Regents of the University of California
[2001] APO 34
•26 July 2001
OFFICIAL NOTICE
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Application : No. 682308 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
Claims 1 and 8 are not fairly based on the matter described in the specification. These claims are the sole disclosure of the terms "amphiphatic peptide capable of assuming a pH-dependent a-helix conformation" and "amphiphatic peptide capable of assuming a b-pleated sheet conformation". There is no real or reasonably clear disclosure of these two classes of compounds in the specification. These two claims, in so far as they purportedly include compounds which fall within the ambit of the two terms, but, go beyond GALA and the amphiphatic cationic peptides are not fairly based.
The phrase "the polyamine comprises dioleoylphosphatidylethanolamine" renders claim 13 unclear, as the named compound is clearly not a polyamine.
All 15 claims of the opposed specification are novel.
Claims 1 to 4 of the opposed specification are obvious in light of R. Parente et al., Biochemistry (1990) 29:8720-8728 an article referred to in the specification itself. Claims 5 to 15 are non-obvious and involve an inventive step.
There is patentable subject matter in the opposed application, applicant given 60 days to amend.
PATENTS ACT 1990
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Re:Patent Application No. 682308 in the name of The Regents of the University of California, opposition under Section 59 by The Dow Chemical Company
BACKGROUND
Patent application number 40278/93, in the name of The Regents of the University of California, was filed under the provisions of the Patent Cooperation Treaty on 5 April 1993 claiming priority from basic applications USSN 07/864,876 and 07/913,669 dated 3 April 1992 and 14 July 1992 respectively. The application was advertised as accepted on 2 October 1997.
The Dow Chemical Company (Dow) filed a notice of opposition on 15 December 1997. A Statement of Grounds and Particulars was served by Dow on 16 March 1998. An amended Statement of Grounds and Particulars was filed on 11 January 1999. Service of evidence-in-support of the opposition was completed on 16 February 1999 following extensions of time totalling eight months. No evidence in answer was served by the applicant.
The matter was set for hearing for 13 September 2000. By facsimile of 11 September 2000, Peter Maxwell of Peter Maxwell and Associates, attorney for the applicant, advised that the applicant would not be represented at the hearing and provided written submissions.
The matter was heard in Canberra on 13 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 - IP Section, The Dow Chemical Company.
THE OPPOSITION
The relevant Statement of Grounds and Particulars is the amended statement filed on 11 January 1999 which 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 dated of 3 April 1992 and 14 July 1992 and to the filing date of 5 April 1993.”
Evidence in support of the opposition consists of statutory declarations by Geoffery William Tregear with exhibits GWT1 to 54; Susan Sau Heng Wong with exhibits SSHW-1 to 6 and David Henry Solomon with exhibits DHS1 to 17. No evidence in answer was served.
THE INVENTION
The specification as filed
The specification as filed states that this invention is in the field of oligonucleotide delivery and gene therapy. At page 7, the invention is summarised in the following terms:
“In light of the aforementioned problems of direct gene delivery, this invention contemplates a self-assembling polynucleotide delivery system utilizing a combination of one or more, preferably two or more of the following functional components: DNA-masking components, cell recognition components, charge -neutralization and membrane-permeabilization components, and subcellular localization components.”
It is clear from page 8 that each functional component in this system is able to perform its indicated function and also are capable of assembling or disassembling with the polynucleotide as required.
The term “polynucleotide” as defined on page 10, 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 "DNA-masking component" refers to a molecule capable of masking all or part of the polynucleotide, thereby increasing its circulatory half-life by inhibiting attack by degrading reagents present in circulation, such as nucleases. Specific masking components are described such as polyethylene glycol (PEG) covalently linked to a DNA-associating moiety or by associating the DNA with lipids, specifically cationic lipids.
The "cell recognition component" of the invention is defined on page 13 as a molecule capable of recognising a component on the surface of a targeted cell. On page 18, it is indicated that the cell recognition element of the invention is a molecule capable of recognising a component on the surface of a targeted cell, covalently linked with a DNA-associating moiety. Specific cell recognition components include molecules such as antibodies to cell surface antigens, ligands for cell surface receptors, peptide hormones, etc.
