Search

Australian Patent Office

Search AustLII

▼
Search Options
×
Close
  • Specific Year
    Any

Evolva SA [2017] APO 57 (14 November 2017)

Last Updated: 14 November 2017

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Evolva SA [2017] APO 57

Patent Application: 2012342114

Title: Methods and materials for enzymatic synthesis of mogroside compounds



Patent Applicant: Evolva SA



Delegate: Dr Leslie F. McCaffery – Deputy Commissioner of Patents



Decision Date: 14 November 2017

Hearing Date: Written submissions filed on 8 September 2017

Catchwords: PATENTS – examiner objection – clear enough and complete enough disclosure (sufficiency) – is it plausible that the invention can be worked across the full scope of the claim – can the invention be performed across the full scope of the claim without undue burden – the specification is sufficient.

Representation: Patent attorney for the applicant: FPA Patent Attorneys











IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application: 2012342114

Title: Methods and materials for enzymatic synthesis of mogroside compounds



Patent Applicant: Evolva SA



Date of Decision: 14 November 2017

DECISION

The specification is considered clear enough and complete enough for the invention to be performed by the skilled person. I direct the application to proceed to acceptance.

REASONS FOR DECISION

  1. Patent application 2012342114 was filed by Evolva SA (the applicant) on 19 November 2012. A first examination report issued on 28 September 2016, objecting only on the ground of clear enough and complete enough disclosure. Despite amendments filed by the applicant on 31 January 2017 and 30 June 2017 the objection was maintained in second and third reports. An additional objection that Claim 17 lacked support was raised in the second report but this was overcome by amendment and has no bearing on the present consideration. The applicant filed further amendments on 8 September 2017 and also requested a hearing.

  1. The matter was heard on the basis of the written submissions which were also filed on 8 September 2017.

Standard of proof

  1. The examination of the present application is governed by the Patents Act 1990 (the Act) as amended by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (the Raising the Bar Act). Amendments to sections 40 and 49 of the Act apply to the present case as a consequence of Schedule 1, items 55(1)(e) and 55(4)(b) of the Raising the Bar Act – the application was filed before 15 April 2013 but the applicant did not request examination of the patent request and specification for the application until 17 June 2015.

  1. The standard of proof that applies to the examination of the present application is therefore the balance of probabilities – I must accept the present application if satisfied on the balance of probabilities that the application complies with the Act. If I am not so satisfied, then I can refuse the application.

The specification

  1. Mogrosides are a family of triterpene glycosides isolated from the fruits of Siraitia grosvenorii (Swingle), which is also known as Momordica grosvenori (Swingle). Extracts of the fruit are commercially used as natural sweeteners, and four major compounds have been identified as being responsible for the sweetness of the fruit: Mogroside V, Mogroside IV, Siamenoside I and 11-Oxomogroside V. The structures of these compounds are given in Annex A. In general, mogrosides share a common triterpene core, Mogrol, which can be glycosylated with different numbers of glucose moieties to provide various mogrosides.

2017_5700.jpg



Mogrol



  1. The present invention relates to methods and materials for enzymatic synthesis of mogroside compounds, and in particular to glycosylating mogrol using Uridine-5’-diphospho dependent glucosyltransferases (UGTs).

  1. The specification states that 5 UGTs belonging to glycosyltransferase family 1 have been identified that glycosylate mogrol: UGT73C3, UGT73C5, UGT73C6, UGT73E1 and UGT85C2 (SEQ ID NOs: 1-5 respectively). UGT73C3, UGT73C5 and UGT73C6 are from Arabidopsis thaliana, while UGT73E1 and UGT85C2 are from Stevia rebaudiana.

  1. Mogrosides are produced by incubating Mogrol with the UGT and the sugar. Four examples are given, but only Example 4 involves the process of the claims. Example 1 describes the purification of Mogroside V from commercially available monk fruit extracts. Example 2 describes the preparation of Mogrol via the complete hydrolysis of Mogroside V using a pectinase. Example 3 describes the preparation of Mogrosides Ia and Ib via partial hydrolysis of Mogroside V using a pectinase.

  1. Example 4 describes an in vitro screening of the glycosylation of Mogrol with a panel of 230 UGT enzymes. UGT73C3, UGT73C6 and UGT85C2 were found to convert Mogrol to Mogroside Ib. UGT73C5 gave both Mogroside Ia and Ib. UGT73E1 provided Mogroside Ib as the major product, together with a minor product that the applicant suggests arises as a result of glycosylation of the hydroxyl group at the 25-position (the tertiary carbon on the side chain). As shown in the figures below, Mogroside Ia is glycosylated in the 3-position, while Mogroside Ib is glycosylated in the 23-position.

2017_5701.jpg

Mogroside Ia



2017_5702.jpg



Mogroside Ib



  1. The specification states that the UGTs can be produced by chemical synthesis or alternatively by standard recombinant technology. The techniques described for such methods (including the use of expression vectors and different expression systems, various transfection and transformation techniques, and the use of various tags to facilitate detection or purification) appear to be standard in the art.

  1. The specification then goes on to describe functional homologs of the UGTs which are said to also be suitable for use in the methods. A functional homolog is a polypeptide that has sequence similarity to a reference polypeptide and that carries out one or more of the biochemical or physiological functions of the reference polypeptide. Again, the techniques used in these processes appear to be standard in the art and the specification states that:

“[t]echniques for modifying genes encoding functional UGT polypeptides described herein are known and include, inter alia, directed evolution techniques, site-directed mutagenesis techniques and random mutagenesis techniques, and can be useful to increase specific activity of a peptide, alter substrate specificity, alter expression levels, alter subcellular location or modify polypeptide:polypeptide interactions in a desired manner.”[1]

  1. The specification further sets out that sequence alignment, using techniques such as BLAST analysis, may also be used to identify functional homologues. Amino acid similarity allows for conservative amino acid substitutions, and manual inspection can be used to select candidates that contain conserved functional domains. Such domains can be identified by locating regions that are repeated, form some secondary structure (e.g. helices and beta sheets), have positively and negatively charged domains or represent a protein motif or domain. The Pfam database is said to provide consensus sequences for a variety of protein motifs, and sequence alignment may also be used to identify conserved regions in closely related species.

  1. The claims as proposed to be amended on 8 September 2017 are set out in Annex B. Claim 1 is illustrative of the invention and defines a method of producing a mogroside compound by glycosylation of mogrol using a UGT that is:

(a) UGT73C3 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:1;

(b) UGT73C5 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2;

(c) UGT73C6 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:3;

(d) UGT73El polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:4; or

(e) UGT85C2 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:5.

