and
  (b)  on such reasonable terms (if any) as the Commissioner specifies;
permit the party to serve further evidence on the other party.

(5)  The Commissioner must not give a direction under subregulation (1) or grant an application under subregulation (2) or (4) unless the Commissioner:

(a)if he or she proposes to grant an application by a party - is reasonably satisfied that the other party has been notified of the application;  and

(b)if he or she proposes to act on his or her own motion - ensures that the parties are notified of the proposed action;  and

(c)in either case:

(i)gives the parties a reasonable opportunity to make representations concerning the application or proposed action;  and

(ii)is reasonably satisfied that a direction, an extension of time or the serving of further evidence is appropriate in all the circumstances.

In the circumstances, I am satisfied that Emory has been notified, and the parties have had a reasonable opportunity to make representations on the further evidence.  The only question is whether I am satisfied that it is appropriate to allow the serving of the further evidence.  In exercising this discretion I am guided by the decisions of Burchett J in Ferocem Pty Ltd v Commissioner of Patents (1994) AIPC 91-057; 28 IPR 243 and Sackville J in A Goninan & Co Ltd v Commissioner of Patents (1997) AIPC 91-330; 38 IPR 213 on the operation of regulation 5.10(5) in relation to extensions of time. The general principles that flow from these decisions are:

a)The power is discretionary:    Regulation 5.10 confers a broad discretion, which cannot be reduced to imperative compliance with particular requirements.  It is necessary to give genuine and proper consideration to all relevant considerations.  (Ferocem at AIPC 38,208; IPR 247-8,  Goninan at AIPC 39,434; IPR 220)

b)Explanation of delay:             The reasons why the evidence was not served earlier are a relevant consideration, but a satisfactory explanation is not a mandatory requirement.  (Ferocem at AIPC 38,207-8; IPR 247)

c)The public interest:                The public interest in determining a serious opposition on its merits is a relevant consideration.  (Goninan at AIPC 39,435-6; IPR 222)

·         In order to do this, it is necessary for the Commissioner to form a view as to the nature of the evidence that it is sought to adduce, and the significance of that evidence for the opposition proceedings.  (Goninan at AIPC 39,438; IPR 225-6)

·         The public interest is not protected merely because some evidence has already been served.  (Goninan at AIPC 39,438; IPR 225)

d)The interests of the party seeking the exercise of discretion:            The interests of the party seeking the exercise of discretion are a relevant consideration.  (Ferocem at AIPC 38,208; IPR 247)

e)The interests of other parties:            It is relevant to consider the disadvantage to the other party of delays in determining the opposition, and the effect of delays on the efficient and orderly administration of the Patents Office.  (Ferocem at AIPC 38,208; IPR 247,  Goninan at AIPC 39,436; IPR 222)

These considerations seem equally relevant to the determination of the present request for further evidence.  Previous decisions of the Commissioner on further evidence illustrate different aspects of these considerations, but do not represent binding rules.  It also follows from the words of regulation 5.10(5) that, before allowing a party to serve further evidence, I must be satisfied that allowance is appropriate.

The application for further evidence states:

"It has been Emory's position throughout the opposition that its '136 application disclosed for the first time, methods for resolving the enantiomers of BCH-189.  This position has been refuted by BioChem Pharma in the evidence it has filed to date.

However, further evidence, which further refutes Emory’s position, is now available following Emory’s successful application to have Judge Tidwell's protective order for the confidential documents in a related US proceeding altered in respect of those documents to enable their unfettered use in these proceedings.  The decision relating to the documents is dated 19 April 1999 and has been the basis for Emory also applying to adduce additional evidence in these proceedings.  The evidence was not available for production by BioChem Pharma prior to the removal of the protective order.

The further evidence which BioChem Pharma seeks to adduce is an INVENTION DISCLOSURE made by Dennis Liotta, the inventor of the '136 application, to Emory University on 15 May 1991 stating, inter alia, that the priority US application does not disclose any methods for the preparation of enantiomers of BCH-189 and alleging that he had now found such methods."

The evidence is a single document headed "INVENTION DISCLOSURE APPROVAL SHEET".

1. Explanation of delay

The document in evidence was originally confidential by order of a United States court, but is now able to be used without fetter.  This to some extent explains why the evidence was not presented earlier.  While it may have been possible to provide the document earlier (in the same way that other confidential evidence was handled), I do not consider there has clearly been unreasonable delay by Biochem.

1. Nature and significance of the evidence

   The document in evidence appears to be an internal document of Emory, apparently part of the preliminary processes of deciding whether to apply for a patent.  It is not apparent what purpose the document serves within Emory, or the legal significance that attaches to this type of document.

   The relevant part of the document is a statement that (at the date of 15 May 1991 which appears on the document) "No methods for preparing the enantiomers of these compounds exist."  It is clear from other references in the document that this includes US 473318, which is the basic document of the present application.  It is stated in the application for further evidence that this evidence is relevant to the construction of the present application, especially on the question of whether it teaches preparation of the enantiomers.

   I agree that this document is relevant to the construction of the specification.  However, I do not consider it is significant on this point.  At the time of making the request I had already received detailed submissions from Dr Bennett on the construction of the specification, including references to the extensive evidence already on file.  Further, it is not in dispute that the specification does not exemplify a method of preparing enantiomers (see the main decision below).  The new evidence seems to be just more evidence on a point that is either not in dispute, or has already been the subject of extensive submissions.  Viewed in this light, this bare statement of uncertain weight is of low significance to the proper determination of the construction of the patent.

2. The interests of Biochem

   The interests of Biochem lie in favour of having available evidence to support their case.  However, given that the particular evidence is of low significance, Biochem's interest is similarly low.

3. The interests of Emory

   Dr Bennett submitted that Emory would not be taken by surprise as the evidence is a document of Emory's.  Mr Catterns made no submissions.  I take it from this that Emory’s interests are a minor consideration in this matter.

1. Public interest

   The public interest in a correct determination of this opposition also mirrors the low significance of the evidence.

2. Interests of the Patent Office

   The interests of the Patent Office in the orderly processing of matters before the Commissioner are a minor consideration in this matter, and rank behind the interests of the parties.

3. Other relevant considerations

   I am not aware of any other relevant considerations, and none were brought to my attention.

I consider that the significance of the evidence is an important consideration in this case.  On balance, it is clear that a case justifying the exercise of my discretion in favour of Biochem has not been made out.  I refuse the application to serve further evidence.

Confidential evidence

Emory wished to serve as evidence 17 documents that were found as a result of discovery in related proceedings in the US Federal District Court for the Northern District of Georgia.  An initial attempt to have these documents treated as confidential before the Commissioner was unsuccessful in the Federal Court (see Emory University v Commissioner of Patents (1998) AIPC 91-392). Following a change to regulation 4.3 of the Patent Regulations, Emory obtained an order from the Commissioner for Biochem to produce those documents, and a determination under regulation 4.3(2)(b) that they were documents prescribed for the purpose of section 55 (i.e. the documents are not open to public inspection, and are thus held on a confidential basis) (see Emory University v Biochem Pharma Inc (1998) 43 IPR 118). The documents were produced on 12 October 1998, and regulation 4.3(2)(b) was invoked by a Deputy Commissioner. The documents were introduced into evidence by Emory.

