Genetics Institute Inc v Kirin-Amgen Inc (No. 3)
[1998] FCA 740
•25 JUNE 1998
FEDERAL COURT OF AUSTRALIA
PATENTS - appeal from Commissioner of Patents - genetic engineering - recombinant protein of erythropoietin - whether fairly based - whether claim too wide - whether claim improperly covers methods not disclosed in specification - whether different test for “entirely new or revolutionary product” - whether lack of clarity
Patents Act 1952 (Cth) s 40
Kaiser Aluminium & Chemical Corporation v The Reynolds Metal Co (1969) 120 CLR 136 applied
Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232 applied
Farbwerke Hoechst Aktiengesellschaft Vormals Meister Lucius & Bruning v Commissioner of Patents (1971) 45 ALJR 235 mentioned
Martin v Scribal Pty Ltd (1954) 92 CLR 17 applied
Olin Corporation v Super Cartridge Co Pty Ltd (1977) 14 ALR 149 distinguished
CCOM Pty Ltd v Jiejing Pty Ltd (1994) 122 ALR 417 followed
Electric and Musical Industries Ltd v Lissen Ltd (1938) 56 RPC 23 mentioned
Biogen Inc v Medeva Plc [1997] RPC 1 distinguished
Herbert Adams Pty Ltd v Federal Commissioner of Taxation (1932) 47 CLR 222 applied
GENETICS INSTITUTE, INC V KIRIN-AMGEN, INC (NO. 3)
NO. VG 868 of 1995
JUDGE: HEEREY J
DATE: 25 JUNE 1998
PLACE: MELBOURNE
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
VG 868 of 1995
BETWEEN:
GENETICS INSTITUTE, INC
APPLICANTAND:
AND:
KIRIN-AMGEN, INC
RESPONDENTKIRIN-AMGEN, INC
CROSS-APPLICANTGENETICS INSTITUTE, INC
CROSS-RESPONDENTJUDGE:
HEEREY J
DATE OF ORDER:
25 JUNE 1998
WHERE MADE:
MELBOURNE
THE COURT ORDERS THAT:
Patent Application No. 600650 be amended
(a)in accordance with the further amended statement of proposed amendments dated 21 May 1988, a copy of which is annexed hereto and marked “K-A1”;
(b)by deleting the passage commencing with the words “A preliminary attempt ...” on page 64 of the specification and concluding with the words “... naturally occurring erythropoietin” on page 65; and
(c)by deleting claim 39.
Otherwise the appeal and cross-appeal are dismissed.
Order that the applicant Genetics Institute, Inc pay 90 per cent of the costs of the respondent Kirin-Amgen, Inc’s costs of the appeal, including reserved costs.
No order for costs of the cross-appeal.
Note:Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
VG 868 of 1995
BETWEEN:
GENETICS INSTITUTE, INC
APPLICANTAND:
AND:
KIRIN-AMGEN, INC
RESPONDENTKIRIN-AMGEN, INC
CROSS-APPLICANTGENETICS INSTITUTE, INC
CROSS-RESPONDENTJUDGE:
HEEREY J
DATE:
25 JUNE 1998
PLACE:
MELBOURNE
REASONS FOR JUDGMENT
Introduction
Genetics Institute, Inc (Genetics) appeals from a decision of the Commissioner of Patents given by his delegate Deputy Commissioner Mr D Herald on 19 October 1995. Genetics was one of two opponents to Australian Patent Application No. 600650 (the Amgen patent) brought by the respondent Kirin-Amgen, Inc (Amgen). The Deputy Commissioner found that the claims of the patent were novel and involved an inventive step. He found that three claims did not comply with s 40 of the Patents Act 1952 (Cth) because they involved “some minor lack of clarity” and that five claims were not fairly based. He considered that the defects could be readily overcome and allowed Amgen to propose appropriate amendments. He otherwise held that the opposition failed.
The present appeal is confined to the requirements of s 40. Genetics’ case is that the invention claimed:
is not fairly based on the matter disclosed in the specification (s 40(2));
does not fully describe the invention (s 40(2)(a)); and
contains claims which are not clear and succinct and do not clearly define the invention (s 40(2)).
By a cross-appeal Amgen appeals from that part of the Deputy Commissioner’s decision which found some claims lacked clarity or were not fairly based.
The Field of the Invention
The claimed invention relates generally to recombinant procedures which make it possible to produce polypeptide proteins. More particularly the invention concerns the use of recombinant DNA techniques to produce commercial quantities of erythropoietin.
Erythropoietin
Erythropoietin (EPO) is a protein, normally produced in the liver of the foetus and in the kidney of adults, which plays a major role in regulating the rate of red blood cell formation. EPO is responsible for maintaining a sufficient number of red blood cells to oxygenate body tissues adequately. Red blood cells under the control of EPO are formed predominantly in the bone marrow.
EPO is rare. It is only produced in a few cells. Moreover it is a highly regulated gene; it is only “switched on”, even in those few cell types in which it is found, during particular limited windows of time.
The existence of EPO was postulated in 1906 and confirmed in 1953. By 1975 it was known that small amounts of EPO were excreted by the kidneys and that urine provided a source for urinary EPO (uEPO) but only in limited quantities. Publications in 1977 showed that foetal liver was a source of EPO (Zanjani et al) and that the urine of aplastic anaemia patients over-produced EPO (Goldwasser et al). But neither blood nor urine is a practical source of EPO for therapeutic use. Thus until recombinant EPO (rEPO) became available there existed a need for a product which could fulfil the protein’s therapeutic role.
In 1983 the only publicly available information concerning the structure of EPO (that is its amino acid sequence) was a putative amino acid sequence for the first 26 amino acids of the protein.
Genetic information and DNA
The genetic material of any organism is the substance that carries the information determining the properties of that organism. It is the information contained in the genetic material that determines, for example, the colour of flowers and that fish have gills. The genetic material is also responsible for transferring the genetic information from parent to progeny. All the genetic information of an organism is collectively referred to as its genome. The genetic material in all organisms, apart from viruses, is a form of nucleic acid called DNA (short for deoxyribonucleic acid). Thus the complete genetic material of an organism is called its genomic DNA (gDNA).
DNA is a large molecule of repeating subunits called nucleotides. Four different types of nucleotides are found in DNA: adenine (A), guanine (G), thymine (T), and cytosine (C). Nucleotides are commonly referred to as bases.
The nucleotides (A, G, T and C) are joined together end to end in a linear fashion forming a long string of bases. The linear order of bases along a DNA strand is called the DNA sequence. Every DNA strand has a proper direction in which it should be read, i.e. the 5’ (five prime) to 3’ (three prime) direction. This direction is related to the orientation of the sugar-phosphates that are part of the nucleotides. A DNA molecule consists of two of these long strands of nucleotides. The two strands of a DNA molecule are held together by chemical (hydrogen) bonds between bases on opposite strands; A always pairs with T, and C always pairs with G. As a result of this base pairing between DNA strands, DNA resembles a ladder; the paired bases are analogous to the rungs while the sugar phosphate groups of the nucleotides are the side rails. These carefully matched strands twist into a compact spiral commonly referred to as the double helix, discovered by Crick and Watson in 1953.
The consistent pairing of A to T and G to C is referred to as complementarity, thus one strand of DNA in the double helix is complementary to the other. The complementary nature of DNA allows for its faithful reproduction and also enables the ready identification of specific DNA sequences by gene probes.
