SpeeDx Pty Ltd v Rutgers, the State University of New Jersey - [2020] APO 20

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

SpeeDx Pty Ltd v Rutgers, The State University of New Jersey [2020] APO 20

Patent Application: 2014214725

Title:Highly selective nucleic acid amplification primers

Patent Applicant: Rutgers, The State University of New Jersey

Opponent:SpeeDx Pty Ltd

Delegate:Damian Triffett

Decision Date: 24 April 2020

Hearing Date: 3 December 2019, in Canberra

Catchwords: PATENTS – section 59 opposition to grant of a patent – clarity – lack of clarity not established – clear enough and complete enough disclosure – lack of clear enough and complete enough disclosure not established – support – lack of support not established – manner of manufacture – lack of manner of manufacture not established

Representation: Counsel for the applicant: Mr Anthony Franklin
Patent attorney for the applicant: Mr Leonard Mancini of Peter Maxwell & Associates
Counsel for the opponent: Mr Craig Smith
Patent attorney for the opponent: Dr Simon Potter of Spruson & Ferguson

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE

Patent Application: 2014214725

Title:Highly selective nucleic acid amplification primers

Patent Applicant: Rutgers, The State University of New Jersey
Date of Decision: 24 April 2020
DECISION

The opposition fails on all grounds. Subject to appeal, I direct that the application proceed to grant.

I award costs according to Schedule 8 against SpeeDx Pty Ltd.

REASONS FOR DECISION

Background

Patent application 2014214725 in the name of Rutgers, The State University of New Jersey (the applicant) was advertised as accepted on 5 April 2018. SpeeDx Pty Ltd (the opponent) opposed the grant of a patent under s 59 of the Patents Act 1990 (Cth)(the Patents Act).

The opposition

The Statement of Grounds and Particulars (SGP) identified eight grounds of opposition: manner of manufacture, novelty, inventive step, utility, clear and complete enough disclosure, support, best method of performance and clarity. At the hearing, only four grounds were pressed: manner of manufacture, clear and complete enough disclosure, support and clarity.
The parties relied upon evidence by several declarants. Evidence in support consists of declarations by Wayne Lyle Gerlach (Gerlach-1 and Gerlach-2). Evidence in answer consists of declarations by Fred Russell Kramer (Kramer-1 and Kramer-2) and Klaus Ingo Matthaei (Matthaei). Evidence in reply consists of declarations by Wayne Lyle Gerlach (Gerlach-3).
The request for examination in relation to the patent application was filed on 6 December 2016. Consequently, the amendments of the Patents Act brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth) (the Raising the Bar Act) apply to the present application. This includes section 60(3A) of the Patents Act, which provides that the Commissioner may refuse an application if satisfied on the balance of probabilities that a ground of opposition exists. It is the opponent who carries the onus of proof.

The specification

The opposed application claims priority from US61/762,117 filed on 7 February 2013, the contents of which are incorporated into the present specification by reference. The specification as amended on 5 March 2018 comprises description pages from 1 to 78, claims pages from 79 to 84, drawings pages 1/19 to 19/19, and a sequence listing from page 1 to page 5. There are 23 claims, including two independent claims (claims 1 and 9). The claims in full appear in the ANNEX at the end of this decision.

What is the invention as described?

Before commencing to construe the specification, I note what Middleton J said in Eli Lilly and Company Limited v Apotex Pty Ltd:[1]
“It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date.”

The background to the invention

The application is titled “Highly selective nucleic acid amplification primers”.
The Background of the Invention discusses some limitations with the prior art methods of detecting single-nucleotide polymorphisms (SNPs). For example, if the sequence being investigated is an allele, such as a SNP that is present in a mixture with another allele, for example, a wild-type (WT) variant, distinguishing by use of a probe has a practical detection limit of about 3% (not less than about 30,000 target allele molecules in the presence of 1,000,000 molecules of the alternate allele) due to the tendency of amplification of the prevalent allele to overwhelm amplification of the rare allele.[2] Another approach, the Amplification Refractory Mutation System (ARMS), has a practical detection limit of about 1% (not less than about 10,000 target allele molecules in the presence of 1,000,000 molecules of the alternate allele).[3] A further approach, myT^TM primer methodology, has been shown to use a multiple primer system to detect SNPs in the K-ras and B-raf genes with a detection sensitivity of one mutant in 14,000 wild-type (approximately 0.01%).[4]

The background of the invention draws a distinction between “specificity” and “selectivity” of a primer. The specificity is the annealing of a primer to the intended place in a nucleic acid strand and extension of primers bound only to the target sequence.[5] Conventionally, specificity is obtained by making a primer sufficiently long so that under the amplification reaction conditions, primarily during the primer-annealing step, the primer goes to only one place in a nucleic acid strand.[6] The selectivity of a primer is the ability of the primer to distinguish between or among alleles.[7] In order to distinguish between one allele and another a primer typically is made complementary to the sequence that varies between or among alleles, and the amplified product may be detected either by labelled primers, a DNA binding dye, or a labelled probe.[8]
The specification further defines “sensitivity” as detecting a very rare allele in the presence of a very abundant second allele.[9] That is, the primer must not only be “specific” (go to the correct place in the genome), and be “selective” (reject wild type or other abundant sequences similar to the target sequence), but it must be highly selective, that is, “sensitive” enough to detect a few mutant or other rare first sequence in the presence of an abundance of wild type or other abundant second sequence.[10]
The specification specifies that there remains a need for a single-oligonucleotide primer that has the ability to detect and, preferably, to quantify the number of a rare first target sequence, for example, a mutant target sequence, in the presence of a very large number of a second target sequence that differs from the first target sequence by as little as a single nucleotide, for example, a wild-type sequence.[11]

Summary of Invention

The invention is broadly summarised as follows:
“This invention includes a multi-part primer for primer-dependent nucleic acid amplification methods, including particularly polymerase chain reaction (PCR) methods, that is capable of distinguishing between a rare intended target (e.g., a mutant DNA target) and a closely related sequence (e.g., a wild-type DNA target) that differs by a single-nucleotide substitution, sometimes referred to as a single-nucleotide polymorphism, for short, a SNP.”[12]
…
“This invention addresses, inter alia, a major goal of molecular diagnostics, which is to find a sensitive and specific means for detecting extremely rare cancer cells (by virtue of an identifying somatic mutation) in a clinical sample containing very abundant normal cells, and to be able to quantitatively determine their abundance.”[13]

The structure of the multi-part primers of the invention are summarised as follows:

“Multi-part primers useful in this invention have three contiguous sequences (anchor sequence, bridge sequence and foot sequence) that cooperate with one another to achieve very high selectivity in practical amplification reactions, including amplification and detection assays. The anchor sequence serves to hybridize the primer to the target sequence, which is the same (or almost the same) in the intended target and the unintended, mismatched target, in an efficient manner not dissimilar to hybridization of a conventional primer. The bridge and foot sequences, more fully described below, cooperate to impart primer specificity, that is, selectivity for the intended target over the mismatched target. We have discovered that a high degree of selectivity is achieved if the bridge and foot sequences cooperate to make copying of the intended target unlikely rather than likely.”[14]
…

The bridge sequence is mismatched (not complementary) to the target sequence which is referred to as the “intervening sequence” which causes a “bubble” in the duplex structure.[15]

The specification provides a method for measuring the difference in probability that a DNA polymerase extends multi-part primer/unintended-target hybrids relative to the probability that the DNA polymerase extends multi-part primer/intended target hybrids:
“Given the amplification proceeds by exponential doubling, a C_T difference of 10 cycles indicates that the probability of extension of a multi-part primer/unintended-target hybrid is 1,000 times lower than the probability of extension of the multi-part primer/intended-target hybrid; a C_T difference of 13.3 cycles indicates that the probability is 10,000 times lower.”[16]

Examples

The specification provides twelve examples of which I will highlight a few key ones below.
Example 1 is a control assay in which a conventional PCR forward primer 21-nucleotides long was used to amplify a perfectly matched intended target sequence and also to amplify an unintended, mismatched target sequence differing by a single-nucleotide polymorphism that is located near the middle of the sequence to which the primer binds.[17] Real-time kinetic fluorescence curves presented in Figure 5 show that the amplifications produced sufficient double-stranded product, on the order of 10¹² amplicons, to give a detectable signal above background at the point where roughly 20 PCR cycles had been carried out, which is typical for a PCR assay starting with 10⁶ templates.[18]
Example 3 shows the same experiment with a multi-part primer (24-14-5:1:1) according to the invention. The first number, 24, is the nucleotide length of the anchor sequence. The second number, 14, is the nucleotide length of the bridge sequence. The last three numbers, 5:1:1, describe the foot sequence, giving the number of nucleotides that are 5’ of the interrogating nucleotide(s), then the number of interrogating nucleotides, and finally the number of nucleotides that are 3’ of the interrogating nucleotide(s). From Figure 7 it can be seen that the C_T with the unintended target (containing a single-nucleotide polymorphism that is not complementary to the interrogating nucleotide in the foot) gives a DC_T of about 19 cycles between the intended target sequence and the unintended target sequence, which is approximately a 500,000-fold difference in selectivity.[19]
A comparison of Example 3 (Figure 7) with Example 1 (Figure 5) demonstrates a delay of at least two cycles (C_T of 22.9 with multi-part primer and 10⁶ mutant templates (Curve 701 of Figure 7) compared to a C_T of 20 with conventional primer and 10⁶ mutant templates (Curve 501 of Figure 5)) when PCR amplification is begun with 10⁶ copies of the mutant target sequence and the multi-part primer but no wild-type sequence, and separately with 10⁶ copies of the mutant target sequence and a corresponding conventional primer but no wild-type sequence.
Example 4 shows that with the assay of Example 3, the intended target sequence can be distinguished from the unintended target sequence in a sample containing 10⁶ copies of the unintended target sequence and only ten or more copies of the intended target sequence.[20] From Figure 9 it can be seen that a sample with 10 copies of the intended target sequence plus 10⁶ copies of the unintended target sequence is distinguished from a sample with no intended target sequence and 10⁶ copies of the unintended target sequence.[21]
Example 5 investigated the effect of the length of the foot of a multi-part primer on the amplification reaction using the assay of Example 4.[22] Figure 10 shows that shortening the length of the foot delays C_T and gives a better straight-line fit of the data from 10⁶ to 10¹copies of the intended target sequence.[23] Example 5 demonstrates that the shorter the foot length, the less likely it is that amplicons synthesised from abundant unintended target molecules in a sample being tested will obscure the amplicons synthesised from rare intended target molecules that are present in the same sample.[24]
Example 6 investigated the effect on amplification of the circumference of the bubble formed by the bridge sequence of a multi-part primer and the intervening sequence of the intended and unintended target sequences.[25] Figure 11 shows that increasing the circumference of the bubble delays the C_T and gives a better straight line fit of the data from 10⁶ to 10¹ copies of the intended target sequence.[26] Example 6 demonstrates that the bigger the bubble, the less likely it is that amplicons synthesised from abundant unintended target molecules in a sample being tested will obscure the amplicons synthesised from rare intended target molecules that are present in the same sample.[27]
The specification provides a theory as to why decreasing the length of the foot and increasing the circumference of the bubble enhances selectivity:
“The explanation lies in our unexpected realization that at the relatively high temperatures that exist during the annealing stages of a PCR assay, very short foot hybrids only exist for a very short time before they dissociate (measured, perhaps, in tens or hundreds of microseconds). Moreover, the shorter the hybrid, and the larger the bubble circumference, the shorter is the mean time during which that hybrid exists. We conjecture that the shorter the mean persistence time of a particular type of hybrid, the more unlikely it is for a DNA polymerase molecule to encounter one of those hybrids and to then form a stabilized complex with that hybrid that can undergo chain elongation. The key point here is that whether or not a hybrid will form a stabilized complex with a DNA polymerase molecule is a function of the mean persistence time of that hybrid. We believe that the ratio of the mean persistence time of a perfectly complementary hybrid formed with a particular multi-part primer, compared to the mean persistence time of a mismatched (shorter) hybrid formed with the same type of multi-part primer, is greater when the foot length of the primer is decreased and the bubble circumference of the primer is increased. Thus, more stringent multi-part primer designs (shorter feet, longer bubbles) produce shorter lived hybrids that are considerably less likely to form stabilized hybrids with DNA polymerase molecules. Consequently, shorter foot hybrids are not only less abundant, they have a lowered chance of forming a stabilized complex with a DNA polymerase molecule, and this additional discriminatory property accounts for the extraordinary selectivity of multi-part primers.”[28]

