New England Biolabs, Inc v F. Hoffmann-La Roche AG

THE PATENT APPLICATION 9 The complete specification of the Patent Application says that the invention claimed relates to a purified thermostable enzyme. In one embodiment, the enzyme is DNA polymerase purified from Thermus aquaticus and has a molecular weight of about 86,000 - 95,000 daltons. In another embodiment of the invention claimed, the enzyme is produced by a recombinant DNA means. It is claimed that the invention also relates to a process for amplifying existing nucleic acid sequences. More specifically, it relates to a process for producing any particular nucleic acid sequence from a given sequence of DNA or RNA in amounts that are large compared to the amount initially present, so as to facilitate utilisation and/or detection of the sequences, using a thermostable enzyme to catalyse the reaction. 10 The complete specification as lodged comprised 158 pages together with eight pages of figures. It is unnecessary for present purposes to say a great deal about the specific detail of the body of the specification or the detailed claims. However, it is desirable to say something about the structure of the complete specification and the principal claims. 11 The body of the complete specification contains the following headings: Background art Disclosure of invention Brief description of the drawings Best mode and other modes for carrying out the invention Examples i to xviii Claims 12 There are then 101 claims. Relevantly, those claims include the following principal claims: ' 1. A purified thermostable DNA polymerase isolated from a Thermus species which catalyzes combination of nucleoside triphosphates to form a nucleic acid strand complementary to a nucleic acid template strand, said polymerase having a molecular weight of about 86,000 to 95,000 daltons as compared to phosphorylase B by SDS-PAGE. … 8. A stable enzyme composition comprising a thermostable DNA polymerase in a buffered solution containing one or more non-ionic polymeric detergents. … 34. A recombinant DNA comprising at least a sequence encoding all or part of a thermostable DNA polymerase from Thermus aquaticus, said thermostable DNA polymerase when isolated from said Thermus aquaticus being characterized as having a molecular weight of about 86,000 to 95,000 daltons as compared to phosphorylase B by SDS-PAGE. … 75. A method for purifying a thermostable polymerase which comprises treating an aqueous mixture containing said thermostable polymerase with a hydrophobic interaction support under conditions which promote hydrophobic interactions and eluting said thermostable polymerase from said support with a solvent which attenuates hydrophobic interactions. … 84. A method for purifying a recombinant thermostable polymerase produced in a heat labile host cell which method comprises treating the cell lysate with temperatures in the range of at least 45°C to about 90°C and recovering the thermostable polymerase activity.' 13 Other claims are dependent upon those five principal independent claims. Specifically, Claim 3 is in the following terms: ' 3. The thermostable DNA polymerase of Claim 1… wherein said thermophilic bacterium is Thermus aquaticus.' 14 Claims 86 to 101 have been described as omnibus claims. For present purposes it is necessary to have regard only to Claim 86, which is as follows: ' 86. Purified Thermus aquaticus DNA polymerase having a molecular weight of 86,000-95,000 daltons, which enzyme is substantially as hereinbefore described with reference to Example I or Example XIII.'

the PROPOSED AmendmentS 15 NEB contends that the amendments in dispute are precluded by s 104(5) of the Act, which provides that the Commissioner must not allow an amendment that is not allowable under s 102. Section 102 provides as follows: '102 (1) An amendment of a complete specification is not allowable if, as a result of the amendment, the specification would claim matter not in substance disclosed in the specification as filed.

(2) An amendment of a complete specification is not allowable after the relevant time if, as a result of the amendment:

(a) a claim of the specification would not in substance fall within the scope of the claims of the specification before amendment; or (b) the specification would not comply with subsection 40(2) or (3). (2A) For the purposes of subsection (2), relevant time means: (a) in relation to an amendment proposed to a complete specification relating to a standard patent - after the specification has been accepted; or (b) in relation to an amendment proposed to a complete specification relating to an innovation patent - after the Commissioner has made decisions under paragraphs 101E(a) and (aa) in respect of the patent.

(2B) An amendment to a patent request relating to an innovation patent application is not allowable if:

(a) the patent application was provided for in section 79C; and (b) the effect of the proposed amendment would be to convert the application from an application for an innovation patent to an application for a standard patent.