The term “membrane-permeabilizing component” is defined on page 12 and refers to any component that aids in the passage of a polynucleotide across a membrane. A membrane-permeabiliser is a molecule that can assist a normally impermeable molecule such as a polynucleotide to traverse membranes and gain entrance to the cytoplasm of the cell. The term encompasses charge-neutralising components, usually polycations, which neutralise the large negative charge of the polynucleotide and enable it to traverse to the hydrophobic interior of a membrane. Membrane permeabilisation may also arise from amphiphatic molecules, where one portion of the molecule is hydrophobic and another is hydrophilic. The membrane permeabilisers of the invention may be a peptide, bile salt, glycolipid, carbohydrate, phospholipid or detergent molecule. At pages 19 to 21, it is indicated that liposomes and synthetic cationic lipids described as DNA-masking components of the invention may also function as membrane-permeabilisation components. The membrane-permeabilising components of this invention also include polycations that neutralise the large negative charge of polynucleotides. A range of polycations such as polylysine, polyarginine, polyamines and bile salts are described.
In a different described embodiment of the invention, the membrane-permeabilising component can be an amphiphatic cationic peptide. Amphiphatic cationic peptides are peptides whose native configuration is such that the peptide is considered to have a cationic face and a neutral, hydrophobic face. Specific examples of amphiphatic cationic cyclic peptides of this invention are described as gramicidin S and the tyrocidines and in a particularly preferred embodiment the membrane-permeabilising element includes, in addition to the amphiphatic cyclic peptides, either (1) a lipid or (2) a simple polyamine, or both.
The term "subcellular-localization component" is defined at page 13 to mean a molecule capable of recognising a subcellular component within a targeted cell. At page 21 it is indicated that the subcellular localisation element of the invention, which is part of the component, is a molecule capable of recognising a subcellular component in a targeted cell, covalently linked with a DNA-associating moiety. The preferred subcellular component is the nucleus. The nuclear-localisation components include known peptides and various known peptides are described on page 21.
The term "DNA-associating moiety" refers to a molecule or portions thereof that interacts in a noncovalent fashion with nucleic acids (polynucleotides). The moiety is covalently linked to the rest of the functional component (i.e. the cell recognition moiety, subcellular localisation moiety or membrane permeabilising moiety) by conventional means. DNA-associating moieties are preferably major- and minor-groove binders, DNA intercalators, or general DNA binders. DNA associating moieties include polycations.
The relevant independent composition claims of the application as filed are as follows:
"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.
15. A composition for presenting a polynucleotide to a subcellular component of a eukaryotic cell comprising the polynucleotide associated with a cell recognition component capable of recognising said eukaryotic cell.
23. A composition for presenting a polynucleotide to a subcellular component of a eukaryotic cell comprising the polynucleotide associated with a subcellular-localization component capable of delivering the polynucleotide from the cytoplasm of said eukaryotic cell to a subcellular component of said eukaryotic cell.
29. A composition for presenting a polynucleotide to a subcellular component of a eukaryotic cell comprising
(a) the polynucleotide;
(b) a cell recognition component capable of recognising said eukaryotic cell;
(c) a membrane-permeabilizing component capable of transporting the polynucleotide across the cytoplasmic membrane of said eukaryotic cell; and
(d) a nuclear-localization component capable of delivering the polynucleotide from the cytoplasm of said eukaryotic cell to a subcellular component of said eukaryotic cell."
The specification as accepted
The specification as accepted is the same as that filed, save for the inclusion of a table of experimental results on page 31. The claims of the accepted specification are, however, fundamentally different to the claims as filed. The independent claims of the accepted specification (which were introduced as a result of an amendment lodged on 15 July 1997) are as follows:
"1. A composition when used for presenting a polynucleotide to a subcellular component of an animal cell comprising a desired polynucleotide associated with an amphiphatic peptide capable of assuming a pH-dependent a-helix conformation.
8. A composition when used for presenting a polynucleotide to a subcellular component of an animal cell comprising a desired polynucleotide associated with an amphiphatic peptide capable of assuming a b-pleated sheet conformation and a polyamine."