Example 7 investigated the effect of varying the location of the interrogating nucleotide in the foot sequence of the multi-part primer.[29] Figure 12 shows that the window of discrimination (DC_T) between intended target sequences and unintended target sequences increases progressively the closer the location of the interrogating nucleotide is to the 3’ terminus of the foot.[30] The results of Example 7 indicate that preferred locations for the interrogating nucleotide are at the 3’ terminus of the foot (enabling ARMS discrimination) and at the 3’-penultimate nucleotide of the foot (causing two pairs to be prevented from forming, rather than preventing only one base pair from forming).[31]
Example 9 disclosed an experiment utilising the assay method of Example 4 for a different target, B-raf mutation V600E (instead of EGFR mutation L858R) and a 24-14-5:1:1 multi-part primer for that mutation.[32] Figure 14 shows a DC_Tof 23.1 cycles between a sample containing 10⁶ wild-type templates (and no mutant templates) and a sample containing 10⁶ mutant templates in the presence of 10⁶ wild-type templates, which is even greater that the corresponding DC_Tachieved in Example 4 (17.8 cycles).[33]

The Person Skilled in the Art

The person skilled in the art (PSA) was considered in Root Quality Pty Ltd v Root Control Technologies Pty Ltd:[34]
“He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious.”
However, the PSA is not a real person, but an artificial construct that is used as a tool of analysis which is used to make the determination:

“The notional person is not an avatar for expert witnesses whose testimony is accepted by the court. It is a pale shadow of a real person – a tool of analysis which guides the court in determining, by reference to expert and other evidence, whether an invention as claimed does not involve an inventive step.”[35]

At the hearing, and in the applicant’s written submissions, the applicant questioned the impartiality of Dr Gerlach, and the credibility of his evidence.[36] The applicant submits that the opponent (SpeeDx) was derived or spun out of Johnson & Johnson at a time when Dr Gerlach was a director of the latter.[37]
In Gerlach-2, Dr Gerlach states:
“I have been asked by the patent attorneys acting for the opponent to review PCT publication no. WO2013/123552 (see Exhibit WG8) and provide my views regarding subject matter disclosed in that document”[38]
…
“Prior to reviewing WG8, I had not accessed or reviewed the opposed application or any other patent application/s related to it.”[39]

The applicant submits that it is “inconceivable, if not downright impossible”, that Dr Gerlach would select three sequences out of 189 other relevant sequences [in Exhibit WG8] that meet the structural limitations of the opposed application, without having seen the opposed application or at least without having been given information regarding the structural limitations of the claim.[40] It is for this reason that the applicant submits that the evidence of Dr Gerlach should be treated with a great deal of caution.[41]
At the hearing, the opponent submitted that while there is no express statement in Dr Gerlach’s declaration that his evidence was prepared with the assistance from the opponent’s attorneys in directing and focussing his attention on the relevant issues, this information can be implied as it is normal practice for evidence in intellectual property disputes to be prepared this way. The opponent further submitted that in any event, this attack is moot in the present opposition, as the ground of inventive step is not in dispute, which is the only situation where the opponent needs to be shielded from reading the opposed application to avoid impermissible hindsight.

I agree with the opponent’s submission and consider that Dr Gerlach’s evidence should be afforded equal weight to the evidence of the other experts. As such, I will weigh the evidence of the declarants in the usual manner.

Construction

The correct approach to the construction of claims was discussed by Bennet J in H Lundbeck A/S v Alphapharm Pty Ltd:[42]

“the words in a claim should be read through the eyes of the skilled addressee in the context in which they appear … while the claims define the monopoly claimed in the words of the patentee’s choosing, the specification should be read as a whole … it is not permissible to read into a claim an additional integer or limitation to vary or qualify the claim by reference to the body of the specification … terms in the claim which are unclear may be defined or clarified by reference to the body of the specification.”

Construction of claim 1

Claim 1 is the first independent claim. It reads:

“A multi-part nucleic acid amplification primer that distinguishes between a mutant DNA target sequence and a closely related wild-type DNA target sequence sufficiently to enable detection of as few as ten copies of the mutant sequence in a sample containing 100,000 copies of the wild-type sequence by PCR amplification, said primer comprising, in the 5' to 3' direction, the following three contiguous DNA sequences:
an anchor sequence capable of forming a hybrid 15-40 nucleotides in length with the mutant target sequence and with the wild-type target sequence;
a bridge sequence that is at least 6 nucleotides long and that is not complementary to either the mutant target sequence or the wild-type target sequence; and
a foot sequence that is 5-8 nucleotides long, perfectly complementary to the mutant sequence, and mismatched to the wild-type sequence by at least one of the 3' nucleotide or the 3' penultimate nucleotide of the foot sequence, wherein, if the anchor sequence and the foot sequence of the primer are hybridized either to the mutant target sequence or to the wild-type target sequence, there is in the target sequence an intervening sequence at least six nucleotides long that does not hybridize to the primer's bridge sequence, and the bridge sequence and the intervening sequence together create a bubble in the hybrid, said bubble having a circumference of 16-52 nucleotides, and wherein copying said mutant target sequence by PCR utilizing the primer is unlikely, as evidenced by the fact that, if the PCR amplification is begun with 10⁶ copies of the mutant target sequence and the multi-part primer but no wildtype sequence, and separately with 10⁶ copies of the mutant target sequence and a corresponding conventional PCR primer but no wild-type sequence, the threshold cycle utilizing the multi-part primer is delayed by at least two cycles compared to the threshold cycle utilizing the conventional PCR primer.”

Claim 1 defines a multi-part nucleic acid amplification primer in terms of both structural and functional features. With regard to the structural features, the multi-part nucleic acid amplification primer must comprise, in the 5’ to 3’ direction, the following three contiguous DNA sequences: an anchor sequence, a bridge sequence and a foot sequence. The word “contiguous” is not defined in the specification but is known in the art as touching each other at the edges.[43] The parameters of these three structural features, and how these structural features work together to form an intervening sequence and a bubble, are discussed below. Although claim 1 defines a multi-part nucleic acid amplification primer per se, there is an implied process element in the claim. That is, there is an intention to use the multi-part primers to distinguish between rare mutant sequences and wild-type sequences. For this reason, it is implied that a rare mutant sequence needs to be identified before the three structural features of the multi-part primers can be designed.
Claim 1 also defines two functional features. The first functional feature is that the multi-part nucleic acid amplification primer sufficiently distinguishes between a mutant DNA target sequence and a closely related wild-type DNA target sequence. The second functional feature is that copying said mutant target sequence by PCR utilising the multi-part primer is unlikely. The two functional features are discussed in more detail below.

Anchor sequence

The anchor sequence defined in claim 1 must be capable of forming a hybrid 15-40 nucleotides in length with the mutant target sequence and with the wild-type target sequence.

Bridge sequence

The bridge sequence defined in claim 1 must be at least 6 nucleotides long and not complementary to either the mutant target sequence or the wild-type target sequence.

Foot sequence

The foot sequence defined in claim 1 must be 5-8 nucleotides long, perfectly complementary to the mutant sequence, and mismatched to the wild-type sequence by at least one of the 3’ nucleotide or the 3’ penultimate nucleotide of the foot sequence.

Intervening sequence

The intervening sequence is a sequence in the target sequence that is formed when the anchor sequence and the foot sequence of the primer are hybridised either to the mutant target sequence or the wild-type target sequence. The intervening sequence is at least six nucleotides long and does not hybridise to the primer’s bridge sequence. The bridge sequence and the intervening sequence together create a bubble in the hybrid, said bubble having a circumference of 16-52 nucleotides.

Circumference of the bubble

Claim 1 defines the circumference of the bubble being 16-52 nucleotides. The specification defines the calculation of the circumference of the bubble (with reference to Figure 1 extracted below) as “the length of the bridge sequence 105 plus the length of the intervening sequence 109, plus 4 (a pair of nucleotides from the anchor-sequence hybrid and a pair of nucleotides from the foot-sequence hybrid).”[44]

Figure 1. A schematic representation of a primer according to the invention

Functional Feature 1: Sufficiently distinguish between target and wild-type sequences

The first of the two functional features defined in claim 1 is that the multi-part nucleic acid amplification primer must be able to distinguish between a mutant DNA target sequence and a closely related wild-type sequence sufficiently to enable:
“detection of as few as ten copies of the mutant sequence in a sample containing 100,000 copies of the wild-type sequence by PCR amplification.”

While “mutant DNA target sequences” are not explicitly defined in the current specification, the specification defines a SNP as an example of a mutant target sequence that differs from a wild-type sequence at a particular location by a single nucleotide.[45] It follows that a mutant target sequence is any sequence that differs from a wild-type sequence at a particular location. While a mutant DNA target sequence includes a SNP, the term also includes other mutations that differ from the wild-type sequence at a particular location such as insertions, deletions, substitutions etc.
However, the specification provides a clear dictionary definition defining a “closely related” sequence as “a sequence that differs from an intended target sequence by one, two, or at most a few nucleotides.”[46] The Macquarie Dictionary defines “few” as “a small number”.[47] The declarants provided no evidence on the construction of this term. As a result, I construe closely related wild-type DNA target sequence to be a sequence that differs from an intended target sequence by one, two or three nucleotides.
Figure 8 demonstrates that detection of one mutant sequence in a population of 100,000 copies of the corresponding wild-type sequence is enabled.[48] When a multi-part primer of the invention was used to discriminate between L858R mutant and wild-type sequences, the threshold cycle (C_T) for 10 copies of mutant in 10⁶ copies of wild-type was 39.2 compared to 41.1 with 10⁶ copies of wild-type only. As the specification states that these thresholds enabled detection of one mutant sequence in 100,000 wild-type sequences, then by analogy a DC_T of 1.9 cycles must be sufficient to enable detection of as few as ten copies of the mutant sequence in a sample containing 10⁶ copies of the wild-type sequence by PCR amplification. Therefore a DC_T of at least 1.9 cycles between amplification of 10⁶ wild-type sequences and no mutant sequences, and 10 mutant sequences in 10⁶ wild-type sequences, is sufficient to detect as few as 10 copies of the mutant sequence in a sample containing 100,000 copies of the wild-type sequence.

This functional feature is construed as a limiting feature of the claim rather than just descriptive of the field of use. That is, the primer “must” be able to distinguish between mutant and wild-type sequences at the defined level of selectivity. This limiting construction is consistent with the construction given by both the opponent,[49] and the applicant.[50]

Functional Feature 2: Copying mutant target sequence is unlikely

The second of the two functional features defined in claim 1 is that:

“copying said mutant target sequence by PCR utilizing the primer is unlikely, as evidenced by the fact that, if the PCR amplification is begun with 10⁶ copies of the mutant target sequence and the multi-part primer but no wildtype sequence, and separately with 10⁶ copies of the mutant target sequence and a corresponding conventional PCR primer but no wild-type sequence, the threshold cycle utilizing the multi-part primer is delayed by at least two cycles compared to the threshold cycle utilizing the conventional PCR primer.”

In order to determine whether copying the mutant target sequence by PCR utilising the primer is unlikely, an experiment must be performed which tests whether there is at least a two threshold cycle delay when PCR is performed with a multi-part primer and 10⁶copies of the mutant target sequence and no wild-type sequence compared to when PCR is performed with a conventional primer and 10⁶copies of the mutant target sequence and no wild-type sequence.

