Refine Technology LLC v DSM IP Assets BV
[2014] APO 12
•24 February 2014
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Refine Technology LLC v DSM IP Assets BV. 2014 APO 12
Patent Application: 2005229359
Title:Process for cell culturing by continuous perfusion and alternating tangential flow
Patent Applicant: DSM IP Assets BV.
Opponent: Refine Technology LLC
Delegate: Sophina Calanni
Decision Date: 24 February 2014
Hearing Date: 14 October 2012, in Canberra
Catchwords: PATENTS – section 59 – opposition to grant of a patent – opposed on the basis of novelty, inventive step, clarity, fair basis, insufficiency and manner of manufacture – novelty – whether feature inherent in citation – each step of the claimed process was not an inevitable result of the earlier disclosed process – inventive step – whether the documents cited would be ascertained, understood and regarded as relevant – some documents not considered relevant – fair basis – certain claims not limited to the perfusion culture process the specification had described as the invention – opposition successful on minor point of fair basis
Representation: Patent applicant: Mr Ben Fitzgerald of Counsel assisted by Mr David Tadgell and Mr David Longmuir of Phillips Ormonde Fitzpatrick
Opponent: Mr Christian Dimitriadis of Counsel assisted by Dr Vaughan Barlow and Dr David Miles of Pizzeys Patent and Trademark Attorneys
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Title:Process for cell culturing by continuous perfusion and alternating tangential flow
Patent Applicant: DSM IP Assets BV.
Opponent: Refine Technology LLC
Date of Decision: 24 February 2014
DECISION
The opposition fails on all grounds other than a relatively minor point of fair basis.
Claims 21-27 are not fairly based.
The applicant is allowed two (2) months from the date of this decision in which to propose suitable amendments to overcome the above deficiencies.
No award of costs made.
REASONS FOR DECISION
Background
Patent application 2005229359 was filed by DSM IP Assets BV. (“the Applicant”) on 4 March 2005. The application claims priority from EP 04077656.9, 04075703.1, 04077657.7 and 04075702.3 the earliest of which was filed on 5 March 2004. There is no dispute in this proceeding that the claims of the application are entitled to that priority date.
The request for examination in relation to the patent application was filed on 18 January 2007. As a consequence, substantive amendments of the Patents Act brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present patent application. This includes the amendment to subsection 60 (3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition exists. I also note that any subsequent reference to subsections of the Patents Act relates to the Patents Act 1990, prior to amendment by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012.
The application was advertised accepted on 8 January 2009. A notice of opposition to grant of a patent was filed on 8 April 2009 by Refine Technology LLC (“the Opponent”), followed by a statement of grounds and particulars on 8 July 2009. An amended statement of grounds and particulars was filed on 13 March 2013.
The Applicant filed Section 104 amendments on 29 November 2010, after the evidence in support had been completed. The Opponent filed comments with regard to the proposed amendments on 28 January 2011. Leave to amend was granted on 25 March 2011, and the proposed amendments were allowed on 15 July 2011.
The evidence
The evidence in support consists of:
·A statutory declaration from Dr Vaughan Barlow ( Barlow #1) dated 6 April 2010 and 13 supporting exhibits (VB-1 to VB-13);
·A statutory declaration from Jerry Shevitz (Shevitz #1) dated 27 April 2010 and 5 supporting exhibits (JS-1 to JS-5);
·A statutory declaration from Dr Vijay Chiruvolu (Chiruvolu #1) dated 2 June 2012 and 4 supporting exhibits (VC-1 to VC-4);
·A second statutory declaration from Dr Vijay Chiruvolu (Chiruvolu #2) dated 2 June 2012 and 1 supporting exhibit (VC-1);
·A statutory declaration from Dr Michael Doran (Doran #1) dated 28 June 2010 and 16 supporting exhibits (MD-1 to MD-16);
·A second statutory declaration from Dr Vaughan Barlow ( Barlow #2) dated 30 June 2010 and 8 supporting exhibits (VB-1 to VB-8);
·A statutory declaration from Sol Genauer (Genauer #1) dated 2 July 2010; and
·A second statutory declaration from Dr Michael Doran (Doran #2) dated 5 July 2010.
The evidence in answer consists of:
·A statutory declaration from Professor Peter Gray (Gray #1) dated 21 December 2011 and 2 supporting exhibits (PG-1 to PG-2)
The evidence in reply consists of:
·A third statutory declaration from Dr Michael Doran (Doran #3) dated 14 June 2012 and 4 supporting exhibits (MD-1 to MD-4);
·A second statutory declaration from Sol Genauer (Genauer #2) dated 7 July 2012; and
·A second statutory declaration from Jerry Shevitz (Shevitz #2) dated 12 July 2012.
Further Evidence
The opponent filed further evidence consisting of:
·A fourth statutory declaration from Dr Michael Doran (Doran #4) dated 7 December 2012 and a supporting exhibit (MD-17)
The Applicant filed further evidence in response to the Opponent’s further evidence, consisting of:
·A second statutory declaration from Professor Peter Gray (Gray #2) dated ; and
·A statutory declaration from Dr Abraham Bout dated 13 May 2013
The hearing was held on 14 October 2013.
Onus
It is well established under the previous legislation that in proceedings such as these before the Commissioner, the onus rests with the opponent to clearly establish its case in reaching a conclusion on any issue. In F. Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283, Emmett J of the Federal Court found that in opposition proceedings, the Court (and by implication the Commissioner of Patents in her role as a tribunal) should be "clearly satisfied that the patent, if granted, would not be valid". Where questions of fact such as obviousness and existence of invention are involved "the grant should not be refused unless it has been clearly shown that the grounds of opposition have been clearly made out" (Montecatini v Eastman Kodak (1971) 45 ALJR 593).