  1. Other claims include embodiments wherein the UGT is provided in a cell lysate from a recombinant host expressing the UGT or glycosylation is carried out by successive treatment with different UGTs.



The examiner’s objection

  1. The only outstanding issue in the present case relates to whether the application provides a clear enough and complete enough disclosure of the invention set out in the claims, and in particular to whether the specification provides sufficient information to enable the person skilled in the art (PSA) to perform the invention across the full scope of the claims without undue burden or the need for further invention. The gist of the examiner’s objection was that the specification did not provide a principle of general application that would enable the invention across its full scope, and in particular that:

“The present claims recite peptides with at least 90% sequence identity to any one of 5 reference sequences. It is not reasonable to assume (and the applicant admits in their response, by indicating the need to test such peptides for the desired activity) that every single peptide having the recited sequences will have the recited transferase activity.

As such, the present claims are not considered to have a principle of general application. Therefore, in order to work the invention across its full scope (i.e. to say for the PSA to reasonably know which of the recited peptides are encompassed by the claims), the PSA would need to produce every single peptide recited and then take the additional step of assaying each to see which have the desired activity.

Although it may be trivial for the PSA to carry out these actions for any one peptide, the need to produce a complete library of (countless) peptides and then assay each is considered to be much more work than a PSA would typically expect to undertake when putting an enzyme catalysed synthesis into practice.

...

Whilst the PSA would reasonably expect, when putting an enzyme catalysed synthesis into practice, to have to provide the enzymatic peptide and try different reaction conditions to get a viable reaction and then optimise these to get the best yield, they would not reasonably expect (nor would they think that it would be a matter of routine in such cases) to have to develop a library of countless peptides and assay each for the desired activity.”

  1. My understanding of the examiner’s objection is that the level of identity defined by the claims (at least 90%) requires an undue burden of experimentation. There is otherwise no indication in the examination report as to the extent of claim that is considered enabled. The assertion appears to be that only the specific sequences provided (SEQ ID NOs: 1-5) are considered sufficiently disclosed by the specification.

  1. I also note that while the examiner has referred at each report to the extent of work involved in determining the reaction conditions for any given peptide (solvents, buffers, reagent ratios and reaction times), these are in the context of the effort required for each of the peptides falling within the scope of the claims. There does not appear to be any dispute as to the scope of the claims in relation to the reaction conditions used for, and the products obtained by, the glycosylation process.

  1. I will therefore limit my consideration to the question of whether the specification is sufficient across the full scope of polypeptides defined by the claims, and in particular the requirement that they be at least 90% identical.



Relevant Law

  1. The disclosure requirements for a patent are set out in subsection 40(2) as follows:



(2) A complete specification must:

(a) disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art; and

(aa) disclose the best method known to the applicant of performing the invention; and

(b) where it relates to an application for a standard patent—end with a claim or claims defining the invention; and

(c) where it relates to an application for an innovation patent—end with at least one and no more than 5 claims defining the invention.

  1. Paragraphs (a) and (aa) were introduced by the Raising the Bar Act, and replaced the former provision that the specification describe the invention fully, including the best method known to the applicant of performing the invention. The requirement that the disclosure is clear enough and complete enough for the invention to be performed by the skilled person is otherwise referred to as sufficiency. The purpose of this provision was set out in the Explanatory Memorandum, Intellectual Property Laws Amendment (Raising the Bar) Bill 2011 (item 8) as follows:

"The item is intended to modify the wording of paragraph 40(2)(a) of the Act so as to require enablement across the full width of the claims, while adopting language that is consistent with that used in other jurisdictions. The wording in the amendment is similar to s 14(3) of the UK patents legislation, which has been interpreted as imposing this requirement. The wording is also similar to art 83 of the European Patent Convention, which has been interpreted with similar effect. The intention is that paragraph 40(2)(a) be given, as close as is practicable, the same effect as the corresponding provisions of UK legislation and the European Patent Convention.

A specification that provides a single example of the invention may satisfy the requirements, but only where the skilled person can extend the teaching of the specification to produce the invention across the full width of the claims, without undue burden, or the need for further invention.

However, it is expected to be more likely that, where the claims are broad, the specification will need to give a number of examples or describe alternative embodiments or variations extending over the full scope of the claims. This ensures that the monopoly extends only to that which could reasonably be said to be disclosed and no further.

If, on its face, the specification would appear to the skilled person to lack sufficient disclosure, the onus of establishing that the invention is described in enough detail lies with the applicant".

  1. As suggested by the stated intentions of the Explanatory Memorandum, the corresponding UK provisions act is intended to ensure that:

“the scope of the monopoly, as defined in the claims, must correspond to the technical contribution the patentee has made to the art. An aspect of this requirement is that the specification must enable the invention to be performed to the full extent of the monopoly claimed.”[2]

  1. This principle is also consistent with that set out by the Technical Board of Appeal in Exxon/Fuel Oils,[3] and the House of Lords has acknowledged the importance for UK patent law to be aligned with the jurisprudence of the EPO.[4]
  2. Several approaches to sufficiency have developed in UK case law: classical insufficiency, insufficiency by excessive claim breadth and insufficiency by ambiguity.[5] Classical insufficiency arises where the teaching of the patent does not enable the skilled person to perform the invention without further invention, or where “prolonged research, enquiry or experiment” is required in order to work the invention. Insufficiency by excessive claim breadth (sometimes referred to as Biogen insufficiency) arises where there may be an enabling disclosure for something falling within the scope of the claim, but not across the full breadth of the claim. The illustrative examples given in the Explanatory Memorandum are consistent with a consideration of this nature. Insufficiency by ambiguity arises where the skilled person is unable to determine whether or not they have worked the invention.[6] Notably while these seemingly different approaches have developed, as noted in Zipher v Markem, “in every case, however, the purpose behind the objection is to prevent a patentee laying claim to products or processes which the teaching of the patent does not enable in the relevant sense”.[7]
  3. Kitchin J (as he was then) provided the following useful summary of general principles to be followed when assessing whether a specification is sufficient. [8] These were elaborated upon by Kitchin LJ in Regeneron,[9] and reiterated more recently in Idenix:[10]

"The specification must disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these:

(i) the first step is to identify the invention and that is to be done by reading and construing the claims;

(ii) in the case of a product claim that means making or otherwise obtaining the product;

(iii) in the case of a process claim, it means working the process;

(iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims;

(v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification;

(vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim;

(vii) the specification must be sufficient to allow the invention to be so performed without undue burden."