There is another type of nucleic acid called ribonucleic acid, referred to by its abbreviation RNA. RNA, like DNA, is made of a linear chain of nucleotides. (The sugar of RNA (ribose) is slightly different to the one found in DNA (deoxyribose).) Unlike the large double-stranded DNA, RNA molecules have only one strand and are shorter than the DNA molecules, being derived from the transcription (see infra) of particular regions of the DNA.
The genetic information carried in the DNA governs the day-to-day function of a cell through its expression in the form of proteins. All biological reactions are accomplished by proteins which are in effect little engines which have specific functions within the organism. As has been mentioned, EPO is a protein. A length of DNA sequence that codes for production of an entire protein is called a gene. All proteins are assembled from building blocks called amino acids by a complex apparatus that works under the direction of genetic information provided by a nucleic acid sequence. Each gene includes a sequence of nucleotides that directly determines the sequence of amino acids in a corresponding protein. The amino acid sequence in turn determines the function of the protein. All proteins of the cell are therefore determined by the sequence of the genetic material.
Amino acids are represented in DNA by different triplet combinations (triplet codons) of the bases A, C, G and T. A triplet codon is identified simply by the letters representing the bases of each of its nucleotides, e.g., GGA and TAG. For example, having G in the first position, G in the second position, and A in the third position of the triplet codon, would encode the amino acid glycine and a table in common use lists the triplet-amino acid relationships. As there are 64 possible combinations of 3 bases to encode 20 amino acids, there is a degree of what is called degeneracy in the coding such that a single amino acid can be encoded by several different base triplets.
In the making of a protein, the genetic information contained in the DNA instructs the cellular machinery through a two-stage process of expression (manufacture) that involves an intermediate molecule. The first stage of expression is transcription, the process by which parts of the genetic message encoded in the DNA are rewritten in the form of a temporary molecule called messenger RNA (mRNA). This also allows the level of gene expression to be varied and controlled, by regulating the amount of mRNA that is made. The DNA molecule serves as a template, but in this case, the complementary strand is the temporary, intermediate molecule, mRNA (see Figure 1). The second stage of expression is translation, in which the genetic message now coded for in mRNA is translated by complex structures called ribosomes into a sequence of amino acids to form the encoded protein.
Figure 1: Schematic illustration of the general steps involved in the synthesis of an mRNA copy of a gene and the production of complementary DNA (cDNA) (Coppel).
Proteins
As mentioned, proteins are molecules of complex structure which are composed of sub-units of amino acids, of which there are 20 different types. Amino acids are linked together in a linear fashion to form a chain which is referred to as a polypeptide chain.
Protein structure can be viewed from four aspects which are termed the primary, secondary, tertiary and quaternary structure. The primary structure of the protein refers to the amino acid sequence of the polypeptide chain. The secondary and tertiary structure of a protein refers to the particular manner in which the polypeptide chain is folded into a unique three-dimensional structure. The quarternary structure is present when individual proteins combine to make a multi-protein structure.
Glycosylation of Proteins
Many proteins (including EPO) are modified by the addition of one or more carbohydrate chains to some of the amino acids. The carbohydrate chains consist of a string of individual units or residues called monosaccharides (also commonly called sugars). The attachment of carbohydrate chains to a protein is called glycosylation, and the completed protein is called a glycoprotein.
The total amount of sugar added to a protein can be quite substantial. For example about 40 per cent of the weight of the EPO glycoprotein is made up of added sugar, the rest being the polypeptide chain.
Monosaccharides exist in a particular ring form, either a six-membered pyranose ring or the less common five-membered furanose ring. Sugars that exist as six-membered rings are called hexoses. The numbers and types of sugars attached at glycosylation sites depend upon the cell making the glycoprotein. Therefore when a DNA sequence is introduced into a host cell, such as a CHO (Chinese hamster ovary) cell the protein that is expressed may have different sugars attached compared to the same protein made in a different host cell such as a COS-1 (monkey kidney) cell.
Introns and mRNA Splicing
Originally it was assumed that a mRNA transcript would have the same sequence as the DNA from which it was transcribed. While this remains essentially true for bacteria, comparison of DNA in plant and animal cells with mRNA revealed that in many instances the DNA contained sequences which were absent from its mRNA transcript.
By comparing DNA sequences with mRNA molecules from the cytoplasm of a cell, scientists found that most plant and animal DNA contains “intervening sequences” which are normally removed in their totality from the mRNA transcript before the mRNA transcript is shuttled to the cytoplasm for translation. These intervening DNA sequences are referred to as “introns”, while the portions of the DNA that code for a portion of the protein sequence are called “exons” (see Figure 1). The presence of introns in genes is unique to plants and animals and, indeed, bacteria are unable to distinguish between exons and introns. The size and position of introns within genes appears to be random: some introns are short in length while others consist of hundreds or even thousands of bases.
Most plant and animal genes consist of an alternating series of exons and introns. The exons are the sequences which code for the protein and are transcribed into mRNA, which information is then translated into an amino acid sequence to form a protein. The introns carry no information relevant to the formation of a protein, and their primary function, if any, is unknown. Thus during transcription the mRNA copy of gDNA must go through a process in which the introns are removed (mRNA splicing) before the protein can be made (see Figure 1).
By comparing the nucleotide sequence of mature mRNA with that of the gDNA sequence from which it was transcribed, the junctions between exons and introns in the DNA sequence can be assigned.
Genetic engineering
The amount of DNA present in each set of chromosomes in each cell of a human (or most of the higher animals) is approximately 3 billion base pairs. An average gene contains about 1,000 - 2,000 bases of protein-coding information, although the entire gene itself, including control sequences and introns, may be much larger. Thus, to isolate and clone a single human gene from the entire human genome is to embark on a search among an amount of DNA which could contain up to three million genes. This problem has been likened to looking for an ant on Mount Everest.
At first sight, these numbers suggest that gene hunting would be impossible. However, by 1983 powerful tools had been developed to make it possible to isolate a gene of interest, reconstruct it by joining it with DNA sequences from quite different sources, place it into a simpler foreign system, and replicate the gene many times to give a large amount of that single gene. The product is often described as recombinant DNA and the technique as genetic engineering. With these techniques, genes that would not have otherwise been accessible could be isolated, cloned, and characterised. As part of this process, restriction enzymes (sometimes referred to as “molecular scissors”) cut DNA at predefined sequences which are characteristic for a particular enzyme.
Another important cloning tool of genetic engineering is the vector. The vector is a special piece of DNA which is able to carry foreign DNA into a living host cell and to replicate autonomously in that host cell. Vectors are usually derivatives of naturally-occurring small DNA molecules. A critical feature of any vector is that it should possess a site at which foreign (“exogenous”) DNA can be inserted without disrupting any essential function of the vector.
A vector has the ability to replicate autonomously in a host cell of DNA. Using the host cell’s replication machinery the vector DNA, including the foreign gene, is replicated and can be perpetuated indefinitely as a population of clones.
A clone can be defined as a large number of molecules or cells, all identical to one another, and to an original ancestral molecule or cell from which they are derived by replication. A sequence of DNA can be cloned by inserting exogenous DNA into a vector, introducing the vector into a host cell, and then growing the host cell. Cloning of DNA is made possible by the ability of host cells to continue their usual life-style after additional sequences of DNA (vector and exogenous DNA) have been incorporated into their genome.