Grounds of Opposition
The opponent relied on the following grounds of opposition as identified in the amended statement of grounds and particulars dated 1 March 2013:
·Lack of novelty
·Lack of inventive step
·Lack of full description
·Lack of clarity of the claims
·Lack of fair basis in the specification
·Absence of a manner of manufacture
The Specification
A range of cultivation modes can be used in the production of therapeutic proteins. These include batch culture, fed-batch culture and perfusion culture.
The present invention is said to relate to the perfusion culturing of cells, a continuous cell culture mode, where media are continuously exchanged to remove waste and deliver fresh medium to the cultured cells. These systems include a cell retention mechanism to continuously filter the cells from the culture medium and return them to the bioreactor.
At the priority date, numerous cell retention systems for perfusion culture existed, including cross-flow, hollow fiber, acoustic and spin filters.
The specification describes a perfusion culture method where, in the process of culturing, the cells and culture medium are circulated over a filter module comprising hollow fibers. The method described uses an alternating tangential flow within the hollow fiber to diminish aggregate disposal on the filter membrane, and also diminishes aggregation of cells during the perfusion culture process, including aggregation of cells with an inherent tendency to form aggregates (p. 4 lines 1-5).
Using the perfusion process described cell cultures with high cell density and viability can be attained. Specifically, cell cultures with a cell density of at least 80x108 cells per ml and cell viability of at least 90% can be achieved (p. 3 lines 19-20 and 25-28).
The specification acknowledges that systems for high-density perfusion culture existed in the prior art, including the Alternating Tangential Flow (ATF) perfusion culture system described in US 6, 544, 424 (“D1” cited by the Opponents). The specification notes that the perfusion culturing process described in D1 discloses a reduction in the attachment and growth of obstructions on the membrane surface of hollow fibers, but it does not disclose or suggest that cells in the cell culture itself would aggregate less (p. 1a lines 6-9).
The specification includes two examples using PER.C6 cells for the production of human IgG. In the Example 1 the performance of three types of cell retention devices in perfusion culturing are assessed. The retention devices assessed are a spin filter, acoustic separation device and alternating tangential flow unit (ATF-4) with associated hollow fiber filter. The continuous perfusion experiments using the ATF unit demonstrated very high cell densities and product concentrations. Example 2 extends the disclosure of the earlier example to demonstrate the capacity for the ATF-4 perfusion culturing system to be scaled up.
The opposed application ends with 29 claims, including two independent claims 1, 21 and two omnibus claims 28-29.
Claim 1 recites a method for the reduction of the degree of aggregation of cells with an inherent tendency to form aggregates in cell culture. The method includes three key features as follows:
(a)a cell culture comprising a suspension of cells with an inherent tendency to aggregate and culture medium;
(b)circulating the cell culture over a filter module comprising hollow fibers; and
(c)generating an alternating tangential flow within the filter module.
Claims 2-20 are ultimately dependent on claim 1. These claims introduce features relating to the cell type, culture conditions, biological substance produced, and the cell density and viability achieved using the method defined.
Claims 21-27 are directed to a perfusion culture obtainable by the method of the invention. Claim 21 reads:
“A perfusion culture obtainable by a method as claimed in any one of claims 1-10 comprising a cell culture medium and suspension of animal cells with an inherent tendency to form aggregates, wherein said animal cells are present in said culture at a density of 80x106 cells per ml and wherein aggregates of at least 5 cells comprise at most 5% of the total amount of cells.”
Claims 22-27 are dependent on claim 21. The additional features added by these claims relate to the culture cell density and the type of animal cells cultured.
Construction
The only significant differences between the parties in respect of the construction of claim 1 focused on the following phrases:
·reduction in the degree of aggregation; and
·cells with an inherent tendency to aggregate.
What is a ‘reduction in the degree of aggregation?
Based on the evidence adduced by each of the parties (see for example Doran #1 at [6] and Gray #1 at [22]-[24]), it is clear that the skilled addressee would understand the phenomenon of cellular aggregation in cell culture. Further, when referring to the advantages of the invention, the specification states that:
“the perfusion process of the invention leads to less cell aggregation in the culture, and even to a culture being a suspension of single cells without visible aggregates.”
I therefore consider that, in view of the specification as a whole, the skilled addressee would understand the phrase ‘reduction in the degree of aggregation’ to describe a decrease in the level of aggregation; relative to what would have resulted without performing the claimed method.
What are ‘cells with an inherent tendency to aggregate’?
When referring to ‘cells with an inherent tendency to aggregate’, the specification states the following:
“The process of the invention is suitable for culturing animal cells or yeast cell, especially for culturing mammalian cells.
The process of the invention is further especially suitable for culturing cells that easily or inherently form aggregates during culturing, especially during perfusion culturing (so-called aggregating cells).
...
Cells with an inherent tendency to form aggregates (or aggregating cells) are cells that form aggregates of at least 5 cells, the aggregates comprising in total at least 5% of the total amount of cells. Preferably, the aggregates comprise in total at least 7%, more preferably at least 10%, most preferably at least 15% of the total amount of cells.Examples of mammalian cells include: CHO (Chinese Hamster Ovary) cells, hybridomas, BHK (Baby Hamster Kidney) cells, myeloma cells, human cells, for example HEK-293 cells, human lymphoblastoid cells, PER.C6® cells, mouse cells, for example NS0 cells. Examples of yeast cells include Saccharomyces cerevisiae, Phaffia rhodozyma, Kluyveromyces lactis, or yeast cells from the genus Pichia.
