Genentech INC. and Central Sydney Area Health Service v Celtrix Pharmaceuticals Incorporated

[1995] APO 60

official notice

decision of a delegate of the commissioner of patents

Application        :    No. 629820 in the name of GENENTECH, INC. and CENTRAL SYDNEY AREA HEALTH SERVICE.

Title:    Production of Insulin-Like Growth factor Binding Protein.

Action: Opposition under Section 59(1) Patents Act 1952 by Celix Pharmaceuticals Incorporated.

Decision:    Issued            .

Abstract:    The opposition has failed in all but some minor section 40 matters.

patents act 1990

decision of a delegate of the commissioner of patents

Re:Patent Application No. 629820 in the name of GENENTECH, INC. and CENTRAL SYDNEY AREA HEALTH SERVICE and an opposition under section 59(1) of the Patents Act 1952 by CELTRIX PHARMACEUTICALS INCORPORATED.

background

Patent application No. 629820 by  GENENTECH, INC. and CENTRAL SYDNEY AREA HEALTH SERVICE (Genentech) was filed on 10 March 1989 under the provisions of the Patent Cooperation Treaty as PCT/US89/00983 claiming priority of 22 March 1988.  That application was published under the PCT as WO 89/09268, and in Australia was allocated the application number of 32178/89.  The application entered the national phase of processing on 8 August 1990, having undergone Preliminary Examination under the PCT.  The application was advertised accepted on 15 October 1992.  On 19 January 1993 the opponent CELTRIX PHARMACEUTICALS INCORPORATED (Celtrix) filed a notice of opposition and an application for an extension of time to file the Notice of Opposition.  The extension was subsequently granted.

The opposition is proceeding as provided for in section 234(3) of the 1990 Act.  All evidence stages were completed by 14 November 1994 and the matter heard in Canberra on 6 June 1995.

The grounds relied on in the Notice of Opposition are those available under section 59(1)(c) & (d), (e), (g), (h) and (i) of the Patents Act 1952.

Genentech was represented at the hearing by Ms Katrina Howard of counsel and Dr Peter Stearne of Davies Collison Cave (Patent Attorneys) Sydney. 

Celtrix was represented at the hearing by Dr Bill Pickering of F B Rice & Co (Patent Attorneys) Sydney. 

THE SPECIFICATION

The invention is described as relating to an insulin-like growth factor (IGF) binding protein and to means and methods for its production in therapeutically significant quantities.

Two IGF binding proteins, found in different body fluids, have been identified and characterised.  One predominates in adult serum, while the other is found in highest concentrations in amniotic fluid.  For convenience, the designations BP53 for the relevant binding protein in adult serum and BP28 for the binding protein first isolated from amniotic fluid are used in the specification.

The objectives of the invention are described on page 3 of the specification, thus

Although the isolation and purification of BP53 has been described in the literature as shown above, the relatively low concentration of the protein in human plasma and the high cost, both in terms of effort and expense, of recovering in commercial quantities purified protein from the plasma hinder its broad-scale use, either alone or in combination with IGF.

Accordingly, it is an objective of the present invention to isolate DNA encoding BP53 and to produce commercially useful quantities of the protein from a therapeutically acceptable source.

It is a further object to obtain BP53 in a form unaccompanied by the glycosylation associated with the native BP53.

It is an additional object to prepare amino acid sequence and other variants of BP53 that do not substantially adversely affect the biological activity of the protein.

It is yet another object to produce BP53 completely free of other naturally occurring (source) proteins.

The specification contains 29 claims of which claims 1 and 26 are independent claims.

Claim 1

An isolated DNA molecule comprising a sequence that encodes insulin-like growth factor binding protein, wherein said DNA molecule is selected from the group consisting of:

(a)the DNA sequence set forth in Fig 3; and

(b)DNA sequences that are not the DNA sequences defined in (a) and that hybridized (sic) under stringent conditions to the DNA sequence defined in (a).

Claim 26

Insulin-like growth factor binding protein that is unaccompanied by associated native glycosylation, encoded by a DNA sequence that hybridizes under stringent conditions to the DNA sequence set forth in Fig. 3, and that possesses one or both of the biological properties of (a) binding insulin-like growth factor (IGF), or (b) cross-reacting immunologically with an antibody raised against at least one epitope of the corresponding native binding protein.