Many vectors are used to express an exogenous DNA insert, by introducing a vector carrying a gene into a host cell. In this process the introduced gene is transcribed and translated to make a protein product. The gene can be altered so that the host cell is instructed to make large amounts of the new protein. In this way what is normally a rare and difficult to produce protein such as EPO can be made in abundance and purified for use as a drug.
The host cells can be bacteria or various cell lines derived from different mammals. Two commonly used host cells are CHO cells, which derive from Chinese hamster ovary, and COS-1 cells, which derive from monkey kidney. These cell lines can be propagated in laboratories. They readily take up foreign DNA.
Using specialised enzymes, vectors and host cells, it has been possible to prepare what are called gene libraries. There are two main types of libraries: genomic and cDNA. The former is a collection of small pieces of DNA, contained within the self-replicating vectors, that represents the entire genome of the individual from which the DNA was made. A cDNA library is also a collection of small pieces of DNA but it represents only that part of the gDNA which has been transcribed in mRNA by the cell(s) from which the cDNA was made. Thus the content of a cDNA library is limited to the DNA which is actually transcribed in the cells used to construct the library. cDNA libraries have the advantage that they contain the exon sequences reassembled into a contiguous protein coding sequence after the removal of the introns.
To make a genomic library of an organism, the DNA from any somatic cell of that organism is cut into fragments usually ranging in size from 5 to 30 kilobases (a kilobase (kb) is one thousand nucleotide bases). These fragments are a random assortment of stretches of DNA that may or may not include an entire gene. The fragments are inserted into an appropriate vector. Typically, bacterial host cells are transformed with the vector for cloning.
To make a cDNA library, complementary DNA (cDNA) must first be generated. mRNA can be used as a template to make cDNA molecules (see Figure 1). This process is called reverse transcription since it is the opposite of the normal transcription process (ie mRNA obtained from DNA).
Genomic and cDNA libraries may contain hundreds of thousands of different recombinants, each representing a different segment of DNA attached to a plasmid or bacteriophage DNA. In order to select a particular colony or plaque containing a desired gene from a bacterial plate, a technique called colony or plaque hybridisation was in use in 1983.
As explained above, bases of each strand of double stranded DNA are bound to each other through chemical bonds. The chemical bonds occur between A (adenine) and T (thymine), and G (guanine) and C (cytosine). These bases are therefore referred to as being complementary to each other. By the end of 1983, it was possible to synthesise by chemical methods a short stretch of DNA, an oligonucleotide probe, with a defined sequence of bases. Such a molecule can then be used to identify a complementary strand in a mixture of DNA molecules, e.g., a genomic or cDNA library, simply by adding it to the library under appropriate conditions. In a process, called hybridisation, the probe will find its complementary partner (target) and form a double-helical structure with it as long as such a partner exists in the mixture. The hybridisation reaction can readily be carried out under conditions which will distinguish between a perfect match of a probe and its target, and the situation in which the probe has bound to a DNA sequence in a library but one or more base pairs are mismatched.
In order to fish out a particular gene from a library capable of containing up to three million genes, it is necessary to construct a probe with a complementary sequence that will anneal to the gene of interest, but not to the rest of the DNA. If the DNA sequence of the gene of interest was known in 1983, probe design was a relatively straightforward task. Amino acid sequence information could also be used in designing probes, but if little or nothing was known about the DNA sequence of interest, isolating the clone from a library would have been a daunting task.
Confirmation
A significant aspect of all gene cloning efforts in 1983 and today is confirmation that the DNA isolated by hybridisation screening actually encodes the protein of interest. Because the genetic code is universal, a given coding sequence should have the same meaning in all situations. Once the “target gene” (synthetic DNA, cDNA or gDNA) of the desired polypeptide is obtained, it can be introduced into a host cell, either bacterial, animal or plant, by a vector. The host cell treats this new DNA as its own and can be made to transcribe it and translate the resulting mRNA causing synthesis of the encoded protein. The polypeptide is said to have been expressed. That is, the polypeptide can be obtained by the steps of (i) inserting the DNA into a plasmid (vector), (ii) incorporating the plasmid into a host cell, and (iii) culturing the host cell. One caveat is that the commonly used bacterial hosts will not undertake post-translational modifications such as the addition of sugars; nor will they be capable of properly translating a gene that contains intron sequences.
The Amgen Patent
The invention is entitled “Production of Erythropoietin”. The inventor states by way of background:
“The present invention relates generally to the manipulation of genetic materials and, more particularly, to recombinant procedures making possible the production of polypeptides possessing part or all of the primary structural conformation and/or one or more of the biological properties of naturally-occurring erythropoietin.”
The inventor identifies three known alternative methods which can be employed to develop DNA sequences which will encode the protein of interest:
the isolation of a double stranded DNA sequence from gDNA;
the chemical manufacture of a DNA sequence which provides a code for a polypeptide of interest; and
the in vitro synthesis of a double stranded DNA sequence by enzymatic reverse transcription of a small mRNA which has been isolated from donor cells (cDNA).
(Chemical manufacture - method (ii) - has not become an issue in the present proceeding.)
The inventor states that when the entire sequence of amino acid residues of the desired polypeptide is not known the cDNA method is preferable, although it is first necessary to have available a source of donor cells having an abundance of mRNA which encodes the polypeptide of interest. The inventor states that the use of gDNA is the least common of the three methods. The inventor continues to identify the problem to be overcome (p 9 lines 21-27):
“There thus continues to exist a need in the art for improved methods for effecting the rapid and efficient isolation of cDNA clones in instances where little is known of the amino acid sequence of the polypeptide coded for and where ‘enriched’ tissue sources of mRNA are not readily available for use in constructing cDNA libraries.”
The inventor notes that attempts to obtain EPO in good yield from plasma or urine have been relatively unsuccessful. After discussing probing strategies the specification then proceeds to the “detailed description” which reveals the steps the inventor took. I gratefully adopt the summary contained in the Deputy Commissioner’s decision as follows (CB121):
“The major part of the ‘detailed description’ of the invention involves ten examples which:
‘... are specifically directed to procedures carried out prior to identification of EPO encoding monkey cDNA clones and human genomic claims, to procedures resulting in such identification, and to the sequencing, development of expression systems and immunological verification of EPO expression in such systems.’
In essence, the specification details:-
- the identification of monkey EPO using a cDNA library;- the identification of human EPO using a human Genomic library;
-the construction of vectors containing erythropoietin-encoding DNA;
- the development of mammalian host expression systems;
-manufactured genes encoding human erythropoietin and analogues thereof having preference codons for expression in certain hosts; and
- antibodies for identifying erythropoietin.”
The specification ends with 56 claims. Those claims, as the Deputy Commissioner noted, fall into four categories:
claims limited by the DNA sequence encoding human or monkey EPO (claims 14, 17, 18, 39, 45, 46 and 55);
claims limited to variations of those sequences (claims 33 and 34);
claims that are not limited to human or monkey EPO (claims 1, 33 and 48); and
claims to an antibody recognising small parts of those sequences (claim 48).
Claim 1 is in these terms:
“A purified and isolated polypeptide having the primary structural conformation and one or more of the biological properties of naturally-occurring erythropoietin and characterized by being the product of procaryotic or eucaryotic expression of an exogenous DNA sequence.”