It is pertinent to note here that claims 1 and 8 refer to two classes of amphiphatic peptides:
1) capable of assuming a pH-dependent a-helix conformation; and
2) capable of assuming a b-pleated sheet conformation.
These two classes of amphiphatic peptides as membrane permeabilisers of the invention were not, prior to the amendment filed 15 July 1999, specifically described or claimed in the specification.
DECISION
Fair Basis of the Claims
Mr Jones, for the opponent, submitted that claims 1 and 8 of the opposed specification are not fairly based. He asserted that are was no disclosure in the specification of the opposed application of a class of "amphiphatic peptides capable of assuming a pH-dependent a-helix conformation", as used in claim 1, nor any suggestion that such a class even exists. He also stated that there is no disclosure of "an amphiphatic peptide capable of assuming a b-pleated sheet configuration", as used in claim 8.
Mr Maxwell, for the applicant, submitted that the specification as filed and as accepted discloses examples of amphiphatic peptides which exhibit both of the characteristics asserted by the opponent to be absent. He indicated that the appropriate test for fair basis is that the specification contains a "real and reasonably clear disclosure" of the invention claimed: CCOM Pty Ltd v Jeijing Pty Ltd (1993-1994) 28 IPR at 501, 503 and that disclosure without claim is enough. He further stated that the disclosure at example 1G of a DNA-dendrimer complex with the peptide GALA is a clear and reasonable disclosure of an "amphiphatic peptide capable of assuming a pH-dependent a-helix conformation". He also pointed to the statement of the opponent's witness, Tregear at 5.2, which states "the amphiphatic peptide GALA . . . is the only possible support for the term 'amphiphatic peptide capable of assuming a pH-dependent a-helix conformation.'"
The relevant subsection of the Act is:
"40 (3) The claim or claims must be clear and succinct and fairly based on the matter described in the specification."
It is clear from Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 (15 February 2001) that the "description is required to be in the whole specification including the claims". Thus in assessing the fair basis of the claims the phrase "described in the specification" in ss.40(3) is not limited to that material identified in the specification as the description, but, is the specification as a whole, including the claims themselves.
The test to be used is that from CCOM Pty Ltd v Jeijing Pty Ltd (supra) referred to by Mr Maxwell, is there a "real and reasonably clear disclosure" of the two classes of compounds 1) capable of assuming a pH-dependent a-helix conformation and 2) capable of assuming a b-pleated sheet conformation, as currently appears in claims 1 and 8.
Of critical importance to this issue is the membrane permeabilising components of the invention and how they are described and defined in the specification, since, it is the definition of this component in claims 1 and 8 which is in issue.
The specification indicates, on page 12, that the membrane-permeabilising component "refers to any component that aids in the passage of a polynucleotide across a membrane." As indicated in the specification, this term encompasses, in part, charge-neutralising components, usually polycations that neutralise the large negative charge on polynucleotides. Membrane permeabilisation may also arise from amphiphatic molecules which have amphiphatic properties such that one portion of the molecule is hydrophobic and another portion is hydrophilic, permitting them to interact with membranes. The specification also indicates that the compounds described as DNA-masking components in the description may also function as membrane permeabilisation components.
At page 20, the membrane-permeabilising component is a cationic amphiphatic peptide. Amphiphatic cationic peptides are described as those whose native configuration is such that the peptide is considered to have a cationic face and a neutral, hydrophobic face. In a further preferred embodiment, the cationic peptide is cyclic, e.g. gramicidin S and the tyrocidines. In a particularly preferred embodiment the membrane-permeabilising component includes either a lipid or polyamine in addition to the amphiphatic cationic cyclic peptides.
The examples demonstrate the use of cationic peptides such as gramicidin S, polymixin B, polylysine, tyrocydine (similar to gramicidin S, but containing only a single positive charge). The examples disclose the formation of complexes of DNA with the cationic peptides and other components such as polyamines (e.g. Spermidine) and liposomes.