Corresponding conventional PCR primer

While the specification fails to give a dictionary definition of “conventional primer”, what constitutes such a primer is alluded to throughout the specification. For example, the specification states that such a primer is highly specific, typically has a length of 15-30 nucleotides, and has very limited selectivity for one allele over another.[51] The specification also states that the anchor sequence in the current invention, is like, and functions like, a conventional primer,[52] and that DNA anchor sequences that form anchor-sequence/target hybrids generally in the range of 15-30 base pairs.[53] Furthermore the specification states that a conventional primer must be well-designed[54] and could include just the anchor sequence of the multi-part primer.[55]
Gerlach-2 submits that what constitutes a “conventional primer” is subjective, and can encompass a range of variations,[56] and Gerlach-3 submits that this variation includes variations not only to length, but also to the degree of mismatching of the sequence.[57] Dr Gerlach notes that Examples 1 and 2 of the opposed application each refer to a “conventional linear primer” with a mismatched nucleotide, one centrally-located (Example 1) and the other located at the 3’ terminus (Example 2).[58] Dr Gerlach concludes his discussion on this point by asking how many mismatches with the template are permitted before a primer loses its conventional status, as well as where such mismatches are permitted to be located?[59]
Dr Kramer provides the following evidence on what constitutes a “conventional primer”:
·     A PSA would understand it to be a conventional linear primer different from the multi-part primer of the invention (but similar to the anchor sequence in the multi-part primer).[60]
·     A conventional linear primer is obtained by making a primer sufficiently long so that under the amplification reaction conditions, primarily during the primer-annealing step, the primer goes to only one place in a nucleic acid strand.[61]
·     A conventional primer has very limited selectivity for one allele over another and that such a primer is highly specific and has a length of 15-30 nucleotides.[62]
·     A conventional linear primer is similar to the anchor sequence of the multi-part primer of the invention (but obviously having a free 3’ end).[63]

The specification references a “conventional primer” as a conventional linear primer in Examples 1-3.[64] Dr Matthaei’s evidence supports this notion stating that a PSA would clearly understand that the primers referred to as “conventional” primers are linear primers.[65]
While I accept Dr Gerlach’s evidence that a conventional primer may vary in length, I also accept Dr Kramer’s evidence that a conventional primer is between 15-30 nucleotides and is highly specific, having very limited selectivity for one allele over another. Claim 1 however, defines a corresponding conventional primer. The question is whether the word “corresponding” imparts any further limitation on the construction of a conventional primer. The Macquarie Dictionary defines “correspond” as “to be similar or analogous; be equivalent in function, position, amount, etc.”[66] The current specification states that a “corresponding conventional primer” is similar to the anchor sequence in multi-part primers.[67] Therefore I consider while a “corresponding conventional primer” could correspond to the anchor sequence in the multi-part primer, such a primer is not so limited as such a primer need only be similar to the anchor sequence. The question then is how similar does it need to be?
The conventional primer disclosed in Example 1 (SEQ ID NO:1) was 21 nucleotides long, containing the interrogating nucleotide near the middle of the primer sequence (i.e. in the 10^th position from the 5’ end and the 12^th position from the 3’ end).[68] The interrogating nucleotide being complementary to the corresponding nucleotide in the intended target sequence, but not complementary to the corresponding nucleotide in the unintended target sequence.[69] The primers disclosed in Example 2 are conventional linear primers with a 3’-terminal interrogating nucleotide (SEQ ID NO:4) and a penultimate 3’-terminal interrogating nucleotide (SEQ ID NO:5) respectively. These primers are also considered to be corresponding conventional primers within the meaning of claim 1 for two reasons. Firstly, the DC_T between these primers and the multi-part primer of the invention is greater than two cycles (3.5 and 3.8 respectively) when both PCT amplification reactions are begun with 10⁶ mutant target sequences but no wild-type sequence.[70] Secondly, despite the varying locations of the mismatches in these primers to the wild-type sequence (or the unintended target sequence), the comparative PCR amplification reactions to determine whether there is at least a two cycle delay is performed using 10⁶copies of the mutant target sequence with no wild-type sequence. As a result, conventional primers with mismatches to the wild-type sequence, or unintended target sequence, will behave identically when amplifying mutant sequences (or intended target sequences) only. Therefore, the degree of mismatching raised by Dr Gerlach is a moot point when assessing the second functional limitation of claim 1 with regards to the at least two cycle delay.
Given that the degree of mismatching of the conventional primer cannot account for the degree of “similarity” between a conventional primer and a corresponding conventional primer as discussed above, the similarity must relate to something other than the degree of mismatching. The conventional primer used in Example 1 (SEQ ID NO:1) and the second conventional primer used in Example 2 (SEQ ID NO:5) fail to overlap with the anchor sequences of the corresponding multi-part primer, while the first conventional primer used in Example 2 (SEQ ID NO:4) overlaps with the anchor sequence of the corresponding multi-part primer by a single nucleotide at the 5’ end of the conventional primer. While there appears to be no need for the conventional primer to encompass any of the anchor sequence of the corresponding multi-part primer, all exemplified conventional primers are nonetheless in close proximity to the anchor sequences of the corresponding multi-part primer. As a result, I have construed the corresponding conventional primer as limiting the conventional primer to binding the intended target sequence at a similar region of that target sequence. Furthermore, consistent with the evidence, I construe a “conventional primer” as a linear primer of between 15-30 nucleotides in length, wherein under amplification conditions the primer goes to one place in a nucleic acid strand (i.e. specifically binds to the same region as the anchor sequence of the multi-part primer or a region in close proximity to that region).

Threshold cycle

The threshold cycle (C_T) is defined in the specification as the number of PCR cycles needed to synthesise a predetermined detectable number of amplicons in a reaction initiated with a particular number of intended target sequences.[71]

Construction of claim 9

Claim 9 is the second independent claim. It reads:

“An amplification and detection method that is capable of amplifying at least one rare, mutant DNA target sequence in a mixture containing, for each mutant target sequence, a closely related wild-type DNA target sequence, comprising repeatedly cycling a reaction mixture in a primer-dependent amplification reaction having a primer-annealing temperature, and detecting amplified products, said reaction mixture including said at least one mutant target sequence or its closely related wild-type target sequence or both, a DNA polymerase, amplification buffer, deoxynucleotide triphosphates, and for each mutant target sequence a primer pair that includes a multi-part primer comprising, in the 5' to 3' direction the following three contiguous DNA sequences:
an anchor sequence that hybridizes at the primer-annealing temperature with the mutant target sequence and with its closely related wildtype target sequence;
a bridge sequence that is at least 6 nucleotides long and that is not complementary to either the mutant target sequence or its closely related wildtype target sequence; and
a foot sequence that is 5-8 nucleotides long, wherein, the mutant target sequence is perfectly complementary to the foot sequence, and the closely related wild-type target sequence is mismatched to at least one of the 3' nucleotide or the 3' penultimate nucleotide of the foot sequence,

wherein, if the anchor sequence and the foot sequence of the primer are hybridized either to the mutant target sequence or to its closely related wildtype target sequence, there is in the target sequence an intervening sequence at least six nucleotides long that does not hybridize to the primer's bridge sequence at the primer-annealing temperature, and the bridge sequence and the intervening sequence together create a bubble in the hybrid, said bubble having a circumference of 16-52 nucleotides, and
wherein, the probability that during said cycling a multi-part primer/wild-type target sequence hybrid will be extended is at least 10,000 times lower that the probability that during said cycling a multi-part primer/mutant target sequence hybrid will be extended, as evidenced by a DC_T of at least 13.3 cycles; and
wherein the circumference of the bubble and the length of the foot sequence in combination result in a weak foot/mutant-target-sequence hybrid that makes copying the mutant target sequence unlikely, as evidenced by the fact that, if the reaction is begun with said reaction mixture and 10⁶ copies of the at least one mutant DNA target sequence, no wild-type sequence and the multi-part primer, and separately with the reaction mixture containing 10⁶ copies of the at least one mutant DNA target sequence, no wild-type sequence and a corresponding conventional primer in place of the multi-part primer, the threshold cycle (C_T) is delayed by at least two cycles compared to the C_T of the reaction utilizing the conventional primer.”

Claim 9 defines an amplification and detection method that is capable of amplifying at least one rare, mutant DNA target sequence. The construction of “rare mutant” is detailed below. Claim 9 further defines a mixture containing, for each mutant target sequence, a closely related wild-type DNA target sequence, and a method that comprises repeatedly cycling a reaction mixture in a primer-dependent amplification reaction having a primer-annealing temperature, and detecting amplified products. Claim 9 is further limited to said reaction mixture including said at least one mutant target sequence or its closely related wild-type target sequence or both, a DNA polymerase, amplification buffer, deoxynucleotide triphosphates, and for each mutant target sequence a primer pair that includes a multi-part primer comprising both structural and functional features. With regard to the structural features, the multi-part nucleic acid amplification primer must comprise, in the 5’ to 3’ direction, the following three contiguous DNA sequences: an anchor sequence, a bridge sequence and a foot sequence. The parameters of these three structural features, and how these structural features work together to form an intervening sequence and a bubble, are discussed below.

Claim 9 further defines two functional features. The first functional feature is the probability that a multi-part/wild-type target sequence will be extended. The second functional feature is that when the circumference of the bubble and the length of the foot sequence in combination result in a weak foot/mutant-target-sequence hybrid that make copying the mutant target sequence unlikely. The two functional features are discussed in more detail below.

Rare mutant

The specification defines “rare” and “abundant” as meaning that the ratio of intended target sequences to closely related sequences is at least in the range of 1/10³ to 1/10⁷.[72]

Repeatedly cycling a reaction mixture in a primer-dependent amplification reaction

At the hearing and in their written submissions the opponent made the argument that while claim 1 is limited to PCR amplification, claim 9 is not and the primer-dependent amplification reaction defined in claim 9 would include within the claimed monopoly all forms of amplification including methods such as strand displacement amplification (SDA), loop-mediated isothermal amplification (LAMP), rolling circle amplification (RCA), transcription-mediated amplification (TMA), self-sustained sequence replication (3SR), nucleic acid sequence based amplification (NASBA).[73]
The applicant submits that while claim 9 does not contain the words that appear in claim 1 “by PCR amplification”, it is nevertheless, clearly limited to PCR amplification.[74] The applicant submits that claim 9 defines a DC_Tbetween a multi-part primer/wild-type target sequence hybrid extension and a multi-part primer/mutant target sequence hybrid extension “of at least 13.3 cycles”, and thermal cycles only occur in PCR amplification and in none of the other amplification methods listed by the opponent.[75] At the hearing the applicant further submitted that the Ligase Chain Reaction (LCR) raised by the opponent at the hearing is not contemplated within the scope of claim 9 as LCR does not involve cycles, does not use primers, does not use dNTPs, and uses oligonucleotide probes that aren’t extended. Neither parties provided any evidence to support their submissions.
The specification states:
“This invention includes primer-dependent nucleic acid amplification methods, for example PCR methods.”[76]
…
“Primer-dependent amplification reactions useful in methods of this invention may be any suitable exponential amplification method, including the polymerase chain reaction (PCR), either symmetric or non-symmetric, the ligase chain reaction (LCR), the nicking
enzyme amplification reaction (NEAR), strand-displacement amplification (SDA), nucleic
acid sequence-based amplification (NASBA), transcription-mediated amplification (TMA), and rolling circle amplification (RCA). Preferred methods utilize PCR.”[77]
…
“The description that follows, including the Example [sic], describes multi-part primers in connection with PCR amplification reactions starting with DNA targets.”[78]
…
“The number of PCR cycles needed to synthesise a predetermined detectable number of amplicons in a reaction initiated with a particular number of intended target sequences (the threshold cycle, C_T, for that reaction) can be measured”.[79]

While the specification does allude to PCR being merely one example of a primer dependent amplification reaction method, the method of claim 9 is limited to:
“repeatedly cycling a reaction mixture in a primer-dependent, amplification reaction” and including a reaction mixture comprising a DNA polymerase, amplification buffer, deoxynucleotide triphosphates, and … a primer pair”.

