The Regents of the University of California v the Dow Chemical Company
[2001] APO 15
•4 April 2001
OFFICIAL NOTICE
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Application : No. 681735 in the name of The Regents of the University of California
Title: Self-Assembling Polynucleotide Delivery System Comprising Dendrimer Polycation
Action: Opposition under S.59 of the Patents Act 1990 by
The Dow Chemical Company
Decision: Issued
Abstract
The subject matter of claims 1 to 49 and 52 to 66 of the opposed specification was is in substance disclosed in US Serial No. 07/913669. 07/913669 was filed more than 12 months before the filing date of the opposed application and thus the priority date of these claims is the date of filing of the opposed application, 14 July 1994.
The subject matter of claims 50 and 51 of the opposed specification was first disclosed in US Serial No. 08/092200, the listed priority document of the opposed application, and thus these claims have a priority date of 14 July 1993.
Claims 1 to 49 and 52 to 66 of the opposed application are not novel and lack an inventive step in light of the disclosure in Australian patent application 40278/93 as published on 8 November 1993.
Claims 50 and 51 of the opposed application are novel and inventive.
The claims of the opposed application, excluding claim 5, are not fairly based in that they are not limited to the polyamidoamine “PAMAM” class of dendrimer polycations.
There is patentable subject matter in the opposed application the applicant has 60 days to make suitable amendments.
PATENTS ACT 1990
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Re:Patent Application No. 681735 in the name of The Regents of the University of California, opposition under Section 59 by The Dow Chemical Company
BACKGROUND
Patent application number 12400/95, in the name of The Regents of the University of California, was filed under the provisions of the Patent Cooperation Treaty on 14 July 1994 claiming priority from basic application USSN 08/092,200 dated 14 July 1993. The application was advertised as accepted on 4 September 1997 and assigned serial number 681735.
The Dow Chemical Company (Dow) filed a notice of opposition on 3 December 1997. A Statement of Grounds and Particulars was served on the applicant on 3 March 1998. An amended Statement of Grounds and Particulars was filed by Dow on 11 January 1999. Service of evidence in support of the opposition was completed on 16 February 1999 following extensions of time totalling nine months. No evidence in answer was served by the applicant, notwithstanding the allowance of two extension of time requests for service of that evidence.
The matter was set for hearing. By facsimile of 11 September 2000, Peter Maxwell of Peter Maxwell and Associates, attorney’s for the applicant, advised that the applicant would not be represented at the hearing and provided written submissions in relation to the opposition.
The matter was heard in Canberra on 12 September 2000. The opponent was represented by Mr Paul W Jones, patent attorney of Freehills - Carter Smith Beadle. Also present at the hearing was Mrs Karen L. Kimble, Senior Patent Counsel - Intellectual Property Section, The Dow Chemical Company.
THE OPPOSITION
The Statement of Grounds and Particulars filed on 11 January 1999 specifies the following grounds of opposition:
“Section 59
b)that the invention is not a patentable invention because it does not comply with Section 18(1)(a) or (b),
c)that the specification filed in respect of the complete application does not comply with Sub-section 40(2) or (3).
The opponent contests the claim to the Convention priority date of 14 July 1993.”
Evidence in support of the opposition consists of statutory declarations by Geoffery William Tregear with exhibits GWT1 to 66; Susan Sau Heng Won with exhibits SSHW-1 to 5 and David Henry Solomon with exhibits DHS1 to 19. No evidence in answer was served.
THE INVENTION
The present invention is directed to a non-viral direct gene delivery composition and method intended to avoid risks posed by viral vector systems. A non-viral carrier system suitable for gene delivery must be able to surmount many barriers and be able to target the cell of choice as well as transport a polynucleotide into the nucleus of the cell.
The specification of the accepted application refers to the invention in the following terms:
“This invention relates to the field of oligonucleotide delivery systems and gene therapy. In particular, this invention is directed to a self-assembling polynucleotide delivery system comprising a polynucleotide and a dendrimer polycation, and optionally other agents, aiding the delivery of the polynucleotide to a desired sub-cellular location.”
In essence the invention as described in the accepted specification involves the use of a dendrimer polycation which is non-covalently coupled to a polynucleotide of interest. As described at page 8, the dendrimer polycation is capable by itself of delivering the polynucleotide into a cell, and more specifically a sub-cellular location such as the nucleus, with high transfection efficiency.
Other additional agents, such as, DNA-masking components; cell recognition agents; charge-neutralization agents; membrane-permeabilization agents and sub-cellular localization agents can be used in conjunction with the dendrimer polycation to aid delivery of the polynucleotide to the desired sub-cellular location. It is clear from page 8 of the description that each of these other agents is an optional component in the system of the invention, they perform their indicated function and are capable of assembling or disassembling with the polynucleotide as required.
The composition of the invention in its broadest form is defined in claim 1:
1. A composition for presenting a polynucleotide to a subcellular component of a eukaryotic cell, comprising
a polynucleotide; and
a dendrimer polycation operatively coupled to the polynucleotide.
The term “polynucleotide” as defined in the glossary, includes RNA or DNA sequences in either single chain, duplex or multiple chain form as well as various specific modified forms of these.