Example 1G is interesting as it discloses the permeabilising amphiphatic peptide GALA, R. Parente et al., Biochemistry (1990) 29:8720-8728 which is complexed with DNA and the hydrophilic branched polycation macromolecules know as the StarburstTM Dendrimer microparticles. It is clear from example 1G that GALA is a negatively charged peptide, as it was used to neutralise the excess positive charges on the dendrimer used in the complexes of that example.
Example 1G of the specification is somewhat atypical in the context of the invention as described in the rest of the specification. The example is the first in substance disclosure of the use of a negatively charged amphiphatic peptide as a membrane permeabiliser, whereas the bulk of the rest of the description is focussed on positively charged amphiphatic peptides. Never-the-less GALA is an amphiphatic peptide which falls within the definition of a "membrane permeabilizing component" of the invention.
Throughout the specification of the opposed application the only disclosure of the two classes of compounds: 1) capable of assuming a pH-dependent a-helix conformation; or 2) capable of assuming a b-pleated sheet conformation as membrane permeabilisers of the invention is in claims 1 and 8 themselves. The enquiry then is whether that disclosure in the claims is sufficient for fair basis?
The two classes of compounds: 1) capable of assuming a pH-dependent a-helix conformation and 2) capable of assuming a b-pleated sheet conformation as membrane permeabilisers are not defined or described in the specification as a whole in any other place than the claims. The specification describes amphiphatic peptides which have properties such that one portion of the molecule is hydrophobic and another portion is hydrophilic, permitting them to interact with membranes and provide membrane permeabilisation. The invention defined by claims 1 and 8 uses parameters of two classes of compounds, which classes of compounds are not previously described as such, nor reasonably inferable from the specification as a whole. There is nothing in the specification that would suggest to me that a skilled addressee would, on an ordinary reading of the specification as a whole, conceive that the two classes of peptides having features 1) capable of assuming a pH-dependent a-helix conformation and 2) capable of assuming a b-pleated sheet conformation are characteristics of the membrane permeabilisers of the present invention.
Mr Maxwell for the applicant asserts that specific compounds, e.g. GALA and gramicidin S, which have the characteristics now set out in claims 1 and 8 where described and that that is sufficient disclosure. I do not agree. Firstly, it is not a real and reasonably clear disclosure of a class of compounds to merely exemplify a specific compound or two which fall within a class, without providing some, albeit basic, description or definition of the class itself. The Parente article (supra) referred to at page 32 of the specification indicates that GALA is a peptide that can assume a pH-dependent a-helix conformation, however, that is only a disclosure that GALA has that characteristic. There is no disclosure in the specification that a class of such compounds exists, nor is stated not reasonably inferable from the specification that an ability to assume a pH-dependent a-helix conformation are characteristic features of the membrane permeabilisers of the invention. Secondly, there is nothing, even by way of a reference, in the specification to indicate that gramicidin S or the tyrocidines are a peptides that can assuming a b-pleated sheet conformation.
There is no real or reasonably clear disclosure of the two classes of compounds: 1) capable of assuming a pH-dependent a-helix conformation and 2) capable of assuming a b-pleated sheet conformation as membrane permeabilisers in the specification.
The class of permeabilisers for which there is a real and reasonably clear dislcoure in the specification are the amphiphatic peptides, specific types of such peptides are the cationic amphiphatic peptides (preferably cyclic, e.g. gramicidin S) and the negatively charged amphiphatic peptide GALA.
Claim 1 is not fairly based on the matter described in the specification, in so far as it purportedly includes, as membrane permeabilisers, compounds which fall within the definition of "peptides capable of assuming a pH-dependent a-helix conformation" but which go beyond GALA. Claim 8 is not fairly based due to the use of the term "peptides capable of assuming a b-pleated sheet conformation" as membrane permeabilisers, the only class of such permeabilsing peptides disclosed in the specification are the amphiphatic cationic peptides.
On another point, Mr Jones submitted that the claims are not fairly based and do not fulfil the promise of the invention since the claims are not limited to three or more delivery agents being present with the polynucleotide. By way of example, he queried how a negatively charged amphiphatic peptide (GALA) can associate with a similarly negatively charged polynucleotide in the absence of other components?