Preferably, mammalian cells are used, more preferably CHO, NS0, PER.C6® cells. Also preferably, cells known for their aggregating behaviour during culturing (aggregating cells) are used. Most preferably, PER.C6® cells are used.”
The Opponent submitted that the term was unclear and indeterminate, asserting that depending on the cell culture conditions used almost any cell type could be considered to have a tendency to aggregate. As Dr Doran explained in Doran #3 at [35]:
“...I take this term to refer to an inherent quality of a cell, and I take it to mean something different from a cell aggregate, which I interpret as a physical characteristic. There is no indication in the Opposed application as to which cells have an inherent tendency to form aggregates, and which do not. Also, there is no information such as culture conditions that could be used to test cells for this inherent tendency. In the absence of any information in the Opposed application as to how to establish whether a cells has “an inherent tendency to aggregate”, I do not see how the meaning or scope of the claims can be determined, and I cannot see the basis for distinguishing between cell having “an inherent tendency to aggregate” in the Opposed application and the cells that could be used in the ATF system in, for example, D1 or D2.”
Similarly, Dr Shevitz explains in Shevitz #2 at [15]:
“... the Opposed application provides no test (for example, relative to cell medium, cell density, physical aspects of the bioreactor, etc) for determining whether a cell has an inherent tendency to form aggregates. The claims of the Opposed application, insofar as they recite the feature of cells with an inherent tendency to aggregate, therefore lack clarity because the meaning and scope of the claims is not possible to determine by the skilled person. For example, it is not possible to decide whether any animal cells do not aggregate at least under some conditions, which means that the phrases “aggregating cells” or cells that have an inherent tendency to aggregate” potentially encompasses all cells.”
In contrast, the primary interpretation applied by the Applicant was that the term necessarily refers to live cells, specifically a subset of cells that have an inherent tendency to form aggregates. In the evidence adduced by the Applicant, Professor Gray has stated in Gray #1 at [22]:
“At all stages of the development of stirred mammalian cell fermentations up to the Priority Date it had been observed that many cells had an inherent tendency to form aggregates or clumps. Some cell lines have more tendency to form aggregates during culturing than others. Cell essentially exist on a continuum from those cells that tend to stick together – anchorage dependent or adherent cells (ie need anchorage to a stable surface in order to grow, function , and divide) to those cells that exist as a single cell suspension when grown in culture. Many of the important industrial cell lines such as the CHO or PER.C6 cell lines discussed in the Opposed Application are tissue derived cells and retain the natural tendency to stick together and aggregate in clumps.”
While I acknowledge that external factors such as culture conditions may affect the degree of aggregation in cell culture, this does not preclude the skilled addressee from being able to apply an unambiguous meaning to the phrase ‘cells with an inherent tendency to aggregate’. It is clear from the evidence given by the experts that the skilled addressee would be well aware of the problem of cellular aggregation in cell culturing. It is also clear from the context in which the term is used in the description, that it is the Applicant’s intention to define a particular class of cells in which the claimed method demonstrates specific, unexpected advantages. Thus, in my view, reading the specification as a whole, the skilled addressee would understand from the context in which the claims are set that the term ‘cells with an inherent tendency to aggregate’ defines a subset of cells that easily form aggregates when cultured.
Novelty
Subsection 7(1) of the Patents Act states that an invention is taken to be novel unless it is not novel in the light of the prior art. A citation is part of the prior art base for the purposes of novelty if it was published before the priority date of the claim.
The basic test for novelty is the “reverse infringement” test as stated in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd, [1972] RPC 457 at 485-486:
“If carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated.
If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented: Flour Oxidizing Co. Ltd. v. Carr & Co. Ltd. (1908) 25 R.P.C. 428 at 457, line 34, approved in B.T.H. Co. Ltd. v. Metropolitan Vickers Electrical Co. Ltd. (1928) 45 R.P.C. 1 at 24, line 1). A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee."At the hearing, the Opponent indicated that the documents pressed with respect to novelty are:
US 6,544, 424 (Shevitz) 8 April 2003
Furey, J. “Continuous Cell culture Using the ATF System” Genetic Engineering News Volume 20, Number 10, pages 52-53. (“Furey”)
Voisard, D et al., “Potential of Cell Retention Techniques for Large-Scale High-Density Perfusion Culture of Suspended Mammalian Cells” Biotechnology and Bioengineering Volume 82, Number 7, pages 751-765 (“Voisard”)
There is no dispute that each of these documents was published before the priority date of the claim, and is therefore part of the prior art base.
US 6,544,424 (“D1”)
The patent (D1) discloses a filtration system for fluid, in particular biological fluids. The filtration device may be used for the successful production and processing of biologicals, using animal cell culture. In this setting filtration may be used to selectively remove or concentrate certain constituents from the culture media, or to enhance productivity by maintaining a culture in perfusion at high cell concentrations.
The filtration system is described at column 6, lines 13-22 as follows:
“The present invention concerns a fluid filtration system generally comprising a fluid storage vessel, a fluid connector for directing fluid from the vessel through a filter containing compartment, a diaphragm pump which controls the flow of fluid in alternating directions through the filter containing compartment, and at least one fluid harvest port. The system is useful for conducting rapid, low sheer, tangential flow filtration. Such a system has applications in perfusion of cultured animal cells…”
The filter containing compartment is further described at column 7 lines 23-26 as follows:
“Suitable removable filter elements nonexclusively include hollow fiber filters, screen filters, and the like. Most preferably, the removable filter element is a hollow fiber filter or filters consisting of a screen mash.”