  1. These principles were applied by the Delegate in CSR,[11] wherein a three-step approach was taken to determine whether the specification provided a disclosure as required by subsection 40(2):

(i) Construe the claims to determine the scope of the invention as claimed

(ii) Construe the description to determine what it discloses to the person skilled in the art, and

(iii) Decide whether the specification provides an enabling disclosure of all the things that fall within the scope of the claims.

  1. In the present case the examiner’s objection was based on an application of two main concepts: undue burden of experimentation and principle of general application – that is, the arguments were essentially that the claims were insufficient on the basis of excessive claim breadth. I will consider these concepts further before dealing with the case at hand.
  2. The legislation sets out the specification must be clear enough and complete enough for the invention to be performed by a person skilled in the relevant art. The fact that the disclosure need only be enough sets a minimum requirement and it is long-established law that the skilled reader will draw upon their common general knowledge and skills in order to work the invention. In general, the extent of the disclosure necessary to make the patent sufficient will depend upon the nature of the invention, the scope of the claims and the art in which the invention is made.[12] As stated in Novartis v Johnson & Johnson:

“Whether the specification discloses an invention clearly and completely enough for it to be performed by a person skilled in the art involves a question of degree. It is impossible to lay down any precise rule because the degree of clarity and completeness required will vary depending on the nature of the invention and of the art in which it is made. On the one hand, the specification need not set out every detail necessary for performance. The skilled person must be prepared to display a reasonable degree of skill and use the common general knowledge of the art in making routine trials and to correct obvious errors in the specification, if a means of correcting them can readily be found. Further, he may need to carry out ordinary methods of trial and error, which involve no inventive step and generally are necessary in applying the particular discovery to produce a practical result. On the other hand, he should not be required to carry out any prolonged research, enquiry or experiment...”[13]

  1. Notably the person skilled in the art for the consideration of sufficiency is the same as for addressing inventive step. They do not possess any different or greater level of skills, but they have possession of the invention and they are trying to carry out the invention and achieve success, as opposed to an obviousness consideration where they are taken to be searching for a solution in ignorance of the invention.[14] Further in this regard, Lord Hoffmann stated in Kirin-Amgen:

“The skilled person is taken to be trying to make the invention work. If the skilled person would quickly realise that one method would work and another would fail, the specification is not insufficient because the claim is expressed in terms broad enough to include both methods.”[15]

  1. It is clear from the authorities that the sufficiency consideration is dependent on the nature of the technology and the particular circumstances of the case. The concept of what constitutes prolonged research, enquiry or experiment, and the point at which such studies become an undue burden on the skilled person have been considered in a number of UK and EP decisions. In Mentor v Hollister Aldous J noted that:

“The section requires the skilled person to be able to perform the invention, but does not lay down the limits as to the time and energy that the skilled man must spend seeking to perform the invention before it is insufficient.” [16]

  1. Aldous J had regard to the extent of routine trial required to arrive at a workable prototype, an approach which the Court of Appeal subsequently confirmed.[17] Pumphrey J agreed with this approach in Halliburton v Smith,[18] and cautioned that:

“All the same, one must be on one's guard against formulations that gloss the statutory requirement as there is always a risk that they will end up being substituted for it. This is a particular risk where the subject of the specification is very complex and its development would anyway be expected to be accompanied by a great amount of work. What is 'prolonged' in this context? It is always necessary to keep a balance between the interests of the public and the interests of the patentee in the sense that it is necessary to guard against imposing too high a standard of disclosure merely because the subject matter is inherently complex.”

  1. However on appeal, the issue of undue effort was considered in the context of a hypothetical case requiring 20 years of routine work and submissions that the length of time was not a relevant factor, particularly in technologies such as genetic engineering or pharmaceutical science where a great deal of routine work is involved in implementation. Jacob LJ stated:

“We do not accept that extreme submission. Patents are meant to teach people how to do things. If what is ‘taught’ involves just too much to be reasonable allowing for all the circumstances including the nature of the art, then the patent cannot be regarded as an ‘enabling disclosure.’ That is the basic concept behind the requirement of sufficiency and one that lies at the heart of patent law (‘central’ as Lord Hoffmann put it in Biogen v Medeva...). The setting of a gigantic project, even if merely routine, will not do. Moreover the analogy with genetic engineering and pharmaceutical inventions is not apt. The work that goes into bringing them to market relates to testing efficacy and safety – not in actually making the invented product.”

  1. In Regeneron the argument was put to the High Court that the identification of therapeutically active agents against a particular neovascular disease required undue effort by way of research and experimentation, and that the absence of an approved treatment some years after the patent was filed taught towards insufficiency. In the Court of Appeal, Kitchin LJ stated that:

“The judge dealt with this allegation at [200]:

‘Hovering around the case was a suggestion that the process of getting the invention to work in the form of an approved treatment for diseases such as RA involved too much by way of research and experimentation. The claimants pointed to the absence of any such approved treatment. I do not think that this is an adequate evidential approach to an allegation of classical insufficiency in a case such as this, as it imposes too high a standard. What the claimants need to show is that the skilled person would not be able to establish without undue burden whether a given anti VEGF therapy has an effect on angiogenesis in a given disease. The evidence was not really directed to this issue at all. I reject this allegation as well.’

I think the judge was right in reaching this conclusion. As the Board of Appeal said in T609/02 Salk, proving the suitability of a given compound as an active ingredient in a pharmaceutical composition might require years and very high development costs. For this reason, the patent system does not require absolute proof that the compound is approved as a drug before it may be claimed as such. Furthermore, there may be many commercial reasons why a patentee chooses not to carry a particular treatment through to final approval. Indeed, Professor Shima explained in cross-examination that developing drugs involves both a business decision and a major clinical trial. But that does not render a patent insufficient.”[19]

  1. 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 provided 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. This is reflected in the statement by Aldous J in American Home Products v Novartis[20] at [40]:

“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.”

  1. EP and UK decisions have provided some general guidance on factors that come into consideration, including: uncertainty and a lack of predictability, [21] incomplete experimental details[22] and a lack of guidance in the specification including instructions on how to proceed in case of failure.[23],[24]
  2. Some of these types of considerations were reflected in CSR,[25] where the invention (fire resistant gypsum panels) was defined in terms of a number of parameters rather than the technical features that achieved those parameters. The Delegate considered whether the skilled person would reasonably expect the invention to work with anything that falls within the term. In the case of the “high expansion particulate” component, only high expansion vermiculite was exemplified, but the preparation of panels using other non-vermiculite particulates was not considered an undue burden. However other parameters (core density, core hardness, Thermal Insulation Index and fire resistance) were determined by a number of process and starting material variables, and the specification provided no real guidance on how these could be adjusted to achieve the full combination of properties defined by the claims. The lack of guidance, the uncertainty in the research and the degree of trial and error required led to the determination that there was an undue burden required to perform the invention across the full scope of the claims.
  3. I will consider such factors and whether the skilled person would be required to undertake a research programme in my determination of whether there is an undue burden required to work the invention across the full scope of the claims.
  4. An invention may be defined in general terms provided the specification discloses a principle of general application inasmuch as it can be reasonably expected the invention will work with anything falling within the scope of these terms. Lord Hoffmann addressed this in Biogen v Medeva as follows:

“If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them.