The opponents point is an interesting one in relation to claims 1 to 5. From a reading of the specification, it is not clear how a negatively charged amphiphatic peptide would associate with a similarly negatively charged polynucleotide in the absence of other components nor how they would "associate" in any way. Firstly, the opponents argument seems to me to be one not of fair basis but rather of inutility, which is not a ground of opposition. Secondly, it is pertinent to note that the specification discloses that the invention involves the use of one or more functional components, not all of which will be specified in any particular claim. Also from my conclusions below regarding the meaning of the term comprising in the claims, the claims are not exclusive and the presence of other functional components is clearly possible and envisaged. Claims 1 to 5 are fairly based.
The opponent also asserts that the specification as a whole does not disclose dendrimers referred to in claim 7. They contend that the sole disclosure of dendrimers is in example 1G and that it is unclear how dendrimers other than polyamidoamine (PAMAM) dendrimers can be utilised to deliver a polynucleotide to a subcellular component and thus claims not so restricted are lacking in fair basis.
"Dendrimer polycations" is a term used in claim 7 of the opposed specification and falls within the definition of polycations or polyamines which serve as DNA-associating moieties or membrane-permeabilisers of the invention. Apart from the use of the Starburst Dendrimer polycation microparticles in example 1G there is no other specific disclosure of dendrimers. The body of the specification is silent, in a practical sense, in relation to dendrimers other than the dendrimers in example 1G. Notwithstanding those facts, I believe the term dendrimer polycation would be understood by the skilled addressee and the they would recognise those compounds as polycations of the present invention. Claim 7 is fairly based.
Clarity
Submissions from the opponent assert that the specification lacks clarity on the following points:
The meaning and scope of the term "for presenting" as used in the claims is undefined and unclear in the context of the general description;
The term "comprising" used in claims 1, 8, 13, 14 and 15 presents a dilemma since if it is a closed (i.e. exclusive) term that does not permit other components to be present. Then claims must fail for a lack of fair basis since they cannot fulfil the promise of the invention without a series of components being present. The way the term "comprises" is used in claim 1 and claim 13 appears to be contradictory or the term polyamine is not as one might expect;
What is meant by the term "polyamine" as used in claims 6, 8 and 13 is entirely unclear;
The specification as a whole does not disclose dendrimers at all, they are not identified in any functional components but merely rate a mention in example 1G. The meaning and scope of the term dendrimer polycation is entirely unclear.
Firstly, in relation to the meaning of the term “for presenting”, it is appropriate to give its context in the claims. The term is used in each of claims 1 and 8, as follows: "A composition when used for presenting a polynucleotide to a subcellular component of an animal cell . . ". Mr Jones, for the opponent, questions precisely what constitutes 'presentment' in the context of the invention.
It is apparent from a reading of the specification that the invention is concerned with delivery of a polynucleotide of interest to a subcellular location, e.g. a cell nucleus, in order to achieve transfection. As such, using a purposive approach it is apparent that the term "for presenting" entails the delivery of the polynucleotide at, to, or into the subcellular location such that effective transfection can take place. To my mind the term “for presenting” in the claims describes a process whereby the polynucleotide is delivered to, or made available at, or within, the subcellular component. This is based on the plain English meaning of present: 'to furnish or endow with' and the purpose of the invention as described. Neither declarant for the opponent has queried this term and I believe the meaning of the term would be understood by the skilled addressee.
Secondly, in relation to the meaning of the term "comprising". Prior to the decision in Asahi v WR Grace 22 IPR 491 it was a long-standing convention in Australia that where the word "comprises" was used in a patent specification, it should be interpreted non-exhaustively. In Asahi v WR Grace it was held that in the circumstances of that case "comprise" was being used exhaustively. In General Clutch Corp. v Sbriggs Pty Ltd (1997) 38 IPR 359, after a review of the authorities and several dictionaries, the judge concluded that the normal linguistic meaning is that comprising means made up of, composed of, or constituted by the integers listed. Accordingly, the words "comprise", "comprises", or "comprising" must be given an interpretation appropriate to the context of their use. In some situations, the word will clearly exclude the presence of other elements while in other situations, the presence of other elements will clearly not be excluded.