Biochem served evidence responding to the confidential evidence on 5 February 1999.

At the hearing Emory stated that the protective order placed on these documents by the US court had been lifted, so it was no longer necessary to keep these documents confidential in the present action.  I stated that the confidential nature of these documents in the present proceedings derived from the operation of regulation 4.3(2)(b) and not from the US court.  Dr Pickering undertook to apply to have the order under regulation 4.3(2)(b) removed.  The order was removed on 3 June 1999.  Consequently, this decision includes discussion of the confidential evidence.

SUBMISSIONS

One of the unusual aspects of this case was that overseas attorneys were involved in the hearing, and made submissions at the hearing.

The role of overseas attorneys

On 20 March 1997 Emory sought leave for two US attorneys to be allowed to make submissions during the opposition hearing.  This matter was decided by a Deputy Commissioner of Patents (in Emory University v Biochem Pharma Inc (1997) 39 IPR 603) and subsequently reviewed by the Federal Court (in Biochem Pharma Inc v Commissioner of Patents [1998] 184 FCA).  Hill J dismissed the application for review.  Consequently the conduct of the hearing was guided by the conclusion of the Deputy Commissioner.

"In summary, I believe the Commissioner does have a discretion to allow unqualified persons to make oral submissions at a hearing.  However the Commissioner will insist upon a single person being responsible for the conduct of the case for a given party.  This would generally be counsel or a patent attorney who will ensure submissions by unqualified persons are properly made.  Furthermore, when more than one person is to make submissions on behalf of a party, I do not believe the Commissioner's discretion should be exercised automatically.  It should only be exercised where there is a perceived benefit to the outcome of the hearing and consequently I believe this would be when the submissions would facilitate the understanding of the issues by the Hearing Officer."

I also took note of Justice Hill's additional qualification that the hearing officer must

"ensure that the role of the United States attorneys does not expand to such an extent that they can be said to 'conduct' the proceedings"

I informed the parties that the overseas attorneys should not make their submissions whenever they (the overseas attorneys) liked, but only under the supervision of their Australian counsel.

The submissions of the parties

Dr Bennett made submissions on the subjects of construction of the specification, prior claiming, novelty, section 40, obviousness and manner of manufacture.  Mr Krupka provided submissions in relation to the documents that were originally ordered confidential.  Ms Howard made submissions on obviousness. 

Mr Catterns addressed all of these matters in his submissions in answer.  Mr Baechtold and Ms Knowles made submissions on US patent law and addressed issues arising out of the confidential documents. 

Submissions in reply included submissions on US patent law by Mr Zelano.

On the last day of the hearing Dr Bennett provided a number of summaries of the evidence.  I allowed Mr Catterns 2 weeks to file a document summarising the evidence that answered these matters.  This document was filed on 3 June 1999.

THE SPECIFICATION

Before dealing with the substantive issues in this opposition it is necessary to carefully consider the description and the claims of the specification.  The description appears to be straight forward as a matter of construction of the text, but there is a significant difference on the question of what the description discloses as a matter of fact.

The description

The present patent application relates to the compound 2',3'-dideoxy-3'-thiacytidine.  The specification indicates that this compound is known as BCH-189.  However, it is apparent from the evidence as a whole that in this art BCH-189 is the designation given to the b isomer of this compound, in which there is a cis arrangement of the groups on the ring.  (See Figure 1;  it should be noted that while the ring substituents are shown above the ring, this only represents the relative stereochemistry.)  It follows that the terminology "b-BCH-189" (which is used throughout the specification) is technically inaccurate because the "b" is redundant, and that "b-BCH-189" is the same as "BCH-189".  This inaccuracy leads to inconvenience rather than ambiguity in the description.  In this decision I will use the designation BCH-189 in the normal way, i.e. as a shorthand reference to the b isomer of 2',3'-dideoxy-3'-thiacytidine.

BCH-189 has two chiral carbon atoms in its chemical formula, so exists in the form of two enantiomers (or optical isomers) which are mirror images of each other.  The enantiomers are designated as either (+) or (-), depending on how they rotate the plane of polarised light.

The two enantiomers are represented by the formulae shown in Figure 2, which includes the identification of the (+) and (-) enantiomers.  This information is not disclosed in the specification, but is now known in the art (for instance, Coates et al, Antimicrobial Agents and Chemotherapy, 1992, 36, 202;  Exhibit RFE 14 of the Evans declaration in support).

It is not in dispute that BCH-189 was first disclosed at the Fifth International Conference on AIDS held in Montreal between 5-9 June 1989.  Abstract T.C.O.1 of that Conference by Belleau et al refers to the compound and the fact that it is a promising drug candidate for use against AIDS.  The specification admits that BCH-189 was known to possess anti-HIV activity similar to that of the well known nucleoside analogs AZT (3'-azido-3'-deoxythymidine) and DCC (2',3'-dideoxycytidine), but without the toxicity associated with those compounds (page 4, lines 24-27).

Consequently there was a need for sufficient quantities of BCH-189 to allow clinical testing (page 4, lines 27 - 29).  In addition, it is admitted that it is only the b isomer of these types of compounds that exhibits useful biological activity (page 5, lines 4 - 5).  It was also expected that one enantiomer will be inactive (page 6, lines 12 - 13).  It is now known that this is incorrect -  the two enantiomers are equipotent, but one of the isomers is less toxic than the other.  [This is revealed in AU 651345 at page 2, lines 4 - 10 (Exhibit RFE 13 of the Evans declaration), and Coates et al, Antimicrobial Agents and Chemotherapy, 1992, 36, 202 (Exhibit RFE 14 of the Evans declaration).]  This is an understandable error based on the fact that often one isomer is more active than the other.

The specification states that the invention relates to the selective synthesis of the b isomer of 2',3'-dideoxy-3'-thiacytidine (i.e. BCH-189) and related compounds, and the synthesis of enantiomerically enriched BCH-189 and related compounds (page 1, lines 9 - 12).  The related compounds have different pyrimidine groups attached to the oxathiolane.  The specification also relates to intermediates in which the hydroxymethyl group is protected (page 8, lines 4 - 34), as well as intermediates without the pyrimidine group (page 7, line 30 to page 8, line 2).  The specification also states that it relates to enantiomerically enriched BCH-189.  (Figure 4, and the text that relates to this Figure;  e.g. page 9, lines 14 - 16, page 18, line 18 to page 21, line 20.)

Before dealing further with the specification it is necessary to comment on the term "enantiomerically-enriched" or "enantiomerically enriched" (the two terms being synonymous).  The declarants Marcuccio, Evans, Mander, Longmore and Danylec give conflicting views on the meaning of this term.  At a literal level, this term means that the material is enriched in one of the enantiomers.  This is exemplified in the declaration in support of Dr Evans (at para 8.3, for instance):

"Strictly speaking, the term 'enantiomerically-enriched' means no more to me, and I believe to others of skill in the art, than a mixture that is not a perfect 50/50 mixture of the two enantiomers.  For example, an enantiomerically-enriched preparation could be a 51/49 mixture of the two enantiomers."