The Deputy Commissioner’s decision
The essence of the Deputy Commissioner’s decision on the fair basing issue is contained in the following paragraphs (CB133):
“The attack on fair basis is essentially that the claims should be limited to the specific sequences of tables 5 and 6, to methods for producing those sequences, and to variants of those sequences specifically referred to.
Tables 5 and 6 disclose the specific DNA sequences for human and monkey erythropoietins. The specification also teaches that as a result of the invention DNA hybridization processes can be used to locate the erythropoietin gene position “in the human, monkey and other mammalian species[’] chromosomal map”. This statement is made presumably in reliance upon the well-known substantial homology of gene sequences across species. Further, it is well known that there is a redundancy in the DNA coding for any particular amino acid; and that one can make conservative substitutions for amino acids without making significant changes in the properties of the protein. It seems to me that, properly considered, the discovery of a natural DNA sequence is tantamount to the discovery of a class of compounds - which class would be readily understood by a person skilled in the art. Accordingly I am satisfied that there is sufficient teaching to provide a fair basis to claims to erythropoietin unlimited either by species or specific structure. (And I would also observe that if it was subsequently found that a particular variation of the sequence gave rise to new and surprising results, the law of selections would apply.)”
This is a convenient point to note the way I have approached the Deputy Commissioner’s decision. The appeal is of course a complete rehearing and included a great body of evidence which was not before the Deputy Commissioner. However I have found the Deputy Commissioner’s reasons helpful as providing a conceptual framework for the complex and technical issues in this case.
Onus and Standard of Proof
It was not disputed that Genetics, as opponent, bore the onus of proof. In reality this is an original proceeding: Kaiser Aluminium & Chemical Corporation v The Reynolds Metal Co (1969) 120 CLR 136 at 142. The principles governing refusal of a patent application are stated in Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232 at 244-5:
“... it is well settled that the Commissioner ought not to refuse acceptance of an application and specification unless it appears practically certain that letters patent granted on the Specification would be held invalid. As Menzies J. has pointed out, he will not normally have before him the material necessary for the formation of a concluded opinion. Moreover, whereas refusal of acceptance is final, acceptance is not: the application may be opposed after acceptance on any of the grounds mentioned in s.56, and, if a patent is granted, its validity is open to attack in proceedings for infringement or for revocation. So, in McDonald v. Commissioner of Patents [(1913) 15 CLR 713] (a case in which the validity of a patent granted on the specification may be thought to have been very doubtful) this Court allowed an appeal from the Commissioner, Griffith C.J. saying: ‘I think that it is only in a clear case, where it is obvious that a patent cannot be granted, that the Commissioner should reject an application altogether’ [at 717].
On the other hand, it is not to be overlooked that the Commissioner has a duty to the public as well as to the applicant for a patent, and, if it appears manifest that a valid patent could not be granted, the Commissioner not merely has power, but is under a duty, to reject the application under s.46.”
Similarly in Farbwerke Hoechst Aktiengesellschaft Vormals Meister Lucius & Bruning v Commissioner of Patents (1971) 45 ALJR 235 at 239 Gibbs J said:
“In the case of an appeal against a refusal by the Commissioner to accept a specification, the Appeal Tribunal will allow the appeal unless it clearly appears that a patent granted on the specification will be invalid, because a refusal is final whereas an acceptance is not”.
In Martin v Scribal Pty Ltd (1954) 92 CLR 17 at 97, Taylor J said:
“... it is right to construe a claim with an eye benevolent to the inventor and with a view to making the invention work - this is an application of the old doctrine ut res magis valeat quam pereat.”
There was some argument about a passage in the joint judgment of Stephen and Mason JJ in Olin Corporation v Super Cartridge Co Pty Ltd (1977) 14 ALR 149 at 172 where their Honours, speaking of the patent then in suit, said:
“This is not a case in which the inventor has conceived of and brought into existence an entirely new or revolutionary product which stands so far in advance of, and apart from, previous developments that it works a radical transformation in the field in which it is introduced, as, for example, the invention of the electric light globe. In such a case the inventive step or the merits of the invention may be so great that it may be proper to reward the patentee with a monopoly in the product or article, unlimited by reference to the actual process according to which it is produced. Then it may be said the monopoly conferred is proportionate to the great benefit which has been given to the public by the patentee’s disclosure. Such a case, so it seems to us, is far removed from the present where the invention, though possessing the requisite element of inventive ingenuity to support the process claim, is not of a kind to justify a claim to the product whether made pursuant to the process or not.”
Although Barwick CJ agreed generally with Stephen and Mason JJ (at 151) it may be doubted whether he agreed with the passage just stated. His Honour said (at 152):
“The question whether the claim is fairly based is not to be resolved, in my opinion, by considering whether a monopoly in the product would be an undue reward for the disclosure. Rather, the question is a narrow one, namely whether the claim to the product being new, useful, and inventive, that is to say, the claim as expressed, travels beyond the matter disclosed in the specification.”
The remaining member of the Court, Gibbs J, did not discuss the point.
Counsel for Genetics did not shrink from submitting that the passage in the judgment of Stephen and Mason JJ was wrong. He contended, correctly I think, that it was not part of the ratio in Olin. Also, in my view, it would add a complicating new issue to cases of this nature if the Commissioner, or the Court on appeal or in a revocation suit, had to make a finding as to whether an invention worked a “radical transformation”. For example, it might well be said that the Amgen patent, although undoubtedly of great therapeutic benefit and commercial importance, does not rank with the electric light globe, or the steam engine, or the printing press. It is not a case where the inventor is the first to set foot on a new continent. Rather, the evidence discloses that recombinant technology in general was well known at the priority date but there was a race to obtain a recombinant version of this particular protein.
In any event, I do not approach the case on the basis that the Amgen patent discloses any kind of super invention in the sense discussed. The question is whether the specification provided a “real and reasonably clear” disclosure of the invention: see generally CCOM Pty Ltd v Jiejing Pty Ltd (1994) 122 ALR 417 at 432-437.
As to clarity, the claim must
“define clearly and with precision the monopoly claimed so that others may know the exact boundaries of the area within which they will be trespassers. Their primary object is to limit and not to extend the monopoly.
...
The claims must undoubtedly be read as part of the entire document, and not as a separate document; but the forbidden field must be found in the language of the claims and not elsewhere.”
Electric & Musical Industries Ltd v Lissen Ltd (1938) 56 RPC 23 at 39. See also Martin v Scribal Pty Ltd (1954) 92 CLR 17 at 59.
Applicable Statute
The parties were not in agreement as to whether s 40 of the 1952 Patents Act or s 40 of the 1990 Patents Act was applicable. Despite some drafting differences, it was accepted that both had the same effect. I agree with counsel for Genetics that the 1952 Act is applicable. The validity of a patent application which was commenced prior to the commencement date of the 1990 Act (30 April 1991) and not finally dealt with or determined by that date is by virtue of the provisions of Ch 23 of the 1990 Act to be determined under the 1952 Act: see especially s 234(2) and (3).
Section 40 of the 1952 Act is as follows:
“40(1) A complete specification -
(a)shall fully describe the invention, including the best method of performing the invention which is known to the applicant; and
(b) shall end with a claim or claims defining the invention.