The term “dendrimer polycation” is defined at page 14 and refers to a three-dimensional, highly ordered oligomeric and/or polymeric compound having a positively charged surface. These dendrimers are bulky three-dimensional polymers formed by reiterative reaction sequences starting from a smaller core molecule or designated initiator, such as ammonia, that may be prepared in varied molecular weights and sizes. An example of the dendrimer polycations are the “Starburst Cascade Polymers” described by Tomalia et al. Angew. Chem. Int. Ed. Engl. 29:138 (1990).
The dendrimer polycation and the other agents/components are generally, and preferably, associated with the polynucleotide of interest via non-covalent interactions.
DECISION
Priority
The opposed application, filed on 14 July 1994, claims priority of 14 July 1993 from US Serial No. 08/092,200. 08/092,200 is a continuation-in-part application of US Serial No. 07/913669 (for brevity 913669), filed 14 July 1992.
Mr Jones, for the opponent, submitted that no claims of the present application are entitled to the priority date afforded by 08/092200 because 913669 discloses transfection mediated by a DNA-dendrimer complex and it was lodged more than 12 months before the filing date of the opposed specification. In rebuttal to Mr Maxwell’s written submissions, which I have summarised below, Mr Jones also stated that s.96 has not been utilised by the applicant and even if the applicant sought to utilise the provisions of s.96 that would not be possible because the preconditions of that section have not been satisfied.
Mr Maxwell in his written submissions states that:
the earlier application (913669) was abandoned;
the opponent has not adduced evidence to support the argument that 913669 should not be disregarded by reason of s.96 of the Act;
in any event, priority is assessed on a claim by claim basis and loss of priority, if found, only extends to the subject matter disclosed in the earlier document.
The provisions of Section 96 of the Patents Act referred to by Mr Maxwell, allow the Commissioner, at the request of the applicant, to disregard an earlier application made in a Convention country in specific circumstances.
The applicant has not requested that 913669 be disregarded under s.96 of the Act. If the applicant were to make such a request from the information before me, and as has been pointed out by Mr Jones, the conditions for the grant of a request under s.96 appear not to have been satisfied.
Firstly, it is a requirement of s.96(1) that 913669 was at the time of filing of the present application "withdrawn, abandoned or refused without becoming open to public inspection". Mr Maxwell, for the applicant, has submitted that 913669 was abandoned but has not adduced any evidence to that effect nor has it been established that if 913669 was abandoned it was without it becoming open to public inspection. Secondly, it is a requirement of s.96(1)(c) that 913669 "has not been used as the basis of claiming a right of priority in a Convention country under a law of that country corresponding to this Part". However, 913669 is listed as one of the basic documents for accepted Australian patent application 40278/93 (682308) which would mean that the requirement of s.96(1)(c) cannot be met.
As 913669 is not disregarded, it is a document relevant to my consideration of the priority date of the claims of the opposed specification. I need to determine what subject matter of the opposed specification, if any, is in substance disclosed in 913669.
913669 is entitled “Self Assembling Polynucleotide Delivery System”. The specification describes the field of the invention as “direct gene delivery that does not involve the use of viral vehicles.” The invention is described on page 8 as “a self-assembling polynucleotide delivery system utilising a combination of one or more” of the following functional components:
DNA-masking components;
Cell recognition components;
Charge-neutralisation and membrane-permeabilization components; and
Subcellular localization components.
Claim 1 of 913669, which encapsulates the described primary objective of the invention, is:
"1. A composition for presenting a polynucleotide to a subcellular component of a eukaryotic cell, said composition comprising the polynucleotide associated with a membrane-permeabilizing component capable of transporting the polynucleotide across the cytoplasmic membrane of said eukaryotic cell."
The ‘polynucleotide’ of 913669 is described and defined in identical fashion to the polynucleotide of the opposed specification. The ‘membrane-permeabilizing component’ of 913669 is described in a general sense as any component that aids in the passage of a polynucleotide across a membrane. This component encompasses, in part, charge-neuteralizing components, usually polycations. At page 22 the polycationic dendrimers described by D.A Tomalia (supra) are specifically mentioned, among other polycations as membrane-permeabilizers. The Tomalia reference is the same one which has also been referred to in the present opposed specification.
At page 37 of 913669 there is example 1G, the first paragraph of which is as follows:
“To find better chemically-defined alternatives to the polyamine polymers such as polylysine, we have employed the hydrophyllic branched polycation macromolecules also know as the StarburstTM Dendrimer microparticles, Tomalia et al,. supra, to form a complex with DNA or with DNA and the permeabilizing amphiphatic peptide GALA.”
Thus in example 1G of 913669 we have a disclosure of the use of a dendrimer polycation to form a composition with a polynucleotide in order to provide a transfection medium. Example 1G also discloses a dendrimer / DNA / GALA-peptide conjugate used for transfection. Relevantly, example 1G of 913669 is, as far as I can determine, word for word the same as example 1 of the opposed application.
913669 in substance discloses and claims (claims 1 to 13) compositions of a polynucleotide of interest and a membrane permeabilizing agent, wherein the membrane permeabilizing agent can be a dendrimer polycation. A composition of DNA and a dendrimer polycation, without and with GALA, is specifically exemplified. This constitutes a disclosure of claims 1 to 14 and 58 of the opposed specification which relate to a polynucleotide and a dendrimer polycation composition.
Claims 15 and dependent claims 16 to 29 of the opposed specification relate to a composition as per claim 1 further comprising a membrane-permeabilizing agent, wherein said membrane permeabilizing agent is operatively coupled to the dendrimer polycation. Such a composition is disclosed in claim 1 generally and specifically in claims 10 to 14 of 913669. Example 1G of 913669 is also a disclosure of a polynucleotide (DNA) conjugated with dendrimer polycation and the GALA peptide. The dendrimer and the GALA peptide are operatively coupled by virtue of their co-association with the DNA.