It is therefore clear that in one embodiment D1 describes a process of cell culturing where the cell culture is circulated over a filter module comprising hollow fibers, and that the use of a diaphragm pump generates an alternating tangential flow within the filter module. However, other than indicating that the system may be used in the perfusion culture of animal cells, the citation is silent with regard to the specific types of cells used in the cell culture.
Thus the critical question to consider when assessing if D1 anticipates the present claims is whether a person following the directions of the citation would have inevitably used cells with an inherent tendency to aggregate in performing the method described. D1 does not exemplify the use of described filtration system for the culture of cells, rather it focuses on describing components of the filtration system While the use of the system is discussed, the citation is silent with respect to the cell types to be used. I note that the cells discussed in the specification are cells commonly used in cell culture for the purpose of producing biotherapeutic proteins. However, the Opponent has not adduced any evidence that skilled addressee following the disclosure of D1 would inevitably use any specific cell line, much less a subset of cells that have inherent tendency to aggregate. Therefore I am not satisfied that D1 contains clear and unmistakeable directions to use cells with an inherent tendency to aggregate.
All of the claims incorporate the feature of a cell culture comprising a suspension of cells with an inherent tendency to aggregate, thus the Opponent has not established that the claims lack novelty in light of US 6,544,424.
Furey (“D2”)
D2 describes perfusion cell culture using the Alternating Tangential Flow (ATF) system. The system described is essentially the same as that described in D1, namely a hollow fiber perfusion system with attached diaphragm pump and control system that create an alternating tangential flow through the hollow fibers.
As with the earlier citation, the question of anticipation is dependent on whether a person following the directions of the citation would have inevitably used cells with an inherent tendency to aggregate when performing the method described. The citation teaches that the hollow fiber ATF system may be used with suspension cells. In Figure 3 of the citation, results for cell concentration, culture viability and monoclonal antibody concentration are provided for a cell culture system using a hollow fiber module and an alternating tangential flow. There is no disclosure of the cell type used in this culture system. Whilst I acknowledge that some suspension cells may have an inherent tendency to aggregate, I cannot find any evidence that all suspension cells would have this characteristic. Therefore I am not satisfied that D2 contains clear and unmistakeable direction to use cells with an inherent tendency to aggregate.
It follows then that claims 1-29 are not anticipated by D2.
Voisard (“D3”)
This document focuses on cultivation of mammalian cells in perfusion culture. The review states that the major technological limitation in the scaling-up of these systems is the need for retention devices to enable perfusion of medium as needed. The cell retention techniques discussed in the review include hollow fibers devices such as the ATF system.
As with the earlier documents, D3 does not specifically discuss the types of cells used in the ATF perfusion culture system. In fact, the citation specifically states that “published cell culture data are missing to evalutate the real potential of this technology”.
Thus for reasons similar to those given above, claims 1-29 are not anticipated by D3.
Inventive Step
The Opponents opposed all claims under this ground, submitting that the claimed invention was obvious on the basis of the common general knowledge alone, and the common general knowledge in combination with a large number of documents as set out in the statement of grounds and particulars.
Section 7 of the Act sets out that:
”(2) For the purposes of this Act, an invention is taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to the person skilled in the art in light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with the information mentioned in subsection (3).
(3) The information for the purposes of subsection (2) is; (a) any single piece of prior art information; or (b) a combination of any 2 or more pieces of prior art information;being information that the skilled person... could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded as relevant and, in the case of information mentioned in paragraph (b), combined as mentioned in that paragraph.’
The test for obviousness is whether it would have been a matter of routine to proceed to the claimed invention.
“The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.” (Aicken J in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12 at [45]; [1981] HCA 12; (1981) 148 CLR 262 at 286)
More recently, the High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59 at [51] - [53]; [2002] HCA 59; 212 CLR 411 at [51] - [53] approved the approach taken in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at 187 in which Graham J had posed the question:
“Would the notional research group at the relevant date in all the circumstances directly be led as a matter of course to try [the claimed invention] in the expectation that it might well produce a useful [desired result]?”
The invention to be considered when assessing inventive is the invention as claimed. As noted by Jagot J in Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162:
“...in Danisco at [326] one principle which Bennett J identified as orthodox having regard to the reasons “as enunciated by the High Court in Aktiebolaget, Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) (2007) 235 CLR 173 [(Lockwood v Doric (No 2)] and Wellcome and by the Full Court in Lundbeck [H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151 ; [2009] FCAFC 70] and Apotex”, and which was not disturbed in Novozymes A/S v Danisco A/S [2013] FCAFC 6, is that:
In assessing obviousness, it is necessary first to determine the nature of the claimed invention and the inventive step described in the Patent. This may involve ascertaining the starting point of the inventive step, sometimes described in terms of an existing problem for which the inventor found a solution. The obviousness of the invention as claimed is then assessed by reference to common general knowledge in Australia at the priority date.”
The problem
The identification of the problem is a crucial to assessing the inventiveness of the claimed invention. In the present case, the application does not explicitly identify the problem to be solved. However, in describing the advantages of the invention, the specification states that:
“It has surprisingly been found that by perfusion culturing of animal, in particular mammalian, cells or yeast cells according to the invention, extremely high viable cell densities can be obtained, where as the cell culture further displays an extremely high cell viability. Furthermore, it was found that the perfusion process of the invention leads to less cell aggregation in the culture, and even to a culture being a suspension of single cells without visible aggregates. This is a surprising finding because the use of low shear conditions, such as in perfusion cell culturing, typically does not lead to disaggregation of cells. Cell aggregation during perfusion culturing is disadvantageous, because process control is more difficult, due to for example, the heterogeneity in metabolic profiles of cells within the cell aggregates. This is especially troublesome if cells form aggregates of 5 cells or more and when the aggregates comprise in total 5% or more of the total amount of cells.”