(2C) An amendment of a complete specification relating to a patent is not allowable if:

(a) the patentee or the patentee's predecessor in title failed to ensure the provision to the Commissioner of the information required by subsection 45(3) or section 101D in relation to the patent; and (b) the effect of the proposed amendment would be to remove a lawful ground of objection under paragraph 18(1)(b) or 18(1A)(b) to the specification arising from the existence of some or all of the information not provided.

(3) This section does not apply to an amendment for the purpose of correcting a clerical error or an obvious mistake made in, or in relation to, a complete specification.' 16 The Commissioner's delegate dealt with the amendments in categories. The parties agree that it is appropriate for me to deal with the amendments in the same fashion. 17 There are three categories of amendment that are still in dispute in the appeal, apart from the matter presently before the High Court of Australia. The three areas of the complete specification to which the disputed amendments relate are as follows: (1) the definition of 'thermostable enzyme'; (2) the tense and wording of Examples V, VII, VIII, IX, XI and XIII; (3) the level of purity in Example XIII.

DEFINITION OF THERMOSTABLE ENZYME 19 Under the heading relating to modes for carrying out the invention there are several definitions. The definition 'thermostable enzyme' and the paragraphs that follow it, are as follows: ' As used herein, the term "thermostable enzyme" refers to an enzyme which is stable to heat and is heat resistant and catalyzes (facilitates) combination of the nucleotides in the proper manner to form the primer extension products that are complementary to each nucleic acid strand. Generally, the synthesis will be initiated at the 3´ end of each primer and will proceed in the 5´ direction along the template strand, until synthesis terminates, producing molecules of different lengths. There may be a thermostable enzyme, however, which initiates synthesis at the 5˘ end and proceeds in the other direction, using the same process as described above. The thermostable enzyme herein must satisfy a single criterion to be effective for the amplification reaction, i.e., the enzyme must not become irreversibly denatured (inactivated) when subjected to the elevated temperatures for the time necessary to effect denaturation of double-stranded nucleic acids. Irreversible denaturation for purposes herein refers to permanent and complete loss of enzymatic activity. The heating conditions necessary for nucleic acid denaturation will depend, e.g., on the buffer salt concentration and composition and the length and nucleotide composition of the nucleic acids being denatured, but typically range from about 90 to about 105°C for a time depending mainly on the temperature and the nucleic acid length, typically about 0.5 to four minutes. Higher temperatures may be tolerated as the buffer salt concentration and/or GC composition of the nucleic acid is increased. Preferably, the enzyme will not become irreversibly denatured at about 90 to 100°C.' [emphasis added] 20 The first relevant amendment is to the first sentence of the above extract, to read as follows: 'As used herein, the term "thermostable enzyme" refers to an enzyme which catalyses (facilitates) combination of the nucleotides in the proper manner to form the primer extension products that are complementary to each nucleic acid strand, and is stable to heat and is heat resistant to the extent that it would be effective for the amplification reaction described herein i.e., the enzyme does not become irreversibly denatured (inactivated) when subjected to the elevated temperatures for the time being necessary to effect denaturation of double-stranded nucleic acids.' [emphasis added] 21 Thus, the effect of the amendment, as a matter of syntax, is to reorganise the language and to insert, by way of qualification of the phrase 'is stable to heat and is heat resistant', the words emphasised. As is apparent, the emphasised words already appear in substance in the next succeeding paragraph of the complete specification. 22 NEB contends that, as a result of the amendment, the complete specification would claim content not in substance disclosed in the complete specification as filed and that, as a result of the amendment, certain claims would not in substance fall within the scope of the claims of the complete specification before amendment. NEB says that that is because of the effect of the amendment on the scope of claim 8 and its dependent claims, 9 to 11 inclusive. 23 Each of claims 8 to 11 inclusive relates to a 'stable enzyme composition comprising a thermostable DNA polymerase'. NEB says that, when the definition of 'thermostable enzyme' is not limited to an enzyme that is understood to be conventionally heat resistant, the scope of those claims and Claim 86 is impermissibly broadened. NEB relies on assertions made in a statutory declaration by Renato Morona, a senior research officer in the Department of Molecular Biosciences at the University of Adelaide. 24 Dr Morona's declaration contains the following: 'The term "heat resistant" was a statement of fact and unqualified. However, the term is now qualified such that the enzyme only needs to be heat resistant to the extent that it would be effective for the amplification reaction described. I consider that the normal meaning for heat resistant has been expanded to include enzymes that previously may not have been considered "heat resistant." It is well known in the art that the temperature and time necessary to effect denaturation of double-stranded nucleic acids depends on the character of the nucleic acid, and on the buffer and salt concentration and composition. Thus, one can envision conditions that decrease the temperature at which nucleic acids are denaturated, effectively lowering the standard by which enzymes can be classified as heat resistant. Accordingly, enzymes that previously were not captured by the unqualified term "heat resistant" are now included as a result of the amendment proposed. This amendment to the definition of the term "thermostable enzyme" affects my ability to understand the invention described' 25 I do not find that assertion helpful. Dr Morona does not suggest that the term 'heat resistant' is a term of art that has some special meaning different from the way in which it would be understood in ordinary English. He simply asserts that the normal meaning of the term has been expanded to include enzymes that previously may not have been considered to be heat resistant. 26 It is patently obvious that the specification is using the term 'heat resistant' in a particular context. That context is that of polymerase chain reaction, being 'the amplification reaction' referred to. No one could suggest that the specification called for an enzyme that was resistant to heat at any level. It can only refer to an enzyme that is relatively resistant to heat, namely, heat at a level that is required for the amplification reaction referred to. Without the amendment, the definition could only make sense by reference to what follows in the succeeding paragraph. That is to say, it must be resistant to the level of heat that is required to effect denaturation, such that it does not become irreversibly denatured, or inactivated, at that level of heat. 27 As a matter of syntax, I do not consider that the amendment has any effect other than to qualify the scope of heat resistance. As a matter of strict syntax, a statement that an enzyme is heat resistant, without qualification, is wider than a statement that the enzyme is heat resistant to a particular extent. In any event, in the context in which the phrase 'heat resistant' is used, it is clear that it refers to resistance to the level of heat that is to be applied in order to effect denaturation of double-stranded nucleic acids without causing the enzyme to be irreversibly denatured or inactivated. 28 The amendment does not broaden the claims. I do not consider that the amendment is precluded by s 102(1) or s 102(2)(a).