(2) The claim or claims shall be clear and succinct and shall be fairly based on the matter described in the specification.”
Priority date
Of a number of possible priority dates, the earliest is 13 December 1983, that being the earliest of a number of claimed priorities based on United States patent applications. In the circumstances of the present case it is in the interests of Amgen to have as late a priority date as possible (the later the date, the more knowledge available to the skilled addressee and the less difficulty in working the invention). Since 13 December 1983 was accepted, tacitly at least, by both sides, I shall treat that as the priority date.
Skilled Addressee
The relevant skilled addressee is a molecular biologist skilled in the production of recombinant proteins.
Witnesses
All witnesses were thoroughly and skillfully cross-examined. I was particularly impressed with the evidence of Professors Mattick, Gray and Schofield who were called on behalf of Amgen. I feel confident in relying on their testimony.
Genetics’ Primary Case - Fair Basing
Genetics argued that the claims are “avariciously” broad because they purport to include human EPO cDNA which is not disclosed by the specification. It was said that the invention only disclosed
(i)the isolation from a genomic library of the gene that encodes human EPO; and
(ii)the isolation from a cDNA library of the gene that encodes monkey EPO.
and the subsequent expression of these proteins in host cells.
There was said to be no relevant disclosure of the isolation of the gene that encodes human EPO by the use of a cDNA library.
Conclusion on Genetics’ Primary Case
I accept Amgen’s argument that the object of the invention was to produce biologically active EPO in sufficient quantities for therapeutic use. The problem was that no one knew the sequence of the DNA encoding for EPO. Once the sequence was disclosed in the specification, the skilled addressee could use that sequence to produce EPO with existing technology.
That sequence is disclosed in Table VI. The intron/exon boundaries in the gDNA are disclosed and identified. They are identified by the use of monkey cDNA and two boundaries are confirmed by comparison with the tryptic fragments of urinary EPO set out in Table I.
One of the splice sites was further verified by sequencing of the human cDNA clone (see p 49 of the specification). Further, the splice site at exon 3/4 was at a region of perfect homology between the monkey and the human sequences (Schofield CB3199). Table I also provided sequence confirmation for about 75 per cent of the protein. In addition, N-terminal sequencing of the CHO produced EPO was identical to that of the naturally occurring urinary EPO. The coding sequence is correct from its 5’ end to its 3’ end and produced rEPO (recombinant EPO) with the full range of biological activity tested. Finally, in addition to the coding region, Table VI discloses substantial 5’ and 3’ untranslated regions that provide a description of a wide population of cDNAs that could be isolated from transfected host cells (see Symons T161-162). As Professor Symons acknowledged, one could easily tailor the 5’ and 3’ ends of the genomic DNA (as was done in Example 7B), insert that modified gDNA into a COS or CHO cell and isolate back out a cDNA that contained the coding region and the tailored 5’ and 3’ ends.
The evidence clearly demonstrates that a skilled addressee would have relied on the information in Table VI as disclosing the human cDNA sequence. In particular, I accept the evidence of Professor Mattick:
“The patent specification, however, unequivocally states that the inventor made cDNA encoding human EPO, sequenced it, and used that sequence to confirm an amino acid difference between human and monkey EPO, both of which are disclosed in the patent specification.” (CB 2977)
“The real value of a cDNA sequence is the information which it reveals. This information is provided in Table VI in the patent specification and can be used to obtain a physical copy of the cDNA if required, using standard techniques known to persons ordinarily skilled in the field.” (CB 3025)
“The essential value of a ‘cDNA’ sequence is not as a physical entity but in the information it contains about the DNA protein-coding sequence. This information can be obtained by generating a cDNA and sequencing it, as did the inventor of the [Amgen] patent application. Because this information originates from the genomic DNA, this same information is provided by a genomic sequence when the intron and exon boundaries are provided, as they are in the patent specification.” (CB 2977)
See also Professor Schofield (CB3191, T636 and T640) and Professor Klinken (CB2834).
The information the patent gives - an analogy
In the course of argument there was some discussion of analogies.
Counsel for Genetics likened the Amgen case to that of a treasure hunter who discovers a map giving directions to buried treasure on a desert island. Counsel said that Amgen were trying to prevent anyone else from obtaining the treasure, even by a route different from the one shown on the map.
However a more apt analogy in my view is that of treasure in a castle. The castle has many gates, each with a combination lock (this being a modern castle). The combination for each lock is the same. Anyone who knows the combination can enter the castle. Finding the treasure may require some further time and trouble but this will merely be a matter of carefully searching through every room and cupboard in the castle. The critical knowledge is the combination of the locks. Without that, it is impossible to enter the castle. Once you have that, entry can be obtained through any gate. With reasonable time and effort the treasure will be discovered.
I think the protein coding sequence, the essential information contained in Table VI, is analogous to the combination of the castle locks.
To extend the analogy, it may be that the first time Amgen entered the castle the gate was reached by a particularly difficult route. It was necessary to swim across a crocodile-infested moat. But once the combination is known anyone can simply walk across the drawbridge and open the main gate.
Thus once the protein coding sequence is known, the same route (gDNA) does not have to be followed. Nor need the tissue source be the same.
Biogen Inc v Medeva Plc
Important guidance is provided by the recent decision of the House of Lords in Biogen Inc v Medeva plc [1997] RPC 1. As far as I am aware, this is the first reported decision on patent litigation in the area of genetic engineering at ultimate appeal level in the United Kingdom or Australia.
The patent in suit was for an artificially constructed molecule of DNA carrying a genetic code which, when introduced into a suitable host cell, would cause that cell to make antigens of the virus hepatitis B (HBV).
One of the issues in the case was whether, for the purposes of fixing the priority date, the invention was supported by matter disclosed in an earlier patent application called Biogen 1: Patents Act 1977 (UK) s 5(2)(a). According to Asahi Kasei Kogyo KK’s Application [1991] RPC 485, this meant that for matter to be capable of supporting an invention it had to disclose the invention in a way which would enable it to be performed by a person skilled in the art, in other words there had to be “enabling disclosure”.
Lord Hoffmann, with whom all other members of the House agreed, commenced his discussion of this issue by noting a decision of the Technical Board of Appeal of the EPO in Genentech I/Polypeptide expression (T292/85) [1989] OJ EPO 275 (EPO here stands not for erythropoeitin but for European Patent Office). Lord Hoffmann said of that case (at 48-49):
“... the applicants had invented a general principle for enabling plasmids to control the expression of polypeptides in bacteria and there was no reason to believe that it would not work equally well with any plasmid, bacterium or polypeptide. The patent was therefore granted in general terms.
...In fact the Board in Genentech I/Polypeptide expression was doing no more than apply a principle of patent law which has long been established in the United Kingdom, namely, that the specification must enable the invention to be performed to the full extent of the monopoly claimed. If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them.
Thus if the patentee has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect: see May & Baker Ltd. v. Boots Pure Drug Co. Ltd. (1950) 67 R.P.C. 23, 50. On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.