In addition, the declarants for both the Opponent and Applicant have acknowledged that the phenomenon of cellular aggregation was a known problem in cell culturing ( Doran #1 at [6] and Doran #3 at [24]; Gray #1 at [21]-[22]) . It was also known that it was important to control the size of such cellular aggregates to avoid problems associated with ineffective delivery of oxygen and nutrients required to maintain cell growth and viability.
As a consequence I consider the problem addressed by the application relates to providing an alternative means for the prevention or minimisation of the formation of cell aggregates in cell culture. While I appreciate that the application also refers to the attainment of high cell densities and cell viability, I do not consider these factors to represent the primary problem addressed by the application. I note however that it is generally accepted that increased cell density and cell viability is preferable when culturing mammalian cells for the purpose of producing therapeutic proteins.
The person skilled in the art
In view of the problem to be solved, I consider that the person skilled in the art would be a person with qualifications and significant experience in cell culturing, in particular cell culturing for the purpose of producing biopharmaceuticals.
Common General Knowledge
As a preliminary matter I note that the Opponent’s submissions with regard to the common general knowledge took as the starting point hollow fiber perfusion systems. The general state of the art and other perfusion systems were not discussed in any significant detail. However, the evidence in reply represents the Opponent’s opportunity to reply the evidence adduced by the Applicant in the evidence in answer. It is instance the Opponent has not challenged a number matters the Applicant considered to represent the common general knowledge. As such, I consider that the evidence shows that the following matters are common general knowledge.
Mammalian cell expression systems can be used for the production of therapeutic proteins such as recombinant proteins and vaccines and monoclonal antibodies.
Mammalian cell culture is a highly experimental science, with many factors influencing the outcome of the cell culture, as well as the quantity of a protein produced in cell culture. These include the cell line and culture media used, cell culture conditions such as pH and oxygen levels and the cell culturing approach employed.
The three most common cell culture production modes are batch, fed-batch, and perfusion culture.
In batch and fed-batch culture cells are grown in stirred tank reactors, where stirring promotes oxygen transfer and supports the establishment of uniform conditions such that cells are exposed to the same concentrations of nutrients, waste products, temperature and pH. At the priority date of the opposed application, batch and fed-batch culture techniques had generally been the accepted form of animal cell culture at the scale required for the production of therapeutic proteins.
Perfusion culture
In perfusion cell culture, cells are retained in a part of the culture system, and nutrients/ and oxygen are allowed to flow through the stationary cells, thus effecting nutrient/waste exchange. A major advantage of perfusion culture is the higher cell numbers, cell viability and productivity that can be achieved relative to batch and fed-batch modes.
An important variable in perfusion culture is the cell retention technique employed in the perfusion system. Cell retention or separation relies on the physical or chemical properties of the cells being retained such as cell size, density or electrical charge. The most widespread cell retention techniques include retention by size, namely filtration based techniques, and retention by density. Common filtration based techniques include spin-filter and hollow fiber systems, whereas common density based techniques include plane settlers and acoustic separators.
Cellular aggregation
Cellular aggregation was a well known problem in the area of cell culture at the priority date. The aggregation of cells in culture has the potential to result in heterogeneous cultures, which in turn lead to inconsistent culture outcomes and can affect the protein expressed. As a result, the person skilled in the art would seek to keep cell aggregation within acceptable limits.
A range of factors are known to have an effect on aggregation within a cell culture. These include the cell line used, selection of the medium and bioreactor conditions, with adverse conditions causing cell damage and promoting aggregation of cells within the culture. Methods for controlling the level of aggregation were also known before the priority date. These included:
·Controlling medium composition;
oReducing calcium ion concentration; and
oUsing low salt and high amino acid media.
·Treatment of the cell culture with polymers, carbohydrates or DNAse; and
·Controlling the level of shear within the culture.
The Opponent submitted that the application of an alternating tangential flow to overcome problems with cellular aggregation in perfusion culture systems with hollow fibers formed part of the common general knowledge (Opponent’s submissions [47]). The evidence of Dr Doran and Dr Chiruvolu is said to support this submission.
Dr Doran (Doran #1 at [6]) stated:
“I therefore believe that cellular aggregation was a well known problem in the area of perfusion cell culture using hollow fibers, and indeed in cell culturing in general, prior to 5 March 2004. ... It therefore would have been obvious to me prior to 5 March 2004 to apply an alternating tangential flow within a perfusion cell culture system in order to minimise the formation of cellular aggregates or otherwise to reduce the number of cell aggregates that may have already formed prior to the application of the alternating tangential flow.”
Similarly, Dr Chiruvolu (Chiruvolu #2 at [11]) discussed experiments he had conducted comparing the ATF hollow fiber system to other perfusion culture systems, and stated that:
“Based on the experiments described above, it therefore became my opinion by 2003 at the latest that perfusion cultures with an alternating tangential flow system utilizing a hollow fiber filter were inherently suited to minimizing aggregation of cell in culture as a routine procedure, and hence one that as a matter of course would minimize cellular aggregation relative to other systems...”
The Opponent has not provided any evidence that establishes that the use of an alternating tangential flow to overcome problems with cellular aggregation in perfusion culture systems with hollow fibers formed part of the common general knowledge at the priority date. The evidence provided by Dr Doran and Dr Chiruvolu is purely based on their experience using the ATF perfusion system. I do not consider this evidence to equate with that of the relevant skilled person in Australia at the priority date.
Is the invention obvious in light of common general knowledge alone?