AMENDMENTS TO TENSE 29 In the complete specification as filed, certain of the 18 examples set out were expressed in terms that implied that the processes described had actually been carried out by the inventors. For example, in the specification as filed, the last three sentences of Example XIII and the first sentence of Example XIV were in the following terms: 'Active fractions with no detectable nuclease(s) were pooled and run on a silver stained SDS-PAGE mini gel. The results show a single ~ 88-92 kd band with a specific activity of ~ 200,000 units/mg. This specific activity is more than an order of magnitude higher than that claimed for the previously isolated Taq polymerase and is at least an order of magnitude higher than that for E. coli polymerase I.' EXAMPLE XIV 'The Taq polymerase purified as described above in Example XIII was found to be free of any contaminating Taq endonuclease and exonuclease activities.' [emphasis added] 30 The tense used in the extract cited clearly implies that the process described had been carried out. The past tense is used throughout Examples V, VII, VIII, IX, XI and XIII in the same way. It now appears that that is not the fact. Hence it is desired to amend to describe what would be expected to happen rather than what did in fact happen. Following the amendment, the extract cited above would read as follows: 'Active fractions with no detectable nuclease(s) are pooled and run on a silver stained SDS-PAGE mini gel. The results should be a single ~ 88-92 kd band with a specific activity of ~ 200,000 units/mg. The specific activity obtained should be more than an order of magnitude higher than that claimed for the previously isolated Taq polymerase and is at least an order of magnitude higher than that for E. coli polymerase I.' EXAMPLE XIV 'The Taq polymerase purified as described above in Example XIII should be free of any contaminating Taq endonuclease and exonuclease activities.' [emphasis added] 31 The effect of this category of amendments is to make it clear that the processes described had not been carried out. That, however, is not a reason for rejecting the amendments. NEB contends that the amendments are not allowable by reason of s 102(2)(b) because they would result in the specification not complying with s 40(2)(a) of the Act. That provision requires, relevantly, that the specification disclose the best method known to the applicant of performing the alleged inventions. 32 NEB says that, when the specification is amended in the terms requested, which make it clear that the experiments originally put forward as a disclosure of the best method had never in fact been performed, the specification can no longer be regarded as disclosing the best method known to Hoffmann of performing the alleged invention. NEB says that, at best, the specification so amended would disclose only predictions or hypotheses put forward by Hoffmann as to the results that may or may not be obtained, should the experiments described be conducted. 33 Assuming that that is what the specification as amended would disclose, that is not a deficiency. There is no requirement of the Act that the best method disclosed in a specification must have actually been performed by an applicant. If the prediction or hypothesis disclosed does not in fact achieve the predicted or hypothesised result, that may be a ground of invalidity, to the extent that the so-called invention would have no utility. However, that is not the question presently under consideration. It may be that in a revocation suit there will be complex evidence as to whether predicted or hypothesised results will be achieved. Nevertheless, there is no requirement of s 40, or any other provision of the Act, that the best method known to an applicant of performing the invention has actually been carried out, so long as the best method known is in fact disclosed. 34 There is no substance in NEB's contention. This category of amendments is not precluded by ss 104(5) and 102.