The use of the terms "comprising" in claims 1 and 8 and "further comprising" (claims 5 to 7) do not provide a clear indication of whether the term is used in an exhaustive or non-exhaustive sense in the claims themselves. In such an instance it is appropriate to refer to the description to assist in determining in what sense the terms is used. I believe it is clear from a reading of the description that the compositions of the invention involve a polynucleotide in combination with one or several functional components. The invention as described can involve the use of more than one functional component in association with the polynucleotide. It is apparent in the context of the invention as described that the term "comprising" as it is used in claims 1 and 8 is used in a non-exhaustive, i.e. non-exclusive, sense.
The term comprising also appears in claim 11 as follows: "wherein the amphiphatic peptide is selected from the group comprising gramicidin S and tyrosidines". Notwithstanding the paragraph above, given the context in claim 11, I believe the term "comprising" is used in an exhaustive sense. Thus the amphiphatic peptides of claim 11 are limited being selected from gramicidin S and the tyrosidines, exclusively.
Thirdly, the opponents have queried the clarity of the term "polyamine" and particularly its use in claim 13, where allegedly, the polyamine comprises dioleoylphosphatidylethanolamine (DOPE). The specification at pages 20 and 21 indicates that the membrane-permeabilising component of the invention can include in addition to the amphiphatic cationic cyclic peptides either 1) a lipid or 2) a simple polyamine, or both. One compound, amongst others, described as a suitable lipid of the invention is phosphatidylethanolamine (PE). The lipid dioleoylphosphatidylethanolamine (DOPE) and its use is disclosed in example 1. The preferred polyamines described are spermine or spermidine. The description makes no reference to dioleoylphosphatidylethanolamine (DOPE) being a polyamine.
As has been stated at paragraph 3.9 of the Solomon declaration, "DOPE cannot, in my opinion, be considered either simple or a polyamine." I agree. I note in passing that claim 8 of the specification as filed includes a reference to dioleoyl phosphatidylethanolamine as a phospholipid used in the compositions of the invention. The reference to DOPE being a polyamine in claim 13 of the specification as accepted appears to me to be an error. The phrase "the polyamine comprises dioleoylphosphatidylethanolamine" in claim 13 renders the claim not clear.
Fourthly, in relation to dendrimers. The opponent asserts that dendrimers are not identified in any functional components described in the specification, but merely rate a mention in example 1G and the meaning and scope of the term dendrimer polycation is entirely unclear. I have dealt with the issue of the disclosure of dendrimer polycations above under the heading of fair basis. However, I do not agree that the term dendrimer polycation is unclear. Solomon at paragraph 2.4(c) of his declaration indicates that "dendrimers, including starburst dendrimers, were well known and used in Australia long before the priority date" and that "some dendrimers have a positively charged surface, that is that the dendrimer is a dendrimer polycation." Hence, I believe the term dendrimer polycation would be clearly understood by the skilled addressee.
Lastly, claim 11 specifies that the amphiphatic peptide of claim 10, to which it is appended, is selected from gramicidin S and tyrosidines. It has been made clear in the specification that gramicidin S and tyrosidines are cationic peptides, ie positively charged. However claim 10 specifies that the amphiphatic peptide has one face that is negatively charged. It is unclear how the cationic peptides gramicidin S and tyrosidines have one face that is negatively charged as required by claim 10. Claim 11, in that it is appended to claim 10 is not clear.
Novelty
Mr Jones submitted that since the claims of the opposed specification are not fairly based on the specification as lodged, they can at best take the 15 July 1997, the date of lodgement of the amendment which introduced those claims in present form, as their priority date. Accordingly, he asserted that those claims are prior published and lacking novelty in light of the specification lodged in respect of the present application as it was published on 8 November 1993.
Although the tests for novelty and fair basis are not the same I cannot agree with Mr Jones' argument. The disclosure in the specification which is sought to be used of the purpose of novelty, as has been submitted by Mr Jones, also serves to support for the claims in so far as fair basis is concerned. Thus, whatever is fairly based cannot be held not novel and whatever is not fairly based cannot be used as an anticipation.