This means anything from a 51/49 mixture to a 100/0 mixture would be enantiomerically enriched.  However, the specification cannot be read in a void.  Enantiomeric enrichment must be viewed in the context of the relevant art.  The specification relates to the stereocontrolled synthesis of compounds that have a pharmaceutical relevance.  I believe that the enrichment that is referred to should be assessed as a level that is useful in the art.  Professor Mander stated in his declaration in answer (at para 8.2):

"When I read the specification and claims of Application No 658,136, I understand the term 'enantiomerically enriched' to mean a significant enrichment in one of the enantiomers."

Mr Danylec stated in his declaration in answer (at para 11):

"I have been asked to comment on my interpretation of the meaning of the term 'enantiomerically enriched'.  I believe that this term clearly refers to a chemical composition that is significantly enriched with one enantiomer of a racemate.  The term is actually self-defining."

Enrichment of less than 90%, for instance, would probably not be useful.

Turning now to the detail of the description, there is considerable difficulty in determining what method of preparing enantiomers of BCH-189 is disclosed.  The specification discloses three methods of preparation, each of which has deficiencies:

Øthe first method is the method that is explicitly exemplified;

Øthe second method is an alternative method that is not exemplified;  and

Øthe third method is a variation on the second method using borohydride as the reducing agent.

1. The first method

The specification describes in detail the preparation of BCH-189 and analogs exclusively in the b arrangement by reference to three exemplified syntheses.  The general approach is shown in Figure 1 of the specification and the specific syntheses are shown in Figures 2 to 4 (Figures 1 and 4 are reproduced in Annex 1 of this decision).  The key feature of all these syntheses is that the coupling of the oxathiolane to the pyrimidine using tin chloride leads exclusively to the b isomer.  This is the basis of the selective synthesis of BCH-189.  In relation to Figure 1, the specification goes on to state:

"This procedure can be tailored to produce BCH-189 or BCH-189 analogs that are enantiomerically-enriched at the 4' position by selecting an appropriate R protecting group to allow stereoselective enzymatic hydrolysis of 3 by an enzyme such as pig liver esterase, porcine pancreatic lipase, or subtilisin or other enzymes that hydrolyze 3 in a stereoselective fashion.  The resulting optically active 3 can be converted to enantiomerically-enriched carboxylate 4 and coupled with a silyated pyrimidine base as above to produce enantiomerically-enriched BCH-189 or BCH-189 analogs."

[page 10, lines 4 - 15]

Enantioselective hydrolysis of 3 is not exemplified.  The worked examples of the invention further state:

"Fig. 4 illustrates the synthesis of enantiomerically-enriched BCH-189 and its analogs.

[page 18, lines 18 - 19]

The specification clearly teaches that the enzymatic hydrolysis of 24 to 25 using pig liver esterase yields enantiomerically enriched 25 (page 19 - 20), which is then converted to enantiomerically enriched BCH-189 (page 20 - 21).

Dr Liotta, who is listed as an inventor of the present invention, comments on this matter in his declaration in answer.

"7.  Of the two synthetic schemes illustrated in Scheme 1, our group initially focused its effort on Route A [which is essentially the Figure 4 process], because it appeared to be a more efficient process.  After numerous experiments, which included the evaluation of various enzymes, we identified a synthetic reaction route that included the use of pig liver esterase, porcine pancreatic lipase, or subtilisin, to resolve the ester of 2-hydroxymethyl-5-oxo-1,3 oxathiolane, followed by condensation of the desired resolved enantiomer of the 1,3-oxathiolane with a cytosine base in the present (sic) of tin chloride.  This is one of the methods disclosed in the present application.

8.  After a number of person-months of research on this method, and after filing the parent application of this application, it was discovered that the method does not work, because the tin chloride used to condense the 1,3-oxathiolane with the base caused racemization of the resulting nucleoside."

Consequently it is now clear that the process of Figure 4 of the specification does not produce enantiomerically enriched BCH-189.  Surprisingly, Emory have not chosen to correct the erroneous statements in the specification.  The skilled addressee seeking to work the invention would have tried the Figure 4 process, because that is indicated to be the preferred method.  It was suggested that the skilled addressee would then have moved on to the second method (discussed below).  A skilled addressee would be likely to abandon the Figure 4 process for the second process if they realised that their lack of success was due to the impossibility of the method rather than poor technique.  In my experience it is not uncommon to repeat unsuccessful reactions, making routine variations to the process, to try and obtain success.  It is likely that the skilled addressee would have eventually recalled that acids cause thioketals to open (and thus racemise), and that tin chloride is a Lewis acid.  At this point the skilled addressee would have passed on to the second method -  but their experience would leave them suspicious.

1. The second method

The only reference to the second method in the specification as accepted is in the passage of text bridging pages 10 and 10a.  (Pages 10 and 10a are reproduced in Annex 2 of this decision.)  The meaning of this passage was discussed extensively at the hearing.  Detailed and differing analyses of the individual words of the text were pressed on me by the parties.  I do not think that a fair reading of this paragraph is achieved by dissecting the text.  Rather the paragraph should be read as a whole, in the context of its position in the total text, in order to appreciate its meaning.  It is clear that the text refers back to the process illustrated in Figure 1 because of the references to compounds 1, 5 and 6.  The sentence starting "Additionally" indicates that the protecting group R could be "an additional recognition site for an enzyme to be used later in an enantio-selective hydrolysis reaction".  While the word "additional" seems to be poorly chosen, the essence of this sentence is that the R group can be a group that is capable of enantioselective hydrolysis by an enzyme.  The word "later" is also poorly chosen, but it seems reasonable to read the later hydrolysis reaction as a deprotection of 5 to 6.  I am satisfied that the simple meaning of this paragraph is that the R group can be selected so that it can be removed by enzymatic hydrolysis of 5 to 6.  This is the second method of preparing enantiomerically enriched BCH-189.

I was invited to use the text of the specification before amendment as an aid to construction (as allowed by section 116).  I do not find it necessary to do so.

The specification contains no examples of enzymatic hydrolysis of a compound of formula 5.  There is, however, an example of hydrolysis of the butyrate ester 24 using pig liver esterase.  This yielded optically active butyrate 24 (40%) with an enantiomeric excess of 40%, and the alcohol 25 with unspecified enantiomeric excess.  It is reasonable to assume that the alcohol 25 is also produced with an enantiomeric excess of 40%.

Thus the details of the second method of preparing BCH-189 are inferred from the specification rather than given explicitly.  It is this absence of specific detail which gives rise to the dispute in the present case.  I consider that the second method has the following general steps:  the compound 1 is protected with a butyryl group;  the protecting group is left on, and 1 is converted to 5 using the process in Figure 1;  and the compound 5 is enantioselectively hydrolysed to give 6.  Prima facie, this method will yield BCH-189 when the group Y is hydrogen.