The specific features of a phospholipid and liposomes set out in claims 22 to 25 of the present application are disclosed in claims 6 to 9 of 913669. The membrane permeabilizer being a bile salt as set out in claim 29 of the present application is in claim 14 of 913669.
| Claims of 681735 (feature) | Disclosure in 913669 |
| 30 & 31 (subcellular-localization agent) | claim 23 & page 24 |
| 32 & 33 (nuclear localization agent) | claims 24 - 25 & page 24 |
| 34 to 38 (intercalating agents) | claims 26 - 27 & page 26 |
| 39 (intercalating agent coupled to ligand) | claim 20 & page 28 |
| 40 (intercalating agent coupled to permeabilizer) | pages 26 and 27 |
| 41 (specific intercalating agent) | claims 27 & 36 |
| 42 (single stranded polynucleotide linker) | claim 46 |
| 43 (DNA associating moiety - dendrimer cation) | claim 47 |
| 44 (major- or minor - groove binder) | claim 18 |
Claims 45 to 49 of the opposed specification relate to the composition of claim 1 further comprising a ligand targeted to a receptor located on the eukaryotic cell surface which ligand is operatively linked to the dendrimer polycation. This is disclosed in claim 16 of 913669 which defines the ligand being operatively coupled to a DNA-associating moiety. The DNA-associating moiety can be a polycationic dendrimer as described at page 26 of 913669.
The subject matter of claims 50 and 51 of the opposed specification involves fusogenic polypeptides operatively coupled to the dendrimer polycation. The fusogenic peptides are defined as peptides that when added to two separate bilayer membranes can bring about their fusion into a single membrane. The feature of fusogenic peptides is not described, exemplified nor claimed in 913669. There is no in substance disclosure of fusogenic peptides in 913669.
Claims 52 to 56 of the present application include the feature of a DNA masking moiety, this feature is disclosed in claims 30 to 32 of 913669. Claim 57 of the present application specifies the polynucleotide of the composition is hybrid vector, this is disclosed at page 12 of 913669 since hybrid vectors fall within the definition of polynucleotide. The definition of polynucleotide in the present application and in 913669 are the same. Present method claims 59 to 66 are disclosed at claims 40 to 45 of 913669
In conclusion, the subject matter of claims 1 to 49 and 52 to 66 is in substance disclosed in US Serial No. 07/913669. 07/913669 was filed more than 12 months before the filing date of the opposed application and thus the priority date of these claims is the date of filing of the application, 14 July 1994.
The subject matter of claims 50 and 51 was first disclosed in document 08/092200, the listed priority document of the opposed application, and thus these claims have a priority date of 14 July 1993.
Novelty
Mr Jones provided specific submissions in relation to two documents that the opponent contends anticipate the claims of the opposed application. I will deal with each in turn.
i) Australian Patent Application 40278/93, Exhibit GWT-65, “Szoka 2”
Australian patent application 40278/93 “Szoka 2” is another application in the name of The Regents of the University of California. The listed inventors are Francis Szoka (hence “Szoka 2”) and Jean Haensler which are the same as the present application. Szoka 2 lists US Serial No. 07/913669 (913669), which I have referred to above, as one of its priority documents, the other being US Serial No. 07/864876 filed 3 April 1992.
Szoka 2 was made open to public inspection on 8 November 1993 which is before the priority date for claims 1 to 49 and 52 to 66 of the opposed application as determined under the heading of priority dates above.
The Szoka 2 specification contains a relatively large proportion of information which is identical to, or differs only in minor respects from, the information in the present opposed specification. More particularly, Szoka 2 incorporates substantially all of the disclosure of 913669 and as far as I can determine has the same 48 claims, word for word, as set out in 913669.
The test for determining whether an invention lacks novelty is the "reverse infringement test" as stated by Aiken J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd, (1977) 137 CLR 228 at 235:
“The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement.”
In assessing the teaching or disclosure of the prior art, one has to consider what the skilled addressee is being taught and what they would have done on reading the citation, General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd, (1972) RPC 457 at 485:
“To anticipate the patentees claim, the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented ... A signpost, however clear, upon the road to the patentee's invention will not suffice.”
Applying this test, it is clearly evident given the high degree of conformity between Szoka 2 and 913669 and my conclusions under the heading of priority dates above that Szoka 2 as published contains clear and unmistakable directions to do what the specification of the opposed application asserts as the invention. Thus, claims 1 to 49 and 52 to 66 of the present application are not novel by virtue of the disclosure in Szoka 2.
Szoka 2 was not published before the priority date of claims 50 and 51 of the opposed application and cannot prior publish those claims. As I have pointed out in my consideration of priority dates above, the subject matter of claims 50 and 51, i.e. the additional use of fusogenic peptides, is nowhere disclosed in Szoka 2. Szoka 2 is not a document which would render claims 50 and 51 not novel by virtue of 7(1)(c) of the Act.
ii) European Patent Application 271180, Exhibit GWT-66 “Dow 9”
European patent application 271180 in the name The Dow Chemical Company “Dow 9” is entitled ‘Starburst conjugates’. The first listed inventor, among various others, is Donald A. Tomalia whose publications and research on dendrimer polycations has been quoted in the present opposed application. Dow 9 was published on 15 June 1988, prior to the priority date of all claims of the opposed specification.