Since Genentech I/Polypeptide expression the E.P.O. has several times reasserted the well established principles for what amounts to sufficiency of disclosure. In particular, in Exxon/Fuel Oils (T 409/91) [1994] O.J. E.P.O. 653, paragraph 3.3, the Technical Board of Appeal said of the provision in the European Patent Convention equivalent to section 14(5)(c) of the Act:
‘Furthermore, Article 84 EPC also requires that the claims must be supported by the description, in other words, it is the definition of the invention in the claims that needs support. In the Board’s judgment, this requirement reflects the general legal principle that the extent of the patent monopoly, as defined by the claims, should correspond to the technical contribution to the art in order for it to be supported, or justified.’” (Bold emphasis added)
Before the trial judge (Aldous J) and in the Court of Appeal the issue was regarded as being whether Biogen I disclosed a method of making the antigen HBsAG as well as the antigen HBcAG. Lord Hoffmann’s view was that the Court of Appeal should not have disturbed the affirmative answer of Aldous J to that question. However his Lordship continued (at 50):
“But the fact that the skilled man following the teaching of Biogen 1 would have been able to make HBcAg and HBsAg in bacterial cells, or indeed in any cells, does not conclude the matter. I think that in concentrating upon the question of whether Professor Murray’s invention could, so to speak, deliver the goods across the full width of the patent or priority document, the courts and the E.P.O. allowed their attention to be diverted from what seems to me in this particular case the critical issue. It is not whether the claimed invention could deliver the goods, but whether the claims cover other ways in which they might be delivered: ways which owe nothing to the teaching of the patent or any principle which it disclosed.
It will be remembered that in Genentech I/Polypeptide expression the Technical Board spoke of the need for the patent to give protection against other ways of achieving the same effect ‘in a manner which could not have been envisaged without the invention’. This shows that there is more than one way in which the breadth of a claim may exceed the technical contribution to the art embodied in the invention. The patent may claim results which it does not enable, such as making a wide class of products when it enables only one of those products and discloses no principle which would enable others to be made. Or it may claim every way of achieving a result when it enables only one way and it is possible to envisage other ways of achieving that result which make no use of the invention.
One example of an excessive claim of the latter kind is the famous case of O’Reilly v. Morse (1854) 56 U.S. (15 How.) 62 in the Supreme Court of the United States. Samuel Morse was the first person to discover a practical method of electric telegraphy and took out a patent in which he claimed any use of electricity for ‘making or printing intelligible characters, signs, or letter, at any distances’. The Supreme Court rejected the claim as too broad. Professor Chisum, in his book on Patents (vol. 1, § 1.03[2]) summarises the decision as follows:
‘Before Morse’s invention, the scientific community saw the possibility of achieving communication by the “galvanic” current but did not know any means of achieving that result. Morse discovered one means and attempted to claims all others.’” (Bold emphasis added)
Lord Hoffmann then applied those principles to the Biogen 1 patent as follows (at 51-52):
“I return therefore to consider the technical contribution to the art which Professor Murray made in 1978 and disclosed in Biogen 1. As it seems to me, it consisted in showing that despite the uncertainties which then existed over the DNA of the Dane particle - in particular, whether it included the antigen genes and whether it has introns - known recombinant techniques could nevertheless be used to make the antigens in a prokaryotic host cell. As I have said, I accept the judge’s findings that the method was shown to be capable of making both antigens and I am willing to accept that it would work in any otherwise suitable host cell. Does this contribution justify a claim to a monopoly of any recombinant method of making the antigens? In my view it does not. The claimed invention is too broad. Its excessive breadth is due, not to the inability of the teaching to produce all the promised results, but to the fact that the same results could be produced by different means. Professor Murray had won a brilliant Napoleonic victory in cutting through the uncertainties which existed in his day to achieve the desired result. But his success did not in my view establish any new principle which his successors had to follow if they were to achieve the same results. The inventive step, as I have said, was the idea of trying to express unsequenced eukaryotic DNA in a prokaryotic host. Biogen 1 discloses that the way to do it is to choose the restriction enzymes likely to cleave the Dane particle DNA into the largest fragments. This, if anything, was the original element in what Professor Murray did. But once the DNA had been sequenced, no one would choose restriction enzymes on this basis. They would choose those which digested the sites closest to the relevant gene or the part of the gene which expressed an antigenic fragment of the polypeptide. The metaphor used by one of the witnesses was that before the genome had been sequenced everyone was working in the dark. Professor Murray invented a way of working with the genome in the dark. But he did not switch on the light and once the light was on his method was no longer needed. Nor, once they could use vectors for mammalian cells, would they be concerned with the same problem of introns which had so exercised those skilled in the art in 1978. Of course there might be other problems, but Biogen 1 did not teach how to solve them. The respondents Medeva, who use restriction enzymes based on knowledge of the HBV genome and mammalian host cells, owe nothing to Professor Murray’s invention.” (Non-italicised emphasis in original; bold emphasis added).
A critical feature of the case for present purposes is that the Biogen 1 patent did not disclose the coding sequence. In narrating the state of the art at the relevant time, Lord Hoffmann said (at 38):
“In 1978, however, the HBV genome had not yet been sequenced. A reliable technique for sequencing had been invented by Professor Gilbert, but it was laborious and slow. It was not until six months after the filing of Biogen 1 that the whole genome was sequenced by Valenzuela and others in the University of California at San Francisco (Nature, Vol. 280, 815-819). The genes which coded for the antigens were found to have no introns. It is because of this discovery and other advances in the state of the art that Biogen conceded that, by the date of its European filing [21 December 1979], the method by which HBV antigens could be made was obvious. But the information was not available in 1978.”
The inventor had purified some DNA from a Dane particle and cut it into fragments with restriction enzymes chosen to digest the DNA at as few sites as possible. (The Dane particle had been discovered by D S Dane et al in 1970. It is a circular molecule of DNA in a protein core surrounded by a protein surface and is the infective agent of HBV.) The inventor then employed established techniques of recombinant DNA technology to ligate the fragments to a ready-made and commercially available vector pBR322 and introduce that to E.coli.
The principal claim in the patent was, as Lord Hoffmann pointed out (at 40), for any recombinant DNA molecule which expressed the genes of any HBV antigen in any host cell. Moreover the invention had claimed a generalisation of the method actually used. As Lord Hoffmann said (at 40) the inventor
“... had made his DNA molecule from a standard pBR322 plasmid and large fragments from Dane particle DNA, chosen simply on the basis that they should be large. This was a technique imposed upon him by lack of information about the coding sequences. Thereafter, he employed conventional means to express the DNA in a conventional bacterial host. The claim was for any method of making a DNA molecule which would achieve the necessary expression.”
The fundamental difference which distinguishes the present case from Biogen is that in the Amgen patent the coding sequence is disclosed. The patent thus discloses a “principle capable of general application” and discloses a beneficial property which is common to the class. It cannot be said of it that it “discloses no principle which would enable other products [of the class] to be made”.
Source of Tissue
Genetics argued that it was critical for the production of EPO via the human cDNA route to have an “enriched” human tissue source, that is to say a cell or cell type which was, at the time, producing EPO mRNA in quantities which could be reliably detected. It was contended that at the priority date such a tissue was not identified and therefore a cDNA library which could contain EPO cDNA was not available.
However the evidence shows that at the priority date foetal liver was recognised as a source of human EPO: see the paper by Professor Congote of McGill University, Montreal published in 1977 (CB 2880) and also Zanjani et al 1977 (CB 2887), and 1981 (CB 1183) and Sherwood (CB1621) which although published in 1984 reviews scientific knowledge which had been in existence for some time and would have been available to the skilled addressee in 1983.