As a result, I consider that PCR amplification is an implied feature within the scope of claim 9, as none of the other primer-dependent amplification reactions raised by the opponent comprise all of the reaction components and conditions defined in claim 9.

Anchor sequence

The anchor sequence defined in claim 9 must hybridise at the primer-annealing temperature with the mutant target sequence and with its closely-related wild-type target sequence. Claim 9, unlike claim 1, does not limit the anchor sequence to be capable of forming a hybrid 15-40 nucleotides in length.
The specification states that the anchor sequence typically forms a probe-target hybrid 15-40 nucleotides in length, preferably 15-30 nucleotides in length, and more preferably 20-30 nucleotides in length.[80] The specification further states that the anchor sequence is usually (but not necessarily) perfectly complementary to the template sequence, and it is usually located approximately 14 nucleotides from the 5’ end of the foot sequence and can usually be 15-40, 15-30 or 20 to 30 (such as 20 to 24) nucleotides in length.[81]
Dr Gerlach states that the anchor sequence defined in claim 9 is of unspecified length,[82] and forms hybrids of undefined length with the mutant and wild-type sequences.[83] Dr Matthaei does not contest this evidence.
Dr Kramer submits that the anchor sequence in claim 9 is defined functionally stating:
“Regarding the anchor sequence, claim 9 defines it functionally: in the amplification reaction it hybridizes to both the mutant and to the wild-type sequences at the primer-annealing temperature. Further, it is 5´ to the interrogating nucleotide, which is opposite the foot. The opposed application teaches, that because the anchor hybridizes to both targets during primer annealing (page 7), it is like, and functions like, a conventional primer (page 8), which means that its length is preferably 15-30 nucleotides, as is typical
for a conventional primer (page 8). A functional description of an anchor that is the functional description of a typical conventional primer is all that a person skilled in the art requires to appreciate the structure of the anchor sequence.”[84]

I consider the anchor sequence defined in claim 9 to not be limited to any particular length, so long as the length is such that the anchor sequence hybridises at the primer-annealing temperature with the mutant target sequence and with its closely related wild-type target sequence. This construction is consistent with the lack of any defined length in the claim, with the fact that specification only includes preferable lengths for the anchor sequence, and the fact that the evidence does not suggest that an anchor sequence would be known in the art to be of any particular length.

Bridge sequence

The bridge sequence defined in claim 9 must be at least 6 nucleotides long and not complementary to either the mutant target sequence or its closely related wild-type target sequence.

Foot sequence

The foot sequence defined in claim 9 must be 5-8 nucleotides long, perfectly complementary to the mutant sequence, and mismatched to the closely related wild-type sequence by at least one of the 3’ nucleotide or the 3’ penultimate nucleotide of the foot sequence.

Intervening sequence

The intervening sequence is a sequence in the target sequence that is formed when the anchor sequence and the foot sequence of the primer are hybridised either to the mutant target sequence or the wild-type target sequence. The intervening sequence is at least six nucleotides long and does not hybridise to the primer’s bridge sequence at the primer-annealing temperature. The bridge sequence and the intervening sequence together create a bubble in the hybrid, said bubble having a circumference of 16-52 nucleotides.

Circumference of the bubble

Claim 9 defines the circumference of the bubble being 16-52 nucleotides, and the calculation of the circumference of the bubble has been discussed previously.

Functional Feature 1: Sufficiently distinguish between target and wild-type sequences

The first of the two functional features defined in claim 9 is that:
“the probability that during said cycling a multi-part primer/wild-type target sequence hybrid will be extended is at least 10,000 times lower than the probability that during said cycling a multi-part primer/mutant target sequence hybrid will be extended, as evidenced by a DC_T of at least 13.3 cycles.”
The specification states that given that amplification proceeds by exponential doubling, a C_T difference of 13.3 cycles indicates that the probability of extension of a multi-part primer/unintended-target hybrid is 10,000 times lower than the probability of extension of the multi-part primer/intended-target hybrid.[85]
Figure 7 demonstrates that the C_T with the unintended target (containing a single-nucleotide polymorphism that is not complementary to the interrogating nucleotide in the foot) gives a DC_T of about 19 cycles (18.2 cycles) between the intended target sequence (Curve 701) and the unintended target sequence (Curve 702), which is approximately a 500,000-fold difference in selectivity (2¹⁹ is 524,288).[86]
Therefore in order to determine whether the probability that during said cycling a multi-part primer/wild-type target sequence hybrid will be extended is at least 10,000 times lower than the probability that during said cycling a multi-part primer/mutant target sequence hybrid will be extended, a PSA would be required to perform the experiment outlined in Example 3 (Figure 7) with the proposed multi-part primer to determine whether the DC_T is at least 13.3 cycles.

Functional Feature 2: Copying mutant target sequence is unlikely

The second of the two functional features defined in claim 9 is that:

“the circumference of the bubble and the length of the foot sequence in combination result in a weak foot/mutant-target-sequence hybrid that makes copying the mutant target sequence unlikely, as evidenced by the fact that, if the reaction is begun with said reaction mixture and 10⁶ copies of the at least one mutant DNA target sequence, no wild-type sequence and the multi-part primer, and separately with the reaction mixture containing 10⁶ copies of the at least one mutant DNA target sequence, no wild-type sequence and a corresponding conventional primer in place of the multi-part primer, the threshold cycle (C_T) is delayed by at least two cycles compared to the C_T of the reaction utilizing the conventional primer.”

In order to determine whether the circumference of the bubble and the length of the foot sequence in combination result in a weak foot/mutant-target-sequence hybrid that makes copying the mutant target sequence unlikely, an experiment must be performed which tests whether there is at least a two threshold cycle delay when PCR is performed with a multi-part primer and 10⁶copies of the mutant target sequence and no wild-type sequence compared to when PCR is performed with a conventional primer and 10⁶copies of the mutant target sequence and no wild-type sequence.
The formation of a weak foot/mutant-target-sequence hybrid is considered to be an inevitable result when copying the mutant target sequence is unlikely. The specification provides a theory that hybrids that do form between the foot and the target are relatively weak, so the mean time during which they persist is very short (perhaps a hundred microseconds), which is a contributing factor as to why there is an extremely low probability of a stable (extendable) complex being formed between a hybrid (even a perfectly complementary hybrid) and a DNA polymerase molecule.[87] The declarants provided no evidence on this point and as a result, I’m satisfied that the construction of this second functional feature in claim 9 is identical to that of claim 1.

Clarity

It is a requirement of subsection 40(3) of the Act that the claims must be clear. This requirement is understood to be satisfied if a person could ascertain “whether or not what he proposes to do falls within the ambit of the claim”.[88]
As noted in Flexible Steel Lacing Company v Beltreco Ltd[89]; cited with approval in Austal Ships Sales Pty Ltd v Stena Rederi Aktiebolag:[90]
“The consideration is whether, on any reasonable view, the claim has meaning. In determining this, the expression in question must be understood in a practical, common sense manner.”

The Opponent made two clarity arguments with respect to the product claims, and one clarity argument with respect to the method claims.[91]

Ability of primers to hybridise to an unfixed set of target sequences

The opponent’s first clarity argument is that the product claims claim primers that are defined by reference to their ability to hybridise with an unfixed set of target sequences (i.e. an external requirement that is not fixed).[92] The opponent submits that the multi-part primer is defined by reference to three contiguous DNA sequences, of which each is defined by reference to an interaction with two unspecified sequences.[93]
At the hearing the opponent submitted that while the skilled addressee may be able to determine whether a particular primer falls within the scope of claim 1 by reference to a specific and known mutant and wild-type sequence, if the skilled person was provided with a primer of a certain length, it is not possible to exclude the possibility that the primer falls within the scope of claim 1.
The applicant responds by submitting that this is a non-existent problem for two reasons.[94] Firstly, claim 1 refers to a mutant DNA target sequence and a closely related wild-type DNA sequence which are clearly defined in the specification.[95] Secondly, all relevant primers for the purposes of the invention will necessarily be designed for the purpose of detecting a very rare mutant target in a very abundant wild-type target which can be identified by database searches.[96]
The applicant argues that there is no support in the evidence that it is not possible to arrive at a determination that the primer does not fall within the scope of claim 1.[97] Dr Gerlach, in relation to determining whether a primer would infringe claim 1, states in his second declaration that it would be “extremely onerous”[98] and states in his third declaration that it would be “extremely difficult if not impossible in some cases”.[99]
Dr Kramer’s evidence states that:

“In relation to the first point, that the “target sequences” are not adequately defined, this is a ridiculous assertion. The whole purpose of PCR amplification assays such as those described in the Opposed Application is to design primers that will amplify and detect a particular target sequence, for example a mutant target sequence for the identification of a cancer gene. Before the primers for the assay are designed the intended target sequence will be known.”[100]

I agree with the evidence of Dr Kramer in so far as the multi-part primer defined in claim 1 can only be designed once the rare mutant target sequence and the closely related wild-type sequences are known. For example, it is only when the target mutation is known that the foot sequence can be designed as claim 1 defines that there must be a mismatch to the wild-type sequence at either the 3’ nucleotide or the 3’ penultimate nucleotide. Similarly, the two functional limitations of the claim can only be tested once both the mutant and wild-type sequences have been determined.
As previously discussed, I consider that there is an implied process element in claim 1, such that a rare mutant sequence needs to be identified before the three structural features of the multi-part primers can be designed. Therefore, the clarity argument regarding the ability of the primers to hybridise with an unfixed set of target sequences is rendered moot.

Comparative performance of a “corresponding conventional primer”

The opponent’s second clarity argument is that all the claims include functional limitations referable to the comparative performance of the multi-part primer, measured against another primer (a ‘conventional PCR primer’ or a ‘conventional primer’) that is not defined in a manner capable of delineating a fixed monopoly.[101] The opponent submits that as different conventional primers will exhibit different amplification rates, there are consequently numerous potential baseline points from which to gauge the delay of at least two cycles.[102] Furthermore, the opponent submits that for a given mutant DNA target sequence, there is more than one primer that may be described as being a conventional primer for that sequence,[103] and there is no evidence that the rate of amplification of the mutant target sequence will be the same for every member of the set of primers that may be considered to be conventional primers, and the skilled person would understand, from basic principles of primer design, that this will not be the case.[104]
The applicant responds by submitting that both categories of conventional primers (“well-designed conventional PCR primer” and “conventional primer consisting of just the anchor sequence of the multi-part primer”) are expected to yield perfect amplification (amount of amplicon doubling every cycle).[105]
The specification states that the amount of delay (DC_T) in the threshold cycle between amplification reactions wherein a multi-part primer according to this invention replaces a well-designed conventional primer depends on how well the conventional primer is designed, but typically, comparing to a conventional primer consisting of just the anchor sequence of the multi-part primer, the delay is at least two amplification cycles, often at least three cycles, and sometimes at least eight cycles, or even ten cycles.[106] Therefore, the specification seems to be suggesting a delay of two cycles is the minimum delay expected, with the delay often being longer.