This document discloses the group of compounds known as dense star polymers, “Starburst polymers”, and the use of these polymers as carriers for agricultural, pharmaceutical and other materials. The star polymers fall within the class of compounds which have been referred to in the opposed specification as dendrimer polycations. The background of the invention indicates that the dense star polymers have significant advantages which can provide a means for the delivery of high concentrations of carried material, controlled delivery, targeted delivery and/or multiple species delivery or use into an organism or cells of an organism.
The invention involves the formation of conjugates of various molecules of interest with the starburst polymer, said conjugates being suitable in a variety of applications where specific delivery of the molecules of interest into cells is desired.
Claim 1 of 271180 is as follows:
"1. A starburst conjugate which comprises at least one starburst polymer associated with at least one unit of at least one carried material."
The starburst polymers referred to in claim 1 fall within the definition of compounds referred to as dendrimer polycations in the opposed specification. The term “associated with” used in claim 1 of Dow 9 is defined on page 13 to mean that the carried material(s) can be encapsulated or entrapped within the core of the dendrimer and/or dispersed partially or fully throughout the dendrimer. I believe the term “associated with” clearly encompasses the concept of “operatively coupled” as used in claim 1 of the opposed specification. More specifically the concepts of encapsulation and entrapment referred to in Dow 9 are disclosures of non-covalent association which is indicated as a preferred method of operative coupling in the opposed specification.
The “carried material” referred to in claim 1 of Dow 9 is a generic term which is not specifically defined in the body of the specification. Obviously the term refers to the material which is “carried” by the starburst polymer, but that is of limited value in assessing the precise nature, characteristics or extent of the materials themselves. In the absence of any definition or more explicit criteria to establish what are suitable carried materials of the invention disclosed in Dow 9 I believe it is reasonable and appropriate to consider the class(es) of materials specifically described and exemplified as “carried materials”.
At page 13 of Dow9 a range of entities which are preferred carried materials are described, they are, a drug, pesticide, radionuclide, chelant, chelated metal, toxin, antibody, antibody fragment, antigen, signal generator, signal reflector, signal absorber, fragrance, pheromones or dyes. I note that there is no specific mention of polynucleotides or polynucleotide type materials in the range of materials specifically referred to.
Mr Jones referred me to page 16 of the specification where viruses and viral fragments are mentioned as carried materials, to support the assertion that polynucleotides are disclosed in Dow 9. The reference to viruses or viral fragments at page 16 is not further explicit as to what in fact is meant. At paragraph 7.2 (a) of the Treager declaration it is indicated that viruses are substantially composed of polynucleotides and viral fragments may be polynucleotides. I agree, viruses contain polynucleotides, however, they may also contain protein elements, specifically when one talks of a ‘virus’ per se. Similarly it is not clear whether the reference to viral fragments is to fragments of viral DNA/RNA or in fact to viral protein fragments, eg antigenic viral protein fragments. I do not believe this constitutes clear and unmistakable directions to the use of polynucleotides, as such, as carried materials.
More generally, the examples of Dow 9 which relate to preparation of conjugates with polycations exemplify carried materials such as aspirin, pseudoephidrine, salicylic acid, chelated metals, monoclonal antibodies, herbicide 2,4-D, flourescein, and limonene. The nature of compounds which have been disclosed as carried materials in Dow 9 does not include polynucleotides nor any compounds which I would regard as being similar to polynucleotides. The compounds specifically mentioned and/or exemplified are, relatively speaking, simple, small, monomeric compounds which cannot, in my opinion, be favourably compared to the polynucleotide class of compounds.
I am mindful of the statement in General Tire & Rubber Co (Supra) that the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented.
“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.”
I believe that the present situation is clearly one where Dow 9 provides a signpost which points to the use of starburst polymers as carriers for various materials to deliver the material into a cell of interest. While Dow 9 provides that signpost, the nature and type of carried materials disclosed does not provide clear and unmistakable directions to the use of polynucleotides as carried materials. Dow 9 falls short of ‘planting the flag’ at the precise destination as the present opposed application.
Dow 9 does not provide clear and unmistakable directions to use dendrimer polycations as carriers to deliver polynucleotides to a sub-cellular location, e.g. the nucleus, of a target cell. Dow 9 does not deprive the claims of the opposed specification of novelty. I will consider the document further under the heading of inventive step.
In conclusion on the issue of novelty, claims 1 to 49 and 52 to 66 of the opposed application are not novel in light of the disclosure in Australian patent application 40278/93 as published on 14 October 1993. Claims 50 and 51 of the opposed application are novel.
Inventive Step - Obviousness
As I have indicated above claims 1 to 49 and 52 to 66 of the opposed specification are prior published by, and not novel in light, of Australian patent application 40278/93 “Szoka 2”. It follows from my conclusions above in relation to priority date and novelty and also in light of the vast similarity between the disclosure of Szoka 2 as published and the present opposed application that Szoka 2 renders claims 1 to 49 and 52 to 66 obvious and lacking in an inventive step.
Szoka 2, while published before the priority date of claims 1 to 49 and 52 to 66, was not published until after the priority date of claims 50 and 51. Thus it is not a document to which I can refer in relation to inventive step for claims 50 and 51.