LEVEL OF PURITY IN EXAMPLE XIII 35 The amendment proposed under this head involves changing the wording of the last three sentences of Example XIII and the first sentence of Example XIV to read as follows: 'Active fractions substantially free of detectable contaminating nuclease(s) are pooled and run on a silver stained SDS-PAGE mini gel. The result should be essentially a single ~ 88-92 kd band as compared to phosphorylase B given a value of 94,000. The pooled fractions should have a specific activity of ~ 200,000 units/mg. The specific activity obtained should be more than an order of magnitude higher than that claimed for the previously isolated Taq polymerase and is at least an order of magnitude higher than that for E. coli polymerase I. EXAMPLE XIV The Taq polymerase purified as described above in Example XIII should be substantially free of detectable contaminating Taq endonuclease and exonuclease activities.' [emphasis added] 36 NEB contends that the proposed amendments as shown by the emphasised words would not be allowable under ss 102(1) and 102(2)(a) because, as a result of the amendments, the specification would claim content not in substance disclosed in the specification as filed. NEB says that Claim 86 would not in substance fall within the scope of the claims of the specification before amendment because the effect of the amendment would be to broaden the scope of Claim 86. Example XIII presently refers to a polymerase that is free from contamination; Claim 86 would therefore refer only to a polymerase purified to the extent described by Example XIII. If that degree of purification is relaxed, there would logically be a broadening of Claim 86. 37 However, an amendment may be allowed if the amended claim will in substance fall within the scope of the claims of the specification before amendment. The use of the plural 'claims' in s 102(2) shows that it was not intended merely that the amended claim must fall within the scope of that claim prior to its amendment. It is necessary, therefore, to look at the other claims of the specification as filed in order to see their scope: see AMP Incorporated v Commissioner of Patents (1974) 3 ALR 283 at 290. 38 The language of Claim 86 is not without difficulty. It is not entirely clear what is meant by an enzyme that 'is substantially as hereinbefore described with reference to… Example XIII'. However, whatever might be the intended scope of that phrase, it must operate as a qualification of what goes before, namely: 'Purified Thermus aquaticus DNA polymerase having a molecular weight of 86,000 - 95,000 daltons.' 39 That phrase must be considered in the light of Claim 3. Claim 3, construed by reading the language of Claim 1 into it, is as follows: A purified thermostable DNA polymerase isolated from Thermus aquaticus, said polymerase having a molecular weight of about 86,000 to 95,000 daltons as compared to phosphorylase B by SDS-PAGE. That is to say, Claim 86, without the qualification would, in effect, be the same as Claim 3. Thus, Claim 3 is broader than, and includes, Claim 86. It follows that Claim 86 following the proposed amendments would not be broader than Claim 3 and ss 102(1) and 102(2)(a) would not preclude the proposed amendments.

CONCLUSION 40 None of the grounds relied on by NEB has been made out. It follows that the appeal should be dismissed with costs. I certify that the preceding forty (40) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Emmett.

Associate: Dated: 14 December 2004 Counsel for the Applicant: B N Caine SC, C Dimitriadis

Solicitor for the Applicant: Blake Dawson Waldron

Counsel for the Respondent: DKCatterns QC, SCG Burley