EVIDENCE

Evidence in support consists of statutory declarations from:

1. KEVIN ALAN WARD, Senior Principal Research Scientist of the CSIRO Division of Animal Production, Prospect NSW, together with 14 Exhibits;

1. GERALD WAYNE BOTH, Programme Leader and research scientist of CSIRO Division of Biomolecular Engineering, North Ryde, NSW, together with one exhibit; and

1. YVONNE WILCOX, Librarian, of the University of New South Wales Libraries.

Evidence in answer consists of statutory declarations from:

1. ROBERT J CRAWFORD, Director of Bresatech Limited, a South Australian biotechnological company, together with one exhibit;

1. ANTHONY JOHN MASON, Senior Research Fellow at Prince Henry's Institute of medical Research, Melbourne, together with 6 exhibits.

Evidence in reply consists of a statutory declaration by KEVIN ALAN WARD, who also provided evidence in support.

SUBMISSIONS

At the hearing Celtrix only relied on the grounds of obviousness and non-compliance with section 40.

Celtrix argued that

.the evidence of Dr's Ward and Both establishes that if the person skilled in the art has a sample of the pure protein then it is a matter of routine to find the nucleotide sequence which encodes the protein and to reproduce the protein in commercially useful amounts. 

.the scope of the claims was too broad due to the use of the term "hybridized under stringent conditions" as it encompassed a broad range of sequences which were not described.

.the terms "isolated", "hybridized under stringent conditions", "confers immunogenicity", "cleavable", "unaccompanied" and "predetermined amino acid residue" are unclear and indefinite.

Celtrix referred to the decisions in

The Wellcome Foundation Limited v V.R. Laboratories (Aust.) Propriety Limited 148 CLR 262 where Aickin J. at page 286 and, Elconnex v Gerard Industries 22 IPR 551 at page 570.

In summary, Genentech argued that

.the evidence of the applicants is to be preferred to that of the opponent as

(a)the opponent's witnesses have used unacceptable hindsight reasoning.

Technograph Printed Circuits Ltd v Mills & Rockney (Electronics) Ltd. (1972) RPC 346 at 363.

Palmer v Dunlop Perdriau Rubber Co Ltd (1937) 59 CLR 30 at 61.

(b)the evidence of Dr Both is almost identical to that of Dr Ward, and ought to be disregarded.

(c)one of the applicants witnesses, Dr Mason, had knowledge of the cloning and characterisation of BP53 at the relevant time.

.the opponent's evidence establishes that only one publication, Maniatis et al, formed part of the common general knowledge.  On the basis of this publication alone, the invention cannot be shown to be obvious.

.the evidence of the applicants shows that after many failed attempts, Genentech designed a probing strategy involving the use of pools of mixed probes (of long internal sequences) under conditions of low stringency hybridization.  There is no evidence that such a strategy had been used before, nor that it was suggested by the prior art.

.the test for obviousness (that is, whether the hypothetical addressee faced with the problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention - Welcome v VR Laboratories (supra) and Allsop v Bintang (1989) 15 IPR 686 at 700) is not satisfied. There is no clear expert evidence from which to draw the conclusion that "the hypothetical non-inventive person skilled in the art" in Australia at the priority date, given the prior art, would as a matter of routine, have taken the steps that Genentech took to arrive at the invention. On the other hand, the evidence of the applicants' witnesses is that the procedures used were innovative and not routine.

.the invention in this case was not obvious regardless of whether the correct question to ask is:

(a) was the particular sequence obvious? or

(b) was the method by which the sequence was identified obvious?

The English courts ask whether the method was obvious

Genentech's patent (1989) RPC 147, per Mustill LJ at 274 and 276, and per Purchas LJ at 213.

Chiron Copr v Organon Tecknika & Anor (1994) FSR 202.

The US courts ask whether the product was obvious

In re Bell (1993) 26 USPDQ2d 1529

In re Deuel (1995) 34 USPDQ2d 1210.

.Lack of fair basis has not been alleged in the Statement of Grounds and particulars and therefore cannot be relied on.

Diamond Scientific Co v CSL Ltd (1992) AIPC 90-927 at 38,699.

.Terms in claims must be given their plain and unambiguous meaning.  If they are not clear, it is permissible to resort to the body of the specification to define or clarify.

Interlago AG v Toltoys Pty Ltd (1973) 13 CLR 461 at 479.