European patent application 271180 “Dow 9” was published before the priority date of all claims of the opposed specification and as such is a document relevant to a consideration of the inventive step of the present claimed invention.
The assessment of whether an invention lacks an inventive step, ie whether it is obvious, can be made against the common general knowledge alone or the common general knowledge considered together with a document or act, provided the document or act could reasonably be expected to have been ascertained, understood and regarded as relevant to work in the relevant area by a person skilled in the art.
The general test to be applied in determining obviousness is stated in The Wellcome Foundation Limited v V. R. Laboratories (Aust) Pty Ltd (1980-1981) 148 CLR 262, specifically at 286:
“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.”
Courts have used the problem/solution approach to assist in making determinations under the heading of obviousness/inventive step in order to avoid the criticism of ex post facto analysis. I will use that approach here. The problem may be formulated from a reading of the specification in light of the surrounding facts.
I believe the problem as it is described in the opposed specification can be expressed as:
To provide a non-viral polynucleotide delivery system of high transfection efficiency in eukaryotic cells which avoids the drawbacks of prior systems.
Given the problem I have set out above, I need to consider whether Dow 9 is a document that could reasonably be expected to have been ascertained, understood and regarded as relevant to work in the relevant area by a person skilled in the art. I believe, given the subject matter of Dow 9, that it is a document that would reasonably be expected to have been ascertained and understood by a person skilled in the art when faced with the problem above. The crucial question, in my opinion, is whether the person skilled in the art would have regarded Dow 9 as relevant to work in the relevant area. In order to answer that question it is necessary to consider the disclosure of Dow 9 in more depth.
As has been set out previously, Dow 9 discloses conjugates of synthetic molecules (starburst polymers) used in the carriage of agricultural, pharmaceutical and other materials into cells. As mentioned above under the heading of novelty, there is no specific disclosure in Dow 9 of the starburst polymers being conjugated with polynucleotides per se and being used to transport the polynucleotides into cells in any practical sense. Dow 9 also does not provide any specific disclosure that the materials can effectively be carried into a subcellular location such as the nucleus of a cell, as opposed to into the cell generally. There are references in Dow 9 to delivering a material to a particular determinant or locus of a target organism at pages 8 and 12. There is absolutely no disclosure or suggestion in Dow 9 of the starburst conjugates being used to deliver polynucleotides into the nucleus of eukaryotic cells in order to achieve transfection.
Dow 9 appears superficially attractive as a document which might disclose non-viral elements for carriage of polynucleotides, but, the substance of the disclosure falls short of what one might regard as being clearly relevant to the problem of the present application. There is nothing in Dow 9 to lead the skilled reader to the conclusion that starburst polymers can be or could be used to deliver polynucleotides to a subcellular location, such as the nucleus, of eukaryotic cells. It would not be immediately ‘obvious to try’ the use starburst polymers to effect transport of polynucleotides into the nucleus of a eukaryotic cell from the disclosure in Dow 9. Hence, I consider the person skilled in the art in seeking to inform themselves of possible non-viral carrier systems for polynucleotides would not have regarded Dow 9 as relevant to the problem the invention seeks to overcome.
I consider the issue of whether the skilled reader would regard Dow 9 relevant to the problem the invention seeks to overcome and whether the disclosure of Dow 9 deprives the current claims of an inventive step to be inextricably linked. Dow 9 fails to provide sufficient indication or teaching for the skilled reader to consider starburst polymers as being useful to deliver polynucleotides to a desired sub-cellular location.
The likelihood of success necessary to render a routine investigation obvious was considered in Beecham Group Ltd's (Amoxycillin) Application (1980) RPC 261 at 290:
“It is clearly established that, for a particular step or process to be obvious .... it is not necessary to establish that its success is clearly predictable: Johns-Manville Corporation's Patent [1967] RPC 479 at 494.
It will suffice if it is shown that it would appear to anyone skilled in the art but lacking in inventive capacity that to try the step or process would be worthwhile: Technograph Printed Circuits Ltd v. Mills & Rockley ( Electronics) Ltd [1972] RPC 346 per Lord Reid at 355 and 356; Johns- Manville, supra, per Lord Diplock LJ at 493 and 494; Tetra Molelectric Ltd v. Japan Imports Ltd [1976] RPC 541 at 581, 583-4.”
I do not believe that the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from Dow 9 to the present invention. There is little in the disclosure of Dow 9 that might suggest to anyone skilled in the art but lacking in inventive capacity that to try starburst polymers (or more generally dendrimer polycations) to deliver polynucleotides to the nucleus of a cell to achieve transfection would be worthwhile.
Mr Jones for the opponent, submitted that Dow 9 when read in light of the common general knowledge in the art rendered the claimed invention obvious. He referred me to paragraph 7.2 of the Treager declaration for matters of common general knowledge. I have studied paragraph 7.2 of the Treager declaration very carefully but it does not indicate nor assert that it is common general knowledge that dendrimer polycations have been or are known to be “operatively coupled” or conjugated with polynucleotides. Nor anywhere in the Treager declaration is there any indication that it is common general knowledge that dendrimer polycations can be used to transport polynucleotides to the nucleus of eukaryotic cells.
I note in passing that Solomon, at paragraph 4.2, in considering the invention disclosed in the opposed specification indicates “the PAMAM polymers further appear to be uniquely structured as they appear to function to introduce DNA in to the cytoplasm of the cell, and to transport the DNA into the nucleus without the necessity of incorporating additional functional agents.” However, Solomon does not assert that this characteristic or property of dendrimers was common general knowledge before the priority date of the present application.