A key element in the second method is that the R group remains intact from compound 1 to compound 5.  In this regard, the conversion of 3 to 4 is a problem step.  The conversion is by reduction followed by acylation.  The process is explained as:

"The lactone 3 is treated with a reducing agent;  for example, diisobutylaluminum hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminum hydride (that can be commercially purchased as a 3.4 molar solution in toluene, referred to as 'Red-Al'™), and NaBH₄, followed by a carboxylic anhydride, to produce the carboxylate 4."
[page 9, lines 30 - 36]

The lactone 3 in which R is butyryl is the compound 24.  The specific reduction and acylation of 24 taught would probably be by the process that converts 25 to 26, i.e. reduction by DIBAL-H (which is the normal abbreviation for diisobutylaluminum hydride) and acylation with acetic anhydride (page 20, lines 10 - 26).  Mr Zelano stated from the bar table that this process also converts the butyryl ester group to an acetyl ester.  This is a key point, so I will quote his words exactly:

"when you look at the conditions that Emory describes for what would be the next step, reduction of compound number 24 to the diprotected compound, when you look at that step, they apply a certain reducing agent, DIBAL, of certain conditions, in combination with acetic anhydride, then I submit if you do that to the butyrate you wind up with an acetyl group"

While this is probably evidence on a technical matter (despite the use of the words "I submit"), it was not objected to, and its accuracy was not disputed.  Instead, Ms Knowles submitted that the acetate form of 5 could still be used to produce BCH-189 (see next paragraph).  The reducing properties of DIBAL-H are a matter within my personal knowledge as a person trained in chemistry.  Once this matter was brought to my attention, it was clear to me that DIBAL-H would be expected to reduce the butyrate ester to the alcohol, and I would take notice of the reducing properties of DIBAL-H if there were any objection to this evidence.  I accept that the compound of formula 4 that would be produced would have R = R' = acetyl, and the compound of formula 5 that would be produced would have R = acetyl.  The selected R group (i.e. butyryl) would not remain in place until it is enantioselectively hydrolysed.

Clearly this version of the second method would not produce the compound 5 that is alleged.  Ms Knowles stated that the acetate form of 5 could be converted to the butyrate.  This is probably correct, but it is not the process asserted in the specification.  Equally, the acetate of 5 could be subjected to enantioselective hydrolysis, but this is also not the process asserted to be the second method.  [I note that the acetate of 5 would be compound 3a of the article "Enzyme-Mediated Enantioselective Preparation of Pure Enantiomers of the Antiviral Agent 2',3'-Dideoxy-5-fluoro-3'-thiacytidine (FTC) and Related Compounds" by Hoong et al in Journal of Organic Chemistry, 1992, 57, 5563, which is Exhibit RFE-17 of the Evans declaration in support.  Hoong did not subject 3a to hydrolysis with an esterase (see Table II), so it is not apparent whether enantioselective hydrolysis of this compound is possible.  Comparison with the acetate 4a suggests that the enantiomeric enrichment might not be useful.]

I note that Emory's later patent application number15617/92 (now sealed as 665187) discloses the reduction of the butyryl ester of 3 using lithium tri-tert-butoxyaluminohydride.  While this is not confirmation that DIBAL-H will reduce the ester group, it is interesting that DIBAL-H is not used.

1. The borohydride version of the second method

The second method fails in the reduction step.  The general description also refers to carrying out the reduction of 3 using sodium borohydride (NaBH₄).  Sodium borohydride would not be expected to reduce the butyrate, so the compound 5 that would ultimately be produced should have the butyryl group intact.  I consider that the specification discloses a method that might prepare enantiomerically enriched BCH-189.  It is not possible to say whether the method would produce that material as it was not carried out.

The specification also refers to carrying out the reduction using Red-Al.  I do not know whether Red-Al would reduce the ester, so I will apply the benefit of the doubt in favour of Emory and assume it does not.  Consequently the specification also discloses a method involving a Red-Al reduction which could prepare enantiomerically enriched BCH-189.  For simplicity, I will refer to the method as the borohydride method, but it must be understood that this includes the alternative use of Red-Al.

The specific method of preparing enantiomerically enriched BCH-189 that is disclosed by the specification is:

i)the compound 1 is protected with the R group butyryl;

ii)the protecting group is left on and 1 is converted to 5 using the process in Figure 1;

iii)the conversion of 3 to 4 is carried out using NaBH₄ (or Red-Al) as the reducing agent;  and

iv)5 is enantioselectively hydrolysed to give 6.

This method is represented diagrammatically in Figure 3.


Having determined that the specification discloses the borohydride version of the second method of preparation of enantiomerically enriched BCH-189, I must determine the support for that method that is presented in the specification.  Apart from the matters already discussed as the basis for the inference that the second method exists, I note that Figure 4 discloses the preparation of the lactone 24 (which is the key intermediate).  The reduction using NaBH₄ (or Red-Al) is not exemplified, or discussed in the specific terms.  The attachment of the pyrimidine group to oxathiolane rings with different protecting groups is exemplified in Figures 2-4 (i.e. the conversion of 4-type compounds to 5-type compounds).  The enzymatic hydrolysis of an ester group is exemplified in Figure 4 (conversion of 24 to 25).

The butyryl ester of 5 can be successfully subjected to enantioselective hydrolysis.  This fact is not found in the specification, but in the article "Enzyme-Mediated Enantioselective Preparation of Pure Enantiomers of the Antiviral Agent 2',3'-Dideoxy-5-fluoro-3'-thiacytidine (FTC) and Related Compounds" by Hoong et al in Journal of Organic Chemistry, 1992, 57, 5563 (Exhibit RFE-17 of the Evans declaration in support;  Table II on page 5564 is particularly relevant).  However, it was pointed out that the enzymatic hydrolysis reaction carried out by Hoong utilised acetonitrile as a cosolvent.

"CH₃CN was included to facilitate the solubility of the substrate in the buffer.  If the reactions were performed under nonhomogenous conditions, the enantioselectivities were much lower (ca. 40% ee) and difficult to reproduce.  These results suggest that under nonhomogenous conditions the rate of dissolution was rate determining such that the substrate/enzyme ratio was much smaller, thereby negating the enzymes' inherent kinetic preference for one of the enantiomers.  Indeed, in the case of pivalate and valerate esters, the low solubility of these esters required either additional amounts of CH₃CN and/or further dilution of the reaction mixture to effect complete solubility.  This problem was compounded by a significant reduction of enzyme activity with greater than 25% (v/v) CH₃CN."
[Hoong, page 5565, column 1;  references omitted]

The patent specification makes no reference to a cosolvent.  This suggests that even the borohydride version of the second method does not work, as it produces an inadequate enantiomeric enrichment.  It seems that the use of a cosolvent is essential in order for the enzymatic hydrolysis to produce a useful enantiomeric enrichment (i.e. of the order of 90% ee, rather than the 40% obtained without acetonitrile), and that the role of the cosolvent is exactly that -  to ensure that the lactone dissolves in the solvent system.  It was submitted that the person skilled in the art would use a cosolvent as a matter of routine if they found that the lactone did not dissolve.  This submission is essentially a statement of common sense for an organic chemist.  Dr Easton commented on this point (in his declaration in answer at para 18):

"Enzymatic reactions are typically carried out in water with the addition of a small amount of cosolvent if necessary to solubilize the components at neutral pH to mimic an in vivo condition."