As discussed above, I do not consider that the use of alternating tangential flow to overcome problems with cellular aggregation in perfusion systems forms part of the common general knowledge in the art. It therefore follows that the skilled addressee would not directly be led as a matter of course to use alternating tangential flow in the expectation that it may reduce aggregation within a cell culture. Therefore, the invention is not obvious in light of common general knowledge alone.
Ascertained, understood and regarded as relevant
Under section 7(3)(b) of the Patents Act, a claimed invention will lack an inventive step in light of the common general knowledge considered together with information in a single document, provided that the document or act could reasonably be expected to have been ascertained, understood and regarded as relevant to work in the relevant art in the patent area by the person skilled in the art.
The Opponent relied on a large number of diverse documents in the field of cell culturing. While they have pressed all documents listed in the Statement of Grounds and Particulars, written submissions for the hearing were only provided for the following documents. I will limit my consideration of inventive step to these documents.
D1 US 6,544,424 (Shevitz) 8 April 2003
D2 Furey, J., 2000, “Continuous Cell culture Using the ATF System” Genetic Engineering News Volume 20, Number 10, pages 52-53.
D3 Voisard, D et al., 2003, “Potential of Cell Retention Techniques for Large-Scale High-Density Perfusion Culture of Suspended Mammalian Cells” Biotechnology and Bioengineering Volume 82, Number 7, pages 751-765
D4 Mercille, S. et al., 1994, “Filtration-based perfusion of hybridoma cultures in protein-free medium: Reduction of membrane fouling by medium supplementation with DNAse 1” Biotechnology and Bioengineering, Volume 42, Number 9, pages 833-846 (“Mercille”)
D5 WO 1993/005145 (Celltech Limited) 18 March 1993
D6 Kruse, P. F. and Miedema, E., 1965, “Production and characterization of multiple-layered populations of animal cells” Journal of Cell Biology, Volume 27, pages 273-279 (“Kruse”)
D7 Banik, G. G. and Heath, C. A., 1995, “Partial and Total Cell Retention in a Filtration-Based Homogeneous Perfusion Reactor” Biotechnology Progress, Volume 11, Number 5, pages 584-588 (“Banik”)
D8 Jordan, M. et al., “Tuning of shear sensitivity of CHO cells and its correlation with the size distribution of cell aggregates” in Animal cell technology: developments, processes and products, eds Spier, R. E., Griffiths, J.B. and MacDonald, C. London: Butterworth:Heinemann, pages 418-420. (“Jordan”)
D9 Snabre, P. et al., 1987, “Cell disaggregation behaviour in shear flow” Biophysics Journal, Volume 51, pages 795-807 (“Snabre”)
D10 Moreira, J. L et al., “Aggregate suspension cultures of BHK cells” in Animal cell technology: developments, processes and products, Spier, R. E., Griffiths, J.B. and MacDonald, C. London: Butterworth:Heinemann, pages 411-413 (“Moreira”)
D11 Maiorella, B. et al., 1991, “Crossflow microfiltration of animal cells” Biotechnology and Bioengineering, Volume 37, Number 2, pages 121-126 (“Maiorella”)
D12 A/G Technology Corporation, “Operating Guide” January 1999, A/G Technology Corporation
D13 Yun-Seung K. et al, 1994, “High density culture of mammalian cells with dynamic perfusion based on on-line oxygen uptake measurements” Cytotechnology, Volume 14, pages 183-190
D26 Furey, J., “Continuous and Scaleable Production from a Bioreactor”, poster presentation at the Cell Culture Engineering VII conference, Snowmass Village, Colorado, United States of America, 1-6 April 2002. D27 Furey, J. “Scale-up of a Cell Culture Perfusion Process” Genetic Engineering News, Volume 22, Number 7, pages 62-63 D32 WO 2000/63403 (Introgene B. V.) 26 October 2000
The Opponent submitted that given the technical nature of the field, it can be readily inferred that such documents would have been ascertained. I am satisfied that because mammalian cell culture is a highly experimental, diverse science, the person skilled in the art would seek to inform themselves of advances in the field. I therefore accept that the documents raised for inventive step could have been ascertained. I also accept that the documents would have been understood by the person skilled in the art.
However, I am not convinced that the skilled worker would have regarded all of the documents pressed by the Opponent as being particularly relevant to solving the problem of providing an alternative means for the prevention or minimisation of the formation of cell aggregates in cell culture.
D1-D3, D26 and D27 describe the ATF perfusion culture system. The documents indicate that the ATF system inhibits the attachment of aggregates to the membrane and prevents the formation of gelatin which may clog the filter membrane (see for example, D1 column 15 lines 12-20; D2 pg 53, paragraph bridging columns 2 and 3). These disclosures focus on preventing fouling of the filter membrane. There is no suggestion that the ATF perfusion culture system would minimise the formation of cellular aggregates within the cell culture.
D6 describes the culturing of cells as monolayer equivalents that may represent a system for generating tissue models. For this purpose, D6 discloses the culture of cells as dense populations that form membranes within the culture vessel. It is apparent that the methods described promote cellular aggregation, and therefore said disclosure cannot be considered relevant to the problem addressed by the present application.
D7 analyses the differences that partial and total cell retention have on cell growth, density, viability and the production rate of the cell culture system. The citation does not address the problem of cellular aggregation.
D9 describes cell disaggregation behaviour in red blood cells. I do not consider the problem of aggregation in red blood cells to be equivalent to the problem of aggregation in cell culture.
D12 is the Operating Guide for a cross flow filtration apparatus. In the discussion of operating parameters for the system there is some discussion of membrane fouling and shear sensitivity of cells, but there is no specific disclosure concerning the aggregation of cells. D13 describes a perfusion based culturing system adapted to measure metabolic load of the bioreactor, thus allowing the perfusion rate to be adjusted to meet cellular demand. The citation states that the system can achieve high cell concentrations and viability, however there is no discussion of means for minimising cellular aggregation. I cannot consider D12 and D13 would be regarded as relevant to solving the problem of addressed by the present application.