In the absence of any clear indication that it is common general knowledge for polynucleotides to be conjugated with dendrimer polycations or that dendrimer polycations are known to be used as vehicles to transport polynucleotides to the nucleus of eukaryotic cells there would be no motivation for the skilled worker, having read Dow 9, to consider the use of dendrimer polycations as carriers for polynucleotides as has been claimed in the present application.
The claims of the present application are not rendered obvious in light of the disclosure in Dow 9 alone. The opponent has not adduced evidence to establish common general knowledge which if read together with Dow 9 would render the presently claimed invention obvious.
Manner of Manufacture
Mr Jones, for the opponent, submitted that the present invention is not a manner of new manufacture as no invention is disclosed ‘on the face’ of the opposed specification. He made specific mention of the work of Tomalia (1990 supra) which has been referred to in the opposed specification and elsewhere in relation to the Starburst dendrimer polymers. Mr Jones submitted that the work of Tomalia clearly anticipates the alleged invention and that there is no invention disclosed on the face of the specification.
Mr Jones cited Commissioner of Patents v Microcell Limited 102 CLR 232 at page 251 where it is stated that there is no patentable invention if the claim in the specification could be seen to be;
"nothing but a claim for the use of a known material in the manufacture of known articles for the purpose of which its known properties make that material suitable.”
Mr Jones also cited Philips v Mirabella International 32 IPR 449 where it was stated that whilst an invention could include an alleged invention;
“that threshold requirement of an alleged invention will, notwithstanding an assertion of newness, remain unsatisfied if it is apparent on the face of the relevant specification the subject matter of the claim is, by reason of absence of the necessary quality of inventiveness, not a manner of new manufacture for the purposes of the Statute of Monopolies.”
For the applicant, Mr Maxwell’s submissions indicate:
the opponent’s claim that the opposed application is a mere collocation has not been made out;
the mere existence of the integers as individual substances does not deny the opposed application inventiveness; and
the opponent’s claim is a clear example of argument with the benefit of hindsight.
In order to find that the present opposed specification does not satisfy the ‘threshold requirement’ of an alleged invention as set out in Phillips v Mirrabella above it must be clear from the face of the specification itself that there is nothing which could be regarded as providing the necessary quality of inventiveness. Mr Jones submissions on this issue rest strongly on the assertion that the previous work of Tomalia referred to in the present specification renders the present invention lacking the threshold of invention required.
Mr Jones pointed me specifically to page 7, lines 13 to 18, and page 16 line 26 to page 18 line 19 in the present specification which relate specifically to the work of Tomalia in respect of dendrimer polycations. The reference on page 7 of the specification is as follows:
“Dendrimers are bulky three-dimensional polymers built by reiterative reaction sequences around a core molecule that may be prepared in varied molecular weights and sizes (Tomalia, D.A, et al . . . .”
The reference at page 16 line 26 to page 18 line 19 in the specification discloses that the dendrimers of the invention are three-dimensional oligomeric and/or polymeric compounds which may be prepared as disclosed in various patent documents in the name of the Dow Chemical Company or Tomalia.
So what is disclosed on the face of the specification itself? The specification discloses, as has been referred to above, that dendrimer polycations are three-dimensional polymers/oligomers built by reiterative reaction sequences around a core molecule, they are able to be prepared in a variety of weights and sizes and have an outer surface that is positively charged. The specification on its face also discloses that suitable core molecules comprise at least two reactive residues, that terminal groups which may be attached to the oligomers/polymers should be capable of acquiring a positive charge and that the dendrimer polycation is preferably non-covalently associated with the polynucleotide. The disclosure of the specification, on its face, in so far as it relates to the Dow or Tomalia references, does not go further than this.
At page 8 of the specification, first sentence, it is indicated that the dendrimer polycation is capable by itself of delivering the polynucleotide with high transfection efficiency. This appears to me to be a clear statement of the alleged inventive component of the present invention from the specification itself. It is not indicated elsewhere in the specification that dendrimer polycations are know and accepted to be used to achieve delivery of polynucleotides to the cell nucleus unaided.
Submissions from the opponent that the invention is nothing but the use of a known material in the manufacture of known articles for the purpose of which its known properties make that material suitable are not persuasive. The present specification asserts as the invention a process and composition to deliver polynucleotides to the nucleus of cell using a dendrimer polycation as carrier. Such an invention is not apparent from a fair reading of the disclosure of the specification on its face.
It would appear to me that to go to the references to seek information that is not expressly or by proper inference referred to in the specification is to indulge in the process of evaluating inventive step with the clear benefit of hindsight. That of course is not appropriate. Apart from the information rightly incorporated into the present specification by reference to the Dow or Tomalia (1990 supra) work any further information or disclosure contained in those documents which is alleged to be commonly known and relied upon to deny the present invention of inventiveness must correctly be dealt with under the heading of inventive step.
The present specification does relate to an invention which meets the threshold requirement on the face of the specification, and is a manner of manufacture.