However, it is not apparent whether acetonitrile is a routine cosolvent, or whether other cosolvents would be effective.  It is clear from Hoong that the solvent conditions have a marked effect on the outcome.  While the evidence does not answer this question, it is not necessary to resolve this issue according to the "onus of proof".  It is inherently reasonable that a cosolovent would be used, and the choice of acetonitrile is unsurprising.  I believe it is more likely than not that it would have been a matter of routine to use acetonitrile as a cosolvent.

Turning now to the disclosure of the enantiomers of BCH-189, I note that neither enantiomerically enriched BCH-189 nor a single enantiomer of BCH-189 is exemplified in the specification.  The specification notes (on page 10a) that BCH-189 has a (+) and (-) enantiomer;  this is a matter that would have been apparent to a person trained in chemistry.  The description does not identify which enantiomer is preferred for use as a pharmaceutical.

The significant question is whether this provides sufficient information for a person skilled in the art to carry out the invention.  The skilled addressee would have had to work through the first method, then the DIBAL-H version of the second process, before arriving at the method that might work.  This represents a large amount of experimentation just to get to the third method, and even then the skilled addressee's work is not done.  Two steps are not described in the specification.  First, there is the reduction using NaBH₄ (or Red-Al).  It is left to the person skilled in the art to work out how to carry out this step, and there is no evidence whether it actually works.  Second, there is the enzymatic hydrolysis of the butyryl ester.  It is left to the person skilled in the art to make the variations (albeit routine) necessary to achieve a useful enantiomeric enrichment.  The total effect of the borohydride step and the hydrolysis step being inadequately described is that there is a large amount of additional experimentation required.  Is it enough that it has not been proved how much experimentation in total would be needed?  In this case the evidence shows that many reactions have not proceeded as first thought:  the coupling caused racemisation;  DIBAL-H reduced the ester;  enzymatic hydrolysis required a cosolvent.  In these circumstances the reader is justified in approaching the description of the third method with extreme caution.  It is more likely than not that a heavy burden of experimentation is placed on the person skilled in the art (both to find and then to carry out the third method), and that the specification does not teach the reader to carry out the process shown in Figure 3 of this decision.

Summary of the description

The specification discloses a method of preparing BCH-189 exclusively in the b-conformation by using tin chloride to couple a pyrimidine to an oxathiolane.  This process is clearly disclosed and exemplified.  (This method is the subject of claims 1 to 12, which are not objected to.)

The specification discloses three methods of preparing enantiomerically enriched BCH-189.  The first method (i.e. the Figure 4 method) does not work because the tin chloride causes racemisation of the thioketal carbon.  The second method (i.e. the DIBAL-H version) does not work because the butyryl ester is converted to an acetyl ester by the reduction/acylation step.  The third method (i.e. the NaBH₄ or Red-Al version) might work, and represents the only disclosure of how to prepare enantiomerically enriched BCH-189.  The third method requires a heavy burden of experimentation in order to work the process because it would only be attempted after the first two methods had proved unsuccessful, and there is no explanation of how to carry out two key steps:  the reduction by NaBH₄ (or Red-Al) is not exemplified, and there is no reference to the need to use a cosolvent of acetonitrile for the enzymatic hydrolysis.

The claims

The claims of the specification are directed to a number of aspects of the invention.

Claims 1 to 12 define a method of preparation of the b-isomer of 2',3'-dideoxy-3'-thiapyrmidines.

Claims 13 to 15 define enantiomerically enriched oxathiolanes.

Claims 16 to24 define a method of preparation of oxathiolanes.

Claims 25 to 29, 31, 37 define enantiomerically enriched of 2',3'-dideoxy-3'-thiapyrmidines.

Claim 30 defines a pharmaceutical composition of the (-) enantiomer of BCH-189

Claims 32 to 36 define a method of resolving the enantiomers of 2',3'-dideoxy-3'-thiapyrmidines.

The claims that are in dispute are claims 13 to 15, 20 to 21, and 25 to 37.  These claims are reproduced in full in Annex 3 of this decision.

The plain meaning of the claims is apparent on their face, and no special issues arise.  The claims use the expression "b-BCH-189" or variations on this term.  I found earlier that this term is technically inaccurate, but the meaning is clear (i.e. "b-BCH-189" is the same as "BCH-189").  Two minor clarity matters are discussed in the next section of the decision.

Claim 30 is directed to a composition rather than a compound.  However, it is a composition that is defined only by a single component -  the compound.  In dealing with this claim in my decision I will treat it as a compound claim.  No problems arise from this.  It is already known (and noted in the citations) that the racemate is a pharmaceutically active substance, so the novelty and obviousness of the composition depends on the novelty and obviousness of the compound.

SECTION 59(1)(i) -  Section 40 issues

Section 59(1)(i) makes section 40 issues a ground of opposition under the 1952 Act.  At the hearing Biochem argued that there are a number of section 40 deficiencies with the specification.  These issues are:

ØClaims 13 - 15, 20 - 21, 27, 28 and 37 are not clear due to the use of the term "enantiomerically-enriched" or "enantiomerically enriched";

ØClaims 26 and 27 are unclear as they are directed to BCH-189 but include substituents on the oxathiolane moiety;

ØClaims 25 - 37 are not fairly based;  and

ØThe specification does not fully describe the invention.

Clarity

In discussing the specification above, I decided that the term "enantiomerically-enriched" or "enantiomerically enriched" would be understood by a person skilled in the art as implying a useful level of enrichment.  This is the standard of clarity of expression that was accepted in Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253 at 274:

"Lack of precise definition in claims is not fatal to their validity so long as they provide a workable standard suitable to the intended use"

Consequently, I consider that the term would be understood by a skilled addressee, and the mere fact that it is somewhat imprecise does not render the claims unclear (see also Leonardis v Sartas No 1 Pty Ltd (1996) 35 IPR 23 at 32). The claims are not unclear in this regard.

The second clarity matter relates to claims 26 and 27 only.  Both claims define compounds by reference to a name (BCH-189 in the case of claim 26, and 2',3'-dideoxy-3'-thiacytidine in the case of claim 27) and by reference to a structural formula.  The structural formula is directed to derivatives of the named compound.  This is a regrettable clumsiness.  However, consistent with the normal drafting of the claims of chemical patents, I consider that the precisely drawn structural formulae represent the compounds that are the subject of the claims.  As the structural formulae are directed to simple derivatives of the named compounds, it is clear that the names are more akin to description than definition.  The claims are not unclear in this regard.

Fair basis

The requirement of fair basis is found in section 40(2) of the 1952 Act.

(2)  The claim or claims shall be clear and succinct and shall be fairly based on the matter described in the specification.

The majority of cases on fair basis have been directed to the question of fair basing on a provisional application for the purposes of determining the priority date of the claims.  The priority date of such cases is determined under regulation 3.12(1)(b), where the question is whether the claim is fairly based on "matter disclosed" in the provisional application.  Clearly internal fair basis (i.e. the fair basis of the claims on the specification), which is based on "matter described", is slightly different to fair basing on a basic document.