Thus if the patent has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect... On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.”[26]

  1. Lord Hoffmann subsequently elaborated on the concept of a principle of general application in Kirin-Amgen:

“This gave rise to a good deal of argument about what amounted to a ‘principle of general application’. In my opinion there is nothing difficult or mysterious about it. It simply means 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 which falls within the general term. For example, in Genentech I/Polypeptide expression (T292/85) [1989] OJ EPO 275, the patentee claimed in general terms a plasmid suitable for transforming a bacterial host which included an expression control sequence to enable the expression of exogenous DNA as a recoverable polypeptide. The patentee had obviously not tried the invention on every plasmid, every bacterial host or every sequence of exogenous DNA. But the Technical Board of Appeal found that the invention was fully enabled because it could reasonably be expected to work with any of them.

This is an example of an invention of striking breadth and originality. But the notion of ‘a principle of general application’ applies to any element of the claim, however humble, which is stated in general terms. A reference to a requirement of ‘connecting means’ is enabled if the invention can reasonably be expected to work with any means of connection. The patentee does not have to have experimented with all of them.”[27]

  1. Kitchin LJ considered these authorities in Regeneron and concluded that:

“It must therefore be possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. The products and methods are then tied together by a unifying characteristic or a common principle. If it is possible to make such a prediction then it cannot be said the claim is insufficient simply because the patentee has not demonstrated the invention works in every case.

On the other hand, if it is not possible to make such a prediction or if it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee has made to the art and the claim will be insufficient.”[28]

  1. The requirement that enablement over the scope of the claim (or of a term used within a claim) be based on a reasonable prediction, or that the assertion that the invention work across the full scope of the claim be plausible or credible, has developed as a kind of threshold test for sufficiency in subsequent UK Court decisions – see, for example, the statements of Carr J in GlaxoSmithkline v Wyeth.[29] I note also the statement made by Lord Hoffmann in Conor v Angiotech when comparing the level of disclosure required under sufficiency and inventive step which is indicative of there being a threshold consideration for sufficiency (“if a specification passes the threshold test of disclosing enough to make the invention plausible...”).[30] In Eli Lilly v Janssen,[31] Arnold J employed a two-stage enquiry:

“The first stage is to determine whether the disclosure of the Patent, read in the light of the common general knowledge of the skilled team, makes it plausible that the invention will work across the scope of the claim. If the disclosure does make it plausible, the second stage is to consider whether the later evidence establishes that in fact the invention cannot be performed across the scope of the claim without undue burden. For convenience, I shall divide the second stage into two, first considering whether the invention can be performed without undue burden at all and then whether the claim is of excessive breadth.”

  1. Floyd J recently elaborated on the origins of plausibility as a requirement in disclosure (Warner Lambert v Generics), citing jurisprudence of the Boards of Appeal in the European Patent Office in relation to industrial applicability and inventive step,[32] and specifically Salk,[33] AgrEvo[34] and John Hopkins.[35] He also drew links between the considerations of plausibility under sufficiency, industrial applicability and obviousness, referencing statements by Lord Neuberger in HGS v Eli Lilly[36] and by Lord Hoffmann in Conor v Angiotech[37] before concluding that:

“46. The EPO and domestic cases do, however, indicate that the requirement of plausibility is a low, threshold test. It is designed to prohibit speculative claiming, which would otherwise allow the armchair inventor a monopoly over a field of endeavour to which he has made no contribution. It is not designed to prohibit patents for good faith predictions which have some, albeit manifestly incomplete, basis. Such claims may turn out to be insufficient nonetheless if the prediction turns out to be untrue. A patent which accurately predicts that an invention will work is, however, not likely to be revoked on the ground that the prediction was based on the slimmest of evidence. Thus, the claims will easily be seen not to be speculative where the inventor provides a reasonably credible theory as to why the invention will or might work. The same is true where the data in the specification is such that the reader is encouraged to try the invention.

47. We heard argument as to whether the invention is only to be treated as plausible if the reader of the specification would be encouraged to try the invention with a reasonable prospect of success, thereby bringing the test for plausibility into line with that sometimes used in the context of obviousness. I do not accept that there is any reason to align the tests in this way. A test designed to prevent speculative claiming need go no further than requiring the patentee to show that the claim is not speculative: the specification does not need to provide the reader with any greater degree of confidence in the patentee's prediction than that.”

  1. As an aside I note that the corresponding Australian patent was found to be sufficient under Australian Law by the Federal Court in Apotex v Warner-Lambert.[38] It appears the issue was argued on different evidence, but in any case the law that applied was as it stood prior to the Raising the Bar Act. As a consequence I consider this to be of lesser relevance for the present consideration. I also note that Warner-Lambert v Generics has been appealed to the Supreme Court (Case ID: UKSC 2016/0197), including on the point of “whether (or what) role plausibility should play in the statutory test for sufficiency, and whether a patent should be held insufficient for lack of plausibility even though it is in fact enabled across the full scope of the claim”. I am therefore mindful that there is some uncertainty surrounding the extent to which “plausibility” may be applied to the sufficiency determination under UK Law.
  2. However the recent UK decisions referred to above seem to me to be founded in the principle that the scope of the monopoly, as defined in the claims, must correspond to the technical contribution the patentee has made to the art. If the assertions made in the specification are not plausible then it cannot be reasonably said that the patentee has made a contribution to the art. Moreover, the requirement set out in Regeneron that the claim (or of a term used within a claim) be based on a reasonable prediction, or an assertion that the invention works across the full scope of the claim be plausible or credible, appears to me to be consistent with, or an alternative means of articulating, the concept of a principle of general application as set out by Lord Hoffmann in Kirin-Amgen. An assertion in a patent specification could hardly be considered a principle with broader applicability if the skilled reader would not consider it plausible from a technical viewpoint.
  3. I also consider there is merit in the two-stage approach adopted in Eli Lilly v Janssen – an invention that is plausible may still fail on sufficiency if the specification essentially sets out a research programme and there is an undue burden of experimentation required to put it into practice. If an invention is implausible then it would inherently require an undue burden of experimentation to put it into practice (if at all). Moreover a similar consideration appears to be taken by the EPO, albeit not as a distinct two-stage consideration but rather as part of the consideration of whether there is an undue burden on the skilled person to work the invention across the full scope of the claim – see for example the determination Opposition Division in EP 1169038.[39] In that case the Oppositions Division found that it was not credible that all of the compounds defined by Claim 1 were inhibitors of all members of the heterogeneous protein tyrosine kinase family. The skilled person would therefore be obliged to carry out a research programme to determine which would be suitable for the treatment of a particular kinase, and thus to the treatment of a specific disease. This was considered an undue burden on the skilled person. I note that this decision was subsequently appealed to the Technical Board of Appeals,[40] but not on the ground of sufficiency.
  4. I therefore consider that regard may be had to the guidance provided in recent UK and EPO decisions on sufficiency, including the consideration of plausibility in relation to claims of excessive breadth. Accordingly, in this case I will follow a process of construing the specification and determining:

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?

Application to the present case

  1. Before turning to the specific issues at hand, I note that a significant portion of the applicant’s submissions focussed on the outcome of examination of the corresponding European application and the policy intent of Raising the Bar. In particular the applicant noted that the corresponding EP application has been granted, and near-identical claims have been considered by the EPO to be fully enabled and supported across their full scope by the specification. They submitted that the Australian claims must inherently also be fully enabled and supported across their full scope.

  1. The applicant also noted that the Explanatory Memorandum to the Raising the Bar Act stated that the intention is for paragraph 40(2)(a) to be given, as close as is practicable, the same effect as the corresponding provisions of the UK legislation and European Patent Convention. Refusing claims of substantially identical scope and having the same specification is not the exercise of s40(2)(a) in a way that is “as close as is practicable” to the EPO provisions, when those same claims are deemed allowable under the EPO provisions. There was also no intention for there to be a higher enablement requirement than the jurisdictions on which the provision was based. At no point has the examiner justified why a departure from the EPO approach and standard is warranted or appropriate.

  1. While I acknowledge the intent of the Raising the Bar Act, I find these submissions of little assistance in the present consideration. It may be of assistance to an examiner to refer to foreign examination reports, but the fate of an application in another jurisdiction will not be determinative of the corresponding application here. Indeed it is not unusual for the same application to have different outcomes in different jurisdictions – an application that is granted in one country may be refused in another, and the scope of claims can vary widely on a case by case basis. I particularly note that it is not incumbent on an examiner to justify that any “departure from the EPO approach and standard is warranted or appropriate”. To the contrary, if an examiner has a concern that, on the balance of probabilities, the application fails to meet any of the legislative requirements then they will raise an objection, regardless of whether or not a similar objection has been raised in a foreign jurisdiction. Where the examiner has raised such objection the onus shifts to the applicant to provide submissions or amendments responsive to the issue at hand. Simply referring to the outcome of a corresponding overseas application, in my view, will not discharge this onus.

  1. Turning now to the specification and the question of sufficiency, in the ordinary course of events I would expect supporting material to be provided to support an objection of this nature, and for the applicant to provide sound technical reasons in response. It would also be of assistance for there to be submissions in relation to the skilled person and their common general knowledge. However I am satisfied that I can make this determination from the information on file (and from a cursory consideration of available prior art), and therefore I have not sought further submissions from the applicant on this point.



The person skilled in the art

  1. The specification is construed through the eyes of the person skilled in the relevant art. This is the hypothetical person to whom the specification is addressed:[41]

“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...”[42]

  1. The person skilled in the art is assumed to be a skilled but unimaginative and non-inventive worker in the field of the invention.[43] One formulation describes them as “those likely to have a practical interest in the subject matter of [the] invention”.[44] Notably:

“The identification of the relevant field will, in its turn, determine the characteristics of the notional worker skilled in the art who must provide the answer to the question of whether the invention was obvious. Such characteristics will include the qualifications of the notional worker, the setting in which he or she operates and the practices and techniques that he or she will regard as commonplace and known”.[45]

  1. The examiner stated in their second report that:

“given the presently claimed method is simply a peptide catalysed chemical synthesis, it is not unreasonable to assume that the PSA could be a single synthetic chemist, perhaps a PhD candidate. Furthermore, it would be reasonable to expect said PSA to undergo routine trial and error of the reaction conditions (including trailing [sic] different solvents, buffers, reagent ratios and reaction times) for any given polypeptide.”

  1. I do not entirely agree with this representation of the skilled person. The specification relates not only to the use of UGTs in chemical synthesis, but also to the identification and/or generation of functional homologues. Indeed the issue in dispute relates to whether it is an undue burden to identify such homologues. I therefore consider that “those likely to have a practical interest in the subject matter of the invention” would not be limited to a synthetic chemist, even though they may well be a member of the team. To this end, the applicant did not articulate a specific skilled person, but referred in their submissions to the nature of the experimentation they would undertake and their knowledge in the art. This included having the common general knowledge as to the amino acid changes that are likely to retain the function of the polypeptides, the ability to undertake experiments to generate functional homologues, and the ability to undertake screening of polypeptides to determine their ability to catalyse the glycosylation of mogrol. Given these requirements a biotechnologist is likely to have a practical interest in the subject matter of the invention.

  1. On balance I consider the skilled person would be a team comprising biotechnologists with skills and knowledge of the techniques for the identification and generation of variants (including recombinant techniques), as well as synthetic chemists with a knowledge of the use of enzymes in reactions.



What is the scope of the invention claimed?

  1. The applicant submitted that the claims are directed to:

“methods for producing a mogroside compound using recombinant polypeptides capable of catalyzing glycosylation of mogrol to produce a mogroside compound (i.e., a UDP dependent glucosyltransferase) and having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NOs: 1-5.”

  1. I note that the claims do not explicitly define that the UGTs are capable of catalysing glycosylation of mogrol, but I understand this to be an inherent requirement of the claimed feature of “contacting and glycosylating mogrol with a UGT”. I am satisfied that this is an appropriate representation of the scope of the invention defined by the claims.

What does the specification disclose to the skilled person?