Clarity, Fair Basis and Best Method
Mr Jones submitted that the phrase “for presenting a polynucleotide” is unclear as used in the preamble to composition claim 1. From a reading of the specification and in seeking to apply a construction to claim 1, it would appear to me that the preamble of claim 1 constitutes words of purpose for the composition claimed. Those words of purpose limit the composition claim only in so far as the composition must be at least suitable to achieve the intended purpose. In that context the term “for presenting” would appear to me to mean that the polynucleotide is delivered to, or made available at, the location specified, that location is a subcellular component. I also note that Solomon, who is one of the opponent’s experts, appears to use the phrase “for presenting a polynucleotide” at paragraph 3.16 of his declaration without seeming to have any difficulty with its meaning. I believe the meaning of the phrase would be clear to the skilled addressee.
Mr Jones indicated that a number of claims are unclear in that the term “about . . to . . ” is used to qualify ranges in those claims. Examples of claims of this type are I believe claims 8, 12 and 13 etc where a range is defined in the form ‘about X to Y’. I do not agree with the opponent and consider that the opponent is reading these claims with studied criticality. The issue is whether the addressee would be able to construe such ranges and arrive at a meaning. I believe that the addressee, wishing and willing to arrive at a reasonable construction, would quite readily be able to construe such ranges, and as such the claims are not unclear.
On a related point, claim 9 contains the phrase “wherein the dendrimer polycation further comprises 0 to about 90% terminal active residues”. At paragraph 4.3(b) of the Solomon declaration he asserts that it is unclear "how a dendrimer polycation can be said to comprise 0% terminal reactive residues, and yet be capable of operatively coupled to a polynucleotide". At first glance the claim does lack clarity, however, this point is put to rest by referring to the description which is acceptable to give meaning to a feature in a claim which would otherwise be unclear.
Pages 17 and 18 of the description refer to the concept of ‘terminal’ groups. The terminal reactive residues of claim 9 are referred to at the top of page 18 and are not the cationic amine groups of the dendrimer itself but additional or substitute groups that may be attached to the dendrimers and which are capable of acquiring a positive charge. Such reactive residues other than the terminal cationic groups are hydroxyl, cyano, carboxyl etc. As pointed out on page 18 the dendrimer polycation may comprise none (0%) of these terminal reactive residues over and above the cationic groups of the dendrimer or alternatively anywhere up to 90% of the terminal reactive groups. Claim 9 is clear.
Submissions for the opponent that claim 26 is unclear as it recites ‘further comprising a polycation’ are not considered persuasive. I concede that the term polycation in claim 26 can in abstract be construed to include the cationic dendrimers which are already present as per claim 1. However, I believe the phrase ‘further comprising a polycation’ in claim 26 refers to polycations other than the dendrimer polycations, such as the non-dendrimer polyamines. This is made clear from the use of the phrase "further comprising a polycation" in claim 26 in addition to the dendrimer polycation of claim 1 and from the nature of cations specified in claims 27 and 28 appended to claim 26.
Submissions for the opponent assert that the claims of the specification are not fairly based because:
· it is a requirement of the opposed specification that the subsidiary delivery agents be covalently linked to a DNA-associating moiety. Claims 18, 30 to 32, 45 to 48 and 56 are not limited in that manner;
· the “charge ratios” disclosed in claim 14 are of such breadth as to render the claim inconsistent with the disclosure of the specification;
· it is unclear how dendrimers other than PAMAM dendrimers can be utilised to deliver a polynucleotide to a subcellular component and the claims are not restricted to the use of PAMAM dendrimers but relate to the class of dendrimer polycations as a whole.
In relation to the first point claim 18 defines a composition comprising a polynucleotide, a dendrimer polycation and a membrane-permeabilizing agent in the form of the amphiphatic peptide GALA. Treager at paragraph 4.2(c) of his declaration states that “it is apparent from the description on page 25, lines 16 to 19 and from the examples, in particular page 53, lines 12 to 14, that the GALA peptide must be covalently attached to the dendrimer.” The passage on page 25 begins “In a still more preferred embodiment, an amphiphatic peptide such as GALA may be covalently attached to the cascade polymer.” This statement and the example on page 53 indicate that the peptide GALA may be covalently linked to the dendrimer polycation, however, to construe them to mean that covalent attachment must be the case would in my opinion be incorrect.
Firstly, if one looks at claim 15, which claim 18 is dependent upon, it refers to the membrane permeabilizing agent (ie GALA) being operatively coupled to the dendrimer. It is clear from a reading of the specification as a whole the operative coupling is not limited to covalent linking, indeed, the preferred form of operative coupling is non-covalent association. Secondly, it appears from page 19, lines 9 and 10, that “The membrane-permeabilizing agent may be coupled to the dendrimer polycation by covalent or electrostatic forces.” Hence, the membrane-permeabilizer GALA can be operatively coupled to the dendrimer by electrostatic or non-covalent means. This is also supported by example 1 which discloses the addition of the peptide GALA to a dendrimer / DNA solution and it is manifest that the peptide GALA is in no way covalently bonded to the dendrimer. Example 1 describes a situation where the “peptide GALA was added, it was added so that the negative charges on GALA neutralised the excess charges on the dendrimer” which is a disclosure of non-covalent association. Hence I do not see a lack of fair basis in claim 18 on this issue. Using similar reasoning I do not consider that claims 30 to 32, 45 to 48 or 56 lack fair basis.
In relation to the second dot point, Treager at paragraph 4.2(b) states that claim 14 says nothing about the “charge ratio”, ie the ratio of positive charges to negative charges. He further states that claim 14 would, given the polymeric nature of dendrimers and polynucleotides, encompass a polynucleotide to dendrimer charge ratio of 280:1 to 28,000:1 and that this is inconsistent with the rest of the specification and the specification is silent as to how such a large amount of polynucleotide could be included.