But, in any case, with the sequence information disclosed in the Amgen patent a reliable probe could be created to screen tissues in which EPO was being made at quite low levels, such as adult human kidney. Further, non-human cells (eg COS-1 or CHO cells) transfected with human EPO gDNA all became suitable sources from which EPO mRNA might be extracted: Professor Klinken (CB2836), Professor Mattick (CB2996, 3003), Professor Schofield (T652-4).
Difficulty of Production
Genetics argued that, assuming a suitable source tissue was available, obtaining human EPO cDNA would not have been straightforward or reliable. For example, the mRNA might not be correctly spliced, or might be otherwise aberrant. Considerable evidence was presented concerning two attempts to isolate a human EPO cDNA from cells transfected with gDNA. One was within the laboratories of Amgen by Dr Lin (p 55 and Figure 3 of specification and confidential Exhibit PLM 21). The other was that of Wojchowski et al (CB 2124). In both cases the resultant cDNA was unusual in some respect. Significantly however, this could be quickly recognized by reference to the sequence presented in the patent and steps taken using routine methods available in 1983 to obtain a complete and uninterrupted protein coding sequence. In the case of Wojchowski et al this was the construction of a hybrid sequence composed partly of cDNA and partly of gDNA. A substantial body of evidence was presented therefore that human cDNA or DNA sequences containing an uninterrupted coding region could be obtained: Professor Mattick (CB 2989), Professor Klinken (CB 2841-2), Professor Gray (CB 2679, 2681), Professor Schofield (CB 3185-6). I find this evidence persuasive. Genetics has not discharged the onus on this issue.
And in any case, once the sequence is disclosed the skilled addressee need not follow any particular route to the invention, but may take the most convenient one: Professor Mattick (CB 2978-8, 2995), Professor Schofield (CB 3193), Professor Symons (T285, 295). Once you have the combination, it is not necessary to brave the crocodiles in the moat again.
There was also significance in the fact that Genetics produced no evidence of a failed attempt to make the invention work in accordance with the specification. The nearest approach was the evidence of Dr Olsen, an employee of an American firm called Human Genomic Sciences (HGS). In 1993 HGS had constructed over 250 cDNA libraries representing normal and malignant tissue, foetal and adult. At the request of a German licensee of Genetics they searched in those libraries but were unable to identify EPO.
However, HGS did not use a radio labelled probe specific for EPO to isolate an EPO cDNA as is taught by the patent (T354). Furthermore the majority of the libraries were constructed from tissue sources that were not known to express EPO. In fact no effort was made to confirm that the tissues had first made EPO mRNA (T354-6). Moreover the primer design was very poor (T423).
In any case it is not disputed that human EPO mRNA is rare. The point is that the invention enables you to find it in a library using routine screening methods even though the mRNA may be very rare indeed: Mattick (T440-1).
The meaning of “cDNA”
There was considerable evidence and argument as to the meaning which the expression “cDNA” would convey to a skilled addressee at the priority date. The Genetics case was that the expression meant, and meant only, a physical entity, that is to say a DNA molecule that is the product of a laboratory process in which mRNA is copied into DNA using the enzyme reverse transcriptase. The resultant DNA molecule contains the entire protein coding region and very substantial parts of the 5’ and 3’ untranslated sequences.
Amgen did not dispute that “cDNA” could bear the meaning contended by Genetics. However Amgen argued that the expression could, according to context, also bear several secondary meanings including not only DNA molecules but also information - in this case the protein coding sequence of EPO.
In construing language, whether technical or trade terms or ordinary English words, context is everything. A party who asserts that a word can bear a particular meaning (which his opponent accepts) will often find it difficult to establish that the word can never, in any context, bear some other meaning for which his opponent contends. As Dixon J said in Herbert Adams Pty Ltd v Federal Commissioner of Taxation (1932) 47 CLR 222 at 228-229:
“... it is always less difficult to show that a word has a wider meaning than it is to establish a specialized use. For an extension of meaning involves no abandonment of the use in respect of things to which it would in any case apply; but a uniformly restricted application among any class of persons is necessary in order to establish that it has among them a narrower meaning and that meaning only.”
On the evidence, I do not think Genetics has made out its case on this issue.
More fundamentally however, the question of meaning was approached by both sides as though a finding as to which meaning “cDNA” bore would resolve a legal issue. In a forensic context, a dispute as to the meaning of words frequently has such a consequence. For example, in Herbert Adams the issue was whether “sponge” fell within the meaning of the term “cakes” in sales tax legislation. The High Court held that it did. As a result, the goods were not exempt from sales tax.
I am not persuaded that the present case is of that character. While the term “cDNA” appears on a few occasions in the Amgen patent, including in the claims, it does not do so in any context where it could be said the skilled addressee would or would not be able to work the invention, depending on the meaning “cDNA” conveyed. In other words, this is not a case where the specification says “take cDNA and do such and such with it” and the Court is asked to find that “cDNA” would convey to a skilled addressee meaning X and that, given that meaning, the addressee could not produce something answering the description of the claims. Rather I think the question is whether, given the information in the specification, and regardless of what label is put on that information, the skilled addressee could produce the invention claimed.
Clarity
Genetics argued that a number of the claims lacked clarity.
It was said that the use of the term “primary structural conformation” was not clear. I accept the contention of counsel for Amgen that the term “primary structural conformation” is clear and means “amino acid sequence”. The amino acid sequence of naturally-occurring human and monkey EPO is disclosed in the specification in Tables V, VI and VII. The skilled addressee would understand the term “primary structural conformation” to mean the amino acid sequences of human EPO and monkey EPO disclosed in those Tables: Professor Klinken (T609-612).
The skilled addressee would further have understood claim 1 (and the other polypeptide claims, namely, 2-13, 16, 38, 45-54 and 56) to include amino acid sequences of EPO of additional species which could be obtained by using a probe based on the nucleotide sequences disclosed in the Tables, using standard techniques available in the art in December 1983: Genetics concession (T250), Professor Mattick (CB3017), Professor Schofield (CB3199).
In addition to having an amino acid sequence of naturally occurring EPO, a polypeptide of claim 1 must also have one or more of the biological properties of EPO. The hearing officer considered that the term “biological property” was unclear. Accordingly Amgen seek an amendment which would insert at p 18 line 14 of the specification the following:
“The term ‘biological property of naturally-occurring erythropoietin’ is herein defined to include the in vivo or in vitro activity of immunological function or characteristic of naturally-occurring erythropoietin which (1) causes bone marrow cells to increase production of reticulocytes or red-blood cells, or (2) causes bone marrow cells in culture to increase iron uptake or hemoglobin synthesis, or (3) enables an erythropoietin-specific immunological response or production of erythropoietin-specific antibodies.”
In my opinion this amendment is necessary and appropriate and the patent should be amended accordingly.
A skilled addressee would have been able to determine whether a polypeptide had such a property using standard tests for EPO activity, namely, radioimmunassay, in vitro assay and in vivo assay (as disclosed in the Specification), as at December 1983: Professor Mattick (CB3003-5).
The additional and last integer of the claim, that is, “characterised by being the product of procaryotic or eucaryotic expression of an exogenous DNA sequence” is a description of the physical characteristics of the polypeptides of the claim. This may be referred to as a “limitation by result”: see No-Fume Ltd v Frank Pitchford & Co Ltd (1935) 52 RPC 231, 238. Thus the claim is not a process claim.