  1. In their response of 30 June 2017, the applicant submitted that:

  • The specification teaches the PSA that UGTs of Arabidopsis thaliana or Stevia rebaudiana are useful in the production of mogrosides. This surprising discovery that is described in the specification gave rise to the claimed method.
  • The specification identifies 5 specific UGT polypeptides - see Example 4.
  • The specification teaches that the UGT polypeptides can be produced by any suitable method including chemical synthesis, recombinant technology and expression systems - see pages 3 to 5.
  • The specification teaches that a functional homolog can be utilised - see pages 5 to 7. By virtue of being a "functional" homolog, the claimed polypeptides must be able to catalyse glycosylation of mogrol to produce mogroside.
  • The specification at page 6 describes that functional homologs can be identified by analysis of nucleotide and polypeptide sequence alignments includes giving due consideration to conserved sequences.
  • The ability of a functional homolog to catalyse glycosylation of mogrol and to therefore be suitable for use in the claimed method of producing a mogroside can be tested by following the screening and reactions set out in Example 4.

  1. I consider this to be a reasonable summary of what the specification discloses.

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?
  1. As noted above the threshold for plausibility is a low one, and may be based on the slimmest of evidence. Indeed in HGS v Eli Lilly,[46] Lord Neuberger stated that in some cases a "plausible" or "reasonably credible" claimed use, or an “educated guess", can suffice. The only issue in question here is whether it is plausible that polypeptides which have as low as 90% identity would be capable of catalysing the defined glycosylation reaction.
  2. The specification provides a general discussion of the manner in which functional homologues may be generated. I also understand that conservative substitution of amino acids in proteins is widely practiced, and that the properties of the resulting variants can be predicted with some certainty, particularly where the active binding regions of the proteins are known. However whether such a prediction may be reasonably made will depend on the specific facts of the case – in some cases a lesser level of identity could be considered plausible while in others higher levels may be more plausible. In the present case the properties of UGTs appear to be well-known in the art, and they are also known to contain the following conserved protein domain (UDPGT):[47]

[FW]x{2}[QL]x{2}[LIVMYA][LIMV]x{4,6}[LVGAC][LVFYAHM][LIVMF][STAGCM][HNQ][STAGC]Gx{2}[STAG]x{3}[STAGL][LIVMFA]x{4,5}[PQR][LIVMTA]x{3}[PA]x{2,3}[DES][QEHNR].

  1. All of the sequences shown in SEQ ID NOs: 1-5 contain this consensus sequence. The prior art suggests that this consensus sequence is involved in binding to the uridine-5’-diphospho moiety of the sugar nucleotide. Plant UGTs are also characterised by the presence of a C-terminal consensus sequence comprising 44 amino acids, which corresponds to the signature motif, UDPGT, termed the plant secondary product glycotransferase (PSPG) box. Structural studies have also been carried out to determine the binding domains, and in particular the sugar acceptor and sugar donor regions which are thought to be located in the N- and C-terminal Rossmann-like domains respectively. [48]
  2. Given the prior art knowledge of the structure and function of UGTs, I can see no apparent reason why the skilled person would not consider it plausible that functional variants to a level of identity of at least 90% could be identified and would be useful in the process defined. I therefore consider 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?
  1. Having determined that it is plausible that the invention can be worked across the full scope of the claim, it remains to determine whether this would be an undue burden on the skilled person.

  1. The gist of the examiner’s latest objection was that there was an undue burden because the skilled person would need to identify each and every possible polypeptide with 90% identity to each of the defined sequences, and then take the additional steps of assaying each to see whether it catalysed the glycosylation reaction. The examiner argued that it was not reasonable to assume that every single peptide defined would have the recited transferase activity. It would not be a matter of routine for the skilled person to develop a library of “countless” peptides and assay for the desired activity.

  1. As an initial point, I do not agree with the assertion that the claims include polypeptides that do not have transferase activity. As mentioned previously, I consider the claim inherently requires the polypeptide to be capable of catalysing the reaction, and the reference to the peptides as being glucosyltransferases would inherently mean that the peptide has such a function. The applicant also argued that they are not required to show, make and test every single polypeptide that can be utilised in the claimed method and that the specification must only provide sufficient information for the skilled person, armed with their common general knowledge, to determine which polypeptides can be used in the claimed method. This submission appears to be consistent with the guidance in the Explanatory Memorandum that a single example may satisfy the sufficiency requirements, but where the claims are broad the specification will need to provide a number of examples or embodiments extending across the full scope of the claims.

  1. The consideration is therefore whether the embodiments provided are enabling for the full scope of the claims, and whether the skilled person would be able to determine which of the polypeptides having greater than 90% identity would have transferase activity and whether this would be an undue burden – put differently, is the skilled person required to undertake a research programme in order to work the invention across the full scope of the claims?

  1. The examiner’s objection suggested that the skilled person would need to generate a library comprising all of the polypeptides encompassed by the claim, and then to assay them in order to determine whether or not they catalysed the glycosylation reaction. This would indeed represent a research programme, though I doubt that a researcher would take the approach of preparing each and every polypeptide for testing if they were seeking to work the invention and generate functional homologues. But more importantly, the examiner’s objection does not appear to take into account the guidance provided in the specification and the common general knowledge of the skilled person. To this end, the applicant stated that:

“... 90% sequence homology limited by the structure-function relationship does not give rise to an interminable number of polypeptides. A mere 10% sequence variation in the context of the functionality of the polypeptide needing to be retained is in fact a very limited set of polypeptides. A monopoly to these polypeptides is therefore commensurate with the applicant’s contribution to the art.

In the currently claimed invention the specification teaches the PSA the premise of the invention – being that a UGT from a non-native source is useful for mogroside synthesis. This was previously unknown. The specification goes on to identify 5 specific polypeptides, or functional analogs thereof, that are able to catalyse glycosylation of mogrol to produce a mogroside and can therefore be used in the claimed method to do just that. Again this function of these polypeptides was previously unknown.

But armed with that information, the only variable for the PSA to consider is which functional homologs of those 5 polypeptides can also be used. As detailed in the above submissions and the responses of Annexure 2 and 3, that determination does not require any inventive thought or research by the PSA. Making polypeptides is a routine technique in the art.

Sequencing the polypeptides to confirm they have at least 90% identity to the 5 specific polypeptides is a routine technique in the art. And armed with the CGK, the PSA has knowledge as to which amino acid changes are likely to retain the function of the polypeptide. And in case there is any doubt that a candidate polypeptide is a functional homolog that can catalyse glycosylation, the specification provides the PSA with a very clear example (Example 4) for them to follow. Not one of these steps required inventive ingenuity.

Nor do they amount to undue burden in the context of a technology where it is routine to produce/express and screen large numbers of polypeptides.”