Evidence from Mason's declaration is that the terms objected to are clear.

THE DECISION

Obviousness

The law in Australia in regard to obviousness under the 1952 Patents Act, was laid down in the High Court decision in Minnesota Mining and Manufacturing Company and Another v. Beiersdorf (Australia) Limited, 144 CLR 253. This required that in order that an allegation of obviousness be made out it must be established that the information relied upon had become part of the common general knowledge in Australia of those engaged in the particular art to which the invention belongs, at the priority date of the application in suit. At page 292, Aicken J. stated:

"The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade.  It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge."

Firstly, I must determine who is the "non-inventive worker in the field of technology".  That is, a skilled but non-inventive worker in the relevant field of technology in Australia who knows the common general knowledge in the art in Australia  (American Cyanamid v Ethicon, (1979) RPC 215 and Sunbeam Corp v Morphy-Richards (Aust) Pty Ltd, (1961) ALJR 212).

The specification is directed to recombinant DNA techniques for producing commercial quantities of the particular IGF binding protein (BP53) required.  The "person skilled in the art" in this case is a molecular biologist skilled in the recombinant technology used to manufacture DNA molecules.

Dr's Ward, Both, Mason and Crawford all fit this category.

The test for obviousness in this instance is given in The Wellcome Foundation Limited v V.R. Laboratories (Aust.) Propriety Limited 148 CLR 262 where Aickin J. at page 286

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 is 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.

Thus, I must not be concerned with what steps Genentech actually took to determine the DNA molecule encoding BP53 but what steps the skilled addressee would have taken.  It is unnecessary for me to consider the approach of either the UK or the US courts as the matter is straight forward.

Dr Ward provides in paragraph 14 of his first declaration a series of standard steps the person working in this field would have taken to produce recombinant BP53 at the priority date knowing the common general knowledge and having access to purified BP53.

However, Dr Ward provided no evidence of a person working in the field actually using these steps to produce recombinant BP53.  Dr Ward has only provided me with what appears to be a theoretical dissertation about how "other persons skilled in the art" could have produced the DNA molecule encoding BP53.  He has not provided me with any experimental data to support his argument.  Even without experimental data, a theoretical argument, based on established common general knowledge, may be acceptable.  In this case, however, there is strong evidence to the contrary.

Dr Crawford, in evidence in answer, says at paragraph 11

The declarations of Dr Wood exhibited to Dr Mason's declaration and discussed in detail at paragraphs 21 and 22 .... show that standard molecular biology procedures did not work.  This is clearly demonstrated by the number of failed experiments.  Particularly, hybridization probes based on the N-terminal amino acid sequence of the insulin-like growth factor binding protein did not work, nor did selected probes based on tryptic peptides of the insulin-like growth factor binding protein.  It was only when hybridizations were carried out simultaneously with three specific pools of probes under low stringency conditions that the DNA encoding insulin-like growth factor binding protein was identified.  This procedure was totally unpredictable from standard methodologies known in the art as of the priority date of the claims of the genentech/CSAHS application. (Dr Wood is a co-inventor)

I accept that the difficulties encountered by the applicant would have been encountered by the non-inventive worker using "Maniatis" or any other standard technique to obtain the DNA sequence encoding BP53 since there is no evidence to the contrary.

I also accept Genentech's submission that the practical difficulties they encountered in cloning the DNA molecule encoding BP53 were overcome in an inventive and innovative manner.  There appears to have been no teaching or suggestion in the prior art of using a probing strategy involving pools of mixed probes (of long internal sequences) under conditions of low stringency hybridization. 

On the evidence presented, I am led to the conclusion that the opponent has not established its case.  In my view, the opponent's theoretical argument has not been able to refute the evidence from the applicant's experts.  It is clear to me that there were practical difficulties in the way of determining the sequence of the DNA molecule encoding BP53 which had to be overcome in a non-routine inventive manner [Gadd & Mason v Manchester Corp (1892) 9 RPC 516, Acme Bedsteads v Newlands Bros. (1929) 58 CLR 689, Schwer v Fulham & Robinson (1910) 11 CLR 249].

Therefore I do not find the invention claimed to be obvious.

Section 40

Celtrix has submitted that the specification does not comply with section 40 of the Act because:

(a) Claims 1 to 24 are not clear and are indefinite in respect to the use of the term "isolated".