Fair basis on a basic document is assessed using the "real and reasonably clear disclosure" approach (for example, Hoffman-La Roche & Co AG v Commissioner of Patents (1971) 123 CLR 529 at 538 - 9 and CCOM Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260 at 278). The small number of cases dealing with internal fair basis have also applied the "real and reasonably clear disclosure" test, but without argument as to whether this is the appropriate test (see Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 at 95 and Patent Gesellschaft AG v Saudi Livestock Transport and Trading Co (1997) 37 IPR 523 at 530).

Dr Bennett submitted that as the matter has not been directly decided by the courts, it is open for me to find that there should be a different test applying to internal fair basis.  The requirement from the Act for fair basis on the "matter described" rather than "matter disclosed" does suggest a more stringent test could apply to internal fair basis than fair basing on a basic.  However, it is not necessary for me to form a view on whether a different test applies to internal fair basing (and what that test should be) as I consider that the key claims 25 - 31 and 37 are not fairly based according to the traditional test of "real and reasonably clear disclosure".

In Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 the question of internal fair basis was considered. The "real and reasonably clear disclosure" was explained 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]

The analysis required is not a mere comparison of text in the claim with text in the description.  This would be the kind of over meticulous verbal analysis disapproved of in CCOM Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260. It is necessary to have regard to the description as a whole (for example, see the detailed analysis used by the Federal Court in CCOM).  The relevant claims of the present application relate to compounds (being enantiomers of BCH-189 and its derivatives claimed in claims 25 - 31 and 37) and methods of resolving derivatives of BCH-189 (claims 32 - 36).  The preparation of enantiomerically enriched BCH-189 is disclosed in Figure 4 of the specification (and its accompanying text), but as we now know that process does not produce the desired enrichment.  It is well established that "there cannot be a real and reasonably clear disclosure if there is no disclosure" (CCOM Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260 at 284). In the present case there is an apparent disclosure of the Figure 4 process, but it is an illusion. As a matter of fact, there is no disclosure of the Figure 4 process. Mr Catterns did not argue that Figure 4 provided fair basis for the claims. On the contrary, he argued that the enantiomers are implicit, and the disclosure of the second method is sufficiently clear to provide fair basis. The second method disclosed in the specification can produce enantiomerically enriched BCH-189 when the reduction is carried out using NaBH₄ (or Red-Al).  The borohydride version of the second method is not stated in simple words, but is hidden amongst the other methods, and it was only with difficulty that I was able to find it.  This does not sit easily with the concept of a broad or general disclosure.  The facts of this case are similar to those in Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd (1987) 15 FCR 382. In Coopers case the claims of the petty patent specified DGBE as forming at least 50% of the solvent.  The provisional application referred to DGBE, but only obliquely.

"I proceed now to the second question -  was it 'fairly' so based?  In my opinion, it was not.  The invention claimed in the petty patent is the pour-on formulation comprising a pyrethroid in admixture with a topically acceptable carrier comprising 50 wt per cent of DGBE.  The whole emphasis of the invention claimed has changed from the description in the provisional.  There we are told that the pyrethroid is the essential thing.  Its application by a pour-on method is advocated.  DGBE is mentioned as a possible, but by no means preferred, solvent system.  Now, in the petty patent, we are told that the carrier is not the thing.  This involves a significant point of departure.  It is not merely a matter of detail or mechanics or even a change of composition.  It involves an attempt to place a very different complexion upon the character of the invention.  …  Put differently, by dealing with DGBE in such an oblique fashion, the provisional tends to conceal the claim later asserted that the invention is the solvent system and not the pyrethroid.  Given the minor, inconsequential role attributed to DGBE by the provisional, the specification cannot be said to foreshadow 'fairly' the claim later made for DGBE as the key element in the invention."
[page 400]

This is highly relevant to the present case.  There is so little information in relation to the borohydride version of the second method (including the enzymatic resolution step), and this information is hidden within the misleading information in relation to the first method and the DIBAL-H form of the second method, that it cannot be said that there is a real and reasonably clear disclosure of the preparation of the enantiomers of BCH-189.  Thus claims 25-31 and 37 are not fairly based on the matter described in the specification.

Was diastereomer separation a matter of routine?

It was submitted that diastereomer formation would have been a routine way of separating the enantiomers.  There is very little evidence on this point.  For instance:

"For such separation [of enantiomers], many methods existed.  One of these methods involved reaction of the two enantiomers of interest, with a chiral reagent and fractional crystallisation of the two resulting salts.  The principle of this method is that the resulting salts have differing solubilities in the crystallisation solvent and thus easily separated."
[Evans declaration in support, para 6.14]

"In 1990 I formed diastereomeric salts of BCH-189 using di-p-toluoyl-L-tartaric acid.  Di-p-toluoyl-L-tartaric acid is one of the six chiral acids mentioned in paragraph 11 of Dr Liotta's Declaration.  I used three different solvent systems, IMS (industrial methylated spirits), methanol and methanol plus acetone.  After salt formation I obtained, using each of the three solvent systems, enantiomeric excesses of 40% or better.

In summary, using di-p-toluoyl-L-tartaric acid [to form a diastereomeric salt], I performed, in 1990, a resolution of BCH-189 which was at least as successful as the only resolution of enantiomers described in Emory's '136 application."
[Blatcher declaration in reply, para 6 - 7]

This evidence establishes that diastereomeric salt formation was straight forward, and a matter of routine.  However, it does not establish that it was routine to achieve a useful level of enantiomeric enrichment (since 40% ee is not useful).  While there may have been an expectation of success, the evidence suggests that extra effort would be needed to achieve success.  On the basis of the evidence available it is not clear that success is possible as a matter of routine.  Consequently, claims 25 - 31 and 37 are not obvious in this regard.

Conclusion on obviousness

I found that the problem in the present case is "to find a compound having improved pharmaceutical properties relative to BCH-189 " (in relation to claims 25 - 31 and 37) and "to find a method of resolving the enantiomers of the specific BCH-189 derivatives" (in relation to claims 32 - 36).

The common general knowledge is that compounds such as BCH-189 are a racemate, and that it was desirable (and possible) to separate enantiomers.  Based on this knowledge, both of the problems reduce to the key question of whether it would have been a matter of routine to use chiral chromatography, enzymatic resolution or diastereomer formation to separate the enantiomers of BCH-189 and its derivatives, and whether it would have been a matter of routine to find conditions under which these processes would have been successful.

I found that the evidence establishes that chiral HPLC would have been a routine technique to try.  However, it was not a matter of routine to separate the enantimers of BCH-189 (as success was only achieved with difficulty, and not routinely:  note Lubrizol).  It was, however, a matter of routine to separate the enantiomers of some derivatives of BCH-189.  Consequently, claims 25, 28 - 31, which are directed to enantiomers of BCH-189, are not obvious.  Claims 26 and 27, which are directed to enantiomers of derivatives of BCH-189, are obvious.