None of the evidence directly addresses the issue of whether different “corresponding conventional primers” will exhibit different amplification rates, or whether they are expected to yield perfect amplification. Dr Kramer refers to Example 1 (Figure 5) where the results:
“show that the amplifications produced sufficient double-stranded product, on the order of 10¹² amplicons, to give a detectable signal above background (the threshold cycle, abbreviated ‘C_T’) at the point where roughly 20 PCR cycles had been carried out, which is typical for a PCT assay starting with 10⁶ templates.”[107]
Dr Kramer’s evidence indicates that a conventional primer yielding perfect amplification will typically have a C_T of roughly 20 cycles. Dr Gerlach provides no evidence that other well-designed primers will have different rates of amplification. Dr Gerlach’s evidence instead focussed on the clarity of the term “conventional primer”, which was the original thrust of the opponent’s pleadings in the SGP:

“The lack of guidance or certainty around what constitutes [emphasis added] a “conventional” primer makes it problematic to determine whether a threshold cycle delay of two cycles during amplification of the mutant using the multi-part primer versus the “conventional” primer is actually met.”[108]

As discussed above under construction, I consider that the scope of the term “corresponding conventional primer” can be given a meaning using the rules of construction. A “corresponding conventional primer” is a linear primer of between 15-30 nucleotides in length, wherein under amplification conditions the primer goes to one place in a nucleic acid strand, and wherein the primer binds to the target sequence at a similar region of the target sequence as the anchor sequence of the corresponding multi-part primer.
The onus is on the opponent to establish, on the balance of probabilities, that the scope of the claims are not clear. The opponent provides no evidence that corresponding conventional primers construed as above, would not yield perfect amplification. Therefore, despite the fact that for a given mutant DNA target sequence, there is more than one primer that may be described as being a conventional primer for that sequence, without evidence to the contrary, the expectation is that all corresponding conventional primers would yield perfect amplification resulting in a workable baseline point with which to gauge the delay of at least two cycles.
As a result, I consider the scope of claims 1-23 to be clear.

Clear enough and complete enough disclosure

Paragraph 40(2)(a) as amended by the Raising the Bar Act requires that the claimed invention be described in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art.
It is clear that this provision requires that the PSA must be able to perform the invention across the scope of the claim without undue burden or inventive skill.[109] In Evolva SA[110] (Evolva) the Deputy Commissioner considered paragraph 40(2)(a), and having drawn guidance from European and UK decisions, adopted the following approach to assessing a clear and complete enough disclosure:
What is the scope of the invention as claimed?
What does the specification disclose to the skilled person?
Does the specification provide an enabling disclosure of all the things that fall within the scope of the claims, and in particular:
(a) Is it plausible that the invention can be worked across the full scope of the claim?
(b) Can the invention be performed across the full scope of the claim without undue burden?
This approach has subsequently been adopted by delegates of the Commissioner,[111] and while the section 40 provisions as amended by the Raising the Bar Act were recently considered by the Federal Court for the first time in Encompass Corporation v InfoTrack Pty Ltd,[112] the detail of the approach to considering clear enough and complete enough disclosure was not at issue. I will adopt the Deputy Commissioner’s approach to considering this ground.
The Supreme Court in the UK recently provided further guidance with regard to the plausibility consideration in Warner-Lambert Company LLC v Generics (UK) Limited (t/a Mylan) and ors[113] (Warner-Lambert). Warner-Lambert considered the plausibility element of clear enough and complete enough disclosure with respect to a second medical use (Swiss style) claim. In a majority decision, the conclusions of the lower courts with regard to the plausibility threshold were overturned, with Lord Sumption (with whom Lords Reed and Briggs agreed) stating:
“They [the Court of Appeal] considered that the threshold was not only low, but that the test could be satisfied by a ‘prediction … based on the slimmest of evidence’ or one based on material that was ‘manifestly incomplete’. Consistently with that approach, they considered (paras 40, 130) that the Board’s observations in SALK laid down no general principle. I respectfully disagree. The principle is that the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true. … The test is relatively undemanding. But it cannot be deprived of all meaning or reduced, as Floyd LJ’s statement does, to little more than a test of good faith. Indeed, if the threshold were as low as he suggests, it would be unlikely to serve even the limited purpose that he assigns to it of barring speculative or armchair claims.”[114]

He then commented that “[p]lausibility is not a term of art, and its context is inevitably influenced by the legal context” and identified a number of considerations relevant to the context of second medical use claims:

“First, the proposition that a product is efficacious for the treatment of a given condition must be plausible. Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion. As Lord Hoffman observed in Conor Medsystems Inc v AngiotechPharmaceuticals Inc [2008] RPC 28, para 28, ‘it is hard to see how the notion that something is worth trying or might have some effect can be described as an invention in respect of which anyone would be entitled to a monopoly’. But, third, the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, ie not just because there was an abstract possibility that it would work but because reasonable scientific grounds were disclosed for expecting that it might well work. The disclosure of those grounds marks the difference between a speculation and a contribution to the art. …Fourth, although the disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true. … Sixth, … the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. … Seventh, sufficiency is a characteristic of the disclosure, and these matters must appear from the patent. The disclosure may be supplemented or explained by the common general knowledge of the skilled person. But it is not enough that the patentee can provide that the product can reasonably be expected to work in the designated use, if the skilled person would not derive this from the teaching of the patent.”

While Sumption LJ’s comments were made in the context of second medical use claims, this notion is generally applicable.
The Explanatory Memorandum directs to the corresponding provisions of UK legislation and the European Patent Convention in relation to the application of section 40(2)(a) as amended by the Raising the Bar Act. Sumption LJ in Warner-Lambert has drawn from the body of UK and European cases in arriving at his conclusion, and accordingly I consider this judgment highly persuasive with regard to the application of the approach set out in Evolva. Further, while it is clear that the Supreme Court has adopted a higher threshold with respect to plausibility than that adopted by the lower courts in the UK, I do not view the reasoning as inconsistent with the Deputy Commissioner’s statements in Evolva. It remains the case that, as set out in Evolva, the consideration is one of technical credibility or believability. Plausibility may be a low threshold, but it is a threshold nonetheless, and is not satisfied by mere speculation or assertion.
The second limb of the enablement test is whether performing the invention across its full scope would constitute an undue burden. The concept of an undue burden was discussed in Evolva. Having considered UK and European authorities the Deputy Commissioner concluded:
“My understanding of these authorities is that the emphasis in relation to undue burden has been on the nature of the work that is required by the skilled person in view of the guidance in the specification. To this end, one approach has been to ask whether the skilled person would be required to undertake a ‘research programme’ in order to perform the invention.”[115]

A feature which is defined in broad terms will be allowable if it can be understood to be a principle of general application – which was described by Lord Hoffmann in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd as:

“an element of the claim which is stated in general terms. Such a claim is sufficiently enabled if one can reasonably expect the invention to work with anything that falls within the general term.”[116]

However, the requirements of section 40 cannot be avoided merely by the incorporation of a functional limitation restricting the scope of the claims to only those products or elements that have the relevant activity or function. It is still necessary that the invention can be performed across the scope of the claims without an undue burden.[117] In American Home Products Corporation v Novartis Pharmaceuticals UK Ltd, Aldous LJ made the following observations in relation to enablement in the context of functional limitations to a claim:

“There is a difference between on the one hand a specification which requires the skilled person to use his skill and application to perform the invention and, on the other, a specification which requires the skilled person to go to the expense and labour of trying to ascertain whether some product has the required properties. When carrying out the former the skilled person is trying to perform the invention, whereas the latter requires him to go further and to carry out research to ascertain how the invention is to be performed. If the latter is required the specification would appear to be insufficient.

…

The judge held that the number of possible derivatives was vast and whether any particular molecule derived from rapamycin would work at all was impossible to predict with certainty. Many derivatives would not exhibit immunosuppressant activity. Those which involved small changes to the side chain would be the most likely to work. Thus the skilled person could make up a list of possibles, with those believed to be the most likely at the top of the list. Even so, finding appropriate derivatives, if they existed, would involve a systematic and iterative process. Further, when a derivative which had appropriate activity had been identified, it would be impossible to be certain that it did not exhibit unpredictable defects. To discover whether it did would require further tests which would take a long time.

The very uncertainty and unpredictability found by the judge meant that the skilled person was being required to carry out research. The duty upon the patentee is to provide a description which enables the skilled person to perform the invention, in this case across the breadth of the claim; not to supply a starting point for a research programme. …

…the specification has to be sufficient to enable the invention to be performed. There is a difference between research to find out which derivatives work and the application of the teaching in the specification with appropriate skill and tenacity. In this case the specification tells the skilled man where to start but, upon the construction of claim 1 sought by the patentees, it leaves him to ascertain by research what will work. Once it is appreciated that a claim which encompasses derivatives has to be sufficient across its breadth, the extent of the research task becomes apparent. The number of derivatives is vast and the task of ascertaining which will satisfy the functional part of the claim will also be vast and correspondingly burdensome.”[118]

What is the scope of the invention as claimed?

I have construed claim 1 as defining a multi-part nucleic acid amplification primer comprising three structural components, an anchor sequence, a bridge sequence and a foot sequence, wherein the primer has two functional limitations.
I have construed claim 9 as defining an amplification and detection method comprising repeatedly cycling a reaction mixture in a primer-dependent amplification reaction, wherein the reaction mixture includes a multi-part nucleic acid amplification primer comprising three structural components, an anchor sequence, a bridge sequence and a foot sequence, wherein the primer has two functional limitations.

What does the specification disclose to the skilled person?

The specification provides information on preparing highly selective multi-part primers for detecting rare mutations, as well as providing thermodynamic information outlining a theory on how such primers are sensitive enough to detect rare mutations.

Plausibility

The first limb of the test outlined in Evolva asks: Is it plausible that the invention can be worked across the full scope of the claim?
The opponent submits that the experimental evidence falls short of establishing the plausibility requirement in four different respects. Firstly, there is insufficient evidence provided to make it plausible that the relevant method will work across the scope of the structural limitations.[119] Secondly, there is insufficient evidence provided to make it plausible that that, for any given mutant target sequence, routine variations of a multi-part primer falling within the broad structural requirements of the claims will result in a multi-part primer capable of meeting the required detection levels.[120] Thirdly, there is insufficient evidence to make it plausible that the relevant method will work for all mutant target sequences, as in all three examples the target mutant sequences involved a single SNP.[121] Fourthly, there is insufficient evidence to make it plausible that the method will achieve the required selectivity for all methods of amplification.[122]
I will now consider each of these four arguments in turn. With regard to the first argument, the applicant submits that this is a meaningless argument as the argument ignores the two functional limitations of the claims.[123]
The test in Evolva is whether it is plausible that the invention can be worked across the full scope of the claim. As I have already discussed above, the full scope of the claims is narrowed by two functional limitations. The Deputy Commissioner in Evolva identified the question to be answered as:

“whether it is plausible that polypeptides which have as low as 90% identity would be capable of catalysing the defined glycosylation reaction.”[124]

After considering what was known about conservative substitutions and the binding domain of the proteins, the Deputy Commissioner concluded:

“I can see no apparent reason why the skilled person would not consider it plausible that functional variants to a level of at least 90% could be identified and would be useful in the process defined.”[125]

Therefore, applying Evolva to the present case, I construe the technical question as: Is it plausible that multi-part primers, other than those disclosed in the current specification, could be designed that would meet both functional limitations of the claims?

Turning now to the evidence, Dr Gerlach in his second declaration, in relation to the functional parameter defined in claim 1 of detecting at least 10 copies of mutant sequence in a sample containing 100,000 copies of the wild-type sequence, states:
“The proposition that all [emphasis added] of the primer sequences encompassed could achieve this functional performance parameter during an undefined PCR amplification reaction using undefined wild-type and mutant sequences is not plausible or probable.”[126]

Similarly, in relation to the functional parameter defined in claim 9 of requiring a 10,000 times lower probability of extending a multi-part primer/wild-type target sequences compared to extending a multi-part primer/mutant target sequence, Dr Gerlach states:

“The proposition that all [emphasis added] of the primer sequences encompassed by claim 9 could achieve this functional outcome during an undefined amplification reaction using undefined wild-type and mutant target sequence is not plausible or probable.”[127]

It is important to note that the Deputy Commissioner in Evolva was not saying that every possible variant of greater than 90% identity would have to achieve the functional outcome, as the opponent appears to be arguing here. Dr Gerlach’s evidence is that it is not plausible that all primer sequences meeting the structural limitations of the claims would meet the functional limitations of the claims. However, the scope of the present claims are limited to multi-part primers that meet both the structural and functional requirements. I consider that it would be at the very least plausible that further multi-part primers meeting the structural limitations (other than those exemplified in the current specification) could be identified that would be capable of meeting the required functional limitations. It would be plausible as the specification provides thermodynamic and kinetic data that underlies the theory behind the design of the multi-part primers of the invention.[128] This data is considered to provide the technical credible theory underpinning why it would be plausible that multi-part primers meeting the structural limitations of the claims, would also be capable of meeting the two functional limitations.