  1. I find these submissions persuasive. The specification provides sufficient guidance as to the manner in which variants may be generated and tested, and none of this presents any apparent difficulties that would require the skilled person to undertake any prolonged research or experimentation that would be considered an undue effort in this field of technology. Furthermore, as discussed under the question of plausibility, the structure and function of UGTs is well-known, and prima facie the skilled person would be able to predict with some certainty the effect that certain changes would have on the transferase activity, even where those changes were made within the (known) active domains. While this could involve a reasonable degree of experimentation or trial and error, and indeed may even be time-consuming, the nature of the work does not appear to me to constitute a research programme.

  1. On that basis I consider the specification is clear enough and complete enough for the invention to be performed by a person skilled in the art.





Conclusion

  1. The specification meets the requirements of subsection 40(2)(a). This being the only outstanding objection I direct that the application proceed to acceptance.





Dr Leslie F. McCaffery

Deputy Commissioner of Patents





Annex A







Mogroside V











Mogroside IV





























Siamenoside I













11-oxomogroside V

Annex B



1. A method of producing a mogroside compound, comprising contacting and glycosylating mogrol with a Uridine-5'-diphospho (UDP) dependent glucosyltransferase (UGT) polypeptide that is:



(a) UGT73C3 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:1;



(b) UGT73C5 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2;



(c) UGT73C6 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:3;



(d) UGT73El polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:4; or



(e) UGT85C2 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:5.



2. A method of producing a mogroside compound, comprising contacting and glycosylating mogrol with a cell lysate prepared from a recombinant host expressing a UGT polypeptide that is:



(a) UGT73C3 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1;



(b) UGT73C5 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2;



(c) UGT73C6 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:3;



(d) UGT73El polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:4; or



(e) UGT85C2 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:5.



3. A method of producing a mogroside compound, comprising:



(a) contacting and glycosylating a mogrol with a one or more Uridine-5'-diphospho (UDP) dependent glucosyltransferase (UGT) polypeptides;



(b) contacting and glycosylating a mogrol with a cell lysate prepared from a recombinant host expressing a one or more UGT polypeptides;



(c) (i) contacting and glycosylating a mogrol in a first reaction vessel with a one or more Uridine-5'-diphospho (UDP) dependent glucosyltransferase (UGT) polypeptides;

(ii) contacting and glycosylating the intermediate compound in a second reaction vessel with the one or more UGT polypeptides; and



(iii) recovering the one or more mogroside compounds produced in step (ii); or



(d) (i) contacting and glycosylating a mogrol in a first reaction vessel with a cell lysate prepared from a recombinant host expressing a one or more UGT polypeptides;



(ii) contacting and glycosylating the intermediate compound in a second reaction vessel with the one or more UGT polypeptides; and



(iii) recovering the one or more mogroside compounds produced in step (ii), wherein the UGT polypeptide is:



(a) UGT73C3 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1;



(b) UGT73C5 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2;



(c) UGT73C6 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:3;



(d) UGT73El polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:4; and



(e) UGT85C2 polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:5.



4. The method of any one of claims 1 to 3, wherein:



(a) the glycosylation is effected by the activity of the polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2 and the mogroside compound is mogroside Ia;



(b) the glycosylation is effected by the activity of one or more polypeptides having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 1-5 and the mogroside compound is mogroside Ib; or



(c) the glycosylation is effected by the activity of the polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:4 and the mogroside compound is a mogroside compound glycosylated at C25-OH.



5. The method of any one of claims 1 to 3, wherein the UGT polypeptide is a recombinant UGT polypeptide.



6. The method of claim 1, wherein the UGT polypeptide is produced by chemical synthesis.



7. The method of claim 5, wherein the recombinant UGT polypeptide is produced in a cell lysate of a recombinant host.



8. The method of any one of claims 1 to 3, 5 or 7, wherein the UGT polypeptide contains a tag sequence located at either a carboxyl or an amino terminus of the UGT polypeptide.



9. The method of claim 8, wherein the tag sequence comprises a green fluorescent protein (GFP), a glutathione S transferase (GST), a HIS tag, a Flag tag, a chloroplast transit peptide, a mitochondrial transit peptide, an amyloplast peptide, a signal peptide, or a secretion tag.



10. The method of any one of claims 2, 3 or 7, wherein the recombinant host is a microorganism transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors.



11. The method of any one of claims 2, 3 or 7, wherein the recombinant host is an insect cell system infected with recombinant virus expression vectors.



12. The method of any one of claims 2, 3 or 7, wherein the recombinant host is a plant cell system infected with recombinant virus expression vectors or transformed with recombinant virus expression vectors.



13. The method of any one of claims 2, 3 or 7, wherein the recombinant host is a mammalian expression system harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells or from mammalian viruses.



14. A method for producing a mogroside compound, comprising:



(a) adding one or more recombinant polypeptides capable of catalyzing glycosylation of mogrol to produce a mogroside compound and having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 1-5 and a plant-derived or synthetic mogrol to a reaction mixture; and synthesizing the mogroside compound thereby; and



(b) recovering the mogroside compound produced in step (a) from the reaction mixture.



15. A method for producing a mogroside compound, comprising:



(a) adding a cell lysate prepared from a recombinant host expressing one or more recombinant polypeptides capable of catalyzing glycosylation of mogrol to produce a mogroside compound and having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: l-5 and a plant-derived or synthetic mogrol to a reaction mixture; and synthesizing the mogroside compound thereby; and



(b) recovering the mogroside compound produced in step (a) from the reaction mixture.



16. A method of producing a mogroside compound, comprising:



(a) (i) adding one or more recombinant or synthetic polypeptides capable of catalysing glycosylation of mogrol to produce a mogroside compound and having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 1-5 and a plant-derived or synthetic mogrol to a reaction mixture; and producing the mogroside compound; wherein the one or more recombinant or synthetic polypeptides is produced in a recombinant host or by chemical synthesis; and

(ii) recovering the mogroside compound produced in step (a)(i) from the reaction mixture; or



(b) (i) adding a cell lysate prepared from a recombinant host expressing one or more recombinant polypeptides capable of catalyzing glycosylation of mogrol to produce a mogroside compound and having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: l-5 and a plant derived or synthetic mogrol to a reaction mixture; and synthesizing the

mogroside compound; and



(ii) recovering the mogroside compound produced in step (b)(i) from the reaction mixture;



(c) (i) contacting and glycosylating mogrol in a first reaction vessel with a one or more recombinant polypeptides capable of catalyzing glycosylation of mogrol to produce a mogroside compound and having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: l-5;



(ii) contacting and glycosylating the intermediate compound in a second reaction vessel with the one or more recombinant polypeptides capable of catalysing glycosylation of mogrol to produce a mogroside compound and having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 1-5; and



(iii) recovering the one or more mogroside compound produced in step (ii); or



(d) (i) contacting and glycosylating mogrol in a first reaction vessel with a cell lysate prepared from a recombinant host expressing a one or more recombinant polypeptides capable of catalyzing glycosylation of mogrol to produce a mogroside compound and having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: l-5;



(ii) contacting and glycosylating the intermediate compound in a second reaction vessel with the one or more UGT polypeptides; and



(iii) recovering the one or more mogroside compound produced in step (ii).