D32 describes the modification of human cells for the production of therapeutic proteins. In one embodiment the invention described relates to the PER.C6 cell line, the cell line used in the Examples of the opposed application. The citation does not consider cellular aggregation or means for controlling cellular aggregation. As such, I cannot conclude that the person skilled in the art would regard this document relevant.
The remaining documents each provide some consideration of means for reducing cellular aggregation within a cell culture. For that reason D4, D5, D8, D10 and D11 are considered relevant for assessing the inventiveness of the claimed invention.
Is the invention obvious in light of the citations?
In order for the Opponent to establish that the claimed invention lacks an inventive step they must demonstrate that when culturing aggregating cells the addressee would directly be led as a matter of course to :
(1)culture the cells in a hollow fiber perfusion system; and
(2)that an alternating tangential flow is used in that system.
The citations considered relevant to assessing inventive step use various different systems for culturing the cells, and the control of aggregation using various different means.
D4 describes a cross-flow filtration perfusion system and analyses the effect of various parameters on cell growth rate. The citation specifically teaches that addition of DNAse 1 to the cell culture prevented membrane fouling and the formation of cell aggregates.
D5 describes a cell culture process for the growth of adherent cells where aggregation is eliminated by controlling the ratio of inorganic ions and amino acids in the medium. The method described is not limited to any particular mode of cell culturing, though the examples relate to batch cultures.
D8 describes the culture of adherent cells and analyses the formation of cellular aggregates under different conditions. The citation describes the effect of cell culture medium, DNAse 1 and shear force on the aggregation of cells. The citation teaches that the addition of DNAse 1 is effective at protecting the cell against damage by shear force.
D10 describes the role of agitation in minimising cell aggregation, specifically teaching that aggregate sizes decrease with agitation rate. The skilled addressee would be aware that agitation can be achieved by various means.
D11 seeks to establish the operating parameters in a tangential flow filtration perfusion system. They identify shear forces within the cell culture as the main cause of cell damage and lysis. As the person skilled in the art is aware that cell damage can promote cellular aggregation, they would seek to reduce shear forces in the culture system to avoid cellular aggregation.
D4, D5, D8, D10 and D11 describe various parameters that may be altered or controlled to minimise cell aggregation. However, none of these documents provide any motivation for selecting a hollow fiber perfusion system to culture aggregating cells, let alone a hollow fiber perfusion system that uses alternating tangential flow, in the expectation that using such systems would reduce aggregation of cells with an inherent tendency to aggregate. As such, I do not consider that the skilled addressee would directly be led to using a hollow fiber perfusion system with an alternating tangential flow. Therefore, a lack of inventive step has not established.
Insufficiency
The legal test for sufficiency is set out in the High Court decision in Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd ( 2001) HCA 8; 207 CLR 1; 177 ALR 460; 75 ALJR 518 at [25]:
"The question is, will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions of prolonged study of matters presenting initial difficulty?"
The Opponents argued that although the opposed application seeks to differentiate itself from the prior art on the basis of a reduction in the level of cellular aggregation within the culture, no guidance is provided as to how to perform the methods to achieve this reduction in cellular aggregation. They stated that the examples provided in the application simply use “off the shelf” equipment in accordance with its intended purpose. It was suggested that the claimed reduction of aggregation and high cell densities may be achieved by the manipulation of particular cell culture parameters, however the specification is silent with regard to any such manipulation.
Having considered the specification as a whole, it is apparent that the invention described relates to the use of a hollow fiber perfusion system with alternating tangential flow for the purpose of reducing the degree of cellular aggregation. There is no suggestion that the results achieved rely on the use of particular cell culture parameters.
Thus, in my view, based on the examples provided and the general disclosure of the invention, the skilled worker would be able to work the method from their common general knowledge without further invention. I therefore find that the specification is fully described.
Clarity
The Opponent has pressed the present ground in view of three issues relating to:
· Aggregation of cells;
· Use of the term obtainable within the claims 21 to 27 (The perfusion culture claims); and
· Omnibus claims 28 and 29.
Aggregation of cells
I have previously discussed the matter relating to aggregation of cells under Construction. In my view, the skilled addressee would be capable of interpreting the phrases ‘reduction in the degree of aggregation’ and ‘cells with an inherent tendency to aggregate’ as discussed above (see What is a “reduction in the degree of aggregation”? and What are cells with “an inherent tendency to aggregate”?). I agree with the Applicant’s submission that while the phrases may be inexact or difficult to construe, the specification provides a ‘workable standard’ suitable to the intended use as per Henriksonv Tallon Ltd [1965] RPC 434. As such, the use of these phrases is not fatal to the clarity of these claims.
The perfusion culture claims
Referring to Merk v Sankyo [1991] APO 27, the Opponent argued that the use of the term "obtainable by" does not limit the perfusion culture of Claims 21 to 27 to a culture produced by the process claimed. Instead, the claims encompass any cell culture that could be produced by any process, and is only limited to being capable of production by the process recited and claimed. I agree with this conclusion, however, note that I do not consider that as a result the claims are unclear, as it is clearly apparent that scope of claims 21-27 can be established.
I note that the Applicant indicated at the hearing that it was not their intention to claim any methods other than the methods taught in the specification. The Applicant indicated that they would seek to amend the claims to resolve this issue.