With regard to the second argument, the applicant submits that this argument is wrong as whilst the sequences change, the principles and techniques such as the thermodynamics of primer design are universal.[129] The applicant submits that these principles of thermodynamics allow the findings from one gene to be extrapolated to another.[130] I consider the opponent’s second argument to be more one of “undue burden” rather than plausibility, as whether “routine variation” is required to work the invention is a consideration when assessing undue burden. I consider undue burden below. For the same reasoning above, I consider it would be at the very least plausible that further multi-part primers meeting the structural limitations (other than those exemplified in the current specification) could be designed that would be capable of meeting the required detection levels.
With regard to the third argument, the applicant submits that the reactions are made plausible by the fact that they have been demonstrated in three different mutant/wild-type models.[131] The applicant further submits that SNPs are the most difficult ones to discriminate, and the other mutations, insertions and deletions, are relatively easier to discriminate because they destabilise the hybrids to a much larger extent that the substitutions.[132] I agree with the applicant’s submission.
The Summary of the Invention discusses that the multi-part primers of the invention are capable of distinguishing between a rare intended target and a closely related sequence that differs by a single-nucleotide substitution, sometimes referred to as a single-nucleotide polymorphism.[133] I have already considered it plausible that further multi-part primers meeting the structural limitations (other than those exemplified in the current specification) could be designed that would meet the required detection levels of a SNP, so I see no reason why it would not be plausible that multi-part primers could be designed to detect other mutations that destabilise hybrids to a greater extent than do SNPs.
With regard to the fourth argument, this argument is moot as I found above at [64] that “PCR amplification” is an implied feature of claim 9.
In summary, I consider that it would be at the very least plausible that further multi-part primers meeting the structural limitations (other than those exemplified in the current specification) could be designed that would be capable of meeting the required functional limitations.

Undue burden

The second limb of the test outlined in Evolva asks: Can the invention be performed across the full scope of the claim without undue burden?
The consideration of what constitutes an undue burden is necessarily dependent upon the nature of the technology, and factors relevant to the consideration include the level of predictability in the art and the level of guidance in the specification.[134]

The opponent submits that because the applicant has claimed so broadly, that results in an undue burden on a skilled addressee. This undue burden is said to come from:

(i)Not knowing what starting point should be adopted in selecting a multi-part primer to trial, within the broad structural limitations in the claims;
(ii)Not knowing what variations should be attempted in the design of a multi-part primer (i.e. anchor, bridge and foot parts) to try and achieve the promised selectivity for a given mutant sequence;
(iii)Not knowing what amplification conditions to use in assessing the various multi-part primers that are being trialled;[135] and
(iv)Developing one or more suitable conventional primers in each case to measure amplification rates[136]

I will now consider each of these arguments in turn.

Starting point to trial

In response to the opponent’s first argument, the applicant references the specification at pages 46 and 47 which describes in detail the straightforward design of multi-part primers according to the invention.[137] The applicant further submits that the specification indicates the preferred lengths for each of the foot sequence, the bridge sequence, and the anchor sequence.[138]

In my view the specification discloses that the most preferred embodiment for the structural limitations of the multi-part primer are a foot sequence of 6-7 nucleotides, an anchor sequence of 24 nucleotides, a bridge sequence of 14 nucleotides, and a bubble circumference of 32 nucleotides.[139] This would form the starting point for the multi-part primer to trial, and a PSA could make these multi-part primers without undue burden.

Variations to achieve promised selectivity

In response to the opponent’s second argument, the applicant submits that the variations that should be attempted in selecting a multi-part primer to trial within the broad structural limitations of the claim are increasing the bubble size and decreasing the foot length.[140]
Dr Matthaei’s evidence submits that the opposed application sets out very clearly the methods by which the skilled addressee can determine whether any particular primer comes within the scope of the claim, and that these methods are not “difficult or onerous”.[141] For example, Dr Matthaei’s evidence states:
“with respect to the limitation that there be a delay of 2 cycles when a multi-part primer is compared to a conventional primer, the assay for this test is set out in Example 1 of the Opposed Application. The skilled addressee, seeking to know whether the primer exhibited the 2 cycle delay would run PCR assays as set in Example 1 to measure the delay in C_T.”[142]
…
“with respect to the second functional limitation of claim 1, namely, that the primer can distinguish between a mutant DNA target and a closely related wild-type DNA target sufficiently to enable detection of as few as ten copies of the mutant sequence in a sample containing 100,000 copies of the closely related sequence by PCR amplification, the skilled addressee would run the PCR assays set out in Example 4 of the Opposed Application.”[143]
…
“All the experiments in Example 1 and 4 are not onerous. They are not difficult and as they have already been set out for the skilled addressee, the experiments do not need to be redesigned.”[144]

Dr Kramer provides evidence of what a PSA would do to design a primer that meets both the functional and structural limitations of the claims, and submits that these methods would not involve an undue burden of experimentation.[145] Dr Kramer outlines the steps involved in designing a multi-part primer that meets the functional limitations of the claim which include identifying the nucleotide sequence of the rare intended mutant target that you wish to selectively amplify, design of the multi-part primer based on the top illustration in Figure 2, and what modifications to a “failed” multi-part primer are required to enable the functional limitations to be met.[146] Dr Kramer identifies that such modifications include shortening the foot sequence and increasing the circumference of the bubble.[147] Dr Kramer repeatedly emphasises that only “routine experimentation” is required to test whether a multi-part primer meets the functional limitations of the claims, and to determine which modifications of that “failed” multi-part primer design will enable a revised multi-part primer design to meet the functional limitations of the claims.[148]

The opponent further submits that the experimental evidence falls far short of supporting the existence of a principle of general application, as the experiments in the application do not demonstrate a predictable basis for achieving a multi-part primer for any given target sequence that will be capable of achieving the required detection level.[149] The opponent further cites the evidence of Dr Matthaei regarding predictability, which states that it is well known in the art that results from other experiments with different sequences will not yield data that can be extrapolated.[150]

In response the applicant references the following parts of the opposed specification that demonstrate that shortening the foot length and increasing the circumference of the bubble, provide a predictable basis for achieving a multi-part primer for any given target sequence that will be capable of achieving the required detection level.
Firstly, the Summary of the Invention teaches that as a general consideration for design of multi-part primers, increasing the circumference of the bubble and shortening the foot increases the delay in amplification of the target sequence.[151]
Secondly, in the Detailed Description of the Invention it is stated that:
“… experimental observations demonstrate that shorter foot lengths and/or larger bubbles cause hybrid formation to be considerably less likely. And shorter foot lengths and/or larger bubbles result in increased selectivity against mismatched wild-type templates, which is evidenced by the enhanced linearity of plots of C_T versus the logarithm of the number of intended target molecules. In order to gain an understanding of why this is so, we examined the thermodynamics of formation of a foot hybrid under equilibrium conditions that exist during the annealing stages of PCR assays.”[152]

Thirdly, the specification contains a detailed explanation for why decreasing the length of the foot and increasing the circumference of the bubble enhances selectivity.[153]

The applicant responds to the opponent’s reference to Dr Matthaei’s evidence on predictability by submitting that the fact that the experiments were in respect of a single mutant sequence is not detrimental, as the noted effects (high selectivity) are coming from the structural variations, not the sequence.[154] The applicant concludes that the experiments detailed in the specification provide a plausible basis for predicting that, with routine experimentation, a primer with very high selectivity can be achieved.[155]
In my view, it is clear from the evidence what methods the skilled addressee can follow to determine whether any particular primer falls within the scope of the claim, and what variations should be attempted in the design of a multi-part primer to try and achieve the promised selectivity for a given mutant sequence i.e. the bubble size should be increased and the foot length should be decreased. Furthermore, a PSA could make these variations without undue burden, or without the need for undertaking a research programme.

Amplification conditions

In response to the opponent’s third argument, the applicant submits that while amplification conditions are important for successful amplification, they in general do not impart selectivity on the priming process.[156]
The specification provides details of the amplification and detection methods that will work with the invention. For example, successful amplification conditions are detailed for Examples 1,[157] 3[158] and 4[159].
The opponent further submits that for each of Examples 9 and 10 (the two examples that use V600E and T790M), a number of variables were selected that can themselves have an impact on amplification rates.[160] The applicant noted in their submissions that this was evidence provided by counsel and was not suggested by Dr Gerlach.[161] Dr Gerlach merely states that there are a vast number of sequences encompassed by claim 1, and no amplification conditions specified at all.[162] As outlined above, clearly the specification outlines amplification conditions for each of the examples given. Dr Matthaei responds to Dr Gerlach by taking the reference to there being no amplification conditions in the claim, as the patent specification as a whole recites specific conditions such as those set out on page 59.[163]
The applicant argues that while these are important variables for obtaining efficient amplification in PCR, they do not impact selectivity of mutant amplification while supressing the amplification of wild-type sequences.[164] While this evidence from counsel is not afforded any weight, I note there is evidence from Dr Matthaei that the skilled addressee faced with claim 1 would appreciate that the specific conditions for running the assay would require routine optimisation particularly with respect to temperatures.[165] Dr Matthaei goes on to state:
“This could be simply achieved by utilizing a gradient of temperatures across the block. A skilled addressee would be able to use the results from such an experiment to determine what conditions to run the claimed method with the claimed primers. Gradient cyclers were as at the priority date, common general knowledge.”[166]

I am persuaded by the evidence of Dr Matthaei that relevant amplification conditions are provided in the specification and the optimisation of the described conditions to suit the identification of different rare mutations would be routine and could be done without undue burden. In my opinion the evidence of Dr Gerlach falls short of refuting this.

Suitable conventional primers

I have already dealt with the construction of conventional primers above. I consider that a PSA would be able to design such conventional primers and use such primers to measure amplification rates without undue burden.

Conclusion on undue burden

The opponent concludes by arguing that there is no evidence presented in the application that supports a conclusion that this would involve other than an undue burden.[167] It is the opponent that bears the onus of proof and must provide sufficient evidence to positively establish, on the balance of probabilities, that there would be undue burden on the PSA to perform the invention across the full scope of the claims. As discussed above, I am not satisfied that the evidence is sufficient to discharge this burden.

Support

Subsection 40(3) as amended by the Raising the Bar Act requires that the claims must be supported by matter disclosed in the specification. The requirement of support can be summarised as requiring that the scope of the claims “should correspond to the technical contribution to the art”.[168]
The requirement of support has been more fully explained as follows:
“in other words it is the definition of the invention in the claims that needs support. In the Board’s judgement, 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. This means that the definitions in the claims should essentially correspond to the scope of the invention as disclosed in the description. In other words, as was stated in Decision T 26/81, the claims should not extend to subject-matter which, after reading the description, would still not be at the disposal of the person skilled in the art. Consequently, a technical feature which is described and highlighted in the description as being an essential feature of the invention, must also be a part of the independent claim or claims defining this invention.”[169] (emphasis in the original, citations omitted)

To determine whether the requirements of support are satisfied the following steps were set out in CSR Building Products Limited v United States Gypsum Company:[170]
i.construe the claims to determine the scope of the invention as claimed,
ii.construe the description to determine the technical contribution to the art, and
iii.decide whether the claims are supported by the technical contribution to the art.
There is substantial overlap in the submissions of the opponent in relation to section 40(3) and section 40(2)(a), in relation to whether there is an enabling disclosure. I have already considered these submissions above and found that there is an enabling disclosure for the claims defining the invention.
The opponent submits that the scope of the claims exceeds the technical contribution provided by the application, as the applicant has discovered that it can make a limited set of multi-part primers that achieve the promised level of selectivity for three mutant sequences that it has tested, but it seeks to monopolise the use of a much broader range of multi-part primers in respect of all mutant sequences if the skilled person finds that they work.[171]
The opponent submits that the requirement that the claims correspond with the technical contribution is sometimes described by reference to a requirement of “plausibility”.[172] The opponent cites BASF Corporation where the Delegate, after reviewing UK and European case law, said of the relevant claims under consideration:[173]
“It is, in my view, consistent with the UK and European case law and the Explanatory Memorandum, that the specification must make it plausible or credible that the combinations of agents defined in the claims will actually result in synergistic mixtures in order for the technical contribution to the art to support the claim.”