17. A method for transferring a sugar moiety to a C24' position, C3' position, both C24' and C3' positions, or C25' position of mogrol, comprising contacting the mogrol with a recombinant polypeptide having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 1-5, and a UDP-sugar under suitable reaction conditions for the transfer of the sugar moiety to the mogrol, wherein a mogroside Ia, mogroside lb, a mogroside compound glycosylated at C25-OH, an isomer thereof, and/or a mogroside composition thereof is produced upon transfer of the sugar moiety.



18. The method of claim 17, wherein:



(a) the sugar moiety is glucose, the glycosylation is effected by the activity of the polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2, and mogroside Ia is produced upon transfer of the glucose moiety to mogrol;



(b) the sugar moiety is glucose, the glycosylation is effected by the activity of one or more the polypeptides having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: l-5, and mogroside lb is produced upon transfer of the glucose moiety to mogrol; or

(c) the sugar moiety is glucose, the glycosylation is effected by the activity of the polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:4, and mogroside I is produced upon transfer of the glucose moiety to mogrol.



19. The method of claim 17, wherein the mogroside compound is mogroside Ia; wherein the glycosylation is effected by the activity of the polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2.



20. The method of claim 17, wherein the mogroside compound is mogroside lb; wherein the glycosylation is effected by the activity of one or more the polypeptides having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 1-5.



21. The method of claim 17, wherein the mogroside compound is a mogroside compound glycosylated at C25-OH; wherein glycosylation is effected by the activity of the polypeptide having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:4.









[1] Specification at page 5, line 30 to page 6, line 5.

[2] Regeneron Pharmaceuticals Inc and Bayer Pharma AG v Genentech Inc [2013] RPC 28; [2013] EWCA Civ 93 at [96].

[3] Fuel Oils/Exxon T 409/91.

[4] Generics (UK) Limited v H Lundbeck A/S [2009] UKHL 12; [2009] RPC 13; [2009] All ER 955.

[5] Zipher Ltd v Markem Systems [2008] EWHC 1379 (Pat); [2009] FSR 1 at [363] to [375].

[6] Kirin-Amgen Inc v Hoechst Marion Roussel [2005] All ER 667; [2004] UKHL 46; [2005] RPC 9 at [121] – [131].

[7] Zipher v Markem ibid at [362].

[8] Eli Lilly and Company v Human Genome Sciences Inc [2008] EWHC 1903 (Pat); [2008] RPC 29 at [239].

[9] Regeneron v Genentech ibid at [95] to [103].

[10] Idenix Pharmaceuticals Inc v Gilead Sciences Inc [2016] EWCA 1089.

[11] CSR Building Products Limited v United States Gypsum Company [2015] APO 72.

[12] Idenix v Gilead ibid at [135].

[13] Novartis AG v Johnson & Johnson Medical Ltd [2009] EWHC 1671 (Pat).

[14] Zipher v Markem ibid at [366].

[15] Kirin-Amgen v Hoechst Marion Roussel ibid at [128].

[16] Mentor Corporation v Hollister Incorporated [1991] FSR 557 at 561.

[17] Mentor Corporation v Hollister Incorporated [1993] RPC 7 at 13.

[18] Halliburton Energy Services Inc v Smith International (North Sea) Ltd [2005] EWHC 1623 (Pat) at [133].

[19] Regeneron v Genentech ibid at [157]-[158].

[20] American Home Products Corporation v Novartis Pharmaceuticals UK Limited [2001] RPC 8.

[21] Eli Lilly v Human Genome Sciences ibid at [257] – [260].

[22] Biopolymers/MIT T 0639/95.

[23] Amorphous silica/INEOS T 1743/06.

[24] Telomerase/GERON T 1456/06.

[25] CSR v United States Gypsum ibid.

[26] Biogen Inc v Medeva plc [1996] UKHL 18; [1997] RPC 1 at [48]- [49].

[27] Kirin-Amgen v Hoechst Marion Roussel ibid at [112]-[113].

[28] Regeneron v Genentech ibid at [100]-[101].

[29] GlaxoSmithkline UK Limited v Wyeth Holdings LLC [2016] EWHC 1045 (Ch) at [94].

[30] Conor Medsystems Incorporated v Angiotech Pharmaceuticals Incorporated [2008] UKHL 49 at [37].

[31] Eli Lilly and Company v Janssen Alzheimer Immunotherapy [2013] EWHC 1737 (Pat) at [258].

[32] Warner-Lambert Company LLC v Generics (UK) Limited (trading as Mylan) and ors [2016] EWCA Civ 1006 at [30] to [47].

[33] AP-1 complex/Salk Institute for Biological Studies T 0609/02.

[34] Triazole herbicides/AgrEvo T 0939/92.

[35] AP-1/John Hopkins University School of Medicine T 1329/04.

[36] Human Genome Sciences Inc v Eli Lilly & Co [2011] UKSC 51; [2012] RPC 6.

[37] Conor v Angiotech ibid.

[38] Apotex Pty Ltd v Warner-Lambert Company LLC (No 2) [2016] FCA 1238.

[39] Available at https://register.epo.org/application?number=EP00922102&lng=en&tab=doclist.

[40] Dasatinib/Bristol Myers Squibb T 0488/16.

[41] General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (1971) 1A IPR 121 at 134.

[42] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; 49 IPR 225 at [70]- [71].

[43] Minnesota Mining and Manufacturing Co & 3M Australia Pty Ltd v Beiersdorf (Aust) Ltd [1980] HCA 9; (1980) 144 CLR 253 at 293.

[44] Catnic Components v Hill & Smith Ltd [1982] RPC 183.

[45] Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59 at 153; [2002] HCA 59; (2002) 212 CLR 411 at 465.

[46] Human Genome Sciences Inc v Eli Lilly ibid at [107].

[47] Yonekura-Sakakibara K. and Hanada K., An evolutionary view of functional diversity in family 1 glycosyltransferases, The Plant Journal (2011), 66, 182-193.

[48] Yonekura- Sakakibara K. and Hanada K, ibid.

Print

Download

Cited By

Join the discussion