Genetics also complained of lack of clarity in claims 33 and 34 which were as follows:
“33. A DNA sequence coding for a polypeptide analog of naturally-occurring erythropoietin.
34. A DNA sequence coding for [phe15] hEPO, [Phe49] hEPO, [Phe145] hEPO, [His7] hEPO, [Asn2des-Pro2 through Ile6] hEPO, [des-Thr163 through Arg166] hEPO or [D27-55] hEPO.”
However the evidence establishes that a skilled addressee could routinely have made substitutions to the amino acid sequences and thereby obtained EPO analogues or variants: Professor Mattick (CB2989-90, 3024, 3022-5) Professor Firkin (CB2328-9).
Glycoproteins - Claim 39
On pp 64-65 of the specification it is stated:
“A preliminary attempt was made to characterize recombinant glycoprotein products from conditioned medium of COS-1 and CHO cell expression of the human EPO gene in comparison to human urinary EPO isolates using both Western blot analysis and SDS-PAGE. These studies indicated that the CHO-produced EPO material had a somewhat higher molecular weight than the COS-1 expression product which, in turn, was slightly larger than the pooled source human urinary extract. All products were somewhat heterogeneous. Neuraminidase enzyme treatment to remove sialic acid resulted in COS-1 and CHO recombinant products of approximately equal molecular weight which were both nonetheless larger than the resulting asialo human urinary extract. Endoglycosidase F enzyme (EC 3.2.1) treatment of the recombinant CHO product and the urinary extract product (to totally remove carbohydrate from both) resulted in substantially homogeneous products having essentially identical molecular weight characteristics.
Purified human urinary EPO and a recombinant, CHO cell-produced, EPO according to the invention were subjected to carbohydrate analysis according to the procedure of Ledeen, et al. Methods in Enzymology, 83 (Part D), 139-191 (1982) as modified through use of the hydrolysis procedures of Nesser, et al., Anal.Biochem., 142, 58-67 (1984). Experimentally determined carbohydrate constitution values (expressed as molar ratios of carbohydrate in the product) for the urinary isolate were as follows: Hexoses, 1.73; N-acetylglucosamine, 1; N-acetylneuraminic acid, 0.93; Fucose, 0; and N-acetylgalactosamine, 0. Corresponding values for the recombinant product (derived from CHO pDSVL-gHueEPO 3-day culture media at 100 nM MTX) were as follows: Hexoses, 15.09; N-acetylglucosamine, 1; N-acetylneuraminic acid, 0.998; Fucose, 0; and N-acetylgalactosamine, 0. These findings are consistent with the Western blot and SDS-PAGE analysis described above.
Glycoprotein products provided by the present invention are thus comprehensive of products having a primary structural conformation sufficiently duplicative of that of a naturally-occurring erythropoietin to allow possession of one or more of the biological properties thereof and having an average carbohydrate composition which differs from that of naturally-occurring erythropoietin.”
Claim 39 is for:
“39. A non-naturally occurring glycoprotein product of the expression in a non-human eucaryotic host cell of an exogenous DNA sequence consisting essentially of a DNA sequence encoding human erythropoietin said product possessing the in vivo biological property of causing human bone marrow cells to increase production of reticulocytes and red blood cells and having an average carbohydrate composition which differs from that of naturally occurring human erythropoietin.”
It is now common ground that the figures for Hexoses (1.73 and 15.09) are an error. It is not common ground that they would have been so recognised at the priority date. Amgen had the tests done by an expert glycobiologist, Dr Yu, who apparently did not pick up the error.
Genetics argued that the passage quoted on pp 64-65 meant that all the glycoprotein products of the invention (i.e. recombinant proteins expressed in COS-1 or CHO cells although not in bacteria) must have as one of their three characteristics “an average carbohydrate composition which differs from that of naturally-occurring erythropoietin”. Therefore, it was said, there was no support for any claim to a polypeptide product which does not exhibit the feature of an average carbohydrate composition which differs from that of naturally occurring EPO. No claims other than claim 39 deal with this feature. Hence, it was said, they are not fairly based. Claim 39 does deal with it, but in an unclear way because it does not give any guide as to the extent of the difference.
I do not agree with the Genetics construction argument. The expression “comprehensive of” can ordinarily indicate inclusion of something within a greater whole. In the specification I think it is used in that sense. The specification is not saying that this particular feature is an essential element of all products of the invention.
However there remains the problem of the incorrect hexose data and the suggested lack of clarity in claim 39.
Amgen sought an amendment. In its final form this amendment had the effect of omitting the paragraph on p 65 commencing “Purified human urinary EPO ...” and concluding with “... analysis described above”. In other words the specification as amended would only refer to the Western blot and SDS-PAGE analysis as a standard of comparison.
But this would posit a vague and uncertain criterion expressed in terms of “somewhat higher molecular weight” and “slightly larger” size. There is no practical utility since such a test would rely on an analytical procedure which is known to have a degree of imprecision and require direct comparison to human urinary erythropoietin, a substance that is particularly difficult to obtain. (As to this see Professor Symons T283, Dr Browne T516.) Since there is no other test disclosed relative to claim 39 I think it should be removed from the patent, along with the passage commencing with “A preliminary attempt ...” on p 64 and ending with “... naturally-occurring erythropoietin” on p 65.
Cross-Appeal
Amgen formally cross-appealed against the Deputy Commissioner’s rejection of some claims, but was content to accept the amendments proposed.
I shall therefore order that, in addition to the insertion of the definition of “biological properties” and the deletion of claim 39 and the associated passage at pp 64-65 already referred to, amendments be made in terms of Amgen’s notice of proposed amendments dated 21 May 1998.
Costs
There will be an order that Genetics pay Amgen’s costs, including reserved costs, of the appeal, subject to a modest reduction for Amgen’s failure on the claim 39 issue. I would assess that reduction as 10 per cent. There will be no order for costs on the cross-appeal.
Assessor
As a consequence of my ruling in Genetic Institute Inc v Kirin-Amgen Inc (No. 2) (1997) 149 ALR 247 an assessor was appointed under s 217 of the Patents Act 1990 (Cth). The assessor was Professor Ross Coppel MBBS (Melb), BMed Sc (Melb), DTM&H (Lon), PhD (Melb), MASM, Head of Department of Microbiology, Monash University.
The scientific issues in this case were said by counsel opposing the appointment of an assessor to be “not difficult” (see 149 ALR at 251). They turned out to be very difficult indeed, at least for me. I note that in Biogen the House of Lords had the assistance, described by Lord Goff of Chieveley as “invaluable”, of two expert advisers ([1997] RPC at 31), a description which certainly applies to the assistance provided by Professor Coppel. I record my gratitude for his help.
I certify that this and the preceding thirty-one (31) pages are a true copy of the Reasons for Judgment herein of the Honourable Justice Heerey
Associate:
Dated: 25 June 1998
Counsel for the Applicant: Mr B Caine Solicitor for the Applicant: Davies Collison Cave Counsel for the Respondent: Dr A Bennett SC with Ms K Howard Solicitor for the Respondent: Sprusons: Solicitors Date of Hearing: 4 - 22 May 1998 Date of Judgment: 25 June 1998
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