Omnibus claims
I note that the Australian Patent Office Manual of Practice and Procedure (at 2.11.2.3.9) clearly states that:
“Omnibus claims which contain words such as "substantially as described herein" are to be construed as being limited to the features of the invention identified by the subject of the claim, in their preferred form as described in the specification. As a general rule, an omnibus claim is directed to the broadest form of the invention identified by the claim, with the various features of that invention being in their preferred form. In order to identify the features of an omnibus claim, examiners should have regard to the text of the specification, such as the consistory statement, the objects of the invention and the examples.
...
Where the omnibus claim refers generally to the examples or drawings, any prior art examples or drawings contained in the specification are taken to be outside the scope of the omnibus claim, on the basis that this would be an "absurd result" (see Henriksen v Tallon Ltd [1965] RPC 434). However, if the prior art examples or drawings are referred to specifically in the omnibus claim (such as by number or letter), then these are to be construed as being within the scope of the claim and a novelty objection should be taken accordingly.”
Accordingly, I do not agree with the Opponent’s submission that the claims also encompass methods of perfusion culture using spin filters and an acoustic device as the means for cell retention. Rather, I consider the omnibus claims are limited to methods where the perfusion culture system comprises a hollow fiber filter module, and the flow within the filter module is an alternating tangential flow.
Fair Basis
100. Subsection 40(3) of the Patents Act requires that the claims of a specification must be fairly based on the matter described in the specification. The Lockwood Security Products Pty Ltd v Doric Products Pty Ltd decision, [2004] HCA 58, 217 CLR 274, at [69], put this as a requirement that there be a real and reasonably clear disclosure of what is claimed.
101. The Opponents argued that claim 1 and dependent claims are not fairly based because the specification does not provide any real and reasonably clear disclosure for a method for reduction of the degree of aggregation of cells with an inherent tendency to form aggregates. It was said that the opposed application provides no guidance to the skilled person as to what the “reduction of the degree of aggregation” is relative to, or as to the conditions to be employed in determining whether cells have “an inherent tendency to aggregate”, other than by relying on the knowledge of the skilled person and the prior art.
102. I have previously determined that in view of the specification as a whole the skilled addressee would understand the meaning of each of these phrases. Further, I consider that the specification provides a real and reasonable disclosure of the matter defined by the present claims, and therefore claim 1 and its dependent claims are fairly based on the specification.
103. The Opponents also argued that claims 21 to 27 are not fairly based insofar as they are to perfusion cultures “obtainable” using the methods of the earlier claims. Earlier in the consideration of clarity, I found that in relation to claims 21-27, the use of the phrase “obtainable by” within the claim does not limit the perfusion culture claimed to a culture produced by the process claimed.
104. The specification sets out that the “present invention discloses a process for culturing cells by perfusion culturing of a cell culture...wherein the cell culture is circulated over a filter module comprising hollow fibers, ... and wherein the flow within the filter module is an alternating tangential flow. In a further embodiment,
“the invention discloses a perfusion culture comprising a cell culture medium and a suspension of animal cells with an inherent tendency to aggregate, wherein said animal cells are present in said perfusion culture at a density of at least 80x106 cells per ml, and where aggregates of at least 5 cells comprise at most 5% of the total amount of cells” (p. 1 lines 18-21).
105. The specification explicitly refers to the perfusion culture in a number of locations in the description as one produced according to the process of the invention (see p. 3 lines 19-23 and p. 4 lines 1-10). Thus, I consider that the present specification only provides real and reasonably clear disclosure of producing a perfusion culture with the claimed properties by using the process of the invention where the cells are circulated over a filter module comprising hollow fibers, and wherein the flow within the filter is an alternating tangential flow.
106. Claims 21-27 are not limited to perfusion cultures produced according to the process of the invention. As a consequence, I consider the subject matter claimed by claims 21-27 travels beyond the disclosure of the specification and therefore claims 21-27 lack fair basis. I note that at the hearing the Applicant stated that it was not their intention to claim any methods other than the methods taught in the specification, and indicated that they would seek to amend the claims to resolve this issue.
Manner of Manufacture
107. Section 18(1)(a) requires that an invention must be a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. Manner of manufacture is assessed by asking whether the claimed invention lacks the necessary quality of inventiveness on the face of the specification (NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15 at [9]; [1995] HCA 15; (1995) 183 CLR 655).
108. The Opponent argued that the invention is not a manner of manufacture because “all of the examples disclosed in the specification of the opposed application use commercially available “off-the-shelf” equipment, the intended purpose of which is the same as the claimed methods, and the intended result of which is the same as the claimed cultures.”
109. While I agree the components of the claimed perfusion system are known, the opposed application defines a new method for the control of cellular aggregation in cell culture using this system. On the face of the specification it is not apparent that the method or the result achieved by implementing the method is known. Consequently, the Opponent has not established that the present claims do not define a manner of manufacture.
Conclusion
110. The opposition is partly successful. The opponent has established that claims 21-27 are not fairly based on the subject matter described in the specification.
111. I consider that there is patentable subject matter within the patent application and I therefore allow the applicant 2 months in which to propose suitable amendments to overcome the deficiencies noted above.
Costs
112. Both parties submitted that costs should follow the event.
113. In the present opposition, the primary grounds for the opposition were novelty and inventive step. The Opponent was not successful in establishing these grounds. In fact, the only ground established related to a minor fair basis issue.
114. I also note that the Applicant proposed amendments to the claims after the Evidence in Support was filed. These amendments introduced the feature of the claims relating to an inherent tendency to aggregate, and that feature was an important feature for the construction of the present claims, as well as for determining the novelty of the claims.
115. Given these two factors I consider it appropriate to make no award costs.
Sophina Calanni
Delegate of the Commissioner of Patents
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