I have already considered plausibility in relation to Subsection 40(2)(a) and will not revisit it here.
The opponent makes the general observation that the structural limitations of the claim are very broad.[174] For example:
·     There is variability as to the location of the foot sequence by reference to the relevant mutation. For example, if the mutation only involves a single SNP, then for the 5 to 8 nucleotide range there are at least eight possible foot sequences.[175]
·     There is considerable variability, both as to the length and sequence of the bridge sequence, but also as to the relative proportions of the bridge sequence and the intervening sequence of the target sequence.[176]
·     The anchor sequence has considerable variability, not only as to its length, but also as to the degree of complementarity that will still result in hybridisation.[177]

The opponent argues that it is the structure of the multi-part primer that dictates its function and cites the evidence of Dr Gerlach who states:
“the inventors of the opposed application have not actually determined what structural features their multi-part primers specifically require to meet the functional requirements stated in the claims.”[178]

The opponent further submits that the applicant accepts that making a primer within the broad structural limitations of the claims will not necessarily provide a primer that provides the promised benefit of being able to detect a rare mutant target sequence.[179]
The applicant responds by arguing that the technical contribution to the art is clearly identified and the claims are supported by that technical contribution.[180] The applicant submits that the opponent’s argument appears to be based on the premise that in order to be supported, the breadth of the structural requirements of the claim should be narrowed such that the two functional requirements of the claim are invariably met by all multi-part primers meeting the structural requirements.
As discussed above, I am satisfied that the scope of the claims are limited to both a structural requirement and two functional requirements. I see no reason why the claims lack support solely by the inclusion of two functional requirements. The opponent appears to be arguing that the only claims that would be supported are those which define the structural limitation narrowly such that all primers within that structural limitation would necessarily meet the functional requirements of the claim for a given mutant target sequence. In other words, that the applicant’s technical contribution to the art is limited to those primers which by virtue of their structural limitations invariably meet each of the functional requirements.
In my view, this is casting the applicant’s technical contribution too narrowly and in effect would be limiting the applicant to a monopoly on only the particular primers that have been tested to meet the functional requirements for a particular mutant and target sequence. In my view, a better reading of the applicant’s technical contribution to the art is multi-part primers that comprise the three broad structural components (an anchor sequence, a bridge sequence and a foot sequence) and meet the two functional requirements defined in the claims for a given mutant target sequence. This construction allows for the structural components to be altered within the defined ranges to enable the functional requirements to be met for a newly discovered mutant target sequence.
As such, I consider that the claims are supported as they do not extend beyond the technical contribution to the art.

Manner of Manufacture

Section 18(1)(a) of the Act requires that the invention, so far as claimed in any claim, must be a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. The High Court in National Research Development Corporation v Commissioner of Patents (NRDC)[181] laid out the proper question for determination when considering manner of manufacture as:

“Is this a proper subject according to the principles which have developed for the application of s. 6 of the Statute of Monopolies?”[182]

With this at the fore of their considerations in respect of a claim to a process for eradicating weed from a stretch of land, the High Court in NRDC described subject matter that would be considered patentable:

“The point is that a process, to fall within the limits of patentability which the context of the Statute of Monopolies has supplied, must be one that offers some advantage which is material, in the sense that the process belongs to a useful art as distinct from a fine art ... that its value to the country is in the field of economic endeavour.”[183]

More recently, it has been made clear that the assessment of whether a claimed invention is a manner of manufacture is one of substance rather than form:

“Whatever words have been used, the matter must be looked at as one of substance and effect must be given to the true nature of the claim.”[184]

It is a long-standing practice of the Commissioner to raise an objection in relation to “kit” claims under the grounds of manner of manufacture and/or inventive step.[185]
A classic formulation of this approach is given in British Celanese v Courtaulds:
“It is accepted as sound law that the mere placing side by side of old integers so that each performs its own proper function independently of the others is not a patentable combination, but where the old integers when placed together have some working interrelationship producing a new or improved result is patentable subject matter in the idea of working brought about by the collocation of integers.”[186]

Consistent with these authorities, the approach I will take here is to determine what is the substance of the claims, and whether or not the substance is patentable subject matter. I note that the substance of the claim is not necessarily the subject matter of the claim as defined by the words of the claim.

What is the subject matter of the claims?

Claim 22 defines a reagent kit including a DNA polymerase, amplification buffer, deoxynucleotide triphosphates, and for each mutant target sequence a primer that includes a multi-part primer, “suitable for” performing an amplification reaction according to claim 9.
The Macquarie Dictionary defines “include” as “to contain, embrace or comprise [emphasis added], as a whole does parts or any part or element”.[187] As a result, I construe “including” as synonymous with “comprising” such that the kit defined in claim 22 must contain a DNA polymerase, an amplification buffer, deoxynucleotide triphosphates, and for each mutant target sequence a primer that includes a multi-part primer, but may also contain other components.
Claim 23 defines the kit according to claim 22 that includes a fluorescence detection reagent for detecting product from the amplification of each mutant target sequence.
For the same reasons given above, I construe claim 23 as containing the components defined in claim 22 in addition to a fluorescence detection reagent but may also contain other components.

What is the substance of the claims?

The opponent submits that claims 22 and 23 are for a “kit” of parts, and that the components do not have any working interrelationship as that interrelationship only arises in the context of a method claim that directs that they be used together.[188]

The applicant responds by arguing that the kit claims are not a mere collocation of known integers, as the claims define a reagent kit for performing an amplification reaction according to claim 9, and claim 9 is new.[189]
I note that the kits defined in claims 22 and 23 must contain a “multi-part primer”. While the multi-part primer defined in claims 22 and 23 is not limited to any particular multi-part primer by inclusion of this word in the claim, the multi-part primer is limited to being “suitable for” performing the amplification reaction of claim 9, hence is limited to both the structural and functional requirements of the multi-part primer defined in claim 9. As a result, I agree with the applicant that the multi-part primer defined in claims 22 and 23 is new, and the kits defined in claims 22 and 23 do not define a kit of known (or old) parts. As such, consideration of any working interrelationship between the components as argued by the opponent, is not required.
Therefore the substance of claim 22 is a reagent kit comprising a DNA polymerase, amplification buffer, deoxynucleotide triphosphates, and for each mutant target sequence a primer pair that includes the multi-part primer defined in claim 9, and the substance of claim 23 is the reagent kit as defined in claim 22 but further comprising a fluorescent detection reagent. It follows that I am satisfied that the invention defined in claims 22 and 23 is for a manner of manufacture.

Conclusion

The opposition fails on all grounds.

Costs

It is normal in matters before the Commissioner that costs should follow the event. I see no reason to depart from that approach in the present case. I will award costs according to Schedule 8 against the opponent.

Damian Triffett
Delegate of the Commissioner of Patents

ANNEX

A multi-part nucleic acid amplification primer that distinguishes between a mutant DNA target sequence and a closely related wild-type DNA target sequence sufficiently to enable detection of as few as ten copies of the mutant sequence in a sample containing 100,000 copies of the wild-type sequence by PCR amplification, said primer comprising, in the 5' to 3' direction, the following three contiguous DNA sequences:
an anchor sequence capable of forming a hybrid 15-40 nucleotides in length with the mutant target sequence and with the wild-type target sequence;
a bridge sequence that is at least 6 nucleotides long and that is not complementary to either the mutant target sequence or the wild-type target sequence; and
a foot sequence that is 5-8 nucleotides long, perfectly complementary to the mutant sequence, and mismatched to the wild-type sequence by at least one of the 3' nucleotide or the 3' penultimate nucleotide of the foot sequence, wherein, if the anchor sequence and the foot sequence of the primer are hybridized either to the mutant target sequence or to the wild-type target sequence, there is in the target sequence an intervening sequence at least six nucleotides long that does not hybridize to the primer's bridge sequence, and the bridge sequence and the intervening sequence together create a bubble in the hybrid, said bubble having a circumference of 16-52 nucleotides, and wherein copying said mutant target sequence by PCR utilizing the primer is unlikely, as evidenced by the fact that, if the PCR amplification is begun with 10⁶ copies of the mutant target sequence and the multi-part primer but no wildtype sequence, and separately with 10⁶ copies of the mutant target sequence and a corresponding conventional PCR primer but no wild-type sequence, the threshold cycle utilizing the multi-part primer is delayed by at least two cycles compared to the threshold cycle utilizing the conventional PCR primer.

The primer of claim 1 containing a functional moiety located 5' to the anchor sequence, said functional group not hybridizing either to the mutant target sequence or to the wild-type target sequence.

The primer of claim 2, wherein the functional moiety contains a fluorophore and generates a fluorescent signal indicative of amplification.

The primer of claim 1, wherein the foot sequence is 6-7 nucleotides long.

The primer of claim 1, wherein the delay is at least five cycles.

The primer of claim 5, wherein the bubble has a circumference of 28-44 nucleotides.

The primer of claim 6, wherein the bridge sequence and the intervening sequence are of equal length.

The primer of claim 1, wherein the bubble has a circumference of 28-44 nucleotides.

An amplification and detection method that is capable of amplifying at least one rare, mutant DNA target sequence in a mixture containing, for each mutant target sequence, a closely related wild-type DNA target sequence, comprising repeatedly cycling a reaction mixture in a primer-dependent amplification reaction having a primer-annealing temperature, and detecting amplified products, said reaction mixture including said at least one mutant target sequence or its closely related wild-type target sequence or both, a DNA polymerase, amplification buffer, deoxynucleotide triphosphates, and for each mutant target sequence a primer pair that includes a multi-part primer comprising, in the 5' to 3' direction the following three contiguous DNA sequences:
an anchor sequence that hybridizes at the primer-annealing temperature with the mutant target sequence and with its closely related wildtype target sequence;
a bridge sequence that is at least 6 nucleotides long and that is not complementary to either the mutant target sequence or its closely related wildtype target sequence; and
a foot sequence that is 5-8 nucleotides long,

wherein, the mutant target sequence is perfectly complementary to the foot sequence, and the closely related wild-type target sequence is mismatched to at least one of the 3' nucleotide or the 3' penultimate nucleotide of the foot sequence,
wherein, if the anchor sequence and the foot sequence of the primer are hybridized either to the mutant target sequence or to its closely related wildtype target sequence, there is in the target sequence an intervening sequence at least six nucleotides long that does not hybridize to the primer's bridge sequence at the primer-annealing temperature, and the bridge sequence and the intervening sequence together create a bubble in the hybrid, said bubble having a circumference of 16-52 nucleotides, and wherein, the probability that during said cycling a multi-part primer/wild-type target sequence hybrid will be extended is at least 10,000 times lower that the probability that during said cycling a multi-part primer/mutant target sequence hybrid will be extended, as evidenced by a DC_T of at least 13.3 cycles; and wherein the circumference of the bubble and the length of the foot sequence in combination result in a weak foot/mutant-target-sequence hybrid that makes copying the mutant target sequence unlikely, as evidenced by the fact that, if the reaction is begun with said reaction mixture and 10⁶ copies of the at least one mutant DNA target sequence, no wild-type sequence and the multi-part primer, and separately with the reaction mixture containing 10⁶ copies of the at least one mutant DNA target sequence, no wild-type sequence and a corresponding conventional primer in place of the multi-part primer, the
threshold cycle (C_T) is delayed by at least two cycles compared to the C_T of the reaction utilizing the conventional primer.