As I have pointed out under the heading of fair basis above, the classes of amphiphatic peptides 1) capable of assuming a pH-dependent a-helix conformation and 2) capable of assuming a b-pleated sheet conformation as currently set out in claims 1 and 8 are not fairly based. There is however, disclosure of the peptides GALA and the amphiphatic cationic peptides and those disclosures are serve to provide fair basis in respect of those specific compounds or class of compounds.
Consequently, the claims of the opposed specification are novel over the disclosure in the specification of the opposed application as published on 8 November 1993.
Mr Jones also made reference to the disclosure in R. Parente et al., Biochemistry (1990) 29:8720-8728, referred to at page 32 of the specification, anticipating claims 1 to 4.
The Parente article is entitled "Mechanism of leakage of Phosphlipid Vesicle Contents Induced by the Peptide GALA". The article reports experiment results which show that the amphiphatic peptide GALA undergoes a pH-dependent conformational change and is able to induce leakage of contents from within phospholipid vesicles, by virtue of becoming incorporated into the vesicle bilayer. The article postulates that GALA is predominantly a-helical in the membrane which is supported by X-ray diffraction studies. The Parente article discloses information as to the pH-dependent structure of GALA and how that conformation is integral to membrane permeabilisation (i.e. leakage from) in phospholipid vesicles, however, the article falls well short of disclosing the current invention.
The Parente article does not provide any practical instruction, nor examples, of the use of the peptide GALA in association with polynucleotides nor that GALA alone or with any other components might be used to deliver polynucleotides to a subcellular location of a cell. The article does not give clear and unmistakable directions to do what is claimed as the current invention.
The Parente article does not prior publish any claims of the opposed specification, I will consider this article further under the heading of inventive step below.
Inventive Step - Obviousness
Mr Jones for the opponent, submitted that the opposed specification should be held obvious when read in light of the common general knowledge in the art either when read alone or in combination with EP 271180, exhibit GWT-54 (Dow 9). He indicated that all the additional components of the invention: DNA masking, cell recognition, charge neutralisation and membrane permeabilisation; and subcellular localisation components are known and that the invention is simply the mere new uses of known contrivances. He also indicated that the specification discloses on its face that amphiphatic peptides, e.g. GALA, function as membrane permeabilisation agents and thus the mixture of a polynucleotide with an amphiphatic peptide cannot constitute an invention.
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, i.e. 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 using membrane permeabilisers which avoids the drawbacks of prior systems.
Given the problem, I believe Dow 9 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, is whether the person skilled in the art would have regarded Dow 9 as relevant to work in the relevant area.
Dow 9 contains no disclosure of amphiphatic peptides being used to deliver polynucleotides into a cell. What Dow 9 does disclose, which is relevant to the claims generally but most specifically to claim 7, are conjugates of synthetic dendrimer polycation molecules (starburst polymers) used in the carriage of agricultural, pharmaceutical and other materials into cells. 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. There is no disclosure or suggestion in Dow 9 of the starburst conjugates being used to deliver polynucleotides into a subcellular location of eukaryotic cells in order to achieve transfection.
More specifically, in relation to claim 7, there is nothing in Dow 9 to lead the skilled reader to the conclusion that starburst polymers might be combined with membrane-permeabilising amphiphatic peptides 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 in combination with amphiphatic peptides 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 must consider whether the invention is obvious when the disclosure of Dow 9 is combined with the common general knowledge or in light of the common general knowledge alone. The opponent has adduced evidence, and it is clear from the opposed specification itself, that the functional components of the present invention are known. However, the opponent has not adduced evidence to show that it was common general knowledge to use one or a combination of the functional components to deliver a polynucleotide to a subcellular location. Thus the present invention is non-obvious and involves an inventive step when compared to the common general knowledge alone or when read together with the disclosure of Dow 9.