On the subject of enzymatic resolution, I found that esterase reactions were not a matter of routine.  Consequently claims 32 - 36, which are directed to the resolution of the enantiomers of BCH-189 using esterases, are not obvious.

Deaminase and nucleotidase enzymes are also unlikely to have been a matter of routine because of the additional effort that would have been involved in using these enzymes:  either the enzymes were not readily available, or the use of these enzymes requires the introduction of a group solely for the purpose of hydrolysing it (in the case of nucleotidase) or removing a group that must be reintroduced (in the case of deaminase).  Consequently none of the claims are obvious in the light of this process.

Finally, diastereomer formation has not been shown to routinely produce a useful level of enantiomeric enrichment, so is not a matter of routine.  Consequently none of the claims are obvious in the light of this process.

Thus, only claims 26 and 27 are obvious.

SECTION 59(1)(f) -  Manner of manufacture

Biochem alleged that claims 25 - 37 are not a manner of manufacture.

The ground of manner of manufacture is found in section 59(1)(f) of the 1952 Act:

"that the invention, so far as claimed in any claim, is not a manner of manufacture within the meaning of section 6 of the Statute of Monopolies"

The High Court in NV Philips Gloeilampenfabrieken v Mirabella International Ltd (1995) 183 CLR 655 stated that manner of manufacture (in the context of the 1990 Act) is a threshold question, which is assessed by reference to traditional principles. For instance:

"if it is apparent on the face of the specification that the quality of inventiveness necessary for there to be a proper subject of letters patent under the Statute of Monopolies is absent, one need go no further"
[page 664]

"the preferable conclusion is that the phrase 'manner of manufacture within the meaning of section 6 of the Statute of Monopolies' in s 18(1)(a) should be understood as referring to a process which is a proper subject matter of letters patent according to traditional principle"
[page 667]

The High Court in Advanced Building Systems Pty Ltd v Ramset Fasteners (Aust) Pty Ltd (1998) 152 ALR 604 found that the approach in Philips was also relevant to matters under the 1952 Act and reaffirmed the importance of assessing manner of manufacture on the face of the specification (at 615):

"There also were instances in which this lack of inventive step was admitted on the face of the specification.  If so, a grant might properly be refused in the first instance on the footing that the admission of the lack of an inventive step itself disentitled the applicant to argue that even an alleged invention was disclosed."

Manner of manufacture was argued on three bases.  First, on the face of the specification there is nothing to show that the (-) isomer is an invention.  Second, on the evidence in the case, there is no invention because the exemplified process does not work.  Third, there is no vendible product on the face of the specification.

Is the (-) enantiomer an invention of the face of the specification

The specification does not state that the (-) enantiomer of BCH-189 is an invention.  It is true that there is no statement as to what use (or biological activity) there is for the (-) enantiomer, but it would go too far to say that the (-) enantiomer is a mere chemical curiosity.  The specification states that one enantiomer of BCH-189 should be active and the other should be inactive.  While there is no indication that the (-) enantiomer is the active enantiomer, it is a reasonable reading of the description and claims as a whole that there is an implication that the (-) enantiomer is the active enantiomer.  On the face of the specification it is reasonable to conclude that the (-) enantiomer is an invention.

Dr Bennett also submitted that the present case can be compared to that in Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232. The principle in Microcell is summarised in the headnote as:

"It is not an inventive idea for which a monopoly can be claimed to take a substance which is known and used for the making of various articles and make out of it an article for which its known properties make it suitable, although it has not in fact been used to make that article before."

The present case is somewhat different on the facts.  The enantiomer of BCH-189 was known to be an anti-HIV compound, at least as a part of the racemic mixture.  If what was claimed was not more than this, then a manner of manufacture objection might be appropriate.  However, the specification suggests that the enantiomer is better than the racemate (the specification asserts that one enantiomer is more active, but the evidence suggests that one enantiomer is less toxic -  either way there is an advantage, and not merely an analogous use).  On this basis, there is a patentable invention.

Does the process of preparation work (on the face of the specification)

The specification, on its face, discloses a method of preparing the (-) enantiomer.  It is only when the evidence is considered that it is apparent that there is a problem with the specification.  It was argued that if the invention described does not (in fact) work, then there is no invention and thus no manner of manufacture.  The difficult question is whether it is legitimate to have regard to the evidence in order to assess manner of manufacture.

It is clear that manner of manufacture is assessed on the face of the specification, and that care should be exercised in resorting to evidence outside the specification.  In Ramset the majority stated (at 616):

"It was unnecessary to adduce evidence of the prior art base and to compare the invention claimed with the prior art base for the purposes of s 18(1)(b) if the absence of inventiveness appeared on the face of the specification.  Their Honours also said that:

it would border upon the irrational if a process which was in fact but a new use of an old substance could be a 'patentable invention' under s 18 if, but only if, that fact were not disclosed by the specification.

[40]  The present case is not in that category of cases, considered in Philips, where the lack of an inventive step appears on the face of the specification.  It concerns the validity of combination claims in the light of prior publications.  It will be recalled that the Full Court went beyond the text of the specification and placed decisive weight upon the disclosures in the Burke advertisement, the Frimeda advertisement and the RFA Systems advertisement in the Concrete Year Book of 1980.  In that respect, the Full Court was in error in considering under the ground of revocation in s 100(1)(d) matters that could have arisen under other grounds, namely obviousness and lack of novelty, but which either did not arise or were put on one side."
[footnotes omitted]

In the light of Ramset I am not satisfied that it is allowable for me to have regard to evidence outside of the specification in the present case.  Dr Bennett submitted that the information in question is an admission against interest, and should be considered on this basis.  I am satisfied that the fact that the Figure 4 process does not produce enantiomerically enriched material is admissible in the opposition.  I am not satisfied it is admissible for the purposes of the ground of manner of manufacture.

This aspect of manner of manufacture has also not been made out.

Is there a vendible product

The (-) enantiomer is implied to be active as an antiretroviral agent in the specification as a whole.  In this situation the (-) enantiomer is a vendible product, and represents a manner of manufacture.

Conclusion on manner of manufacture

Biochem has not established that the claimed invention is not a manner of manufacture.

Dr Bennett also raised the possibility that I should uphold the opposition on the basis of an inherent power.  This submission was based on a statement of Kitto J in Sami S. Svenden Inc v Independent Products Canada Ltd (1968) 119 CLR 156 at 165:

"the specification is likely to mislead, and for that reason the application ought to be refused in the exercise of those general and inherent powers of the Commissioner and the Court"

Kitto J referred to Alderton and Barry's Application (1941) 59 RPC 56 at 61 - 63 as authority for this proposition. The Alderton case approved an earlier decision of the Comptroller-General in Wainwright's Application (1912) 29 RPC Appendix p xi, that "the COMPTROLLER -  like any other Judge or Court of Justice -  must have the general and inherent powers of preventing fraud being committed on the Crown or an injustice being done to the public" (page xii).  The inherent power seems to be a judicial power, so is probably not possessed by the Commissioner in Australia (due to the separation of powers doctrine).  I do not consider that there is an inherent power for me to refuse the application.