Dr Mason, in paragraph 28 of his declaration, says that the term "isolated" refers to "a DNA molecule not associated with other DNA molecules or sequences", and "in this context, the meaning is entirely clear".  There is no contrary evidence.  I find the term "isolated" to be clear and definite.

(b) Claims 1 and 26 are not clear and are indefinite in respect to the use of the term "hybridized under stringent conditions".

The term seems to me to be adequately defined on page 24 lines 24 to 29.  Dr Ward at paragraph 12 (evidence in reply) says that he "can see no clear direction that the stringency referred to in claim 1 is to be determined according to the conditions set out on page 24 of the specification".  I find the meaning of the claim to be clear and readily apparent by reference to the specification.

(c) Claim 17 is not clear in its reference to "confers immunogenicity".

Dr Mason at paragraph 31 of his declaration says that the term carries its ordinary meaning in the field "that is, that the entity in question is capable of provoking an immune response in an animal."  There is no evidence to the contrary and I accept that the claim is clear and definite.

(d) Claim 18 is not clear in the use of the term "cleavable".

Dr Mason, at paragraph 32, again says the term is clear and there is no evidence to the contrary.  I accept the term is clear.

(e) Claim 26 is not clear in the use of the term "unaccompanied".

Dr Mason, at paragraph 32, again says the meaning of the term is clear.  Dr Mason also says that "whether the glycosylation is `native' ... could be readily determined by one or more standard analytical techniques ..." and provides two references to journal articles to support his claim.  Dr Ward, at paragraph 16 (evidence in reply) disagrees on the basis that the specification does not define the what particular sugar residues constitute "native glycosylation" but does not provide references to journal articles or other exhibits to support his claim.  Genentech in its submissions refers me to a description of "native glycosylation" on page 36 lines 14 to 26 of the specification and Fig 2.

On the basis of the evidence I give more weight to Dr Mason's statement with references and accept that the term "unaccompanied" is clear.

(f) Claim 28 is not clear and is indefinite in respect to the use of the term "predetermined amino acid residue."

Dr Mason, at paragraph 34, says the term is clear and means any amino acid residue of the 265 amino acids of the insulin-like growth factor binding protein" and the specification at page 8 line 14 to page 12 line 9 which describes "at length specific substitutions, insertions, or deletions ...".

Dr Ward says that the term is not clear as "the protein encompasses an inordinate number of combinatorial permutations of BP53." 1.36 x 109 x 64250 possibilities are described at paragraph 14 by Dr Ward.  Similarly large possibilities are described by Dr's Mason and Crawford in their evidence.

In my view, the term is unclear and indefinite because the term "predetermined" does not provide a potential infringer with a clear understanding of exactly which amino acid(s) is/are to be changed.  The claim says that a "predetermined amino acid residue" is "substituted, inserted or deleted".  There is nothing provided to help the potential infringer determine (or predetermine) which amino acid residue is to be "substituted, inserted or deleted".

(g) Celtrix argued that there were "lots" of sequences encompassed in claim 1 by the statement "DNA sequences that are not the DNA sequences defined in (a) and that hybridized under stringent conditions to the DNA sequence defined in (a)" and that the claim was not fairly based.

Genentech submitted that lack of fair basis was not alleged in the Statement of Grounds and Particulars and cannot therefore be relied on now. (Diamond Scientific Co v CSL Ltd (1992) AIPC 90-927 at 38,699).

While agreeing with Genentech's submission, I note that I am still at liberty to raise matters on my own volition (Cooper Ind. v Metal Manufactures 29 IPR 106, ( 1994) AIPC 91-051), however, in my view the term is clear and properly supported in the description as the conditions for hybridization have been clearly stated.

Conclusion

I have found the opposition succeeds only in relation to one minor section 40 matter. 

I afford the applicant 60 days from the date of this decision to propose amendments to overcome the section 40 deficiencies.

COSTS

Normally in actions of this nature costs follow the event.  I have found that the opposition has failed on the obviousness grounds and has succeeded only on the basis of a minor section 40 matter.  Consequently, I believe that the opponent has failed to achieve its major objectives and has lost its opposition.  Therefore, I award costs against Celtrix.

R J Sawyer
Delegate of the Commissioner of Patents

Patent attorneys for the applicant  :  Davies Collison Cave, Sydney

Patent attorneys for the opponent   :  F B Rice & Co, Sydney