I will also further consider the Parente article under this heading. As I have pointed out under the heading of novelty above the Parente article reports experiment results which show that the amphiphatic peptide GALA undergoes a pH-dependent conformational change and is able to induce leakage of contents from within phospholipid vesicles, by virtue of becoming incorporated into the vesicle bilayer. The article postulates that GALA is predominantly a-helical in the membrane. The article discloses information as to the pH-dependent structure of GALA and how that conformation is integral to membrane permeabilisation (i.e. leakage from) in phospholipid vesicles
The Parente article does not give clear and unmistakable directions to do what is claimed as the current invention, however, it does provide a clear pointer the use of GALA as a membrane permeabiliser. At present claims 1 to 4 of the opposed specification are, in their simplest form, to the use of an amphiphatic peptide to achieve membrane permeabilisation.
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 believe that the invention as claimed in claims 1 to 4, in so far as it simply involves the use of membrane permeabilisers, specifically GALA, to achieve delivery of polynucleotides is obvious in light of the disclosure in the Parente article. The results and discussion in the article are such that I believe the skilled addressee would consider their use in the process of the current invention worth trying.
Claims 5 to 7 which involve amphiphatic peptides in combination with lipids and/or polyamines are not rendered obvious by the disclosure in Parente. The subject matter of claims 8 to 15 is not obvious from Parente.
In conclusion the invention as defined by claims 1 to 4 is obvious in light of R. Parente et al., Biochemistry (1990) 29:8720-8728. Claims 5 to 15 are non-obvious and involve an inventive step.
Manner of Manufacture
Mr Jones 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 cited Commissioner ofPatents 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.”
Mr Maxwell, for the applicant, stated that 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.
I have dealt with the issues of inventive step/obviousness above. There remains the question of whether the invention of the opposed specification satisfies the ‘threshold requirement’ of an alleged invention as set out in Phillips v Mirrabella above. The enquiry is whether it is clear, on the face of the specification itself, that there is nothing which could be regarded as providing the necessary quality of inventiveness?
The present specification asserts as the invention a composition when used to deliver polynucleotides to a subcellular location. It describes known materials (components), e.g. membrane permeabilisers, DNA associating moieties etc, and combinations of those known materials which are used to achieve that purpose. The specification does disclose that the individual functional components are known and known to perform their stated individual purpose. However, there is nothing on the face of the specification that would make it obvious to the reader that functional components have been, or are known, to function either individually or to be combined so as to deliver a polynucleotide to a subcellular location.
The assertion by the opponent that the invention is nothing but the use of known materials in the manufacture of known articles for the purpose of which its known properties make that material suitable, are not persuasive. The assertion appears to be heavily based on hindsight.
As a result I believe that the present specification does relate to an invention which meets the threshold requirement of invention on the face of the specification.
CONCLUSION
There is no real or reasonably clear disclosure of the two classes of compounds: 1) capable of assuming a pH-dependent a-helix conformation and 2) capable of assuming a b-pleated sheet conformation as membrane permeabilisers in the specification.
Claim 1 is not fairly based on the matter described in the specification, in so far as it purportedly includes compounds which fall within the definition of "peptides capable of assuming a pH-dependent a-helix conformation" but which go beyond GALA, as membrane permeabilisers. Claim 8 is not fairly based due to the use of the term "peptides capable of assuming a b-pleated sheet conformation" as membrane permeabilisers.
Claim 11 is not clear, in that it purportedly includes cationic peptides, whereas claim 10 which claim 11 is appended to specifies that such peptides are negatively charged.
The phrase "the polyamine comprises dioleoylphosphatidylethanolamine" in claim 13 renders the claim not clear.
All claims of the opposed application are novel. Claims 1 to 4 are obvious and do not involve an inventive step. Claims 5 to 15 are inventive.
The opposed specification relates to an invention which meets the threshold requirement of invention on the face of the specification required to be a manner of manufacture.
There is patentable subject matter in the opposed application I give the applicant 60 days to make suitable amendments.
COSTS
Costs normally follow the event. The opponent has been successful on several grounds of opposition, and as such are, entitled to 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, 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 the allowance of two extension of time requests for service of that evidence. The applicant did not attend the hearing despite the fact that they paid the fee to appear at the hearing. The applicant, via their attorneys, advised the Patent Office two days before the hearing that they would not be represented at the hearing and filed written submissions at that time.
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 likely that the opponent costs would have been no different 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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