The method of claim 9, wherein the at least one mutant target sequence is cDNA.

The method of claim 9, wherein the foot sequence is 6-7 nucleotides long.

The method of claim 11, wherein the delay is at least five cycles.

The method of claim 12, wherein the bridge sequence is at least eight nucleotides long and the bubble has a circumference of 28-44 nucleotides.

The method of claim 13, wherein the length of the bridge sequence is equal to the length of the intervening sequence.

The method of claim 11, wherein the reaction mixture includes a detection reagent for detecting product from the amplification of each intended target sequence.

The method of claim 15, wherein the amplification reaction is a polymerase chain reaction (PCR), and detection is real-time detection.

The method of claim 16, wherein the detection reagent is selected from the group of a double-stranded DNA binding dye and a fluorescently labelled hybridization probe that signals upon hybridization.

The method of claim 16, wherein at least one multi-part primer contains 5' to its anchor sequence, a functional moiety that does not hybridize to either the mutant target sequence or to its closely related wild-type target sequence, wherein the functional group includes the detection reagent that comprises a fluorophore/quencher-labelled hairpin structure and generates a fluorescent signal indicative of amplification.

The method of claim 9, wherein the delay is at least five cycles.

The method of claim 9, wherein the threshold cycle (C_T) of an assay begun with 10⁶ copies of a mutant target sequence is at least 18 cycles later than the CT of an assay begun with 10⁶ copies of its closely related wild-type target sequence.

The method of claim 15, wherein the at least one mutant target sequence comprises at least two mutant target sequences, and wherein the detection reagent for each mutant target sequence includes a fluorophore having a unique identifying colour.

A reagent kit for performing an amplification reaction according to claim 9, said kit including said a DNA polymerase, amplification buffer, deoxynucleotide triphosphates, and for each mutant target sequence a primer pair that includes a multi-part primer.

The kit according to claim 22 that includes a fluorescence detection reagent for detecting product from the amplification of each mutant target sequence.

[1] [2013] FCA 214, 100 IPR 451 at [139].

[2] Specification at Page 1, lines 24-29.

[3] Specification at Page 2, lines 29-31.

[4] Specification at Page 4, lines 23-25.

[5] Specification at Page 1, lines 12-14.

[6] Specification at Page 1, lines 14-16.

[7] Specification at Page 2, lines 1-2.

[8] Specification at Page 2, lines 2-5.

[9] Specification at Page 3, lines 25-26.

[10] Specification at Page 3, lines 26-31.

[11] Specification at Page 4, lines 26-30.

[12] Specification at Page 5, lines 2-6.

[13] Specification at Page 5, lines 26-29.

[14] Specification at Page 8, lines 1-11.

[15] Specification at Page 7, lines 17-19.

[16] Specification at Page 11, lines 20-24.

[17] Specification at Page 25, lines 15-18.

[18] Specification at Page 25, lines 25-30.

[19] Specification at Page 26, line 29 – Page 27, line 15.

[20] Specification at Page 28, lines 28-31.

[21] Specification at Page 29, lines 7-9.

[22] Specification at Page 30, lines 26-27.

[23] Specification at Page 31, lines 9-11.

[24] Specification at Page 31, lines 11-14.

[25] Specification at Page 31, lines 15-17.

[26] Specification at Page 32, lines 1-3.

[27] Specification at Page 32, lines 3-6.

[28] Specification at Page 38, lines 12-32.

[29] Specification at Page 39, lines 1-3.

[30] Specification at Page 39, lines 9-12.

[31] Specification at Page 39, lines 12-15.

[32] Specification at Page 40, lines 4-6.

[33] Specification at Page 40, lines 7-10.

[34] [2000] FCA 980; 49 IPR 225 at [70].

[35] AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30; 257 CLR 356 at [23].

[36] Applicant’s Written Submissions at [38].

[37] Applicant’s Written Submissions at [38].

[38] Gerlach-2 at [3].

[39] Gerlach-2 at [4].

[40] Applicant’s Written Submissions at [46].

[41] Applicant’s Written Submissions at [48].

[42] [2009] FCAFC 70, 81 IPR 228 at [118]-[120].

[43] See Eleanor Lawrence (ed), Henderson’s Dictionary of Biology (first published 1920, 13^th ed, 2005).

[44] Specification at Page 10, line 30 – Page 11, line 1.

[45] Specification at Page 6, lines 23-25.

[46] Specification at Page 6, lines 22-23.

[47] The Macquarie University, The Macquarie Dictionary (first published 1999, 7^th ed, 2006).

[48] Specification at Page 29, lines 9-10.

[49] Opponent’s Written Submissions at [6].

[50] Applicant’s Written Submissions at [18].

[51] Specification at Page 2, lines 5-7.

[52] Specification at Page 8, lines 24-25.

[53] Specification at Page 9, lines 12-13.

[54] Specification at Page 12, line 4.

[55] Specification at Page 12, line 7.

[56] Gerlach-2 at [31].

[57] Gerlach-3 at [67].

[58] Gerlach-3 at [67].

[59] Gerlach-3 at [67].

[60] Kramer-1 at [76].

[61] Kramer-1 at [76](a).

[62] Kramer-1 at [76](b).

[63] Kramer-1 at [76](e).

[64] Specification at Page 55, Example 1; Page 56, Example 2.

[65] Matthaei at [62](a) and (b).

[66] The Macquarie University, The Macquarie Dictionary (first published 1999, 7^th ed, 2006).

[67] Specification at Page 21, lines 15-16.

[68] Specification at Page 55, lines 7-12.

[69] Specification at Page 13, lines 27-29.

[70] The DC_T was calculated by comparing the C_Tof curve 601 and 603 respectively in Figure 6 with curve 701 in Figure 7.

[71] Specification at Page 11, lines 13-15.

[72] Specification at Page 6, lines 19-20.

[73] Opponent’s Written Submissions at [68](d).

[74] Applicant’s Written Submissions at [115].

[75] Applicant’s Written Submissions at [115].

[76] Specification at Page 5, lines 7-8.

[77] Specification at Page 16, lines 23-28.

[78] Specification at Page 5, lines 20-21.

[79] Specification at Page 11, lines 13-15

[80] Specification at Page 9, lines 4-6.

[81] Specification at Page 47, lines 17-20.

[82] Gerlach-2 at [42].

[83] Gerlach-2 at [44].

[84] Kramer-1 at [70].

[85] Specification at Page 11, lines 20-24.

[86] Specification at Page 27, lines 11-15.

[87] Specification at Page 27, lines 24-30.

[88] Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59.

[89] [2000] FCA 890; (2000) IPR 331.

[90] [2008] FCAFC 121; (2008) 77 IPR 229.

[91] Opponent’s Written Submissions at [8](a).

[92] Opponent’s Written Submissions at [8](a)(i).

[93] Opponent’s Written Submissions at [21].

[94] Applicant’s Written Submissions at [56].

[95] Applicant’s Written Submissions at [53].

[96] Applicant’s Written Submissions at [56].

[97] Applicant’s Written Submissions at [57].

[98] Gerlach-2 at [28].

[99] Gerlach-3 at [62].

[100] Kramer-1 at [65].

[101] Opponent’s Written Submissions at [8](a)(ii).

[102] Opponent’s Written Submissions at [32].

[103] Opponent’s Written Submissions at [31](a).

[104] Opponent’s Written Submissions at [31](b).

[105] Applicant’s Written Submissions at [69].

[106] Specification at Page 12, lines 3-9.

[107] Specification at Page 25, lines 26-30.

[108] Gerlach-2 at [31].

[109] Novartis AG v Johnson & Johnson Medical Limited [2010] EWCA Civ 1039 at [74].

[110] [2017] APO 57 at [45].

[2018] APO 4; Grant Fisher v ToolGen Incorporated [2018] APO 65; Gary B Cox v MacroGenics, Inc. [2019] APO 13.

[112] [2018] FCA 421; 130 IPR 387.

[113] [2018] UKSC 56.

[114] Warner-Lambert at [36].

[115] Evolva at [33].

[116] [2005] RPC 169 at [112].

[117] See, e.g., Novartis AG v Johnson & Johnson Medical Limited [2009] EWHC 1671 at [244].

[118] [2001] RPC 159 at [40]-[44].

[119] Opponent’s Written Submissions at [68](a).

[120] Opponent’s Written Submissions at [68](b).

[121] Opponent’s Written Submissions at [68](c).

[122] Opponent’s Written Submissions at [68](d).

[123] Applicant’s Written Submissions at [112].

[124] Evolva at [59].

[125] Evolva at [62].

[126] Gerlach-2 at [30].

[127] Gerlach-2 at [47].

[128] Specification at Page 32, line 11 – Page 38, line 32.

[129] Applicant’s Written Submissions at [113].

[130] Applicant’s Written Submissions at [113].

[131] Applicant’s Written Submissions at [151].

[132] Applicant’s Written Submissions at [114].

[133] Specification at Page 5, lines 2-6.

[134] Evolva at [34]-[35].

[135] Opponent’s Written Submissions at [8](c).

[136] Opponent’s Written Submissions at [76].

[137] Applicant’s Written Submissions at [124].

[138] Applicant’s Written Submissions at [124].

[139] Specification at Pages 9-11.

[140] Applicant’s Written Submissions at [125].

[141] Matthaei at [67].

[142] Matthaei at [68].

[143] Matthaei at [69].

[144] Matthaei at [70].

[145] Kramer-1 at [77].

[146] Kramer-1 at [77].

[147] Kramer-1 at [77](f).

[148] Kramer-1 at [77].

[149] Opponent’s Written Submissions at [64].

[150] Matthaei at [109].

[151] Specification at Page 11, lines 11-13.

[152] Specification at Page 32, lines 7-13.

[153] Specification at Page 38, lines 12-32.

[154] Applicant’s Written Submissions at [107].

[155] Applicant’s Written Submissions at [108].

[156] Applicant’s Written Submissions at [126].

[157] Specification at Page 55, line 3 – Page 56, line 21.

[158] Specification at Page 58, line 10 – Page 60, line 4.

[159] Specification at Page 60, line 5 – Page 60, line 24.

[160] Opponent’s Written Submissions at [71].

[161] Applicant’s Written Submissions at [33].

[162] Gerlach-2 at [30].

[163] Matthaei at [59].

[164] Applicant’s Written Submissions at [120].

[165] Matthaei at [59].

[166] Matthaei at [59].

[167] Opponent’s Written Submissions at [76].

[168] Fuel Oils/EXXON (T409/91) [1994] OJ EPO 653 at 659.

[169] Fuel Oils/EXXON (T409/91) [1994] OJ EPO 653 at 659-660.

[170] [2015] APO 72 at [115].

[171] Opponent’s Written Submissions at [8](b).

[172] Opponent’s Written Submissions at [42].

[173] [2019] APO 34 at [68].

[174] Opponent’s Written Submissions at [43].

[175] Opponent’s Written Submissions at [44].

[176] Opponent’s Written Submissions at [45].

[177] Opponent’s Written Submissions at [46].

[178] Gerlach-3 at [34].

[179] Opponent’s Written Submissions at [47] and [65].

[180] Applicant’s Written Submissions at [116].

[181] [1959] HCA 67; 102 CLR 252.

[182] NRDC at [269].

[183] NRDC at [275].

[184] D'Arcy v Myriad Genetics Inc [2015] HCA 35; 258 CLR 334 at [144].

[185] Patent Manual of Practice and Procedure at 2.9.2.16.2.

[186] British Celanese Ltd v Courtaulds Ltd [1935] 52 RPC 171 at 194.

[187] The Macquarie University, The Macquarie Dictionary (first published 1999, 7^th ed, 2006).

[188] Opponent’s Written Submissions at [81].

[189] Applicant’s Written Submissions at [163].