CONCLUSION

The opposition is successful on the grounds of

Øsection 40 (fair basis and full description),

Ønovelty (claims 25, 28 - 31 and 37),  and

Øobviousness (claims 26 and 27).

Mr Catterns requested the opportunity to amend, should I find against Emory.  The grounds of opposition are successful only in relation to some of the claims (I have made no finding against claims 1 - 24 or the description in relation to these claims).  As there is unobjectionable subject matter in the specification, it is appropriate to allow Emory the opportunity to propose amendments to overcome the deficiencies that I have identified.

I allow Emory 8 weeks from the date of this decision in order to propose suitable amendments.

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.

I have found that the opposition is successful on the grounds of section 40, novelty and obviousness, but is not successful on the grounds of section 40 (clarity), novelty (of claims 26 and 27), obviousness (of claims 25, 28 - 37) and manner of manufacture.  Biochem's success on the substantive grounds of opposition justifies the award of costs in its favour.  However, a very large amount of the evidence (including the further evidences) relates to the ground of obviousness, and Biochem was unsuccessful in a large part of its obviousness case.  However, the unsuccessful obviousness items were not clearly inappropriate, and were unsuccessful only after a careful consideration of the evidence.  On this basis I am satisfied that Biochem should not have its costs reduced on account of its failure on most of the ground of obviousness.

I award costs in accordance with Schedule 8 against Emory University.

Dr S.D.Barker

Delegate of the Commissioner of Patents

5 August 1999

Patent attorneys for the applicant  :  FB Rice & Co, Melbourne

Patent attorneys for the opponent  :  Cullen & Co, Brisbane

ANNEX 1: Figures 1 AND 4 of 658136

ANNEX 2:  PAGES 10 AND 10a OF THE SPECIFICATION

The following is pages 10 (from line 4) and 10a of the specification.  Text that was deleted from the specification during the examination process is shown with a line through it.  Text that was inserted during the examination process is shown in italics.

This procedure can be tailored to produce BCH-189 or BCH-189 analogs that are enantiomerically-enriched at the 4' position by selecting an appropriate R protecting group to allow stereoselective enzymatic hydrolysis of 3 by an enzyme such as pig liver esterase, porcine pancreatic lipase, or subtilisin or other enzymes that hydrolyze 3 in a stereoselective fashion.  The resulting optically active 3 can be converted to enantiomerically-enriched carboxylate 4 and coupled with a silyated pyrimidine base as above to produce enantiomerically-enriched BCH-189 or BCH-189 analogs.

The protecting group R in 1 can be selected to provide protection for the corresponding alcohol until the final step in the synthesis is carried out (deprotection of 5 to form 6).  Additionally, the protecting group can be selected, if desired, to provide an additional recognition site for an enzyme to be used later in an enantio-selective hydrolysis reaction.  Any group that functions in this manner may be used.  For instance, alkyl, silyl, and acyl protecting groups or groups that possess substantially the same properties as these groups can be used.

An alkyl protecting group, as used herein, means triphenylmethyl or an alkyl group that possesses substantially the same protecting properties as triphenylmethyl.  A silyl protecting group, as used herein, means a tri-substituted silyl group having the formula:

R₁
       ½
{ ¾ Si ¾ R₂
       ½
       R₃

[page 10a]  reaction.  For example, the alkyl ester of the b-isomer of BCH-189 can be resolved into its (+) and (-)-enantiomers by treatment with pig liver esterase, porcine pancreatic lipase, or utilising, by methods described in detail herein.

Any group that functions in this manner may be used.  For instance, alkyl, silyl, and acyl protecting groups or groups that possess substantially the same properties as these groups can be used.

An alkyl protecting group, as used herein, means triphenylmethyl or an alkyl group that possesses substantially the same protecting properties as triphenylmethyl.  A silyl protecting group, as used herein, means a tri-substituted silyl group having the formula:

R₁
       ½
{ ¾ Si ¾ R₂
       ½
       R₃

Annex 3:  the opposed claims of 658136

13.  Enantiomerically-enriched 2-hydroxymethyl-5-oxo-1,3-oxathiolane.

14.  Enantiomerically-enriched 2-acyloxymethyl-5-acyloxy-1,3-oxathiolane.

15.  Enantiomerically-enriched 2-acetoxymethyl-5-acetoxy-1,3-oxathiolane.

20.  A method of preparing enantiomerically-enriched 2-acyloxymethyl-5-acyloxy-1,3-oxathiolane comprising the steps of:

(a)  mixing a stereoselective enzyme with a lactone of the formula:

wherein R is an oxygen protecting group to form enantiomerically-enriched 2-hydroxymethyl-5-oxo-1,3-oxathiolane;  and
           (b)  reducing said enantiomerically-enriched 2-hydroxymethyl-5-oxo-1,3-oxathiolane to form enantiomerically-enriched 2-acyloxymethyl-5-acyloxy-1,3-oxathiolane.

21.  The method of claim 20, wherein the reduction of the enantiomerically-enriched 2-butyryloxymethyl-5-oxo-1,3-oxathiolane is accomplished by an addition of a reducing agent followed by addition of a carboxylic anhydride.

25.  The (-)-enantiomer of the b-isomer of 2',3'-dideoxy-3'-thiacytidne (BCH-189).

26.  A (-)-enantiomer of the b-isomer of BCH-189 of the formula:

wherein R is selected from the group consisting of alkyl and acyl, wherein acyl refers to a moiety of the structure -C(O)R' and R' is phenyl or an alkyl group of five carbons or less.

27.  The b-isomer of 2',3'-dideoxy-3'-thiacytidine, which has the formula:

that is enantiomerically enriched with (-)-enantiomer, and wherein R is selected from the group consisting of alkyl and acyl, wherein acyl refers to a moiety of the structure -C(O)R', R' is phenyl or an alkyl group of five carbons or less;  and wherein Y is hydrogen.

28.  The b-isomer of 2',3'-dideoxy-3'-thiacytidine, which has the formula:

that is enantiomerically enriched with (-)-enantiomer.

29.  The (-)-enantiomer of the b-isomer of 2',3'-dideoxy-3'-thiacytidine (BCH-189) substantially free of the (+)-enantiomer of the b-isomer of 2',3'-dideoxy-3'-thiacytidine.

30.  A composition consisting essentially of the (-)-enantiomer of the b-isomer of 2',3'-dideoxy-3'-thiacytidine (BCH-189) together with a pharmaceutically acceptable carrier.

31. The (-)-enantiomer of the b-isomer of 2',3'-dideoxy-3'-thiacytidine (BCH-189) in substantially pure form.

32.  A method for resolving the enantiomers of a nucleoside of the structure:

wherein Y is hydrogen or fluorine and R is an acyl group, comprising treating the nucleoside with an enzyme selected from the group consisting of pig liver esterase, porcine pancreatic lipase, and subtilisin.

33.  The method of claim 32, wherein Y is hydrogen.

34.  The method of claim 32, wherein Y is fluorine.

35.  The method of claim 33, wherein the enzyme is pig liver esterase.

36.  The method of claim 33, wherein the enzyme is porcine pancreatic lipase.

37.  Enantiomerically-enriched b-BCH-189.