While I accept the points made in the Treager declaration they appear to me to be more related to the concept of inutility, ie that the invention won’t work, as opposed to fair basis. I believe there is a real and reasonably clear disclosure and description of the ratio of dendrimer to polynucleotide as set out in claim 14. I would also note in passing that the dendrimer and the polynucleotide are not in all instances the only components of the compositions of the invention. While the charge ratio of dendrimer to polynucleotide may be vastly different in any specific composition there may well be other agents, eg membrane permeabilizers and DNA masking agents, which bring any charge imbalance into check.
In relation to the third dot point. Solomon, at paragraph 4.2, indicates that the specification fails to fully describe the invention and the claims are not fairly based in relation to dendrimers other than the polyamidoamine (PAMAM) dendrimers. He also states “the PAMAM polymers further appear to be uniquely structured as they appear to function to introduce DNA in to the cytoplasm of the cell, and to transport the DNA into the nucleus without the necessity of incorporating additional functional agents.” Solomon further states there is no explanation as to how, or indeed whether, the dendrimer polycations other than those of the PAMAM type could be used for presenting a polynucleotide to a subcellular location.
I must agree with opponent on this point. It would appear to me that except for the general description of the class of compounds known as the dendrimer polycations there is little if anything else in the opposed specification which one might call a real or reasonably clear disclosure of dendrimers other than the PAMAM class. I believe that the specification is ‘wholly silent’, in a practical sense, in relation to dendrimers other than the PAMAM class of dendrimers. This is partly the case given that only PAMAM dendrimers are exemplified and further supported by the lack of general description or information in the body of the specification regarding any dendrimers other than the PAMAM class.
Even if I am wrong on that point, I do not believe that the information provided in the specification is of such a nature or extent that one can reasonably refer to it as broadly describing the large class of dendrimer cations suitable in the process of the present invention. Hence, I consider that the claims of the opposed application, excluding claim 5 which is specifically limited to polyamidoamine dendrimers, are not fairly based in that they are not limited to the polyamidoamine “PAMAM” class of dendrimer polycations.
Mr Jones, for the opponent submitted that as discussed at paragraphs 3.9 to 3.12 of the Treager declaration, the promise of the invention cannot be fulfilled without the inclusion of three or more of the delivery agents and that there was no disclosure of the best method of the invention. I cannot agree with this point. As has been referred to by the opponent, the present specification describes the additional delivery agents as not being essential to the compositions and methods of the invention. Example 13 provides evidence that PAMAM cascade polymers can by themselves achieve transfection into cells without the need of the other delivery agents. Thus the specification shows how the promise of the invention can be achieved, without the need of extra delivery agents.
CONCLUSION
The subject matter of claims 1 to 49 and 52 to 66 is in substance disclosed in US Serial No. 07/913669, which was filed more than 12 months before the opposed application, thus the priority date of these claims is the date of filing of the complete application, 14 July 1994. The subject matter of claims 50 and 51 was first disclosed in document 08/092200, the listed priority document, and thus these claims have a priority date of 14 July 1993.
Claims 1 to 49 and 52 to 66 of the opposed application are not novel, obvious and lack an inventive step in light of the disclosure in Australian patent application 40278/93 as published on 14 October 1993.
Claims 50 and 51 of the opposed application are novel and inventive.
The claims of the opposed application, excluding claim 5, are not fairly based in that they are not limited to the polyamidoamine “PAMAM” class of dendrimer polycations.
There is patentable subject matter in the opposed application I give the applicant 60 days to make suitable amendments.
COSTS
In the normal course of events costs follow the event. In this case the opponent has been largely successful on the grounds of opposition and as such, as a minimum, is entitled to appropriate costs as set out in the schedule.
Mr Jones submitted that in the present case a finding of full costs as between attorney and client, ie in excess of and beyond the scheduled costs, are appropriate given the applicant’s failure to file evidence, to lodge any amendments, or to appear at the opposition hearing. He also indicated that the opposition is of particular importance to the opponent company and that Ms Kimble’s attendance was necessary for preparation of the case for hearing and at the hearing itself.
The applicant did not serve any evidence in answer in these proceedings, notwithstanding their requesting and being granted two extensions of time to serve that evidence. A third extension of time was requested but withdrawn following objection from the opponent. The applicant did not attend the hearing despite the fact that they paid the fee to appear at the hearing and indications that they would appear. The applicant, via their attorneys, advised the Patent Office the day before the hearing that they would not be represented at the hearing and filed written submissions.
The applicants actions in this matter have been less than ideal, but, their actions have not been an abuse of process nor have they overtly hindered the decision making process as such. The applicant is entitled to rely on the accepted application and its asserted validity. On balance, it would appear that the opponent has not been subject to any extra costs or actions due solely to the applicant’s actions in the matter. It is highly likely that the opponent costs would have been greater had the applicant chosen to serve evidence or attend the hearing. Having considered the matter of costs in the present circumstances I do not believe there are clear circumstances to make an award of costs over and above the scheduled amount.
Hence, I award costs as per Schedule 8 of the Regulations against the applicant, The Regents of the University of California.
V. J. Portelli
Delegate of the Commissioner of Patents
Patent attorneys for the applicant : Peter Maxwell & Associates
Patent attorneys for the opponent : Freehills - Carter Smith Beadle
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